Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial.

Increased tumour necrosis factor-α levels have been observed in bronchial biopsies and induced sputum from subjects with severe asthma. We investigated etanercept (ETN) as a therapeutic option for treating moderate-to-severe persistent asthma. In this 12-week, randomised, double-blind, placebo-controlled, phase 2 trial, subjects (n=132) with moderate-to-severe persistent asthma received subcutaneous injections of 25 mg ETN or placebo twice weekly, and were evaluated at baseline, and at weeks 2, 4, 8 and 12. The primary end-point was the change from baseline to week 12 in pre-bronchodilator forced expiratory volume in 1 s (FEV1)% predicted. Secondary end-points included morning peak expiratory flow, FEV1% pred, Asthma Control Questionnaire (5-item version), asthma exacerbations, provocative concentration of methacholine causing a 20% decrease in FEV1, and the Asthma Quality of Life Questionnaire. No significant differences were observed between ETN and placebo for any of the efficacy end-points. ETN treatment was well tolerated, with no unexpected safety findings observed during the study. Clinical efficacy of ETN was not shown in subjects with moderate-to-severe persistent asthma over 12 weeks. However, ETN treatment was a well-tolerated therapy. Studies in specific subsets of patients with asthma with longer-term follow-up may be needed to fully evaluate the clinical efficacy of ETN in this population.

Effects of intrauterine growth retardation and prematurity on spirometric flow values and lung volumes at school age in twin pairs.

Lung volumes and pulmonary expiratory flow values were investigated in 67 children from multiple pregnancies (30 twins, one set of triplets, one set of quadruplets) at the age of 7-15 years. At birth, 30 of 67 children (44%) had intrauterine growth retardation (IUGR, birth weight <-2 SD or birth weight difference between twin-pairs >1.3 SD). The median gestational age was 35 weeks (range, 28-38 weeks), and the median birth weight was 2,050 g (800-3,150 g). Lung functions were measured with a heated pneumotachograph. Data were standardized using height-based reference equations. No differences were found in lung volumes between children with IUGR and those children who had normal birth weight. Gestational age did not correlate with either airway flow rates or lung volumes. Maximum mid-expiratory flow (FEF50) did not correlate with standardized birth weight or with gestational age. In discordant twin pairs, the IUGR twins had significantly lower FEF50 than their normal birth weight counterparts (p=0.03, Z=-2.13). In the whole study group (67 children), children with IUGR had significantly lower FEF50 than children with normal birth weight (p=0.04; CI, 0.3-19.9). We propose that IUGR has the most pronounced effect on the growth of airways, and no detectable influence on lung volumes. This study confirms the crucial effect of appropriate intrauterine growth on subsequent growth on pulmonary airways.

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.

Pulmonary function and respiratory morbidity in school-age children born prematurely and ventilated for neonatal respiratory insufficiency.

We examined 72 children aged 6-9 years to assess the effects of prematurity and ventilator treatment on subsequent lung function and respiratory morbidity. The preterm study group (n = 42) was divided into children with a history of bronchopulmonary dysplasia (BPD) (n = 10), children who had had neonatal respiratory treatment but no BPD (n = 19), and children without severe neonatal respiratory problems (n = 13). The BPD children as a group had markedly lower specific airway conductance and larger residual volume than did the full-term control group, but there were no significant differences in spirometric measurements. The BPD group also had higher respiratory morbidity requiring hospitalizations, particularly during the first 2 years of life, than did the children in the other study groups. Therefore, BPD may improve but does not disappear as age increases. Non-BPD children who had had ventilator treatment as neonates recovered well and suffered no severe respiratory problems after infancy. Pulmonary function parameters in prematurely born children without neonatal ventilator treatment did not differ from those in the full-term control group. Thus, neonatal lung disease seems to be a more important determinant of abnormal pulmonary function at a later age than is prematurity alone.

