Cross-sectional and longitudinal association of the secretoglobin 1A1 gene A38G polymorphism with asthma phenotype in the Perth Infant Asthma Follow-up cohort.

BACKGROUND: Associations between Clara cell secretory protein gene variants (SCGB1A1, also known as CC16, CC10, CCSP and uteroglobin) and the asthma phenotype have been found in five out of eight studies world-wide. No study has investigated the contribution of SCGB1A1 polymorphisms to the development and/or persistence of the asthma phenotype in a birth cohort followed over time. OBJECTIVE: The aim of this study was to determine the role of the SCGB1A1 gene in the development of the asthma phenotype. METHODS: The Perth Infant Asthma Follow-up (PIAF) cohort (n=231 unrelated infants, unselected for asthma and recruited at birth) were seen at 1 month, 6 and 11 years of age, and had a questionnaire, lung function, airway responsiveness (AR) and skin prick tests (SPTs) completed. Blood was taken at 6 and 11 years for total and specific immunoglobulin E (sIgE) and DNA extraction. SPT positivity had at least one positive SPT. SIgE>4 kU/L had at least one sIgE above 4 kU/L. SCGB1A1 A38G (rs3741240), that alters gene transcription, was genotyped using Sau96I restriction digestion of exon 1 PCR products. RESULTS: At 6 and 11 years of age, 33.0% and 29.7% of those genotyped had doctor-diagnosed asthma, and 35.8% and 52.1% had SPT positivity. In cross-sectional analyses, children with 38G/38A or 38A/38A had increased AR at 1 month (1.72-fold, P=0.013); sIgE>4 kU/L [odds ratio (OR)=6.95, 95% confidence interval (CI)=1.35-35.91, P=0.021]; house dust mite (HDM) SPT positivity (OR=7.21, 95% CI=1.09-47.78, P=0.041) and sIgE (4.57-fold, P=0.045) at 6 years; and doctor-diagnosed asthma (OR=3.93, 95% CI=1.24-12.47, P=0.02) and cat SPT positivity (OR=4.34, 95% CI=1.01-18.77, P=0.049) at 11 years. Longitudinal analyses of 6 and 11 years paired data showed that children with 38A/38A had increased persistent sIgE>4 kU/L (OR=11.87, 95% CI=1.97-71.53, P=0.007) and persistent HDM SPT positivity (OR=7.84, 95% CI=1.04-58.92, P=0.045). CONCLUSION: SCGB1A1 A38G may play a role in the development and persistence of the asthma phenotype in childhood.

Placental weight and placental ratio as predictors of later blood pressure in childhood.

OBJECTIVE: A significant inverse relationship between blood pressure and birth weight is firmly established. This association may be the result of fetal adaptations to an adverse intrauterine environment. Further markers of intrauterine growth include the weight of the placenta and the placental ratio (the ratio of placental weight to birth weight). A number of studies suggest that a decreased placental weight or an elevated placental ratio may be independent risk factors for subsequent high blood pressure. The overall evidence for this is, however, inconclusive. The purpose of the present study was to clearly define the relationships between placental weight, placental ratio and subsequent blood pressure during childhood. DESIGN: Prospective cohort study of 2507 singleton children, born at term during 1989-1992. Blood pressures were recorded at ages 1, 3 and 6 years, using a semi-automated oscillometric device. RESULTS: Inverse relationships existed between both systolic and diastolic blood pressure and placental weight, adjusted for current weight at ages 1, 3 and 6 years. The relationships between placental weight and systolic blood pressure were statistically significant at ages 1 and 3 years. There was no consistent relationship between placental weight and later blood pressure within birth weight categories. No clinically or statistically significant association was seen between the placental ratio and either systolic or diastolic blood pressures at any age. CONCLUSIONS: Birth weight, rather than placental weight or their ratio, is the early life factor most importantly related to subsequent blood pressure in childhood.

Adjustment for current weight and the relationship between birth weight and blood pressure in childhood.

