Pediatrics, Surfactant, and Cystic Fibrosis in AJRCCM 2002

     Division of Pulmonary and Critical Care Medicine, Loyola University of Chicago Stritch School of Medicine and Hines Veterans Affairs Hospital, Hines, Illinois

    CONTENTS

    Pediatrics (84)

    Pulmonary Function Testing and Diagnostic Techniques (5)

    Normative Values (1)

    Exhaled Nitric Oxide (1)

    Respiratory Muscles and Mechanics (2)

    Lung Water (1)

    Mechanical Ventilation (3)

    Respiratory Syncytial Virus Bronchiolitis (2)

    Active Infection (2)

    Sleep and Control of Breathing (8)

    Pediatric Asthma (17)

    Genetics (2)

    Epidemiology (7)

    Risk Factors: Air Pollution (3)

    Risk Factors: Aeroallergens (1)

    Airway Inflammation (2)

    Treatment (2)

    Other Pediatric Issues (18)

    Air Pollution (1)

    Passive Smoking (3)

    Lung Development (2)

    Bronchopulmonary Dysplasia (2)

    Congenital Diaphragmatic Hernia (2)

    Infections (3)

    Pulmonary Hypertension (2)

    Interstitial Lung Disease (2)

    Gastroesophageal Reflux (1)

    Surfactant Biology and Disorders (5)

    Pathophysiology (3)

    Deficiency (1)

    Treatment (1)

    Cystic Fibrosis (26)

    Genetics (1)

    Lung Inflammation (5)

    Microbiology (5)

    Pathophysiology and Exercise Performance (9)

    Bone Demineralization and Metabolic Disorders (2)

    Treatment (4)

    Mucolytic Agents (1)

    Lung Transplantation (3)

    PEDIATRICS

    Pulmonary Function Testing and Diagnostic Techniques

    Normative values.

    Maximal flow at functional residual capacity during a partial forced expiratory maneuver is the most popular test of lung function in infants and young children. Because appropriate reference data are lacking, Hoo and coworkers (1) collated data from 459 healthy infants tested on 654 occasions during the first 20 months of life. The most important predictors of maximal flow at functional residual capacity were sex, age, and length. Flow was 20% higher in girls than in boys during the first nine months of life. Models for predicting normal values are presented. The authors conclude that failure to include sex-specific data in prediction equations for maximum flow at functional residual capacity during a partial forced expiratory maneuver may miss significant problems in girls and lead to false diagnoses in boys.

    Exhaled nitric oxide.

    In an occasional essay, Godfrey (2) discussed the ups and downs of nitric oxide in chesty children.

    Respiratory muscles and mechanics.

    To determine whether premature birth per se alters functional development of the lungs, Hjalmarson and Sandberg (3) studied 32 healthy preterm infants (gestational age, 25 to 33 weeks at birth) and 53 healthy full-term infants (gestational age, 37 to 42 weeks). At the same postmenstrual age of 40 weeks (close to term), the preterm infants had a lower functional residual capacity, a lower specific compliance, less efficient gas mixing, higher total ventilation, and higher dead-space ventilation than did the full-term infants. Studies in 20 of the preterm infants revealed a decrease in specific compliance, a decrease in specific conductance, and an increase in the efficiency of gas mixing between 34 and 40 weeks. The authors conclude that preterm birth per se alters the functional development of the lungs through unknown mechanisms.

    The interrupter technique provides a measure of respiratory resistance from recordings of flow and mouth pressure while the airways are occluded during tidal breathing. To characterize the values before and after administration of a bronchodilator in healthy children, Beydon and coworkers (4) studied 91 children (aged 2.9 to 7.9 years). Inspiratory resistance was higher than expiratory resistance before 5 years of age, and the opposite pattern was seen after 5 years. Both resistances decreased with height. Inhaled albuterol produced a 15% decrease in inspiratory resistance and a 12% decrease in expiratory resistance. Sex did not affect the prebronchodilator or postbronchodilator values. The authors conclude that the reported values for resistance measured by the interrupter technique may help in assessing lung function in children who are unable to perform a forced expiratory maneuver.