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. All spirometric parameters were significantly lower in the preterm groups than in the controls, except for the forced vital capacity (FVC) in the prophylactically treated group. Bronchial obstruction was found in 53% of the prophylactically treated group, in 36% of the rescue group, in 67% of the placebo group, and in 0% of the control group. Peak expiratory flow (PEF) and FVC values were higher in those children who received surfactant compared with the placebo group (P < 0.05). In 16 children (40%) born preterm, a beta2-agonist induced an increase in PEF > or = 15% at least three times during 2 weeks of home monitoring; eight children (20%) had abnormal diurnal PEF variation. Multiple regression analysis indicated that the independent variables associated with favorable outcomes in spirometric parameters were surfactant therapy (P = 0.012-0.045) and short intubation time after birth (P = 0.0009-0.0044). Bronchial obstruction, responsiveness to a beta2-agonist, and high diurnal PEF variation are common in children born before 30 gestational weeks. Surfactant supplementation reducing the need for mechanical ventilation or supplementary oxygen after birth may decrease the severity of immaturity related bronchial obstruction in childhood.

Intraindividual variability of infant whole-body plethysmographic measurements: effects of age and disease.

The intraindividual variability of whole-body plethysmographic measurements was studied in a large series of consecutive infants (N = 144), divided into two groups: a group of infants born very prematurely (PM, N = 63), with (N = 28) or without (N = 35) a history of bronchopulmonary dysplasia (BPD), and a group of infants with persistent respiratory symptoms (PRS, N = 81), i.e., wheezing (N = 53) or cough (N = 28). The intraindividual variability was determined within each test and between tests, separated by a 10-min interval. In both study groups, the between-test variability was significantly larger than that within tests. Expressed as the median coefficient of variation (CV), the between-test repeatabilities in the PRS group were 8.0% for thoracic gas volume (TGV), 17.5% for airway resistance (Raw), and 18.4% for specific airway conductance (sGaw), and in the PM group, 8.9% for TGV, 20.4% for Raw, and 20.7% for sGaw. However, the individual range of CVs was large, ranging from 3 to 19% for TGV and from 5 to 55% for sGaw. With respect to TGV, the difference between the groups was statistically significant (P = 0.03). In infants with a history of BPD, there was also a significant negative age dependency in CVs of sGaw (r = -0.50, P = 0. 009), showing larger variation among younger individuals. The presenting symptom (wheezing or cough) in the PRS group did not influence the measurement variability significantly, and neither did the degree of bronchial obstruction. We conclude that on a group basis, the repeatability of infant body plethysmographic measurements may be satisfactory for scientific studies demonstrating pharmacodynamic effects; however, the intraindividual measurement variability should be reported for each test conditions and for infant groups in each study. Due to the large range in individual variation and the influence of age and disease processes on the variation, for an individual child there is only questionable benefit from a given measurement, unless the intrasubject, between-test variability is assessed individually before interventions, such as a bronchodilation test.

Effect of inhaled budesonide therapy on lung function in schoolchildren born preterm.

We investigated the effect of inhaled glucocorticoid (GC) on bronchial obstruction and on bronchial lability in schoolchildren born preterm. Twenty-one children with bronchial obstruction, increased responsiveness to a beta2-agonist, and/or increased diurnal variation in peak expiratory flow (PEF) were selected for an open longitudinal study of the value of inhaled GC. None of these children had an earlier diagnosis of asthma or current GC treatment. Eighteen children with median (range) birth weight 1025 (640-1600) g and gestational age 28 (24-35) weeks, age at study 10.1 (7.7-13) years, were treated with inhaled budesonide in initially high (0.8 mg m(-2) day(-1) for 1 month) and subsequently lower dose (0.4 mg m(-2) day(-1) for 3 months). Daily symptom scores were recorded. Spirometric values were measured in the clinic at the beginning and end of each treatment period. At home, children used a data storage spirometer. After treatment with budesonide for 4 months, spirometric values in the clinic did not significantly change. The median forced expiratory volume in 1 sec (FEV1) was 74% of predicted both at entry and after budesonide treatment. However, the median number of > or = 20% diurnal change in PEF values at home decreased during treatment. According to the present study, inhaled budesonide for 4 months had no significant effect on basic lung function but may decrease bronchial lability in schoolchildren born preterm.

Transcutaneous PO2 recording using two sensors in a neonate with preductal coarctation of the aorta.

Simultaneous transcutaneous PO2 (PtcO2) recordings, done on a neonate having preductal coarctation of the aorta, showed markedly lower PtcO2 values in the lower abdominal quadrant (representing postductal blood) than in the subclavicular area (representing preductal blood). Two-sensor PtcO2 recordings are valuable in documenting pathologic ductal shunts commonly associated with disturbed transitional circulation or cardiac malformation in newborn infants.

