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 microg twice daily for 1 month, 200 microg twice daily for months 2-6, 100 microg 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 microg 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.

Familial high serum PICP: high even in skin interstitial fluid, suppressible by topical corticosteroid treatment.

Circulating C-terminal propeptide of type I procollagen (PICP), mostly originating from bone, is mainly cleared by mannose receptors (MRs) in liver endothelial cells (LECs). We hypothesized that skin macrophage MRs could also play a role in local (in situ) clearance of PICP originating from skin type I procollagen synthesis. We tested this hypothesis in a male subject with a genetic systemic clearance defect, apparently due to an abnormality in MR function in LECs (or in PICP structure). Since skin macrophages may express the same MRs as LECs do, the genetic defect could affect them as well; hence, if elevated PICP concentrations even in skin interstitial fluid (IF) were found in our subject, it would suggest a role for local MR-mediated PICP clearance in skin. Since glucocorticoids (GCs) upregulate MRs in vitro, we measured the effect of topical GC on suction blister fluid (SBF)-PICP of the test person as compared with normal subjects. SBF-PICP was elevated in the case, which was consistent with the hypothesis. Furthermore, the GC-induced decrease was accentuated. The results suggest that skin macrophage MRs can have a role in skin PICP clearance in situ.

Pollen-specific rush immunotherapy: clinical efficacy and effects on antibody concentrations.

BACKGROUND: Studies of rush immunotherapy (RIT) with standardized extracts for the treatment of seasonal pollen allergy are few, especially for birch-pollen RIT. OBJECTIVE: The study was performed to investigate the efficacy of RIT with standardized birch- or timothy-pollen extracts. Further, the serum antibody levels were evaluated for correlation with clinical efficacy. METHODS: This open, longitudinal study included 30 allergic patients treated with RIT and 16 allergic patients serving as a control group. The therapy was continued for 3 years and blood samples were collected at regular intervals for antibody measurements using the Pharmacia CAP System. RESULTS: The RIT was generally well tolerated. An increase in the total and specific IgE concentrations during the early months of RIT was observed, followed by decreased levels. Specific IgG and IgG4 increased continuously for 2 years. The symptom and medication scores were significantly decreased, compared with preRIT, at both the first and third pollen seasons after the start of RIT treatment (P < .0001 and P < .001, respectively). The clinical improvement during RIT was significantly greater compared with the control group (P < .05). The decreased medication and the symptom improvement during the third year of RIT correlated with the relative decrease in specific IgE (rs = .52, P < .05) and with the specific IgG4 level before the start of RIT (rs= -.68, P < .01), respectively. CONCLUSIONS: Our study indicates that RIT with standardized birch- or timothypollen extracts is clinically effective and safe. Measurements of specific antibody levels during treatment may be helpful in monitoring RIT.

Markers of collagen metabolism and insulin-like growth factor binding protein-1 in term infants.

AIM: To study the relation between fetal growth and markers of collagen metabolism and insulin-like growth factor binding protein-1 (IGFBP-1) in term infants. METHODS: Cord vein plasma was obtained from 67 term infants of gestational age 37.1-41.7 weeks (39 appropriate for gestational age (AGA), 11 large for gestational age (LGA; relative birth weight >/= 2.0 SD), and 17 small for gestational age (SGA; relative birth weight 0.05). CONCLUSIONS: In the term fetus, collagen metabolism is primarily dependent on maturity and not on intrauterine growth status, whereas IGFBP-1 reflects intrauterine growth independently of maturity.

Application and efficacy of the multi-dose powder inhaler, Easyhaler, in children with asthma.

With powder inhalers, optimal performance is dependent on the inspiratory flow produced by the patient through the devices. The objective of this open, non-randomized study was to evaluate the suitability of a new, multidose, dry powder inhaler, the Easyhaler, for children with asthma. The peak inspiratory flow (PIF) through the Easyhaler (PIF(EH)) was measured with a pneumotachograph in 120 asthmatic children aged 4-16 yr. The bronchodilatory effect of 0.2 mg salbutamol through the Easyhaler was compared with that of 0.2 mg salbutamol through a metered dose inhaler (MDI) with a spacer, in 15 children with obstruction. The mean PIF(EH) was 56 l/min (range 22-83 l/min). The PIF(EH) correlated significantly with age, height, and absolute peak expiratory flow (PEF), but not with the level of obstruction (PEF percentage of predicted, range 45-146%). Only four children (aged 5, 6, 10, and 16 yr) had PIF(EH) values below 28 l/min, which has been shown in in vitro studies to be the threshold for effective use of the Easyhaler. In 15 children with PEF, < 85% of predicted bronchodilatory effects of 0.2 mg salbutamol through the Easyhaler and from an MDI-cum-spacer were equal. Most children aged 6-16 yr produce PIF values sufficient for the use of the Easyhaler. The gain of 0.2 mg salbutamol from the Easyhaler was equal to that from a new, unprimed, MDI with a spacer in children with asthma.

