Reduced interferon-gamma production in infants with bronchiolitis and asthma.

Infants are at increased risk of developing asthma after acute bronchiolitis. We assessed the hypothesis that cytokine production is related to the development of asthma after bronchiolitis. The smoking history and the presence of atopy or asthma in parents or siblings were recorded and blood mononuclear cell interferon (IFN)-gamma and interleukin (IL)-4 production in response to IL-2 were assessed in 32 infants hospitalized for bronchiolitis and in a subgroup (n = 19) in which pulmonary function tests were performed approximately 4.9 mo later. The presence of asthma was determined by the Delphi consensus method 2 yr after hospitalization. Infants were classified as follows: asthma absent (A, n = 14), possible (Po, n = 9), or probable (Pr, n = 9). Infants with possible and probable asthma had lower IFN-gamma production at the time of bronchiolitis and a trend to lower IFN-gamma production 4.9 mo later when compared with those who had no asthma. At the time of bronchiolitis, IFN-gamma production was: 123 +/- 31 versus 34 +/- 20 versus 21 +/- 14 pg/ml, A versus Po versus Pr (p = 0.02, ANOVA) and 4.9 mo after bronchiolitis, IFN-gamma production was: 147.3 +/- 45 versus 47.4 +/- 30 versus 22.3 +/- 32 pg/ml, No versus Po versus Pr (p = 0.08 ANOVA). IL-4 production did not differ between groups. Infants who went on to develop asthma had more parent smokers (21.4% versus 55. 6% versus 55.6%, A versus Po versus Pr, p < 0.04), lower VmaxFRC (122 +/- 18 versus 77 +/- 7 versus 67 +/- 8% predicted, A versus Po versus Pr, p < 0.02), lower PC40 histamine (6.4 +/- 3.3 versus 1.2 +/- 0.6 mg/ml, A versus Po+Pr, p < 0.03) but no increase in atopy or asthma in their family. Significant positive correlations were found between IFN-gamma production at the time of bronchiolitis and VmaxFRC (r = 0.606) or PC40 histamine (r = 0.648) 4.9 mo after bronchiolitis. Lower IFN-gamma production at the time of bronchiolitis is an indicator of lower pulmonary function and increased responsiveness to histamine 4.9 mo after bronchiolitis and is related to the development of asthma after bronchiolitis in infants.

Factors affecting the prognosis of Ebstein's anomaly during fetal life.

BACKGROUND: The echocardiographic criteria that have been used to evaluate severity of Ebstein's anomaly in utero are the same as those applied after birth. OBJECTIVE: The objective of this study was to establish prognostic criteria that take into account the peculiarities of the fetal hemodynamics. METHOD: The video recordings of eight fetuses with Ebstein's anomaly were retrospectively reviewed. RESULTS: The following indexes had no prognostic significance either on fetal or neonatal outcome: the ratio of functional tricuspid opening over the diameter of the annulus, the degree of displacement of the tricuspid valve opening, and the degree of tricuspid regurgitation. The index of severity (based on the surfaces of right atrium + atrialized right ventricle) and the cardiothoracic ratio had a significant impact only on neonatal survival. The smallest fossa ovalis were found in two fetuses who had hydrops. Fetuses who reached term without problems had higher left ventricular outputs. A positive linear correlation was found between the z score of the left ventricular output and the size of the fossa ovalis (r = 0.81, p < 0.05). CONCLUSION: The prognosis of Ebstein's anomaly during fetal life is not influenced by criteria described for postnatal life and may be related to factors that control the volume load of the left ventricle.

Fetal atrial flutter: diagnosis, clinical features, treatment, and outcome.

OBJECTIVES: To assess clinical features, treatment efficacy, and outcome of fetal atrial flutter. STUDY DESIGN: All atrial flutter cases seen in our unit between 1988 and 1995 were reviewed retrospectively and compared with the pooled data of 37 echocardiographically documented and published cases. RESULTS: Atrial flutter was found in 15 of 49 (30.6%) fetuses who had been referred because of clinically relevant tachyarrhythmia. Mean age at detection was 34+/-4 weeks' gestation. Atrial flutter was incessant in 11 and intermittent in 4, with a mean atrial rate of 442+/-65 beats/min and a mean ventricular rate of 216+/-28 beats/min. A predominance of 2:1 atrioventricular conduction was observed. In 5 of 15 cases another form of arrhythmia (supraventricular tachycardia, chaotic atrial rhythm, ventricular extrasystoles) coexisted with atrial flutter. Eleven fetuses were treated with maternal digoxin, and five subsequently converted to sinus rhythm. Four fetuses received no medication; of these four, two showed brief self-limited episodes of atrial flutter and two were delivered after detection of the arrhythmia. Only one fetus (6.7%), who did not respond to drug therapy, was delivered prematurely because of mild congestive heart failure. Seven neonates were in atrial flutter at birth; rhythm control could be easily achieved with sotalol or digoxin (n = 5), flecainide (n = 1), or electroconversion (n = 1) within the first 2 days of life without any relapse. CONCLUSION: Fetal atrial flutter accounts for approximately one third of all clinically relevant tachyarrhythmia. Although the suppression rate of incessant atrial flutter with digoxin is only 50%, this therapy may be useful for its positive inotropic and negative chronotropic properties. In our experience most fetuses with therapy-resistant atrial flutter and absence of 1:1 atrioventricular conduction do not experience congestive heart failure and do not need to be delivered prematurely. After birth, conversion to sinus rhythm was easily achieved in all neonates.

