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In the literature, bronchial allergen challenge is usually reported to result in an increase in histamine-induced airway responsiveness (AR). The present study investigated the relation between baseline AR and allergen-induced changes in AR. The effect of allergen challenge on AR was investigated in 21 atopic asthmatic patients. Allergen challenge resulted in a significant decrease in PC20 histamine after 24 h. When the group was divided into three subgroups according to baseline PC20 histamine, a significant decrease in PC20 histamine was found only in patients with relatively high baseline PC20 histamine (groups 1 and 2). A significant inverse correlation was found between baseline PC20 and allergen-induced PC20 histamine. The effect of repeated allergen challenge on AR was studied in eight patients. The first allergen challenge resulted in a significant decrease in PC20 histamine; no further decrease in mean PC20 histamine was seen after the second allergen challenge. These results suggest that allergen-induced changes in AR occur mainly in patients with relatively high baseline PC20 values. Once an increase in AR is induced, further allergen challenge does not always result in further increase in AR.

Inhaled corticosteroid has been shown to be effective in the management of asthma. However, there is a lack of studies that assess the effect of cessation after long-term treatment with inhaled corticosteroid. This question was addressed in 28 children with stable asthma, aged 11 to 18 yr of age, who had completed 28 to 36 months of treatment with inhaled corticosteroid (budesonide 200 µg 3 times/day) and inhaled β-2-agonist (salbutamol 200 µg 3 times/day). The children were randomized in a 1:2 ratio in a double-blind study either to continue budesonide (n = 8) during a period of 6 months or to decrease the dose of budesonide (n = 20) within 2 months, followed by placebo for 4 months. Treatment with salbutamol 600 µg daily was continued in both groups. Eight children from the tapering-off group withdrew, mainly due to symptoms of asthma, compared with none in the continuous treatment group. Five patients in the tapering-off group experienced exacerbations for which prednisolone was given, compared with no...

Increased airway hyperresponsiveness is thought to be one of the phenomena underlying nocturnal airway obstruction in asthma. To investigate the mechanisms that influence and modulate this phenomenon, we compared circadian variations in airway responsiveness with AMP and propranolol with the circadian variation in airway responsiveness to methacholine. Inhalation provocation tests were performed at 16.00 and 04.00 h in 16 nonsmoking atopic asthmatic subjects (18 to 42 yr of age), prospectively assigned to Group 1 (mean circadian peak expiratory flow rate [PEFR] variation greater-than-or-equal-to 15%) and Group 2 (

Background: The relationships between allergic symptoms after exposure to house dust, allergy parameters (skin test to house dust mite [HDM], total IgE, HDM-specific IgE, and blood eosinophil counts), and several confounding variables (age, sex, smoking habits, and airway hyperresponsiveness) were evaluated in 235 patients with asthma and chronic obstructive pulmonary disease (COPD). Results: Skin tests had higher diagnostic value (sensitivity plus specificity) for symptomatic allergy than specific IgE (1.45 versus 1.36) or total IgE (1.16). The other allergy parameters gave no additional information on symptoms once the skin test was known. Expressing the skin test relative to the histamine control proved slightly better than uncorrected wheal size, but this probably has limited clinical value. The best cutoff level for a positive skin test was 0.7 when the histamine wheal size was accounted for by division, −6 mm when subtraction was used, and 7 mm for absolute wheal size. These cutoff levels proved equally applicable in various subgroups of patients with asthma and COPD. Only the skin test and female sex were independent predictors of allergic symptoms. Conclusion: We conclude that skin tests to HDM are better predictors for clinical allergy than total or specific IgE levels and eosinophil count, and that they are applicable in most patients with asthma and with COPD.

Skin reactivity (intracutaneous test) to histamine and allergens was studied cross-sectionally in a Dutch asthmatic patient population from childhood to old age (4-75 years). It was found that the histamine skin reactivity rose significantly (p less than 0.05) during childhood, was significantly higher in the 10-15-year age group, and was constant between 20 and 75 years of age. The mean wheal index (histamine ratio) of all allergens was constant during childhood, and decreased after the age of 25 for grass pollen and house-dust mite and after the age of 15 for the other allergens. The prevalence of a positive skin test decreased with age, except for grass pollen. During childhood the indoor allergens, cat dander and house-dust mite, were the most important, while after the age of 15 sensitivity to an outdoor allergen, grass pollen, increased markedly. At all ages house-dust mite was the most important allergen. After the age of 25 the prevalence of every allergen declines. The prevalence of a positive skin test to Cladosporium was unexpectedly high in childhood (10-40%). It can be concluded that the prevalence of a positive skin test declines with age, except for grass pollen. The degree of sensitization in asthmatics peaked in the age groups between 20 and 40 and sensitivity to indoor allergens developed earlier than sensitivity to outdoor allergens.

