Alexander C. Ferguson

Correlation of bronchial eosinophil and mast cell activation with bronchial hyperresponsiveness in children with asthma

Bronchial hyperresponsiveness in asthma has been associated with increased numbers of eosinophils and mast cells in the bronchial airway. It is unclear if these cells are important in the pathogenesis of hyperresponsiveness, and the role of mast cells has been discounted because they are effectively stabilized by beta-adrenergic drugs. Because the pathogenesis of asthma in children may be different from that in adults, and to find out if cellular activation is associated with bronchial reactivity, we studied 17 children with mild to moderately severe chronic asthma who had been treated with intermittent brochodilator therapy and compared their bronchial responsiveness to histamine with the levels of eosinophil cationic protein and mast cell tryptase in broncholavage fluid. The number of eosinophils in lavage fluid was correlated with histamine responsiveness (r = -0.444, p < 0.05) but not with levels of cationic protein (r = 0.33, p = NS). Bronchial responsiveness to histamine was highly correlated with mast cell tryptase (r = -0.714, p < 0.005), but there was no correlation with eosinophil cationic protein (r = -0.355, p = NS). We conclude that in children with chronic asthma mast cells as well as eosinophils contribute to bronchial hyperresponsiveness. Activated mast cells may play a primary role, possibly by tryptase-induced upregulation of bronchial smooth muscle tone.

Genetic variants of the IL13 and IL4 genes and atopic diseases in at-risk children

We studied a cohort containing 368 children at high risk of developing atopy and atopic disorders and 540 parents of those children to investigate whether the IL13 Arg130Gln and C−1112 T polymorphisms were associated with these outcomes. We also investigated whether haplotypes consisting of any two polymorphisms of IL13 Arg130Gln, IL13 C−1112 T and IL4 C−589 T were associated with these phenotypes. In 288 white children, the IL13 130Gln allele was associated with atopy (RR=1.9, P=0.047), and with atopic dermatitis (RR=2.5, P=0.014). The associations were confirmed using a family-based test of association (P=0.027 and 0.030, respectively) in all subjects. In white subjects there were associations of haplotypes consisting of IL13 Arg130Gln and IL4 C−589 T with atopic dermatitis (P=0.006) and with atopy (P=0.009). Our data suggest that the IL13 Arg130Gln polymorphism and haplotypes consisting of IL13 Arg130Gln and IL4 C−589 T were associated with the development of atopy and atopic dermatitis at 24 months of age.

Prolonged impairment of cellular immunity in children with intrauterine growth retardation

Cellular immunity was studied in 17 newborn infants, in eight children aged 1 to 5 years with intrauterine growth retardation, and in age-matched control subjects. At birth T and B peripheral blood lymphocytes were decreased, and delayed cutaneous hypersensitivity to phytohemagglutinin was diminished. In vitro PHA-induced lymphocyte proliferation was similar to that in control subjects but was greater than in healthy adults. In later childhood the numbers of T lymphocytes were normal, but their proliferative capacity was significantly reduced and cutaneous hypersensitivity was minimal or absent. Prolonged impairment of cellular immunity in these children may explain their increased susceptibility to infection and inadequate response to immunization, and predispose to the development of allergic, autoimmune, and neoplastic disease.

Efficacy and safety of high-dose inhaled steroids in children with asthma: a comparison of fluticasone propionate with budesonide.

