Markku Turpeinen

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.

Effects of inhaled budesonide on serum markers of bone metabolism in children with asthma

The effects of inhaled glucocorticoids on serum markers of bone formation were evaluated in asthmatic children. Serum total alkaline phosphatase (AP), bone alkaline phosphatase (BAP), osteocalcin, and the novel marker of bone formation, carboxypropeptide of type I procollagen (PICP), were measured. In the cross-sectional part, long-term glucocorticoid users were compared with sodium cromoglycate (SCG) users. In the boys (n = 16), but not in the girls (n = 11), PICP was significantly lower in the glucocorticoid users than in the SCG users. PICP correlated positively with BAP (n = 54; groups combined, r = 0.29, p < 0.05). In the longitudinal part, the effects of inhaled budesonide or SCG, both used for the first time, were evaluated before and after 1 and 5 months of treatment. The budesonide dose was 800 micrograms/m2/day for 1 month and thereafter half of that. The SCG dose was 30 mg/day throughout the study. Only during budesonide use did osteocalcin and PICP decrease, the median osteocalcin by 8% at 1 month (p < 0.05) and by 6% at 5 months (n = 15), and PICP by 5% at 1 month (p < 0.05) and by 28% at 5 months (n = 7, p < 0.01). AP and BAP did not change significantly. Decreased PICP suggests decreased bone formation rate. PICP might be clinically useful as a marker of early adverse effects of glucocorticoids on bone.

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.

Diffusing capacity of the lung in school-aged children born very preterm, with and without bronchopulmonary dysplasia

The aim of this study was to determine the extent to which bronchopulmonary dysplasia (BPD) affects the diffusing properties of lung tissue in childhood. Pulmonary function in 31 prematurely born children (BW. < 1250 g) was examined at ages 7–11 years. Twenty out of 31 prematurely born children met the criteria for BPD. The remaining 11 children had milder forms of neonatal lung disease. Twenty healthy children of the same age and born at term served as a control group. The diffusing capacity of the lung for carbon monoxide (DLCO) was measured by the single breath method. Lung volumes were determined in a body plethysmograph and expiratory flow rates with a flow/volume spirometer. DLCO values of children with histories of BPD did not differ significantly from those of the prematurely born children without BPD. However, DLCO values in both prematurely born study groups were significantly lower than those in controls born at term. Thoracic gas volumes measured with a body plethysmograph were similar in all groups. Spirometry demonstrated reduced flow rates in both BPD and non‐BPD prematurely born children. The results suggest that some structural changes in lung tissues and airways persist for years in children who are born very preterm regardless of whether they develop BPD or not. Pediatr Pulmonol. 1996; 21:353–360.

Changes in carbohydrate and lipid metabolism in children with asthma inhaling budesonide

In a longitudinal study, antiasthmatic and metabolic effects of budesonide inhalations in initially high (800 micrograms/m2/day for 1 month) and subsequently lower (400 micrograms/m2/day for 4 months) dosage were evaluated in nine children with asthma, aged 5 to 10 years. The FEV1 increased significantly after high dosage (median, 96.5% versus 105.5%; p = 0.0339). After lower dosage, FEV1 was still higher than at the baseline (106% versus 96.5%; p = 0.0339). Clinically, no additional beta2-agonist was needed after 2 weeks of treatment. Serum high-density lipoprotein cholesterol increased significantly by 22% after high dosage (medians, 1.18 versus 1.44 mmol/L). A significant decline to 1.31 mmol/L was observed when the dose was reduced (overall, p = 0.0319). The treatment had no significant effect on serum total cholesterol, on serum triglycerides, on the ratio of high-density lipoprotein to total cholesterol, on the body mass index, or on glucose tolerance. The high dosage increased significantly the ratio of serum insulin to blood glucose, calculated from the areas under the incremental 2-hour curves in the glucose tolerance test (medians, 17.3 versus 23.2 mU/mmol). After lower dosage, the ratio declined significantly to 13.5 mU/mmol (overall, p = 0.0164). No significant changes were observed in plasma cortisol in the 2-hour adrenocorticotropic hormone test. The antiasthmatic effect of budesonide inhalations in a dose of 800 micrograms/m2/day for 1 month was accompanied by detectable changes in lipid and carbohydrate metabolism. These metabolic changes were reversible, and the antiasthmatic effect could be maintained by a dose of 400 micrograms/m2 for 4 months without significant systemic effects. This dose is safe and efficient in the maintenance treatment of childhood asthma.

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.

Eosinophil cationic protein in induced sputum as a marker of inflammation in asthmatic children

We evaluated the usefulness of eosinophil cationic protein (ECP) in induced sputum and in serum as markers of asthmatic inflammation in children. We measured ECP in serum and in total indticed sputum samples from 14 children (7‐11 years) with newly detected asthma before and after treatment, and from ten healthy non atopic controls of the same age. The patients inhaled budesonide, 800 μg/m2/day for the first month and 400 μg/m2/day for the next 5 months, both divided into two doses, and nedocromil, 4 mg three times daily for the following 6 months. In both sputum and serum, ECP levels were higher in the patients than in the controls, but the difference was more distinct in sputum. Significant clinical improvement during the treatment was accompanied by a decrease in sputum ECP. whereas serum ECP did not change. The results suggest that induced sputum is useful as a non invasive source material for evaluating asthmatic inflammation in children, total sputum ECP being more sensitive than serum ECP for diagnosing and monitoring asthma.

The aminoterminal propeptide of type I procollagen: Evaluation of a commercial radioimmunoassay kit and values in healthy subjects

OBJECTIVES Evaluation of the performance of a radioimmunoassay kit for measuring serum concentrations of the aminoterminal extension peptide of human type I procollagen, S-PINP. DESIGN AND METHODS S-PINP concentrations in 229 healthy subjects, 140 females, aged 3.8-81 years, and 89 males, aged 0.9-71 years, were measured with the kit. Because PINP and PICP (the carboxy-terminal propeptide of type I procollagen) are formed in equimolar concentrations, we also calculated the PICP/PINP ratio and compared the S-PINP values to those of S-PICP, which have been shown to correlate with bone formulation rate. RESULTS The sensitivity of the assay was 2.3 micrograms/L, the spiking recovery ranged from 95.5 to 100.3%, the dilution recovery from 79.3 to 103.1%. The intra-assay imprecision was 2.3 to 3.5% (CV), the interassay imprecision within one reagent lot 2.5-5.2% and, between several reagent lots, 2.7 to 6.1% (CV). S-PINP in females over 20 years old ranged from 12 to 90 micrograms/L (x = 39.7, SD = 14.7), in males over 25 years old, from 22 to 89 micrograms/L (x = 49.9, SD = 15.8); the PICP/PINP ratio ranged from 1.5 to 5.2 and from 1.8 to 4.9, respectively. In females under 20 years old, S-PINP ranged from 52 to 820 micrograms/L, in males aged 25 years or younger from 35 to 1404 micrograms/L; the PICP/PINP ratio was 0.44-2.3 and 0.38-2.8. In females under 20 years and males under 25 years, there was a significant negative correlation between S-PINP and age: r = -0.70, p < 0.001 for females, r = -0.52, p = 0.004 for males. In different groups of healthy subjects, the correlation of S-PINP and S-PICP was significant (r = 0.67-0.86, p < 0.001). CONCLUSION The assay performance is good. The significant positive relationship between S-PINP and S-PICP suggests that S-PINP also reflects bone formation rate. Because the clearance of PINP is probably less sensitive to hormonal changes, PINP may prove to be superior to PICP as a marker of bone formation.