Survival of the smallest. Time trends and determinants of mortality in a very preterm population during the 1980s.

In a regionally representative preterm birth cohort, the fetal to first year survival of very preterm infants born at 32 weeks' gestation or less increased from 54% to 66% between 1978 and 1986. This improvement was due to a fall in numbers of stillbirths while neonatal mortality either declined or remained the same. Only among extremely immature preterm babies born at 26 weeks or less was improvement in fetal survival counteracted by an increase in neonatal mortality. Fewer than 5% of complete fetal to first year deaths occurred postneonatally. After the age of 26 gestational weeks, intrauterine growth retardation was a major unfavourable factor, associated with a 3-fold increase in neonatal mortality.

Bronchial lability and responsiveness in school children born very preterm.

We evaluated bronchial lability and responsiveness in 29 prematurely born children (birth weight < 1,250 g) 8 to 14 yr of age, 12 with histories of bronchopulmonary dysplasia (BPD). Flow-volume spirometry, a bronchodilator test, and histamine challenge at the office and home monitoring of peak expiratory flow (PEF) values twice daily for 4 wk with and without a beta2-agonist were performed with a novel device, the Vitalograph Data Storage Spirometer. The spirometric values at the office and the results of home monitoring were compared with those for a control group of children born at term. All spirometric values except FEV1/FVC were significantly lower in the BPD group than in the non-BPD group (p < 0.0001). Ten children (83%) in the BPD group and four (24%) in the non-BPD group had subnormal spirometric values at the office, indicating bronchial obstruction. Of the children with obstruction, 79% reported respiratory symptoms during the preceding year, and 57% had increased diurnal PEF variation and/or responded to administration of a beta2-agonist during home monitoring or at the office. The BPD children were significantly more responsive to histamine than the non-BPD children (p = 0.002). All spirometric values were significantly lower in both preterm groups than in the control group born at full term (p < 0.01). In conclusion, regardless of BPD, bronchial obstruction, bronchial lability, and increased bronchial responsiveness are common in prematurely born children of school age.

Occurrence, predictive factors and associated morbidity of bronchopulmonary dysplasia in a preterm birth cohort.

The occurrence, predictive factors and associated morbidity of bronchopulmonary dysplasia (BPD) was examined in a preterm birth cohort of 712 children, born before 37 weeks of gestation to residents of a geographically defined area between 1978-82. All cases of BPD (N = 16) were born at or before 32 weeks of gestation. The incidence of BPD, based on status at the age of 28 days, was 1 per 1000 live births, but 135 per 1000 live preterms born at or before 32 weeks. Most cases of BPD developed following respiratory distress syndrome (RDS), only one case developing after minimal respiratory symptoms was observed. BPD infants had higher neonatal morbidity, even when compared with preterms of equal gestational maturity, but only a few variables had predictive value with respect to the future development of BPD. Radiologic grading of RDS and associated early cardiologic signs did not increase their predictivity regarding the subsequent development of BPD. Two (12.5%) of the 16 BPD infants died postneonatally. The unfavorable effects of BPD on the health status of preterm infants extended far beyond the neonatal period. The BPD group, which consisted only of 18% of neonatal survivors born at less than or equal to 32 weeks, consumed 53% of all hospital days used by these preterms during the first two years of life. In particular, BPD survivors had markedly more respiratory infections (63%), more neurologic sequelae (37%) and more cases of retrolental fibroplasia (12%) than their non-BPD counterparts.

Prematurity-associated morbidity during the first two years of life. A population-based study.

Two-year patterns of postneonatal morbidity, both chronic and non-chronic, reported for all liveborn preterm infants (n = 612; malformations excluded) delivered in the province of Kuopio, Finland, between 1978 and 1982. The overall readmission rate was 30%, the commonest cause being respiratory infections, surgical disorders (inguinal hernias) and neurological problems. The higher readmission rate in preterms born at less than or equal to 33 weeks of gestation was due to a large proportion of children being admitted with chronic prematurity-associated conditions; preterms without chronic disabilities had similar rates of readmission irrespective of gestational age. Neonatal treatment variables were of little help in the identification of children requiring readmission after neonatal care. Instead, intrauterine growth retardation (IUGR) or being of the male sex significantly increased the risk of subsequent readmission.