Ventriculo-atrial time interval measured on M mode echocardiography: a determining element in diagnosis, treatment, and prognosis of fetal supraventricular tachycardia.

OBJECTIVE: To determine whether M mode echocardiography can differentiate fetal supraventricular tachycardia according to the ventriculo-atrial (VA) time interval, and if the resulting division into short and long VA intervals holds any relation with clinical presentation, management, and fetal outcome. DESIGN: Retrospective case series. SUBJECTS: 23 fetuses with supraventricular tachycardia. MAIN OUTCOME MEASURES: A systematic review of the M mode echocardiograms (for VA and atrioventricular (AV) interval measurements), clinical profile, and final outcome. RESULTS: 19 fetuses (82.6%) had supraventricular tachycardia of the short VA type (mean (SD) VA/AV ratio 0.34 (0.16); heart rate 231 (29) beats/min). Tachycardia was sustained in six and intermittent in 13. Hydrops was present in three (15.7%). Digoxin, the first drug given in 14, failed to control tachycardia in five. Three of these then received sotalol and converted to sinus rhythm. All fetuses of this group survived. Postnatally, supraventricular tachycardia recurred in three, two having Wolff-Parkinson-White syndrome. Four fetuses (17.4%) had long VA tachycardia (VA/AV ratio 3.89 (0.82); heart rate 226 (10) beats/min). Initial treatment with digoxin was ineffective in all, but sotalol was effective in two. Heart failure caused fetal death in one and premature delivery in one. All three surviving fetuses had recurrences of supraventricular tachycardia after birth: two had the permanent form of junctional reciprocating tachycardia and one had atrial ectopic tachycardia. CONCLUSIONS: Careful measurement of ventriculo-atrial intervals on fetal M mode echocardiography can be used to distinguish short from long VA supraventricular tachycardia and may be helpful in optimising management. Digoxin, when indicated, may remain the drug of choice in the short VA type but appears ineffective in the long VA type.

Doppler velocimetric indices from the abdominal and placental ends of the umbilical artery of growth-restricted fetuses.

PURPOSE: In normal pregnancies, as gestation advances, a progressive decrease is observed in the differences between Doppler indices recorded at the 2 extremities of the umbilical cord. The purpose of this study was to determine whether the same pattern is observed in pregnancies complicated by intrauterine growth restriction (IUGR). METHODS: Forty-seven fetuses with sonographic diagnosis of IUGR underwent investigation by Doppler sonography. Blood flow velocities were measured at the abdominal and placental ends of the umbilical cord. The systolic-diastolic ratio, pulsatility index, and resistance index were calculated for each site. The differences in values between the 2 ends of the cord were calculated (abdominal end minus placental end) and then compared with the differences calculated for normal fetuses. RESULTS: In contrast to normal fetuses, IUGR fetuses with abnormal Doppler measurements had significant differences in the pulsatility and resistance indices between the 2 ends of the cord after 28 weeks of gestation. In addition, when compared with normal fetuses, the IUGR fetuses had a significantly greater difference in the values for the 2 ends of the cord for all indices. CONCLUSIONS: These results emphasize the importance of identifying the sampling site for serial Doppler investigations in IUGR-complicated pregnancies.

Cellular immunity is activated and a TH-2 response is associated with early wheezing in infants after bronchiolitis.