Serum markers of collagen metabolism and serum osteocalcin in relation to pubertal development in 57 boys at 14 years of age.

We investigated whether levels of serum collagen markers and serum osteocalcin are related to pubertal growth and development in a cross-sectional study of 57 healthy boys at 14 y of age. The level of the soft tissue marker, serum amino-terminal propeptide of type III procollagen (PIIINP) was higher in boys at Tanner stages G3 versus G2 (p < 0.01). The levels of the markers of bone collagen matrix differed only at a more advanced pubertal stage: the formation markers, carboxy-terminal and amino-terminal propeptides of type I procollagen, and the degradation marker, carboxy-terminal telopeptide of type I collagen were higher only at stage G4 versus G3 (p < 0.01). The marker of bone mineralization, serum osteocalcin was also higher only at stage G4 versus G3 (p < 0.01). Stage G4 was associated with the pubertal growth spurt. The results demonstrate that pubertal development should be taken into account when serum levels of collagen markers and osteocalcin are evaluated, and suggest that an increase in serum PIINP in boys at G3 might predict a normal pubertal growth spurt, but the finding remains to be confirmed in longitudinal studies.

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 induced 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 micrograms/m2/day for the first month and 400 micrograms/ 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.

Collagen formation and degradation increase during growth hormone therapy in children.

A comprehensive set of serum markers of collagen turnover and growth was investigated in a longitudinal study of short children during growth induced by growth hormone (hGH) treatment. The study comprised 18 prepubertal children with short stature who had no other current illness or continuous medication. The growth rates and endogenous GH secretions covered a continuum from subnormal to normal. Before treatment, the concentrations of carboxyterminal propeptide of type I procollagen (PICP), reflecting type I collagen formation, of carboxyterminal telopeptide of type I collagen (ICTP), a degradation product of type I collagen, of amino-terminal propeptide of type III procollagen (PIIINP), a marker for type III collagen formation, of alkaline phosphatase (AP), and of insulin-like growth factor binding protein-3 (IGFBP-3) were within the lower limits of normal. The median IGF-I concentration was lower than the reference. One week after the start of treatment, the serum concentrations of ICTP, PIIINP, and osteocalcin (OC), and the increments in ICTP, PIIINP, and IGF binding protein-3 (IGFBP-3) correlated with the subsequent height velocity. During the 12-month treatment, all markers were higher than those of age-matched references, but only the three collagen markers paralleled the changes in height velocity. In molar concentrations, ICTP increased less than PICP. Throughout the study period, the serum level of ICTP correlated with that of PIIINP, but not with that of PICP. The findings suggest that during hGH treatment, linear body growth is closely associated with collagen formation and degradation.

Very low rate of type I collagen synthesis and degradation in newly diagnosed children with acute lymphoblastic leukemia.

In children with acute lymphoblastic leukemia (ALL), the metabolism of type I collagen, the major collagen of bones, may be changed at diagnosis and during early chemotherapy. In the present study, bone formation and degradation rates were evaluated longitudinally in 35 children with ALL, using two serum markers of bone collagen formation: the amino-terminal (PINP) and carboxyterminal (PICP) propeptides; and a marker of degradation: the carboxyterminal telopeptide of type I collagen (ICTP). These serum markers were determined at diagnosis, during induction treatment (at 1, 4, and 6 weeks), and during consolidation treatment (at 8 and 12 weeks). The changes in the serum markers suggested that, at diagnosis, type I collagen turnover (i.e., both synthesis and degradation) was remarkably low. The median serum levels of PINP, PICP, and ICTP were -2.6 SDS (standard deviation score), -1.5 SDS, and -2.5 SDS, respectively. The PICP and PINP levels declined further during the first week of therapy (p < 0.001), whereas the ICTP levels had risen by end of the induction phase (p < 0.05). By the end of the 12 week interval, the concentrations of the formation and degradation markers had returned to normal (p < 0.01). Our findings suggest that ALL is accompanied by low turnover of bone collagen. The abnormalities are at first aggravated, but then corrected, by treatment.

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.

Fluticasone propionate compared with budesonide: a double-blind trial in asthmatic children using powder devices at a dosage of 400 microg x day(-1).

