Pulmonary interstitial glycogenosis in a patient with trisomy 21.

Pulmonary interstitial glycogenosis is an interstitial lung disease of childhood that has been increasingly reported over the past decade. Here, we present a case of pulmonary interstitial glycogenosis associated with trisomy 21, pulmonary arterial hypertension, and congenital heart disease in a 34 week premature infant.

ALOX5 polymorphism associates with increased leukotriene production and reduced lung function and asthma control in children with poorly controlled asthma.

BACKGROUND: Identification of risk factors for reduced asthma control could improve the understanding and treatment of asthma. A promoter polymorphism in the 5-lipoxygenase gene affects gene expression and response to asthma therapy, but its impact on disease control remains unclear. OBJECTIVE: We sought to determine if the ALOX5 promoter SP1 tandem repeat polymorphism was associated with changes in cysteinyl leukotriene production, lung function, airway inflammation and asthma control score. METHODS: We analysed 270 children, 6- to 17-years old, with poorly controlled asthma enrolled in a 6-month clinical trial (NCT00604851). In secondary analysis, we associated the ALOX5 promoter SP1 tandem repeat polymorphism genotype (rs59439148) with asthma outcomes using both additive and recessive genetic models. We evaluated FEV1 percent predicted, symptom control, exhaled nitric oxide and urinary LTE4 levels. RESULTS: Of all children, 14.8% (40/270) (and 28% (38/135) of African Americans) carried two non-5-repeat variant alleles of rs59439148. Children who were homozygous for variant alleles had significantly higher urinary LTE4 levels (38 vs. 30 nmol/mol creatinine, P = 0.0134), significantly worse FEV1% predicted (84 vs. 91, P = 0.017) and a trend towards worse asthma control. FEV1% predicted values were significantly negatively correlated with urinary LTE4 (r = -0.192, P = 0.009). CONCLUSION AND CLINICAL RELEVANCE: Carrying two copies of a minor variant ALOX5 promoter SP1 tandem repeat allele contributes to increased cysLT exposure as determined by urinary LTE4 levels, reduced lung function and potentially worse asthma control. ALOX5 promoter SP1 tandem repeat genotype may be a risk factor for worse asthma outcomes.

Association of CYP2C19 polymorphisms and lansoprazole-associated respiratory adverse effects in children.

OBJECTIVE: To determine whether cytochrome P450 (CYP)2C19 haplotype associates with lansoprazole-associated adverse event frequency. STUDY DESIGN: Respiratory adverse events from a clinical trial of lansoprazole in children with asthma were analyzed for associations with extensive or poor metabolizer (PM) phenotype based on CYP2C19 haplotypes. Carriers of CYP2C19*2, *3, *8, or *9 alleles were PMs; carriers of 2 wild-type alleles were extensive metabolizers (EMs). Plasma concentrations of lansoprazole were determined in PM and EM phenotypes. RESULTS: The frequency of upper respiratory infection among PMs (n = 45) was higher than that among EMs (n = 91), which in turn was higher than that in placebo subjects (n = 135; P = .0039). The frequency of sore throat (ST) was similarly distributed among EMs and PMs (P = .0015). The OR (95% CI) for upper respiratory infections in PMs was 2.46 (1.02-5.96) (P = .046); for EMs, the OR (95% CI) was 1.55 (0.86-2.79). The OR (95% CI) for ST in EMs and PMs was 2.94 (1.23-7.05, P = .016) vs 1.97 (1.09-3.55, P = .024), respectively. Mean ± SD plasma concentrations of lansoprazole were higher in PMs than in EMs: 207 ± 179 ng/mL vs 132 ± 141 ng/mL (P = .04). CONCLUSIONS: Lansoprazole-associated upper respiratory infections and ST in children are related in part to CYP2C19 haplotype. Our data suggest that lansoprazole-associated adverse events in children may be mitigated by adjusting the conventional dose in PMs. Additional studies are required to replicate our findings.

Outdoor air pollution. Asthma and other concerns.