OBJECTIVE: To determine the role of current weight in mediating the relationship between birth weight and blood pressure within the context of the 'fetal origins' hypothesis. DESIGN: Prospective cohort study of 2507 pregnant women and their singleton offspring, delivered live at term, in Perth, Western Australia between 1989 and 1992. The study commenced at 16 weeks gestation with serial weight and blood pressure measurements recorded through early childhood. RESULTS: Inverse associations were found between birth weight and systolic blood pressure at ages 1, 3 and 6. The effect of birth weight on systolic blood pressure at age 6 reached statistical significance and was increased fourfold in magnitude to -2.3 mmHg [95% confidence interval = (-3.3 to -1.3), P < 0.01] after adjustment for current weight. The interaction term for birth weight and current weight was not statistically significant. Including intermediate weights did not produce a statistically significantly better model but did increase the magnitude of the estimated regression coefficient of birth weight on blood pressure, and only the birth weight and current weight terms were significant CONCLUSIONS: Adjustment for current weight serves to highlight the relationship between birth weight and blood pressure in childhood. Nevertheless, birth weight, rather than birth weight adjusted for current weight, is still the relevant predictor of later blood pressure within the context of the 'fetal origins' hypothesis.

Flow-volume curves in infants with lung disease.

Partial expiratory flow-volume maneuvers have been performed on nine occasions on six infants with a variety of pulmonary problems using a new technique for thoracic compression. The infants were placed within an inflatable bag that was, itself, within a canvas bag. By sudden controlled inflation of the inner bag at end inspiration, partial expiratory flow-volume curves were generated and recorded by means of a face mask and pneumotachograph. By comparing these flow results with those airway resistance and lung volume measurements obtained from the infants in whole body plethysmography and by noting the effect of inhaling a helium/oxygen gas mixture, it was possible to partition the airway obstruction between large and small airways. The presence of small airway obstruction was noted in the absence of changes in airway resistance or lung volume in several instances. A complete evaluation of airway function should include this test of forced expiration for greater understanding and treatment of lung disease in infancy.

Effect of compression pressure on forced expiratory flow in infants.

The effect of the force of compression on expiratory flow was evaluated in 19 infants (2-13 mo of age) with respiratory illnesses of varying severity. An inflatable cuff was used to compress the chest and abdomen. Expiratory flow and volume, airway occlusion pressure, cuff pressure (Pc), and functional residual capacity were measured. Transmission of pressure from cuff to pleural space was assessed by a noninvasive occlusion technique. Close correlations (P less than 0.001) were found between Pc and the change in pleural pressure with cuff inflation (delta Ppl,c). Pressure transmission was found to vary between two cuffs of different design and between infants. Several forced expirations were then performed on each infant at various levels of delta Ppl,c. Infants with low maximal expiratory flows at low lung volumes required relatively gentle compression to achieve flow limitation and showed decreased flow for firmer compressions. Flow-volume curves in each infant tended to become more concave as delta Ppl,c increased. These findings underline the importance of knowledge of delta Ppl,c in interpreting expiratory flow-volume curves in infants.

Longitudinal analysis of lung function growth in healthy children and adolescents.

Lung function and height in 242 8-yr-old and 299 12-yr-old children without known or suspected predisposition to lung disease were measured annually over 6 and 8 yr, respectively. Growth of forced expiratory volume in 1 s (FEV1), vital capacity, and expiratory flow after expiring 50% of vital capacity were statistically modeled by age and height by use of a multivariate normal model for longitudinal data. This method has the flexibility to fit an appropriate (not necessarily linear) mathematical description of average lung function while concurrently modeling the covariance between measures on the same individual. Differences in lung function growth between girls and boys, pre- and post-puberty, showed that girls had a steadier though less pronounced increase in lung function with height. In boys, before puberty there was deficit in lung volume relative to height (not evident in girls), which was compensated for by rapid growth after puberty. The standard error of FEV1 predictions based on current height and age were more than halved when measurements of FEV1, age, and height taken 1 yr before were incorporated. We found evidence for dysanaptic growth in childhood. Fitted models have application to early detection of departures from healthy lung function.

