Anna S. Pelkonen

Exhaled nitric oxide rather than lung function distinguishes preschool children with probable asthma

Background: Respiratory function and airway inflammation can be evaluated in preschool children with special techniques, but their relative power in identifying young children with asthma has not been studied. This study was undertaken to compare the value of exhaled nitric oxide (FENO), baseline lung function, and bronchodilator responsiveness in identifying children with newly detected probable asthma. Methods: Ninety six preschool children (age 3.8–7.5 years) with asthmatic symptoms or history and 62 age matched healthy non-atopic controls were studied. FENO was measured with the standard online single exhalation technique, and baseline lung function and bronchodilator responsiveness were measured using impulse oscillometry (IOS). Results: Children with probable asthma (n=21), characterised by recent recurrent wheeze, had a significantly higher mean (SE) concentration of FENO than controls (22.1 (3.4) ppb v 5.3 (0.4) ppb; mean difference 16.8 ppb, 95% CI 12.0 to 21.5) and also had higher baseline respiratory resistance, lower reactance, and larger bronchodilator responses expressed as the change in resistance after inhalation of salbutamol. Children with chronic cough only (n=46) also had significantly raised mean FENO (9.2 (1.5) ppb; mean difference 3.9 ppb, 95% CI 0.8 to 7.0) but their lung function was not significantly reduced. Children on inhaled steroids due to previously diagnosed asthma (n=29) differed from the controls only in their baseline lung function. The analysis of receiver operating characteristics (ROC) showed that FENO provided the best power for discriminating between children with probable asthma and healthy controls, with a sensitivity of 86% and specificity of 92% at the cut off level of 1.5 SD above predicted. Conclusions: FENO is superior to baseline respiratory function and bronchodilator responsiveness in identifying preschool children with probable asthma. The results emphasise the presence of airway inflammation in the early stages of asthma, even in young children.

Determinants of respiratory system input impedance and bronchodilator response in healthy Finnish preschool children.

In order to study the determinants of respiratory system impedance and bronchodilator response in preschool children, a sample (n=109) of healthy children (age 2·1–7·0 years) attending kindergarten was measured by using the impulse oscillometry. Their selection was based on a standardized questionnaire, negative skin prick test results and clinical examination, and sufficient cooperation. Triple measurements of respiratory resistance (Rrs) and reactance (Xrs) at 5, 10, 15 and 20 Hz, total respiratory impedance (Zrs), the resonance frequency (Fr) and the frequency dependence of resistance (dRrs/df) were performed, to determine individual mean values. Measurements were repeated after inhalation of 300 μg salbutamol (n=89) or placebo (n=19). At the baseline, Zrs and Rrs5‐20 showed negative, and Xrs5‐20, Fr and dRrs/df positive correlations with age, height and weight. However, logarithmic transformed height was the best independent variable for the regression equations of all the oscillometric variables. After inhalation of placebo, none of the oscillometric variables changed significantly. In the salbutamol group, the mean (SD) change in Rrs5 was −0·187 (0·124) kPa l–1 s–1 and –19·2 (10·2)%, corresponding to a lower reference limit of –36·9%. Both the within‐test and between‐test repeatabilities for the measurement of respiratory resistance were acceptable, for Rrs5 the coefficients of variation being 6·2 and 6·1%, respectively. As the overall success rate in our sample was high (89%), the forced oscillation technique seems to be a useful method in assessing respiratory function and bronchial lability in preschool children.

Daily versus as-needed inhaled corticosteroid for mild persistent asthma (The Helsinki early intervention childhood asthma study)

Objective: To compare the effect of inhaled budesonide given daily or as-needed on mild persistent childhood asthma. Patients, design and interventions: 176 children aged 5–10 years with newly detected asthma were randomly assigned to three treatment groups: (1) continuous budesonide (400 μg twice daily for 1 month, 200 μg twice daily for months 2–6, 100 μg twice daily for months 7–18); (2) budesonide, identical treatment to group 1 during months 1–6, then budesonide for exacerbations as needed for months 7–18; and (3) disodium cromoglycate (DSCG) 10 mg three times daily for months 1–18. Exacerbations were treated with budesonide 400 μg twice daily for 2 weeks. Main outcome measures: Lung function, the number of exacerbations and growth. Results: Compared with DSCG the initial regular budesonide treatment resulted in a significantly improved lung function, fewer exacerbations and a small but significant decline in growth velocity. After 18 months, however, the lung function improvements did not differ between the groups. During months 7–18, patients receiving continuous budesonide treatment had significantly fewer exacerbations (mean 0.97), compared with 1.69 in group 2 and 1.58 in group 3. The number of asthma-free days did not differ between regular and intermittent budesonide treatment. Growth velocity was normalised during continuous low-dose budesonide and budesonide therapy given as needed. The latter was associated with catch-up growth. Conclusions: Regular use of budesonide afforded better asthma control but had a more systemic effect than did use of budesonide as needed. The dose of ICS could be reduced as soon as asthma is controlled. Some children do not seem to need continuous ICS treatment.