Despite governmental efforts to improve the quality of outdoor air, a significant number of children growing up in the US are exposed to airborne pollutants. It is now recognized that infants generally at risk for atrophy when exposed to specific environmental airborne pollutants are more likely to develop asthma. Once asthma is established, airborne pollutants are important triggers in causing exacerbations. Airborne ozone and suspended articles are the two most important criteria pollutants with respect to exposure prevalence and suspected adverse health effects in US children. Pediatricians should be involved both in community advocacy programs to improve air quality and as knowledgeable practitioners in discussing practical air pollution avoidance strategies with patients and their families.

Impact of changes in transportation and commuting behaviors during the 1996 Summer Olympic Games in Atlanta on air quality and childhood asthma.

CONTEXT: Vehicle exhaust is a major source of ozone and other air pollutants. Although high ground-level ozone pollution is associated with transient increases in asthma morbidity, the impact of citywide transportation changes on air quality and childhood asthma has not been studied. The alternative transportation strategy implemented during the 1996 Summer Olympic Games in Atlanta, Ga, provided such an opportunity. OBJECTIVE: To describe traffic changes in Atlanta, Ga, during the 1996 Summer Olympic Games and concomitant changes in air quality and childhood asthma events. DESIGN: Ecological study comparing the 17 days of the Olympic Games (July 19-August 4, 1996) to a baseline period consisting of the 4 weeks before and 4 weeks after the Olympic Games. SETTING AND SUBJECTS: Children aged 1 to 16 years who resided in the 5 central counties of metropolitan Atlanta and whose data were captured in 1 of 4 databases. MAIN OUTCOME MEASURES: Citywide acute care visits and hospitalizations for asthma (asthma events) and nonasthma events, concentrations of major air pollutants, meteorological variables, and traffic counts. RESULTS: During the Olympic Games, the number of asthma acute care events decreased 41.6% (4.23 vs 2.47 daily events) in the Georgia Medicaid claims file, 44.1% (1.36 vs 0.76 daily events) in a health maintenance organization database, 11.1% (4.77 vs 4.24 daily events) in 2 pediatric emergency departments, and 19.1% (2.04 vs 1.65 daily hospitalizations) in the Georgia Hospital Discharge Database. The number of nonasthma acute care events in the 4 databases changed -3.1%, +1.3%, -2.1%, and +1.0%, respectively. In multivariate regression analysis, only the reduction in asthma events recorded in the Medicaid database was significant (relative risk, 0.48; 95% confidence interval, 0.44-0.86). Peak daily ozone concentrations decreased 27.9%, from 81.3 ppb during the baseline period to 58.6 ppb during the Olympic Games (P<.001). Peak weekday morning traffic counts dropped 22.5% (P<.001). Traffic counts were significantly correlated with that day's peak ozone concentration (average r = 0.36 for all 4 roads examined). Meteorological conditions during the Olympic Games did not differ substantially from the baseline period. CONCLUSIONS: Efforts to reduce downtown traffic congestion in Atlanta during the Olympic Games resulted in decreased traffic density, especially during the critical morning period. This was associated with a prolonged reduction in ozone pollution and significantly lower rates of childhood asthma events. These data provide support for efforts to reduce air pollution and improve health via reductions in motor vehicle traffic.

Reduced gas transfer at rest and during exercise in school-age survivors of bronchopulmonary dysplasia.

School-age children who survive bronchopulmonary dysplasia (BPD) may have a permanent reduction in alveolar surface area that could limit gas transfer both at rest and during exercise. To test this hypothesis, 10 survivors of BPD, 10 children born prematurely without BPD, and 10 healthy children born at term, 6 to 9 yr of age, underwent treadmill exercise studies. During a three-phase protocol we measured intrabreath acetylene (C2H2) and carbon monoxide (CO) transfer, pulmonary function, and SaO2. Both at rest and during exercise, C2H2 transfer corrected for body surface area was lower in survivors of BPD than it was in children born prematurely without BPD or children born at term. With exercise the transfer of both gases increased sharply over resting values in children born prematurely and at term. In survivors of BPD C2H2 transfer with exercise did increase, but not as much as it did in control subjects, and corrected CO transfer did not change at all. In survivors of BPD and children born prematurely, FEV1 fell during recovery from exercise, but this did not correlate with C2H2 transfer or DL(CO)/VA. Thus, soluble gas transfer at rest and during acute exercise is reduced in children who survive BPD. This is likely explained either by long-term derangements in lung structure or residual right ventricular dysfunction affecting cardiac output.