Prenatal ultrasound biometry related to subsequent blood pressure in childhood.

STUDY OBJECTIVE: To relate measures of fetal growth/size other than birth weight with subsequent blood pressure measured on the same individuals within the context of the "fetal origins of adult disease". DESIGN: A prospective cohort study in which measurements of fetal dimensions obtained by serial ultrasound imaging between 18 and 38 weeks gestation were analysed with reference to systolic blood pressure measurements on the offspring at age 6 years. SETTING: Perth, Western Australia. PARTICIPANTS: A subgroup of 707 eligible mother-fetus pairs from a cohort of 2876 pregnant women and their offspring. The number of mother-fetus pairs varied at each gestational age and by measurement of fetal dimension. Subsequent blood pressure recordings were obtained on approximately 300 of the offspring at age 6 years. MAIN RESULTS: The findings confirmed the inverse association between birth weight and systolic blood pressure at age 6. There was, also, an inverse relation between fetal femur length and systolic blood pressure at age 6, adjusted for current height. Furthermore, an inverse association was demonstrated between a statistically derived measure of fetal growth (conditional z score) between 18 and 38 weeks gestation and later systolic blood pressure at age 6. The effect sizes for all three relations were in the order of 1-2 mm Hg per standard deviation change. CONCLUSION: The mechanisms underpinning the "fetal origins" hypothesis may be operative early in pregnancy and may be reflected in the length of the fetal femur in early to mid-pregnancy.

Diurnal variation in bronchial responsiveness in asthmatic children.

To establish the presence of a diurnal variation in bronchial responsiveness in asthmatic children, the increase of peak expiratory flow rate (PEFR) following sympathomimetic inhalation and the response to bronchial provocation with histamine and hyperventilation of cold dry air (HVCDA) were studied. Twenty-nine patients (20 boys, nine girls, aged 9.3 to 17.8 years) measured PEFR before and after sympathomimetic inhalation three times a day for four weeks. A further 15 patients (eight boys, seven girls, aged 6.9 to 18.0 years) underwent bronchial provocation testing every six hours for 24 hours. A diurnal variation in bronchodilator responsiveness was demonstrated in 55% of the first group. Mean amplitude was 60.8% of patients' mean increase in PEFR following bronchodilators. On grouped data, bronchodilation was greater in the morning than in the afternoon (p less than 0.0005) or in the evening (p less than 0.0005). A diurnal variation in the response to bronchial provocation was also found in the second group, but the timing of the rhythm depended on the stimulus used. On grouped data, airways were most sensitive to histamine at 0400 hours and most sensitive to HVCDA at 1600 hours. The diurnal variation demonstrated in bronchial responsiveness could not be attributed to changes in baseline airway caliber and was present, despite the patients' taking sufficient medication to control their asthmatic symptoms.

Does nifedipine affect the diurnal variation of asthma in children?

Diurnal variations in airway caliber and in bronchial reactivity have been described. The mechanisms underlying these variations are not known. The hypothesis that these variations can be diminished by calcium channel blockers was tested by giving 22 asthmatic children 10 mg of nifedipine or identical placebo three times a day for 4 weeks in a double-blind, randomized, crossover-designed study. Treatment with nifedipine did not diminish the diurnal variations in airway caliber, judged from peak expiratory flow rates, or in bronchial reactivity, judged from bronchodilator responsiveness. Group mean amplitude of the diurnal variation in airway caliber was 10.5% on nifedipine and 10.6% on placebo. Group mean amplitude of the diurnal variation in bronchodilator responsiveness was 75.4% on nifedipine and 69.5% on placebo. There were no differences in mean peak expiratory flow rate between nifedipine and placebo periods. This study did not find any evidence to support the hypothesis that the diurnal variations in airway caliber and in bronchial reactivity can be diminished by calcium channel blockers.

Refractoriness to bronchoconstriction following hyperventilation with cold dry air.