Evening primose oil and fish oil are ineffective as supplementary treatment of bronchial asthma.

The effect of daily dietary supplementation with 15 to 20 mL of evening primrose seed oil or fish oil was assessed by comparison with olive oil as placebo in a cross-over study in 29 asthmatics. During 10 weeks of each regimen, the patients kept record of symptoms, peak expiratory flow rates and medication. Plasma and urine TxB2, PGE2, PGF2 alpha and 6 keto-PGF1 alpha and plasma fatty acid composition of plasma cholesterol esters were measured at the end of each treatment period. There were no differences between regimes with regard to peak flow rates, symptoms, or drug consumption. Plasma PGE2 levels increased during the fish oil treatment but there were no changes in other prostanoids in plasma or urine. The fatty acid pattern of plasma cholesterol esters showed significant differences between the supplementation periods. We conclude that moderate doses of evening primrose oil or fish oil are ineffective as a supplementary treatment of bronchial asthma.

Nocturnal oxygen saturation and body movement in asthmatics treated with controlled-release preparations of theophylline or terbutaline.

Nine adult asthmatics with a history of nocturnal symptoms and with morning dips in peak expiratory flow (PEF) were treated for 10-14 days with 24-h controlled-release preparation of theophylline (Th), or a controlled-release preparation of terbutaline (Te), in a double-blind cross-over experiment. During treatment with 450-900 mg Th in the evening morning, plasma drug levels ranged from 53-95 (mean 73) mumol/l. The Te dose was 7.5 mg twice daily. Morning PEF values during Th (mean 338 l.min-1) and Te (316 l.min-1) were not significantly different. There were no significant differences between the treatments in average nocturnal oximetric O2 saturation (91.9% during Th and 91.0% during Te), or the amount of nocturnal body movement, recorded with a static charge sensitive bed (total number of movements 146 during Th and 120 during Te). No difference between the treatments was seen with respect to assessment by the subjects of sleep quality, which was considered fair or good. The findings suggest that in moderately severe asthma, nocturnal oxygenation and sleep quality were similar during the two treatments.

Once-daily theophylline in the treatment of nocturnal asthma.

The efficacy and side-effects of individually adjusted doses of controlled-release theophylline given once daily in the evening (average dose 650 mg) were compared with those of standard treatment with controlled-release terbutaline 7.5 mg b.d. Thirty-six asthmatics with regular morning obstruction ("morning dipping") were studied over two treatment periods each of two weeks, according to a crossover, randomized, double blind design. Morning peak expiratory flow (PEF) was slightly but significantly higher with theophylline (363 l.min-1) than terbutaline (342 l.min-1). Feelings of dyspnoea on waking in the morning were also less pronounced with theophylline. There were no other differences between the treatment periods during the day or night, with respect to dyspnoea or any the other symptoms. Side-effects were mild and were reported with similar frequencies during both treatments. It is concluded than an individually adjusted dose of once-daily theophylline administered in the evening is at least as effective as conventional therapy with controlled-release terbutaline in preventing nocturnal and early morning asthma, when both drugs are added to regular medication with inhaled sympathomimetics and steroids.

Effect of conventional dose growth hormone therapy for two years on height velocity and height prognosis in girls with Turner syndrome.

The aims of this national multicentre study in Finland were to evaluate whether the height velocity of patients with Turner syndrome would increase with the conventional human growth hormone (GH) therapy regimen normally given to GH-deficient children and whether girls with Turner syndrome actually show GH neurosecretory dysfunction. Finally, the study should show whether GH therapy improves height prognosis and, eventually, final height. Twenty-five girls with Turner syndrome, aged 7.5-14.4 years, entered the study. Their ability to secrete GH was determined and, surprisingly, several would have been classified as having GH deficiency. All girls received GH, 0.1 IU/kg/day (maximum dose 4 IU/day) s.c., and once over 12.5 years old, they also received oestradiol valerate and fluoxymesterone. They showed a convincing increase in height velocity, and rapid growth continued during the second year of therapy. The effect of GH therapy on final height is still unknown. The therapy was remarkably free of side-effects.

Glucose profiles in children two years after the onset of type 1 diabetes.