Intravenous access in infants and children.

At times, nothing is more difficult, time consuming or frustrating than obtaining vascular access in the pediatric patient. Today, technologic improvements in catheter design and imaging techniques have significantly facilitated line placement and increased the available options for vascular access. All clinicians involved in the care of pediatric patients should have knowledge of the various methods available for venous access, as well as their relative indications, advantages and disadvantages. This article discusses various sites used for venous access in the pediatric patient, as well as techniques that may be used by the pediatrician and those that require surgical consultation.

Pulmonary vascular complications of chronic airway obstruction in children.

OBJECTIVE: To study the clinical presentation, treatment, and outcome of pulmonary artery hypertension (PAH) that develops in children with chronic airway obstruction. DESIGN: Case study. SETTING: Academic tertiary care children's hospital. PATIENTS: A 3-year (October 1, 1992, to September 30, 1995) review of the medical records of all children with chronic airway obstruction in whom PAH developed. MAIN OUTCOME MEASURE: The clinical course, including objective laboratory data to measure PAH (cardiac catheterization, echocardiography, electrocardiography) both before and after treatment. RESULTS: Pulmonary artery hypertension developed in 18 patients. It was diagnosed using cardiac catheterization in 13 patients and echocardiography in 5 patients. Obstructive problems include chronic lung disease (9 patients), tracheobronchomalacia (6 patients), adenotonsillar hypertrophy (5 patients), laryngomalacia (4 patients), macroglossia (5 patients), subglottic stenosis (2 patients), and pharyngeal collapse (2 patients). Nine patients were born prematurely and 7 had Down syndrome. Treatments included tracheotomy (7), adenotonsillectomy (5), adenoidectomy (3), laser epiglottoplasty (1), and supplemental oxygen (12). Fourteen patients had documented improvement of PAH as seen from the cardiac catheterization, echocardiography, or electrocardiography findings; in 4 patients, PAH worsened (3 deaths). CONCLUSIONS: Chronic airway obstruction may lead to PAH. In this study, PAH was more likely to develop in premature infants or children with Down syndrome and cardiac anomalies. Surgery or supplemental oxygen will usually improve PAH, but fixed and irreversible PAH developed in patients with the most severe airway disease.

The complete spectrum of neurocristopathy in an infant with congenital hypoventilation, Hirschsprung's disease, and neuroblastoma.

Neuroblastoma, Hirschsprung's disease, and central hypoventilation (Ondine's curse) are considered aberrations of neural crest cell growth, migration, or differentiation, and as such are considered to be under the general heading of neurocristopathy. Their combined occurrence in a newborn infant presenting with total colonic aganglionosis, central hypoventilation, and multifocal neuroblastoma had not been reported previously. A 2.3-kg white full-term girl required endotracheal intubation because of persistent apnea in the first hours of life. She had progressive abdominal distension and failure to pass meconium; a barium enema was performed, which showed microcolon with meconium pellets at the distal ileum. During laparotomy the distal ileum was found to be obstructed with inspissated meconium; an ileostomy and appendectomy were performed. The resected specimens were aganglionic. An additional 20 cm of aganglionic ileum was removed, and a normally innervated ileostomy was constructed. Numerous attempts at extubation failed because of apnea. The results of an extensive apnea workup, including electroencephalogram, magnetic resonance imaging (MRI), bronchoscopy, and pH probe study, were normal. Sleep studies showed congenital central hypoventilation syndrome, and the patient underwent a tracheostomy. At 3 months, an abdominal ultrasound examination performed within a septic workup showed a right suprarenal mass extending across the midline. Thoracic and abdominal MRI scans showed large bilateral adrenal and posterior mediastinal masses. The serum catecholamines and ferritin level were markedly elevated, suggestive of neuroblastoma. In light of the child's multiple problems, the family chose to forgo further workup (including a tissue biopsy) and therapy. In the following 2 months her tumor load rapidly progressed, and she died of respiratory insufficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Denervation of transplanted porcine lung causes airway obstruction.