Fifteen subjects undertook repeated periods of hyperventilation of cold dry air and hyperventilation of warm humidified air followed by cold dry air. Hyperventilation of cold dry air induced a biphasic response with initial bronchodilatation followed by bronchoconstriction. However, exercise produced a greater rise in forced expiratory volume in 1 second (FEV1) than hyperventilation alone. Hyperventilation of cold dry air resulted in a period of refractoriness to a second stress of the same type. Refractoriness induced by exercise or hyperventilation of cold dry air may be the result of refractoriness of the trigger site in the large airways.

Gender related differences in airway tone in children.

The effects of gender, volume history, and inhaled atropine and isoproterenol on lung mechanics were assessed in 16 normal boys and 14 normal girls using lung volumes, flow-volume curves, and oscillatory resistances. Flows were measured from full and partial forced expiratory flow-volume curves. Six girls and 6 boys were studied before and after inhaled atropine, and 10 boys and 8 girls before and after inhaled isoproterenol. Girls demonstrated a significant increase in flows on full and partial curves with a deep inspiration [Vmax-partial 0.73 +/- 0.34 (SD) to Vmax-full 0.80 +/- 0.37 and 0.83 +/- 0.20 to 1.06 +/- 0.29 TLC/s in each group] and following inhalation of isoproterenol on the partial curves only (0.73 +/- 0.34 to 0.93 +/- 0.40 TLC/s). Boys showed a small but significant increase in Vmax with isoproterenol on full curves but not on partial curves. Following atropine, boys demonstrated a significant increase in Vmax on partial flow-volume curves (0.78 +/- 0.28 to 1.00 +/- 0.35 TLC/s) and a significant decrease in specific respiratory resistance (7.6 +/- 2.7 to 5.1 +/- 0.9 cmH2O/s), whereas girls had no such changes. These data suggest that boys have greater resting airway tone than girls and that this tone is less responsive to deep inspiration and isoproterenol independently, although a combination of isoproterenol and a deep inspiration will produce increased flows in boys. Atropine reduces airway tone predominantly in boys, suggesting that the increased resting airway tone in boys is partially mediated via the vagus nerve.

The effect of age on bronchodilator responsiveness.

The relationship between age and bronchodilator responsiveness (BDR) in children has not been studied using objective parameters. The aim of this study was to seek such a relationship in young asthmatic children using dose-response curves (DRC). Fourteen asthmatic subjects (age 3-9 years) with a forced expiratory volume in 1 sec (FEV1) less than 80% predicted were studied after being trained to use a spirometer reliably. Each subject completed a DRC by inhaling 5 doses of salbutamol (albuterol) at 15 min intervals until a cumulative total of 6.84 mg of salbutamol had been administered. FEV1, forced vital capacity (FVC), and forced expiratory flow at mid vital capacity (FEF25-75) were measured before and after each nebulization. In addition, arterial oxygen saturation (SaO2) and heart rate (HR) were measured in some of the subjects. All lung function parameters, SaO2 and HR increased significantly between baseline and completion of the DRC. A significant age effect on BDR was detected in FEV1 and FVC, with older children showing a greater response than young ones. The response had plateaued after the maximum dose in the younger but not in the older children. These findings suggest that the level of response to a bronchodilator increases significantly with increasing age in young asthmatics.

Management of children hospitalized for laryngotracheobronchitis.

During a 12-month period, 527 consecutive admissions for laryngotracheobronchitis (LTB) were reviewed to determine the epidemiology of hospitalized LTB patients and to better define patients who may benefit from therapy other than close observation. Viral cultures were obtained in 442 patients and were positive in 70%. Disease severity at the time of admission was unrelated to patient age or sex. Duration of hospitalization, however, was inversely related to age (p less than 0.001). Laboratory investigations were rarely abnormal or of therapeutic value. Patients who on admission had stridor without sternal and chest wall retractions recovered rapidly and spontaneously; they were frequently discharged within 48 hours and never required artificial airways. Children who had sternal and chest wall retractions on admission experienced longer hospitalizations, frequently received medical intervention such as aqueous mist therapy or racemic epinephrine, and had a 6% risk of requiring artificial airway support. This group of children should be studied selectively for the benefits of specific medical therapies and diagnostic evaluations.