Bronchial hyperresponsiveness (BHR) to methacholine and adenosine 5'-monophosphate (AMP) was studied in 15 allergic asthmatic patients before and 3 and 24 h after allergen challenge with house dust mite (HDM). Subjects attended the clinic on 3 consecutive days. On the first day a control solution was inhaled, and methacholine or AMP challenge was performed 3 h later. The next day HDM was inhaled, and 3 and 24 h later methacholine or AMP challenge was performed again. There were no significant difference in FEV1 baseline value between any of the study days. PD20 HDM, percentage decrease in FEV1, and AUC for both the EAR and LAR were not significantly different in the methacholine and AMP studies. After HDM challenge, PC20 methacholine decreased significantly from a geometric mean (+/- SEM) starting value of 1.39 +/- 0.63 mg/ml to 0.30 +/- 0.78 mg/ml (p less than 0.001) at 3 h and to 0.22 +/- 0.75 mg/ml (p less than 0.001) at 24 h. The magnitude of the decrease in PC20 methacholine at 3 h correlated with the severity of the late asthmatic reaction (LAR) as measured by the percentage fall in FEV1 and area under the curve (AUC) (r = -0.60 and r = 0.55; p less than 0.05). A significant decrease was observed in the PC20 AMP at 3 h, from a geometric mean value of 12.2 +/- 0.96 mg/ml after challenge with the control solution to 4.47 +/- 0.99 mg/ml (p less than 0.05) after HDM challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: The institution of inhaled corticosteroids is generally advocated for effective treatment of patients with asthma. It is yet unknown what is the best time to start inhaled corticosteroid therapy and especially whether delayed introduction is harmful. Phase 1: In a previous study in patients with asthma and COPD, we found that 2.5 years of treatment with a beta(2)-agonist plus inhaled corticosteroid (BA+CS) was more effective in improving the FEV(1) and the provocative concentration of histamine causing a 20% reduction in FEV(1) (PC20) than treatment with a beta(2)-agonist plus anticholinergic (BA+AC) or placebo (BA+PL). Phase 2: We extended this study with 6 months to investigate whether delayed introduction of inhaled CS therapy (800 mu g beclomethasone dipropionate) in the groups previously not treated with inhaled CS (BA+/-AC) could also improve FEV(1) and PC20 to the same degree, A distinction was made between patients with predominantly asthma (high baseline reversibility, Delta FEV(1) greater than or equal to 9% of predicted), and predominantly COPD (low baseline reversibility, Delta FEV(1) Results: Improvement of FEV(1) percent predicted by inhaled CS was comparable both in the asthmatics between phase 1 (13.8% predicted) and phase 2 (8.5% predicted; p=0.13) as well as in the patients with COPD (2.5% and 1.5% predicted, respectively), PC20, however, increased significantly more in the asthmatics in phase 1 (1.77 doubling concentration [DC]) than in phase 2 (0.79 DC; p=0.03). Improvement of PC20 in the patients with COPD was not significantly higher in phase 1 (0.74 DC) than in phase 2 (0.00 DC; p=0.19). Conclusions: Our study indicates that although delayed introduction of inhaled CS in asthmatics leads to similar improvements in FEV(1), improvements in PC20 are significantly less. These findings in patients with longer-existing asthma concur with other findings in newly detected asthma. We suggest that institution of inhaled CS therapy should not be postponed in asthmatics with documented airways obstruction and reversibility.