Reference values for respiratory system impedance by using impulse oscillometry in children aged 2-11 years.

The forced oscillation technique makes it possible to evaluate the mechanical properties of the respiratory system with a minimum of cooperation. The method is therefore especially useful in children. Impulse oscillometry (IOS) is a commercially available version of this technique. There is, as yet, limited information on reference values for IOS in children. The aim of this study was to extend the reference values for IOS variables and to study their correlation with height, weight and age in healthy children. A sample (n = 360) of children (age 2·1–11·1 years) was measured by using impulse oscillometry (IOS; Jaeger, Würzburg, Germany). The sample was based on children attending kindergarten in Finland and children attending primary school in Sweden. Measurements of respiratory resistance (Rrs) and reactance (Xrs) at 5, 10, 15 and 20 Hz, total respiratory impedance (Zrs) and the resonance frequency (Fr) were made. All variables were related to body height. Most of them were also weakly related to weight. Reference equations for children (height 90–160 cm) are presented.

Exercise‐induced changes in respiratory impedance in young wheezy children and nonatopic controls

Exercise‐induced bronchoconstriction (EIB) is a specific sign of active asthma, but its assessment in young children may be difficult with lung function techniques requiring active cooperation. The aim of the study was to assess the normal pattern of exercise‐induced responses of respiratory impedance by using impulse oscillometry (IOS), and to investigate how these responses discriminate wheezy children from control subjects. IOS measurements were performed in a consecutive sample of wheezy children aged 3–7 years (n = 130) and in an aged matched control group of nonatopic children without respiratory symptoms (n = 79) before and after a free running test. After exercise, wheezy children showed significantly larger responses in respiratory resistance (Rrs5), reactance (Xrs5), and the resonance frequency (Fr) than the control subjects. In the control group, the upper 95% confidence limit of the maximal change was 32.5% for Rrs5, 85.7% for Xrs5, and 53.1% for Fr. By using analysis of receiver operating characteristics, the change in Rrs5 distinguished the wheezy children from the control subjects more effectively than change in Xrs5 or Fr. In wheezy children, the response was significantly effected by the outdoor temperature and exercise intensity in terms of maximum heart rate. In conclusion, an increase of 35% in Rrs5 after a free running test can be regarded as an abnormal response. Wheezy children show an enhanced airway response, which is clearly distinguishable from the control subjects. IOS is a feasible method to detect EIB in young children. Pediatr Pulmonol. 2008; 43:538–544.

Ultrastructure of the reticular basement membrane in asthmatic adults, children and infants

Reticular basement membrane (RBM) thickening in asthma is considered to be the result of subepithelial fibrosis. Thus, the RBM in asthma should contain an excess of fibrils identified as interstitial collagen and the ratio of fibril to matrix should be increased above normal levels. Electron micrographs of the RBM were compared with those of interstitial collagen deeper in the bronchial wall using endobronchial biopsy specimens from adult asthmatics (aged 18–41 yrs (n = 10)), children with difficult asthma (aged 6–16 yrs (n = 10)), wheezy infants with reversible airflow limitation (aged 0.3–2 yrs (n = 10)) and age-matched nonasthmatic controls: 10 adults, nine children and nine symptomatic infants with normal lung function. Fibrils in the RBM were significantly thinner (median (range) width 39 (30–52) nm versus 59 (48–73) nm), and fewer fibrils were banded than in the interstitial collagen (ratio of banded to non-banded fibrils 0.08 (0–0.17) versus 0.22 (0–1.3)). The ratio of fibrils to matrix in the thickened RBM of asthmatics did not differ from that of their respective controls (1.34 (0.63–2.49) versus 1.18 (0.31–2.6)). The ratio of fibril to matrix in the thickened reticular basement membrane of asthmatics is normal, and, contrary to what is expected in fibrosis, the fibrils do not resemble those of interstitial collagen.