Diurnal variation of peak expiratory flow rate in asthmatic children.

A diurnal variation in peak expiratory flow rate (PEFR) has been described in normal and asthmatic adults. This variation has been apparent in data reported from children, but the rhythm has not been characterized. Sixty-eight asthmatic children recorded PEFR three times a day for 4 weeks at home. Data were analyzed using paired t-tests, cosinor analysis, and spectral analysis. Fifty subjects (73.5%) had significant diurnal variations in PEFR on paired t-tests. Mean amplitude, derived from cosinor analysis, was 22.6% (SD = 13.2%) of mean PEFR. The trough of the PEFR rhythm occurred at 0345 hours for the group. Spectral analysis confirmed that the major component of the variation in PEFR was due to a rhythm with a period of 24 hours. The amplitude of the diurnal variation was not related to the subjects' age, sex, or medications taken but was inversely related to mean lung function (expressed as percentage predicted).

The role of piperacillin therapy in pulmonary exacerbations of cystic fibrosis: a controlled study.

Piperacillin was evaluated as an antipseudomonas antibiotic in a double-blind controlled trial involving 18 pulmonary exacerbations of cystic fibrosis. Standard antibiotic treatment (flucloxacillin plus tobramycin) was compared with standard treatment plus intravenous piperacillin administered according to two regimens. No added benefit from piperacillin was demonstrable on the basis of improvement in symptoms, physical signs, weight gain, pulmonary function tests, radiologic signs, or sputum Pseudomonas bacterial counts. Some patients experienced sensitivity reactions to piperacillin. In vitro, piperacillin was a potent antibiotic against all beta-lactamase-producing mucoid strains of Pseudomonas aeruginosa; however, in spite of the fact that adequate serum antibiotic concentrations were achieved, sputum bacterial counts did not correlate with either the clinical status or the use of piperacillin therapy.

Lung function values from a longitudinal study of healthy children and adolescents.

From a cohort of 543 healthy children and adolescents, subjects were studied annually to obtain longitudinal data so that precise predictive values for lung volumes and flows from ages 8 to 19 years could be obtained. Strict guidelines for subject selection and pulmonary function testing were used. These data are presented in a readily usable form as equations, graphs, and tables.

The effect of age on oxygen desaturation during histamine inhalation challenge in normal infants.

Arterial oxygen saturation (SaO2) is usually measured during inhalation challenges in infants as desaturation has been demonstrated with provoked bronchoconstriction. We wished to examine whether measurement of SaO2 would provide a simple noninvasive indicator of respiratory function (RF) changes occurring during inhalation challenge in infants. Histamine inhalation challenges were performed longitudinally in 22 normal healthy infants at 4 and 26 weeks of age. RF was measured by calculating maximum forced expiratory flow at functional residual capacity (VmaxFRC) using the rapid thoracic compression technique. Airway responsiveness was assessed using histamine; the provoking concentration (PC) was that which caused a fall in VmaxFRC of at least 40% from baseline. The provocative concentration for an exact fall of 40% in VmaxFRC (PC40) from baseline was derived by linear interpolation. SaO2 was continuously monitored by pulse oximetry. One month old infants had higher SaO2 levels throughout the inhalation challenge in comparison to their SaO2 levels at 6 months of age. Significant falls in SaO2 were observed at the PC at both ages. However, at the age of 26 weeks the infants had greater median falls in SaO2 [PC, 4.5% (95%CI: 3.0, 7.0)] compared to the response at age 4 weeks [3.0% (95%CI: 1.0, 4.0) (P < 0.01)]. Median falls in VmaxFRC at the PC were not different between the ages. These results indicate an age-dependent discordance between airway and SaO2 response in healthy infants during histamine-induced bronchoconstriction.

Parental factors affecting respiratory function during the first year of life.