OBJECTIVE To compare the efficacy and adverse effects of inhaled fluticasone propionate (FP), 400 microgram/d, with those of budesonide (BUD), 800 microgram/d, in children with moderate to severe asthma. METHODS Three hundred thirty-three children, ages 4 to 12 years, receiving inhaled corticosteroids were enrolled in a double-blind, double-dummy, randomized, parallel-group study. After a 2-week run-in phase, 166 children received FP and 167 received BUD for 20 weeks. The primary outcome variable was mean morning peak expiratory flow; the 2 treatments were to be regarded as equivalent if the 90% CI for the treatment difference was within +/- 15 L/min. Pulmonary function, height, and diary cards were assessed at each visit; and morning serum cortisol levels were determined before and after treatment. RESULTS Baseline peak expiratory flow was similar, FP 236 +/- 72 (SD) L/min and BUD 229 +/- 74, increasing after treatment to 277 +/- 41 and 257 +/- 28, a difference between treatments of 12 L/min (90% CI 6-19 L/min; P =.002). Symptom control and use of rescue medication were the same. Cortisol levels after treatment were 199 nmol/L (FP) and 183 nmol/L (BUD) (treatment ratio = 1.09; 90% CI 0.98-1.21; P =.172). Linear growth was less in those receiving BUD (mean difference, 6.2 mm; 95% CI 2.9-9.6; P =.0003). CONCLUSION FP at half the dose was superior to BUD in improving peak expiratory flow and comparable in controlling symptoms. Growth was reduced with BUD compared with FP, but there was no difference in serum cortisol suppression or hepatic or renal function.

Evaluation of serum eosinophilic cationic protein as a marker of disease activity in chronic asthma

BACKGROUND Serum eosinophil cationic protein (ECP) has been promoted as a direct marker of eosinophilic inflammation of the bronchi, especially helpful in patients with asymptomatic asthma. OBJECTIVE To evaluate serum ECP against indirect clinical markers of disease activity, we compared symptom score, bronchial obstruction, bronchial responsiveness, and blood eosinophil counts with serum ECP levels in children with symptomatic and asymptomatic chronic asthma and assessed ECP in others with allergic rhinitis alone. METHODS Twenty-four children with symptomatic asthma, 10 children with asymptomatic asthma, and 16 children with allergic rhinitis were studied. Measurements were made by standardized symptom questionnaire, spirometry, inhalation challenge with histamine or methacholine, blood eosinophil counts, and radioimmunoassay of serum ECP. RESULTS There was no difference in serum ECP levels between the symptomatic asthma, asymptomatic asthma, or rhinitis groups, and most values were within the normal range. Activated eosinophil counts were higher in subjects with symptomatic asthma than in those with asymptomatic asthma but not in subjects with rhinitis. Serum ECP correlated with eosinophil counts (p < 0.01) but not symptom score, forced expiratory volume in 1 second (FEV1), forced expiratory flow, mid-expiratory phase (FEF25-75), or provocative concentration causing a 20% fall in FEV1 (PC20). Symptom scores correlated with PC20 (p < 0.005) and FEF25-75 (p < 0.01). CONCLUSION Serum ECP is a poor indicator of disease activity in chronic asthma and cannot differentiate bronchial from nasal inflammation.

Airway responsiveness to histamine as a test for overall severity of asthma in children

Seventy-eight children who had a history of asthma were studied while they were symptom-free. There was a highly significant correlation between the dose of aerosolized histamine that produced a decrease in FEV1 of 20% and each of the features in the history that indicated severity of asthma. The correlation was strengthened by the combination of these features into a weighted asthma history score. None of the subjects with mildly increased bronchial reactivity had a history score of severe asthma, and none with markedly increased bronchial reactivity had mild asthma. There was also a highly significant correlation between histamine dose and the results of spirometric tests for airway obstruction. However, the correlation between asthma history score and provocative histamine dose was highly significant even in the 21 subjects who were apparently free of airway obstruction at the time of testing. Furthermore, the correlation between asthma history score and histamine dose was stronger than that between asthma score and any spirometric test, indicating that the histamine test more accurately assessed the overall severity of the asthma. Measurement of bronchial responsiveness to histamine is a useful adjunct to history in determining the severity of asthma in an individual and should be considered as an objective way of grading subjects according to severity of asthma in a clinical study.