OBJECTIVE: To determine whether abnormalities of cellular immunity are present and linked to early wheezing after bronchiolitis. METHODS: We prospectively studied 26 infants hospitalized for a first episode of bronchiolitis and without any prior immune, cardiac, or respiratory disease. Blood was obtained at the time of enrollment and 5 months later for the assessment of the total cellular and differential counts, CD4+ (helper) and CD8+ (suppressor/cytotoxic) lymphocytes, and the activation markers CD23 (low-affinity immunoglobulin E receptor) and CD25 (interleukin-2 (IL-2) receptor). The cytokines interferon gamma (T-helper (TH) type-1 cytokine) and IL-4 (TH-2) were measured in plasma and in vitro after stimulation with IL-2 or with the house-dust mite (Dermatophagoides farinae) antigen. A daily log of episodes of wheezing was kept by parents after discharge. RESULTS: We found an increase in blood eosinophils, an increased percentage of CD4+, CD25+, and CD23+ lymphocytes in subjects at 5 months compared with the time of bronchiolitis and with healthy subjects of the same age (p < 0.05). Plasma IL-4 levels, although not different from those of healthy subjects, also increased significantly. Peripheral blood lymphocytes from infants who wheezed produced more IL-4 in vitro, 5 months after bronchiolitis, in response to D. farinae antigen. In babies who wheezed, a positive correlation was found between the total number of days that wheezing occurred and the blood eosinophil count. Babies who wheezed more often (> 20 days) had more peripheral blood basophils and eosinophils, and peripheral blood lymphocytes obtained from these subjects at the time of bronchiolitis produced less interferon gamma on stimulation with IL-2. CONCLUSIONS: Bronchiolitis is followed by activation of cellular immunity, and early wheezing in infants is associated with a TH-2 response.

Efficacy of cromoglycate in persistently wheezing infants.

A prospective study was undertaken to evaluate the efficacy of (sodium) cromoglycate in the treatment of persistent wheezing in 31 children between 4 and 12 months of age. The subjects were randomised to receive either 40 mg of cromoglycate (n = 16) or physiological saline as placebo (n = 15) three times a day by wet nebulisation in a double blind fashion for a period of six weeks. The patients were evaluated with daily symptom scores and respiratory function testing measuring maximal expiratory flow at functional residual capacity (VmaxFRC) before initiating treatment and upon completion. At baseline, mean (SD) symptom scores between the two groups were comparable (cromoglycate 99.5 (29.8), placebo 104.5 (29.7)) as were VmaxFRC expressed as per cent of predicted normals (cromoglycate 48 (28), placebo 46 (20)). Upon completion of the treatment protocol, no significant difference could be found between the two groups for either symptom score (cromoglycate 67.6 (40.2), placebo 58.6 (41.4)), or VmaxFRC (cromoglycate 52 (24), placebo 60 (32)). It is concluded, therefore, that 40 mg of cromoglycate three times a day administered via facemask and wet nebulisation was no more effective than placebo in the treatment of our sample of persistently wheezing infants under 1 year of age.

Comparison of inhaled terbutaline administered by either the Turbuhaler dry powder inhaler or a metered-dose inhaler with spacer in preschool children with asthma.

We compared the bronchodilator response of terbutaline delivered either by a dry powder inhaler, the Turbuhaler, or by a metered-dose inhaler attached to a Nebuhaler inhaler in 10 children with stable asthma who were 3 to 6 years of age. The bronchodilator response did not differ between the two inhalational devices. The dry powder inhaler Turbuhaler is a suitable alternative to a metered-dose inhaler in the delivery of terbutaline to preschool children with stable asthma if adequate inhalational technique is used.

Reference values for Doppler velocimetric indices from the fetal and placental ends of the umbilical artery during normal pregnancy.

A range-gated Doppler ultrasound system combined with a real-time imaging system was used to determine arterial blood velocity values from the fetal and placental ends of the umbilical cord in 269 normal pregnancies between 17 and 40 weeks, menstrual age. The systolic-diastolic ratio (S/D), pulsatility index (PI), and resistance index (RI) were higher at the fetal end compared to the placental end of the cord. The individual differences in these Doppler indices, obtained between the fetal and placental recording sites, were inversely related to menstrual age: S/D: r = -0.38, p < 0.001; PI: r = -0.25, p < 0.001; and RI: r = -0.15, p < 0.01. After normalization for the angle of insonation, the peak systolic velocity was higher and the end-diastolic velocity was lower at the fetal than at the placental end of the cord. It is concluded that routine recordings for Doppler velocimetric indices should take into account the recording site on the umbilical cord in order to reduce methodological sources of variance, especially during midgestation. Furthermore, the data presented here in the form of the median and percentile values are proposed as normal reference values to facilitate this procedure.

A protocol for aerosol therapy in acute hospitalized asthmatics.