In a prospective, longitudinal, population-based cohort study of familial and environmental influences on the development of wheezing respiratory illness in early childhood, we identified infant length, weight, gender, and exposure to maternal cigarette smoking as significant determinants of lung function during the first year of life. A cohort of 237 infants (106 females: 131 males) was evaluated, and 496 lung function measurements were made between the ages of 1-12 months. Respiratory function was assessed using the rapid thoracic compression technique to obtain maximum expiratory flow at functional residual capacity (V'maxFRC). Parental history of asthma and smoking habits during pregnancy were obtained by questionnaire. Data were analyzed using a longitudinal random effects model. Infants with a parental history of asthma and/or in utero passive smoke exposure were compared to a reference group of infants who had no parental history of asthma and in whom neither parent smoked pre- or postnatally. Boys were found to have a consistently lower V'maxFRC (-21.05 mL.s(-1)) throughout the first year of life in comparison to girls (P < 0.05). Maternal smoking during pregnancy was associated with a lower V'maxFRC in both genders in comparison to unexposed infants (P < 0.05). V'maxFRC was unaffected by parental history of asthma. Gender-specific normative equations for V'maxFRC throughout the first year of life were derived for the infant cohort as a whole and also for subgroups of infants, based on parental asthma and smoking history. We conclude that lung function during the first year of life differs between genders and is adversely affected by in utero passive tobacco smoke exposure. Gender-specific predictive equations for V'maxFRC should be used during infancy.

The effect of inhaled adrenaline on lung function of recurrently wheezy infants less than 18 months old.

Inhaled bronchodilators have been shown not to improve lung function in infants with wheeze. This observation has led to the suggestion that airway wall edema may be more important than bronchoconstriction in infants with airway narrowing. Inhaled adrenaline is used to relieve upper airway edema in children with croup and has been demonstrated to improve clinical scores and lower pulmonary resistance in some infants with wheeze associated with bronchiolitis. The aim of the present study was to examine the effect of inhaled adrenaline on lung function in a group of infants with recurrent wheeze. Eleven infants aged 10 to 18 months with a history of recurrent wheeze were studied during an asymptomatic interval. Respiratory function was assessed (1) by measuring maximal expiratory flow at functional residual capacity (VmaxFRC) during a forced partial expiratory maneuver and (2) by measuring conductance of the respiratory system (Grs) using a single expiratory occlusion technique. Following baseline measurements, the infants received 0.5 mg/kg adrenaline by nebulizer and serial lung function tests were repeated at 5 min intervals. Ten infants had abnormal baseline lung function (median VmaxFRC 44.2% predicted; median Grs 34% predicted). Using a random effects model, VmaxFRC and Grs declined significantly at 10 and 5 min after adrenaline, respectively. No significant improvements from baseline were observed in either measurement for up to 30 min following adrenaline delivery. It is concluded that inhaled adrenaline did not relieve airways obstruction in this group of asymptomatic infants with recurrent wheeze.

Methodological aspects of flow-volume studies in infants.

Although valuable information is being obtained using new techniques to assess infant respiratory mechanics, there have been several concerns about the methodology. These relate to the possibility that chloral hydrate may affect flow-volume measurements by altering upper airway caliber. There is also the possibility that physiological changes may be induced by inhalation of non-pharmacologic and pharmacologic nebulized solutions. The aim of this study was to investigate these phenomena in a group of normal infants. Thoracic gas volume was determined and respiratory mechanics measured using the passive and forced expiratory flow-volume techniques. Respiratory function was assessed in infants before and after 1) sleep was induced by administration of chloral hydrate (n = 10, mean age, 21 weeks); 2) inhalation of nebulized saline (n = 10, mean age, 19 weeks); 3) inhalation of nebulized salbutamol (n = 7, mean age, 22 weeks). A fall in tidal volume was found following administration of chloral hydrate but no significant change was seen in any other respiratory parameter. In addition, no change was seen in any parameter post-saline or salbutamol nebulization. This study provides data which support several basic assumptions made about the infant flow-volume techniques and should provide useful background information for future studies using these techniques.