Lung transplantation can be complicated by a form of small airway obstruction known as bronchiolitis obliterans. We tested the hypothesis that lung denervation causes small airway obstruction in young pigs (10 +/- 1 weeks). Control pigs had an innervated native lobe, and study pigs had either a denervated native lobe or a denervated transplant lobe. Transplanted pigs received standard immunosuppression. At 10 weeks we measured isolated left lobe pulmonary mechanics. Dynamic resistance in both study groups was significantly higher than in the lobectomy group, whereas dynamic compliance in both study groups was significantly lower than in the lobectomy group. No significant difference in resistance or compliance was noted between the transplant and reimplant groups. Histologic changes consistent with rejection were noted in the transplant lobes. We conclude that the small airway obstruction noted in this model is due to operative denervation rather than to immunosuppression or rejection.

The effects of talc pleurodesis on growing swine.

Talc pleurodesis is an effective means of preventing recurrent pneumothorax. We have successfully applied talc pleurodesis with thoracoscopy in children with cystic fibrosis presenting with pneumothorax. However, little is known about the effects of talc pleurodesis on lung compliance in growing children. Therefore, six young pigs (10 weeks old, weighing 15 +/- 1 kg) were prepared for study. In each pig, one hemithorax underwent thoracoscopy and talc pleurodesis (TALC). The other hemithorax underwent either thoracoscopy alone or no procedure (CONTROL). Dynamic and static respiratory mechanics were studied 5 and 10 weeks later. Air flow and airway pressure were measured to calculate dynamic transpulmonary and transrespiratory compliance, and static transpulmonary compliance. At 5 weeks, dynamic transpulmonary and transrespiratory compliance were less in the TALC lungs when compared with CONTROL lungs. At 10 weeks, the differences in dynamic transpulmonary and transrespiratory compliance between the TALC and CONTROL lungs had resolved. Static compliance was lower in the TALC lungs than in the CONTROL lungs at both 5 and 10 weeks, but this was significant only at 10 weeks. There was an improvement in static compliance in the TALC lungs between 5 and 10 weeks, but this only approached significance. At autopsy, there were marked adhesions and pleural thickening in the talc lungs. Histological examination demonstrated no differences in lung parenchyma between the TALC lungs and the CONTROL lungs. Talc pleurodesis causes a temporary impairment in dynamic transpulmonary and transrespiratory compliance that resolves with time and growth. Static compliance is more persistently compromised, but a trend toward improvement with time and growth exists.(ABSTRACT TRUNCATED AT 250 WORDS)

Neural control of ANF release in hypoxia and pulmonary hypertension.

Hypoxia causes the release of atrial natriuretic factor (ANF), but the mechanisms are not yet understood. This study examined the relative contribution of pulmonary arterial hypertension, neural pathways, increased heart rate, or increased atrial size to the ANF response. Alveolar hypoxia [fractional concentration of O2 in inspired gas (FIo2) = 0.1] or pulmonary arterial hypertension (25-45 mmHg) was induced for 10 min in four series (n = 4-12 each) of anesthetized, mechanically ventilated pigs. During hypoxia, plasma ANF concentrations increased by 129 +/- 52 (SE) pg/ml (or 271 +/- 105%) over baseline (35 +/- 7 pg/ml; P less than 0.01) (series 1). There was also a significant increase of pulmonary arterial pressure, heart rate, central venous pressure, and pulmonary capillary wedge pressure. Repeated pulmonary hypertension induced by intravenous air infusion caused a repeated and reversible 125 +/- 14% increase (P less than 0.001) of plasma ANF, and this response was totally abolished by lesion of the cervical vagosympathetic trunks (series 2). Lesion of these nerves 1 h before hypoxia also decreased the ANF response to hypoxia by 45-58% (P less than 0.01), whereas responses of heart rate and atrial pressures were unchanged (series 3). The ANF response to hypoxia, expressed in percent of baseline, was not affected by 0.2 mg/kg propranolol (PR) (no PR: 145 +/- 63%; PR: 151 +/- 82%; not significantly different from series 1 and control, series 3), although the increase in heart rate (no PR: 61 +/- 15 beats/min) was almost abolished (PR: 17 +/- 5 beats/min) (series 4). Hypoxia caused no significant changes in right and left atrial peak volume regardless of propranolol, as measured with an electrical conductance catheter. The results indicate that a new neural reflex of probably pulmonary arterial origin mediates approximately 50% of the ANF response to hypoxia. The remaining ANF response remains to be explored further and cannot be explained by conventional release mechanisms such as atrial stretch and pulsatility alone.