Background: Skin prick tests and measurement of specific IgE are important markers of the possible allergic causes of disorders of the upper respiratory tract. Objective: In this study we investigated the association of skin test reactivity and specific IgE positivity to five common aeroallergens separately and of total serum IgE and eosinophil count with nasal allergy symptoms in a random sample of the adult population in The Netherlands. Methods: A cross-sectional study was carried out in a sample of 2167 subjects, aged 20 to 70 years, stratified by age and gender. Nasal allergy symptoms were differentiated into three categories: symptoms after exposure to indoor allergens only, symptoms after exposure to outdoor allergens only, and symptoms after exposure to both indoor and outdoor allergens. Associations were investigated by multiple logistic regression analyses with adjustment for area of residence, gender, age, and smoking status. Results: Skin test and specific IgE reactivity to indoor and outdoor allergens were significantly related to their corresponding nasal symptom groups. Odds ratios increased with increasing number of positive skin test results or increasing levels of specific IgE to allergens in all three nasal symptom groups. For each allergen, a positive skin test result together with a positive specific IgE measurement were the strongest predictors of nasal symptoms. Sensitization to house dust mite was the most prevalent in our study population, whereas the association of skin test reactivity and specific IgE positivity with nasal symptoms was strongest for cat allergen. Skin test and specific IgE reactivity to Cladosporium species were not significantly related to the prevalence of nasal symptoms. Total serum IgE was related to nasal symptoms only in subjects who reported symptoms in response to both indoor and outdoor allergens and only at high levels of IgE. Eosinophil count was associated with nasal symptoms in all nasal symptom groups. Conclusions: Our findings confirm the close relationship of skin test positivity with reported symptoms of nasal allergy in a general population. Specific IgE positivity also shows a close relationship with nasal symptoms in response to allergen exposure in a general population. Skin testing and specific IgE measurement may be considered complementary to one another in diagnosing allergic rhinitis. Total IgE may be considered an indicator of greater dysregulation of the immune system in atopic allergy. Eosinophil count is associated with nasal symptoms, regardless of type and extent of nasal symptoms.

Background - Despite effective treatments, the morbidity and mortality of obstructive airways disease (asthma and COPD) remains high. Home monitoring of peak expiratory dow (PEF) is increasingly being advocated as an aid to better management of obstructive airways disease. The few available studies describing effects of treatment on the level and variation of PEF have involved relatively small numbers of subjects and did not use control groups. Methods - Patients aged 18-60 years were selected with PC20 less than or equal to 8 mg/ml and FEV(1) Results - Improvements in PEF occurred within the first three months of treatment with BA + CS and was subsequently maintained: the mean (SE) increase in morning PEF was 51 (8) l/min in the BA + CS group compared with no change in the other two groups. Similarly, afternoon PEF increased by 22 (7) l/min. Diurnal variation in PEF (amplitude %mean) decreased from 18.0% to 10.2% in the first three months of treatment with BA + CS. Within-subject relations between changes in diurnal variation in PEF and changes in PC20 were found to be predominantly negative (median rho-0.40) but with a large scatter. Relations between diurnal variation ation in PEF and changes in symptom scores, FEV(1), and bronchodilator response were even weaker. Conclusions - In patients with moderately severe obstructive airways disease, PEF rates and variation are greatly improved by inhaled corticosteroids. Since the relation of diurnal PEF variation with PC20 symptoms, FEV(1), and bronchodilator response were all weak, these markers of disease severity may all provide different information on the actual disease state. PEF measurements should be used in addition to the other markers but not instead of them.

An otherwise healthy 44-yr-old man experienced a serious attack of bronchial obstruction after working with resins and hardeners, releasing fumes of a mixture of an alipathic and a cycloaliphatic diamine hardener. Eight hours after deliberate challenge with the hardener a large increase of airway resistance was found. Seventy-two hours after challenge, eosinophilia in the bronchoalveolar lavage (BAL) fluid together with a decrease of peripheral eosinophils was seen. After cessation of contact with this hardener, no more acute episodes occurred, although maintenance treatment with a topical corticosteroid and a beta 2-agonist remained necessary. A BAL performed 1 yr later showed a normal cell distribution. The results suggest that these aliphatic and cycloaliphatic diamine hardeners may be occupational hazards. Eosinophil inflammation may play a causal role.

Eosinophilic granulocytes as well as neutrophilic granulocytes produced leukotriene C4 (LTC4) on stimulation with 1 μM A23187 (Ca2+ ionophore). In healthy volunteers, the LTC4 production in eosinophils was about 3 times the production in neutrophils. Within 15 min >90% of the LTC4 was released into the supernatant. Stimulation of eosinophils and neutrophils together resulted in a synergistic increase in LTC4 production of 306 ± 40%. LTC4 synthesis by hypodense eosinophils was also enhanced if stimulated in the presence of neutrophils. These findings suggest a communication between eosinophils and neutrophils, which may play a role in bronchial asthma.