    Lung water.

    To determine whether lung water is increased in preterm infants, Adams and coworkers (5) did magnetic resonance imaging in 16 preterm (24 to 31 weeks) and 9 term (37 to 42 weeks) infants. Lung water, as reflected by relative proton density, was greater in the preterm infants than in the term infants. Lung water was greater in the dependent than the nondependent regions in both groups. Switching preterm infants from the supine to the prone position caused a rapid redistribution of the signal, with a more even distribution in the prone position. The authors conclude that lung water is greater in preterm than in term infants and is associated with gravity-related changes.

    Mechanical Ventilation

    Data on airway patency in very low birth weight infants with chronic lung disease who were managed with surfactant and high-frequency oscillation ventilation have not been published. Hofhuis and coworkers (6) studied 36 infants with chronic lung disease; the infants had a gestational age of 26.8 weeks and a birth weight of 837 g. At both 6 and 12 months of age, maximal flow at functional residual capacity, measured with the end-tidal rapid thoracoabdominal compression technique, was significantly below normal. Maximal flow at functional residual capacity decreased (Z score of 0.5) between 6 and 12 months of age. At 12 months, maximal flow at functional residual capacity was higher (difference in Z score of 0.6) in children who had initially been managed by high-frequency oscillation ventilation than in children initially managed with conventional ventilation. The authors conclude that airway patency decreases during the first year of life in very low birth weight infants with chronic lung disease and that airway patency at 12 months is greater in infants who had been initially managed with high-frequency oscillation ventilation. An editorial commentary by Jobe (7) accompanied this article.

    Most infants born before a gestational age of 30 weeks have been exposed to chorioamnionitis and aspiration of infected amniotic fluid. To simulate this situation and determine whether susceptibility to injury is related to gestational age, Kramer and coworkers (8) studied lambs delivered at 130 or 141 days of gestation (term is 146 days). In the preterm lambs, both a low and high dose of intratracheal endotoxin (0.1 or 10 mg per kg) caused impaired gas exchange and systemic inflammation. In the near-term lambs, a high dose of intratracheal endotoxin (10 mg per kg) caused lung inflammation without a systemic effect; systemic inflammation occurred when the intratracheal endotoxin was combined with ventilation at a high tidal volume or with intravenous endotoxin. The authors conclude that intratracheal endotoxin produces systemic inflammation in preterm lambs, but not in near-term lambs, unless it is combined with ventilation using high tidal volumes.

    Respiratory Syncytial Virus Bronchiolitis

    Active infection.

    To determine the incidence of respiratory syncytial virus and rhinovirus in acute bronchiolitis, Papadopoulos and coworkers (9) studied 118 infants with acute bronchiolitis. Viruses were detected in 74% of the infants. Of virologically confirmed cases, respiratory syncytial virus was detected in 72%, rhinovirus in 29%, and multiple infections in 20%. After controlling for other factors, multiple regression analysis revealed that rhinovirus was associated with a fivefold greater risk of severe disease. The authors conclude that rhinovirus is second only to respiratory syncytial virus as a causative agent of bronchiolitis in infants and that it is associated with more severe disease.

    Infection with respiratory syncytial virus causes inflammation of the airway mucosa associated with activation of nuclear factor-{kappa} B. Compared with control mice, Haeberle and coworkers (10) found intranasal administration of perflubron six hours after infection with respiratory syncytial virus produced significant inhibition of cellular inflammation in the lungs. Expression of the chemokines, RANTES (regulated upon activation, normal T cell expressed and secreted), macrophage inflammatory protein-1{alpha} , macrophage inflammatory protein-1ß, and macrophage inflammatory protein-2 were decreased in the treated mice. Perflubron markedly decreased the activation of nuclear factor-{kappa} B in the lung. The authors conclude that perflubron reduces lung inflammation in mice infected by respiratory syncytial virus through inhibition of chemokine expression and activation of nuclear factor-{kappa} B.