Decreased vascular compliance after reimplantation of the left lower lobe in young pigs.

The effects of chronic denervation on pulmonary vasculature are not well understood. Three groups of young pigs were prepared: (1) those receiving sham thoracotomy, (2) those having left upper lobectomy alone (innervated left lower lobe), and (3) those receiving left pneumonectomy followed by reimplantation of the left lower lobe (denervated left lower lobe). At 10 weeks after operation, animals were anesthetized and instrumented for study. No changes in baseline pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac output, or pulmonary vascular resistance were observed. With diversion of the entire cardiac output to the left lung or lobe, however, the group with reimplanted lobes had a significantly higher pulmonary artery pressure and pulmonary vascular resistance than the other groups. This may result from chronic denervation of the pulmonary vasculature and receptor upregulation.

Interrelationship of atrial natriuretic peptide, atrial volume, and renal function in premature infants.

Infants experience dramatic changes in fluid balance during the first few days of life, which provides an opportunity to observe the interrelationships of changing atrial size, atrial natriuretic peptide (ANP) secretion, and renal function during a relatively short period. To study these relationships, we examined nine infant boys (mean birth weight 1180 gm and gestational age 30 weeks) at 20 to 28 hours of age and then at four 24-hour intervals. Measurements included plasma ANP concentration, two-dimensional echocardiographic estimations of left and right atrial volumes, Doppler determination of ductus arteriosus patency, creatinine clearance, urine flow rate, urinary sodium excretion, and cyclic guanosine monophosphate (cGMP) excretion. Plasma ANP concentration was found to decrease with age and to correlate with decreasing size of the right atrium, closure of the ductus arteriosus, urinary cGMP excretion, and sodium excretion. We speculate that elevated plasma ANP values in a preterm neonate reflect an expanded volume state. As volume contraction, reflected by decreasing atrial volume and body weight occurs, ANP levels decrease, which may diminish diuresis. These findings are compatible with a significant role for ANP in volume homeostasis of newborn infants.

Furosemide reduces lung fluid filtration in lambs with lung microvascular injury from air emboli.

To study the effects of furosemide on the neonatal pulmonary circulation in the presence of lung injury, we measured pulmonary arterial and left atrial pressures, cardiac output, lung lymph flow, and concentrations of protein in lymph and plasma of nine lambs that received furosemide, 2 mg/kg iv, during a continuous 8-h intravenous infusion of air. Air embolism increased pulmonary vascular resistance by 71% and nearly tripled steady-state lung lymph flow, with no change in lymph-to-plasma protein ratio. These findings reflect an increase in lung vascular protein permeability. During sustained lung endothelial injury, diuresis from furosemide led to a rapid reduction in cardiac output (average 29%) and a 2-Torr decrease in left atrial pressure. Diuresis also led to hemoconcentration, with a 15% increase in both plasma and lymph protein concentrations. These changes were associated with a 27% reduction in lung lymph flow. In a second set of studies, we prevented the reduction in left atrial pressure after furosemide by inflating a balloon catheter in the left atrium. Nevertheless, lymph flow decreased by 25%, commensurate with the reduction in cardiac output that occurred after furosemide. In a third series of experiments, we minimized the furosemide-related decrease in cardiac output by opening an external fistula between the carotid artery and jugular vein immediately after injection of furosemide. In these studies, the reduction in lung lymph flow (average 17%) paralleled the smaller (17%) decrease in cardiac output. These results suggest that changes in lung vascular filtration pressure probably do not account for the reduction in lung lymph flow after furosemide in the presence of lung vascular injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Alveolar hypoxia is a powerful stimulus for ANF release in conscious lambs.