The most important element in the treatment of acute hospitalized asthmatics is salbutamol administered via wet nebulization prescribed usually on a subjective evaluation of the patient's status. This study outlines a novel protocol that incorporates the FEV1 variable as the major objective parameter in a feedback loop. Data from patients admitted in the year prior to the initiation of the protocol (N = 348) were compared with similar data from patients hospitalized the year following institution of the protocol (N = 238). There were no withdrawals from the protocol due to adverse effects nor were there any deteriorations requiring ICU admission. A significant decrease in the length of hospitalization and the number of salbutamol prescriptions per hospitalization was observed after, relative to before, institution of the protocol (2.2 vs. 2.6 days; 2.3 vs. 3.8; p < .05, respectively). It is concluded that this protocol is safe and efficient, and may also be more efficacious than a nonstandardized approach for treating the hospitalized asthmatic child.

Comparison of cardiac output determinants in response to upright and supine exercise in patients with cystic fibrosis.

This study characterizes cardiac output response to progressive submaximal upright cycling in CF patients. Thirty-one CF patients as well as 11 aged-matched CF control subjects completed cardiac output determinations (CO2-rebreathing) at rest, and at submaximal exercise corresponding to 30, 50 and 75 percent VO2max, in both upright and supine positions. The VO2max was similar in three of four groups, but lower in those with severe CF. The cardiac output generally increased with exercise intensity in both positions, except in severe CF. The change from upright to supine posture resulted in a significant increase in SI at rest and for every submaximal exercise in control subjects, but not CF patients. These observations may suggest that the abnormal cardiac output response observed in severe CF could be related to a potential limitation in ventricular diastolic reserve found in all CF patients independent of disease severity which becomes more apparent under increased ventricular preload.

Comparison of cardiovascular adjustments to exercise in adolescents 8 to 15 years of age after correction of tetralogy of fallot, ventricular septal defect or atrial septal defect.

Surgical correction of tetralogy of Fallot (TF) has generally been associated with a reduced maximal exercise tolerance, possibly related to the ventriculotomy inherent to the intracardiac repair procedure. This study documents the exercise hemodynamics of a group of patients operated on for TF who showed similar clinical and functional characteristics, and compares these responses to those of age-matched patients operated on for an isolated ventricular septal defect (VSD) or atrial septal defect (ASD) in an attempt to better understand the role of the ventriculotomy in the exercise limitation. Thirty patients, ages 12 to 19 years, operated on before 5 years of age for complete repair of TF (n = 13), VSD (n = 7) or ASD (n = 10) and 10 age-matched control subjects underwent a progressive maximal cycling test to determine the maximal oxygen uptake (VO2 max), and completed submaximal cycling at intensities of 33 and 66% VO2 max, respectively, to determine the cardiac output (CO2-rebreathing). No significant differences in VO2 max were observed (TF = 37.6 +/- 10; VDS = 34.0 +/- 9.2; ASD = 36.5 +/- 7; controls = 41.3 +/- 6.0 ml/kg/min). The maximal heart rate, however, remained lower in all patient groups in comparison with control subjects (p less than or equal to 0.05) (TF = 178 +/- 14; VSD = 172 +/- 17; ASD = 179 +/- 16; controls = 191 +/- 12 beats/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise after surgical repair of congenital cardiac lesions.

Congenital heart defects arise in approximately 1% of all live births, independent of ethnic and geographical considerations. With the development of new surgical procedures and current technologies a large number of these heart lesions can be surgically corrected in infancy. In the majority of cases patients evaluated some 10 to 20 years after surgery are asymptomatic and can lead a normal life. Despite their satisfactory clinical outcome patients may, nevertheless, show an abnormal pattern of physiological responses when submitted to dynamic exercise. This paper reviews the scientific literature concerning the exercise capabilities and the cardiorespiratory adjustments to exercise in patients surgically corrected for 4 of the most common congenital heart lesions: isolated atrial septal defect, isolated ventricular septal defects, pulmonary stenosis and tetralogy of Fallot. The maximal exercise tolerance of postoperative congenital heart defect patients may usually be related to: (a) the age of the patients at the time of surgery; (b) the severity of the lesions remaining after surgery; and (c) the age of the patients at the time of investigation. Although normal maximal exercise capabilities may be found in a good number of patients operated for either of the 4 lesions considered, this does not imply normal exercise haemodynamics. A general observation made in these 4 groups of patients is that of a subnormal exercise cardiac output which may or may not be fully compensated by an increase in peripheral oxygen extraction. The limitation in exercising cardiac output may, in turn, be attributed to either a subnormal stroke volume or a limitation in the chronotropic response to exercise or a combination of both factors. Residual pulmonary stenosis, increased pulmonary vascular resistance, increased myocardial stiffness are all factors that may contribute to the cardiac output limitation. A thorough explanation of underlying causes for the abnormal haemodynamic response to exercise, however, still remains to be provided.