Eosinophils from normal nonatopic healthy volunteers (195 +/- 106 cells per microliter) were isolated by centrifugation over a discontinuous Percoll gradient, under isotonic conditions, with a recovery of 46.5 +/- 26.2% from whole blood (n = 21; mean +/- SD). More than 90% of the eosinophils (purity greater than 93%) with a density between 1.095 to 1.105 gm/ml were defined normodense. Less than 10% of the eosinophils had a density less than 1.095 gm/ml and were defined hypodense. Isolation of eosinophils of patients with atopic asthma revealed a cell population with 65% to 70% hypodense cells that was independent of the total eosinophilic cell count. In vitro activation of normodense eosinophils, measured by an increase in superoxide production, induced quantities of hypodense eosinophils in the range found in patients with asthma. The amount of hypodense eosinophils induced by different stimuli was in the same order as the increase in superoxide production (antibiotic calcium ionophore A23187 greater than serum-treated zymosan greater than platelet-activating factor greater than N-formyl-methionyl-leucyl phenylalanine). During the stimulation of the normodense cells, no secretion of eosinophilic peroxidase or arylsulfatase B could be measured, even though hypodense eosinophils were produced. Enzymatic activity of arylsulfatase B within the eosinophils remained the same, before and after stimulation. The enzymatic activity of eosinophilic peroxidase in normodense eosinophils (16.6 +/- 9.7 micrograms/10(6) cells) did not change in the normodense fraction but was increased in the induced hypodense cells (34.0 +/- 8.4 micrograms/10(6) cells; n = 7; mean +/- SD; p less than 0.01) after stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to investigate the role of histamine in the late asthmatic reaction (LAR) following house-dust mite (HDM) inhalation, we studied, with hourly intervals, urinary N tau-methylhistamine (an important metabolite of histamine) in 14 allergic asthmatic patients before and after broncho provocation with HDM. Four patients showed an early asthmatic reaction (EAR), while 10 patients developed a LAR as well. In the hour following the EAR a significant increase in urinary N tau-methylhistamine was observed as compared to the control day (0.01 less than p less than 0.05). During the LAR no increase of this metabolite was detected in the urine of the patients. Additionally, histamine was measured in broncho alveolar lavage fluid (BAF) obtained from 6 patients during the HDM-provoked LAR and compared to histamine levels in BAF from patients without a LAR, following broncho provocation. In the LAR group higher histamine levels were found than in the other patient and control groups. For the whole patient group no correlation was found between the degree of bronchial obstruction during the LAR and the BAF histamine values. No difference was found in N tau-methylhistamine in BAF between patients with LAR and controls. Thus histamine metabolite studies in the urine failed to provide evidence of involvement of histamine in the LAR, while further data are needed to interpret the results of local sampling in the lung.

Bronchial hyperresponsiveness to adenosine 5'-monophosphate (AMP) was studied after allergen challenge in allergic asthmatic patients. Measurements were made with and without nedocromil sodium pretreatment. Nedocromil sodium inhibited both the early and late asthmatic reactions (P

Background: The relationships between allergic symptoms after exposure to house dust, allergy parameters (skin test to house dust mite [HDM], total IgE, HDM-specific IgE, and blood eosinophil counts), and several confounding variables (age, sex, smoking habits, and airway hyperresponsiveness) were evaluated in 235 patients with asthma and chronic obstructive pulmonary disease (COPD). Results: Skin tests had higher diagnostic value (sensitivity plus specificity) for symptomatic allergy than specific IgE (1.45 versus 1.36) or total IgE (1.16). The other allergy parameters gave no additional information on symptoms once the skin test was known. Expressing the skin test relative to the histamine control proved slightly better than uncorrected wheal size, but this probably has limited clinical value. The best cutoff level for a positive skin test was 0.7 when the histamine wheal size was accounted for by division, -6 mm when subtraction was used, and 7 mm for absolute wheal size. These cutoff levels proved equally applicable in various subgroups of patients with asthma and COPD. Only the skin test and female sex were independent predictors of allergic symptoms. Conclusion: We conclude that skin tests to HDM are better predictors for clinical allergy than total or specific IgE levels and eosinophil count, and that they are applicable in most patients with asthma and with COPD.

The phenotypic cellular profile of bronchial lavage (BL) and bronchoalveolar lavage (BAL) was studied in 7 single early (SR) and 10 dual asthmatic responders (DR). Lavage was performed, after previously having determined bronchial hyperresponsiveness to histamine and the response to house dust mite (HDM) challenge. The recovered lavage fluid was separated in two fractions, BL and BAL. Total fluid recovery and cell number from the BL and BAL were comparable in both patient groups. Differential cell counting and immunocytochemistry were performed. DR had a significantly higher number of eosinophils and EG2+ cells in BL but not in their BAL. No differences could be found in CD4+, CD8+, and HLA-DR+ cells. A strong correlation was found between eosinophils in the BL+ and EG2+ cells in the BL (r = 0.79, p