The aim of this study was to compare fluticasone propionate (FP) with budesonide (BUD) at a dose of 400 microg x day(-1) in the treatment of children with asthma. Two hundred and twenty nine children with mild-to-moderate asthma, currently receiving 200-400 microg x day(-1) of inhaled corticosteroid, were randomized to receive either 400 microg x day(-1) of FP from the Diskhaler (registered trade mark of the Glaxo Group of Companies) or 400 microg x day(-1) of BUD from the Turbuhaler (registered trade mark of Astra Pharmaceuticals Ltd) for 8 weeks, in a parallel-group, double-blind, double-dummy study. Primary efficacy was assessed by measurement of daily peak expiratory flow (PEF). In addition, pulmonary function tests were performed at each clinic visit and a self-administered patient-centred questionnaire was completed by one parent of each patient at the start and end of study treatment. Mean morning PEF increased following treatment both with FP and BUD, but was significantly higher following treatment with FP during Weeks 1-4 (p=0.015) and Weeks 1-8 (p=0.019). Similar results were found for mean evening PEF and percentage predicted morning and evening PEF. Children receiving FP experienced significantly less disruption in their physical activities (i.e. sports, games) because of their asthma compared to children treated with BUD (p=0.03). Mean cortisol levels increased in both groups, but the increase was significantly higher in the FP group at 4 weeks (p=0.022). Serum and urine markers of bone formation and resorption changed very little and showed no consistent pattern of change. Fluticasone propionate at a dosage of 400 microg x day(-1) from the Diskhaler provided a more rapid and greater improvement in lung function in children with mild-to-moderate asthma than BUD 400 microg day(-1) from the Turbuhaler. Both treatments were well-tolerated, with a similar safety profile.

Changes in bone markers in children with asthma during inhaled budesonide and nedocromil treatments.

We evaluated serum and urinary markers of bone turnover in 14 children with asthma during inhaled budesonide and nedocromil treatments. Both the markers of formation (serum carboxy- and amino-terminal propeptides of type I procollagen and serum osteocalcin) and the markers of degradation (serum carboxy-terminal telopeptide of type I collagen and urinary pyridinium cross-links) decreased (p < 0.05) during budesonide treatment for 6 months. During inhaled nedocromil treatment (for the following 6 months), the markers returned to the normal levels. These transient decreases in the markers of both formation and degradation of bone suggest that inhaled budesonide may slightly decrease the bone turnover rate. However, normal "coupling" between formation and degradation seemed to operate, e.g. a change in one resulted in a corresponding change in the other, so that net bone loss did not necessarily occur.

Latex allergy in children with no known risk factor for latex sensitization.

We describe latex allergy in 11 atopic children, aged 0.7-11.1 years, without any known risk factor. A skin prick-test (SPT) for latex was positive in 8/11, and latex specific IgE was found in all. Latex glove challenge was positive in 9 assessed. These patients demonstrate that latex allergy should be looked for not only in children who have had several operations or those children reporting symptoms from rubber, but also in children with severe atopic eczema, banana allergy, or urticaria or anaphylaxis for which the cause is unknown.

Frequency distribution of breath sounds as an indicator of bronchoconstriction during histamine challenge test in asthmatic children.

In order to study changes in respiratory sounds associated with acute bronchoconstriction and -dilatation, breath sounds of 11 children with asthma (age range, 10-14 years) were recorded at the chest and at the trachea during histamine challenge test and after subsequent bronchodilatation. The changes in frequency spectra of breath sounds were compared with simultaneous changes in forced expiratory volume in 1 second (FEV1). In seven children who responded to histamine with a decrease in FEV1 of more than 15%, there was a significant relationship between percentage change in FEV1 (delta FEV1) and percentage change in median frequency (delta F50) of expiratory breath sounds recorded at the chest (r = 0.865; beta = -0.706, P = 0.0001) and at the trachea (r = 0.888; beta = -1.12, P = 0.0001). The association between breath sound intensity and FEV1 was weaker. Based on ANOVA, the increase of F50 during the challenge test was significantly larger in children who responded to histamine than in those who were non-responsive (P = 0.0016). At the chest, a decrease of 15% in FEV1 corresponded to an increase of 8% in expiratory F50. The provocative dose of histamine inducing a decrease of 15% in FEV1 (PD15FEV1) and the provocative dose causing an increase of 8% in F50 (PD8F50) were significantly related (r = 0.927, P = 0.003). We conclude that spectral analysis of breath sounds can be used to indicate airway obstruction during bronchial challenge tests in children, and may be adapted for tests in pre-school children. The results suggest that the same mechanisms that induce airflow limitation due to inhaled histamine may generate an increase in frequency content of breath sounds in children with asthma.