The relationship of 24-h glucose profiles to age, haemoglobin A1c (HbA1c), and C-peptide concentration was analysed in consecutive, unselected children who had developed Type 1 diabetes 2 years earlier. Seventy-seven children in four age groups (age 2-4 years, n = 9; 5-8 years, n = 14; 9-12 years, n = 26; and 13-17 years, n = 28) were studied. Each child was hospitalized for 2 days for the investigations. Mean blood glucose concentration was 9.7 +/- 4.1 (SD) mmol l-1 in children aged 2-4 years; 10.7 +/- 4.0 mmol l-1 in those aged 5-8 years; 11.3 +/- 3.4 mmol l-1 in those aged 9-12 years; and 9.8 +/- 3.3 mmol l-1 in those aged 13-17 years. Results were > 7.0 mmol l-1 in 69% (range 56-76%) and > 10 mmol l-1 in 49% (39-57%) of the measurements. Values decreased by 30% (21-43%) between 10 pm and 3 am. The nadir of the mean profiles of the groups was always at 3 am. Glucose concentration was mmol l-1 in 25% (14-50%), < 2.5 mmol l-1 in 9.6% (0-21%), and < 2.0 mmol l-1 in 2.7% (0-4.2%) of the children at 3 am; hypoglycaemia was most common in those aged 5-8 years. Of the four profile characteristics used, mean blood glucose predicted HbA1c (R2 = 24.7%, p < 0.00005, multiple linear regression analysis), and slightly more in combination with age (R2 = 32.0%, p < 0.00005).(ABSTRACT TRUNCATED AT 250 WORDS)

Serum insulin profiles in consecutive children 2 years after the diagnosis of IDDM.

We studied associations of 24-h serum insulin profiles with insulin dose, age, gender, haemoglobin A1c (HbA1c) and C-peptide values, as well as blood glucose profiles in 77 consecutive children-nine aged 2-4, 14 aged 5-8, 26 aged 9-12, and 28 aged 13-17 years--2 years after the onset of insulin-dependent diabetes mellitus (IDDM). Mean weight-based insulin doses in the four age groups were similar (0.7 +/- 0.2 U.kg-1.day-1 in all); body surface-area-based doses differed. Insulin doses correlated significantly with the 24-h mean and area-under-the-curve (AUC) values, and with mean values at 03.00 hours of serum insulin in the children aged 5-8 and 13-17 years. The mean insulin concentrations of the age groups (95% confidence intervals) increased with age [6.1 (3.8, 9.7), 7.6 (5.9, 9.8), 10.4 (8.6, 12.4), and 14.0 (11.6, 16.8) mU/l; p < 0.0002]. The 24-h mean of serum insulin together with HbA1c concentration predicted 32% of the variation of mean blood glucose concentrations. Of children aged less than 9 years, 50% had insulin values less than 5 mU/l (healthy subjects' lower reference limit), and 14% were of less than 2 mU/l (detection limit of the assay) at 03.00 hours. At 07.00 hours, 82% had insulin values of less than 5 mU/l, and 36% were of less than 2 mU/l, respectively. Some young children had night-time hypoglycaemia with simultaneous hypoinsulinaemia. Insulin profiles correlated poorly with the HbA1c and peak C-peptide values.(ABSTRACT TRUNCATED AT 250 WORDS)

Mumps infections in the etiology of type 1 (insulin-dependent) diabetes.

The epidemiology of Type 1 (insulin-dependent) diabetes was studied during a period starting after an unusually sharp epidemic of mumps. The number of diabetic cases increased significantly 2-4 years after the epidemic. Incidence rates were highest in geographical areas with the highest incidence of mumps and lowest in areas with the smallest numbers of reported mumps cases. Serological studies employing EIA-assays indicated recent mumps infections more often among newly diagnosed diabetic children than among matched controls although the incidence was low (13% of patients and 4% of controls had serological markers of recent mumps). Those patients, who had had serologically verified recent mumps had more often HLA-DR4 associated risk antigens (Dw4 and Dw14) than other patients. Also clinical history of mumps was obtained more often from diabetic children than from controls as 27% of the patients and 14% of the controls had had clinical mumps during the five years preceding the diagnosis of diabetes. These results confirm several earlier reports suggesting a connection between mumps and Type 1 diabetes and that the onset of diabetes may be delayed by several years.