Persisting airway obstruction in asymptomatic children with asthma with normal peak expiratory flow rates

Twice-daily symptom scores and peak expiratory flow readings were compared with spirometric values (FEV1 and forced expiratory flow rate between 25% and 75% of FVC [FEF 25-75]) measured at 2-week intervals in assessing airway obstruction in 20 children with asthma studied during 16 weeks. Of 56 2-week periods during which symptoms were absent, peak flow was decreased in 30 (54%), FEV1 in 20 (36%), and FEF 25-75 in 37 periods (66%). Peak flow readings were normal in 13 of 70 periods (16%) in which FEV1 was decreased, and in 33 of 113 periods (29%), in which FEF 25-75 was decreased. Of 25 periods in which symptoms were absent and peak flow was normal, 19 (76%) were associated with decreased FEF 25-75. The results confirm previous studies that indicate peak flow readings are a useful addition to symptom diaries. More importantly, they demonstrate that airway obstruction may be present in a large proportion of asymptomatic children with asthma who have normal peak flow rates and suggest that frequent assessment of FEF 25-75 is required, as well as daily monitoring of symptoms and peak flow both in trials of drug therapy and for more optimal assessment of the effectiveness of therapy in clinical practice.

Canadian Pediatric Asthma Consensus Guidelines, 2003 (updated to December 2004): Introduction

Background: Although guidelines for the diagnosis and management of asthma have been published over the last 15 years, there has been little focus on issues relating to asthma in childhood. Since the last revision of the 1999 Canadian asthma consensus report, important new studies, particularly in children, have highlighted the need to incorporate this new information into asthma guidelines. Objectives: To review the literature on asthma published between January 2000 and June 2003 and to evaluate the influence of new evidence on the recommendations made in the Canadian Asthma Consensus Report, 1999 and its 2001 update with a major focus on pediatric issues. Methods: Diagnosis of asthma in young children, prevention strategies, pharmacotherapy, inhalation devices, immunotherapy and asthma education were selected for review by small expert resource groups. In June 2003, the reviews were discussed at a meeting under the auspices of the Canadian Network For Asthma Care and the Canadian Thoracic Society. Data published up to December 2004 were subsequently reviewed by the individual expert resource groups. Results: This report evaluates early life prevention strategies and focuses on treatment of asthma in children. Emphasis is placed on the importance of an early diagnosis and prevention therapy, the benefits of additional therapy and the essential role of asthma education. Conclusion: We generally support previous recommendations and focus on new issues, particularly those relevant to children and their families. This guide for asthma management is based on the best available published data and the opinion of health care professionals including asthma experts and educators.

Decreased rosette-forming lymphocytes in malnutrition and intrauterine growth retardation

The percentage of peripheral blood lymphocytes which spontaneously form rosettes with sheep red blood cells (thymus-dependent lymphocytes) was studied as a sensitive measure of cellular immunity in patients with two forms of malnutrition. The percentage and absolute number of rosette-forming cells was markedly decreased in 10 children with severe protein-calorie malnutrition (16.6%±2.7 SE) p

Short stature and delayed skeletal maturation in children with allergic disease

The frequency of short stature was assessed in 598 children (66% boys, 34% girls) referred consecutively because of asthma or allergic rhinitis. Six percent were of small stature, with heights of less than the third percentile for age. A total of 66 children with small stature were subsequently studied, 36 of whom had asthma. None had received steroids. Children with short stature were predominantly boys (83%, p less than 0.005) and had delayed bone age (less than 2 SD of mean, 34/45), correspondence of bone age with height age (r = 0.93), normal serum thyroxine but increased tri-iodothyronine levels (11/24), and normal insulin-induced growth hormone secretion (12/12). Their heights corresponded only in part to midparental height. The results were the same for those with and without asthma, and the severity of asthma was not related to the degree of growth retardation. The findings suggest that short stature is more common than expected in children with allergic respiratory disease, both asthmatic and nonasthmatic, that their growth potential is good, and that impaired linear growth is not necessarily a result only of asthma but of a more fundamental abnormality possibly associated with the atopic state. They emphasize the importance of considering allergic respiratory disease in the clinical evaluation of children with small stature.