Lung function, airway remodelling and inflammation in symptomatic infants: outcome at 3 years

Background Relationships between early deficits of lung function, infant airway pathology and outcome in symptomatic infants are unclear. A study was undertaken to determine the associations between early lung function, airway histology and inflammation in symptomatic infants with the continuance of respiratory symptoms, lung function and subsequent use of inhaled asthma medication at the age of 3 years. Methods 53 children who underwent lung function measurements and bronchoscopy following referral to a specialist childrens hospital for recurrent lower respiratory symptoms at a mean age of 1 year were followed up at 3 years of age. Assessments were made of respiratory symptoms during the previous year, lung function by oscillometry and atopy by skin prick testing. Individual data on the purchase of asthma medications were obtained from the Social Insurance Institution for the 12 months preceding the follow-up visit. Results 50 children (94%) were re-evaluated, of whom 40 had ongoing airway symptoms. 11/39 (28%) who underwent successful oscillometry had reduced lung function, 31/50 (62%) used inhaled corticosteroids (ICS) regularly and 12/50 (24%) used ICS intermittently. Abnormal lung function at infancy was associated with ongoing airway symptoms (p<0.001) and with the purchase of ICS (p=0.009) and β agonists (p=0.002). Reticular basement membrane thickness in infancy and the numbers of mucosal mast cells, but not eosinophils, correlated significantly with the amount of ICS purchased at 3 years (p=0.003 and p=0.018, respectively). Conclusions Reduced lung function, thickening of the reticular basement membrane and increased density of mucosal mast cells in infancy are associated with respiratory morbidity and treatment needs at age 3 years in this highly selected group of children.

Bronchial response pattern of antigen presenting cells and regulatory T cells in children less than 2 years of age

Background: In early childhood, the ability to mount protective immune responses in the airways is impaired, with increased risk of allergic sensitisation to inhaled allergens. Antigen presenting cells (APC) and regulatory T cells (Treg) are important modifiers of T cell immunity but little is known about their distribution in bronchial mucosa at this age. Here the subset distribution of APC and the appearance of Foxp3+ Treg and bronchus associated lymphoid tissue (BALT) were examined immunohistochemically in children less than 2 years of age with chronic asthma-like symptoms of the lower airways. Methods: Immunophenotyping was performed in situ on bronchial biopsy specimens obtained from 45 infants, 4–23 months of age, under investigation for airway disease. Results: A well developed HLA-DR+ network of APC was present in all samples, approximately 50% of the cells being CD68+ macrophages and the remainder various subsets of dendritic cells. The density of HLA-DR+ cells increased significantly with age but was not related to atopy, clinical symptoms or lung function. Comparing the density of APC subsets and clinical parameters, only the number of intraepithelial CD1a+ dendritic cells was significantly increased in infants who had recently suffered a respiratory infection. BALT structures were identified in 22 children, with no relation to lung function, atopic status or human rhinovirus positivity. Plasmacytoid dendritic cells and Foxp3+ Treg were located primarily within these isolated lymphoid follicles. Conclusion: A bronchial network of dendritic cells and macrophages develops quite rapidly after birth, apparently independent of clinical symptoms or atopy. The high frequency of BALT structures containing putative tolerogenic dendritic cells and Treg suggests that these lymphoid follicles play an important role in bronchial immune homeostasis during infancy.

Effect of neonatal surfactant therapy on lung function at school age in children born very preterm

Our aim was to evaluate long‐term effects of exogenous surfactant therapy on pulmonary functional outcome in children born very preterm. We examined 40 children aged 7–12 years who were born before 30 weeks of gestation with an immature surfactant system, and were randomized to one of three treatment groups: human surfactant given at birth (prophylactic), human surfactant given after development of neonatal respiratory distress syndrome (rescue), and placebo (air) treatment. Spirometric parameters of preterm born children were compared with those of 20 children born at term. In addition, spirometric parameters were monitored twice daily for 4 weeks using a home spirometer.

Airway inflammation in probiotic-treated children at 5 years

To cite this article: Kukkonen AK, Kuitunen M, Savilahti E, Pelkonen A, Malmberg P, Mäkelä M. Airway inflammation in probiotic‐treated children at 5 years. Pediatr Allergy and Immunol 2011; 22: 249–251.