The effect of acute alveolar hypoxia [fractional concentration of O2 in inspired gas (FIo2) = 0.1] for 10 min [arterial PO2 = 37 +/- 4 (SE) mmHg] and of blood volume expansion (7 and 15% of calculated blood volume) on atrial natriuretic factor (ANF) release was examined in groups of awake, instrumented young lambs. Systemic venous plasma ANF concentrations increased 1.6-fold (P less than 0.01) during blood volume expansion of 7%, 1.9-fold (P less than 0.01) during acute hypoxia, and 2.2-fold (P less than 0.005) during blood volume expansion of 15%. In lambs with prior 15% blood volume expansion, alveolar hypoxia further increased ANF concentrations 3.1-fold (P less than 0.01), suggesting synergism between volume and hypoxia stimuli. Hypoxia-induced ANF release correlated best with increased pulmonary arterial pressure, a potential mediator of the ANF response (r = 0.67; P less than 0.016). Increased differences between pulmonary arterial and systemic venous plasma ANF concentrations (from 11 to 134 pg/ml) indicate that hypoxia causes increased release of ANF from the heart rather than decreased metabolism of circulating ANF. Pulmonary arterial plasma ANF during hypervolemic hypoxia had immunological and chromatographic (high-performance liquid chromatography) properties of Pro-ANF-(99-126) [alpha-ANF-(1-28)]. Thus alveolar hypoxia (FIo2 = 0.1) is as potent as 15% blood volume expansion in increasing the concentration of circulating ANF. This newly described endocrine response could be important during alveolar hypoxia to decrease pulmonary vasoconstriction and fluid accumulation in the lung.

Airway obstruction after autologous reimplantation of the porcine lobe.

Bronchiolitis obliterans (irreversible small airway obstruction) is a late complication of heart-lung transplantation. Chronic immune rejection is believed to be the major cause of this complication. Our hypothesis was that denervation might contribute to airway obstruction. To test this hypothesis in the absence of immune rejection, we performed a lobectomy of the upper lobe of the left lung and autologous reimplantation of the lower lobe of the left lung in 13 growing pigs. To serve as age-matched controls, six other pigs had sham left thoracotomy and nine others had a lobectomy of the upper lobe of the left lung alone. Nine to 10 weeks after operation, the animals were anesthetized and the lungs mechanically ventilated. The lobes were then isolated in vivo to measure differential transrespiratory mechanics and volumes. Dynamic compliance was significantly lower in the reimplanted lobe than it was in the contralateral right lung. This was the case after lobectomy of the upper lobe of the left lung or sham thoracotomy. Dynamic resistance was significantly higher in the reimplanted lobe than it was in the contralateral right lung and in the left lung after sham thoracotomy. Measurements of extravascular lung water, dry lobe weight, alveolar cross-sectional area, and volumetric proportions of lung parenchyma and alveolar spaces did not demonstrate abnormal structural growth after reimplantation. We conclude that lobectomy of the upper lobe of the left lung and autologous reimplantation of the left lower lobe leads to adverse changes in flow-dependent measurements of airway patency. Changes in bronchomotor regulation imposed by denervation may contribute to airway obstruction after heart-lung transplantation.

Effect of pulmonary perfusion on lung fluid filtration in young lambs.

To study the effect of pulmonary perfusion on fluid filtration in the newborn lung, we measured pulmonary vascular pressures, cardiac output, lung lymph flow, and concentrations of protein in lymph and plasma of nine healthy, awake lambs, 2-3 wk old, before and during sustained alterations in pulmonary blood flow. A 12% reduction in cardiac output (from partial occlusion of the inferior vena cava) led to a corresponding decrease in lymph flow, consistent with a reduction in net lung fluid filtration. A 20% increase in pulmonary blood flow (from opening an external shunt between the carotid artery and jugular vein) increased lymph flow by approximately 40%, without a significant change in lymph protein concentration. These findings suggest that lung microvascular surface area expanded in response to increased perfusion, with little or no change in filtration pressure. In five lambs, lung microvascular pressure was increased by inflating a balloon catheter in the left atrium to establish full patency of the pulmonary microcirculation. In the presence of left atrial pressure elevation, increased perfusion through the arteriovenous shunt had no significant effect on pulmonary vascular pressures or lymph flow. Thus, in young lambs, modest changes in pulmonary blood flow may affect lung fluid filtration by altering perfused microvascular surface area; this response is inhibited in the presence of left atrial hypertension.