    Sleep and Control of Breathing

    In 18 infants aged 21 days, Bouferrache and coworkers (11) compared two methods of assessing peripheral chemoreceptor function: the hyperoxic test (based on a decrease in minute ventilation) and the alternate breath test (based on alternations in minute ventilation induced by breath-by-breath alternations in inspired oxygen concentrations of 0.15 and 0.21). The decreases in minute ventilation with the two techniques were related to one another (r = 0.69), as were the decreases in mean inspiratory flow (r = 0.70). The hyperoxic test primarily altered tidal volume, whereas the alternate breath test altered both tidal volume and inspiratory time. The hyperoxic test achieved smaller within-subject coefficients of variation for minute ventilation than did the alternate breath test. The authors conclude that the hyperoxic test and alternate breath test of peripheral chemoreceptor function produce similar changes in minute ventilation in infants, but that the hyperoxic test is more reproducible.

    Because avoiding the prone position is linked with a decrease in the incidence of sudden infant death syndrome, Ishikawa and coworkers (12) measured patency of the upper airway in 19 infants and small children (10 to 101 weeks old). The static pressure¨Carea relationship of the passive pharynx was measured in three postures under general anesthesia. Maximum pharyngeal area was smaller in the prone position with the neck rotated than in the supine position: 0.44 versus 0.56 cm². Pharyngeal closing pressure was lower in the supine position with the neck rotated (-2.83 cm H₂O) than in the supine position with the face straight up (-4.45 cm H₂O) and was further decreased in the prone position with the neck rotated (-0.27 cm H₂O). Pharyngeal closing pressure was above atmospheric pressure in half the subjects in the prone position, whereas all subjects had a negative pharyngeal pressure in the supine position. The authors conclude that the prone position increases collapsibility of the upper airway of infants and young children.

    To determine the pattern of growth for tissues surrounding the upper airway, Arens and coworkers (13) did magnetic resonance imaging in 92 healthy children between 1 and 11 years of age. In the midsagittal plane, the distance between the mental spine (point that the genioglossus is inserted into the mandible) and the clivus (passing through the centroid of the soft palate) was related linearly to age (r = 0.86). The dimensions of the tongue, soft palate, nasopharyngeal airway, and adenoids increased with age and maintained a constant proportion to the distance between the mental spine and the clivus. In the axial plane, the transverse distance between the mandibles was related to age (r = 0.78). The width of the tonsils, intertonsillar region, parapharyngeal fat pads, and pterygoids maintained a constant proportion to the intermandibular width with age. The authors conclude that the skeleton of the lower face grows linearly along the sagittal and axial planes between the first and eleventh years of life.

    To determine the efficacy and tolerance of an oral jaw-positioning appliance in children with sleep apnea, Villa and coworkers (14) studied 32 patients (aged 4 to 10 years). Nineteen patients were randomized to 6 months treatment with the device, and 13 served as control subjects. Four treated patients and five untreated patients were lost to follow-up. Of the 14 treated patients, 9 (64%) showed a 50% or greater decrease in the apnea¨Chypopnea index. Symptoms of sleep apnea decreased in all treated patients and completely resolved in half. Untreated patients showed no change. The authors conclude that use of a jaw-positioning appliance is effective in treating sleep apnea in children and that the appliance is reasonably well tolerated.

    Harrington and coworkers (15) studied cardiovascular autonomic function in 10 infants who had experienced an apparent life-threatening event and 12 control infants. The studies were done during slow wave sleep and REM sleep. Five of the 10 infants who had experienced a life-threatening event had obstructive sleep apnea. Breathing during sleep was normal in the other five infants and in all of the control infants. In response to 45-degree head-up tilts, the infants with obstructive sleep apnea had a decreased heart rate response, and three developed marked hypotension. The infants with sleep apnea also had altered variability of heart rate and blood pressure and an increased threshold for arousal during REM sleep. The authors concluded that half of infants with an apparent life-threatening event have obstructive sleep apnea and that this subgroup also has abnormal autonomic cardiovascular control.

    To evaluate cardiac structure in children and adolescents with obstructive sleep apnea, Amin and coworkers (16) did echocardiography on 28 children with obstructive sleep apnea and 19 children with primary snoring. Left-ventricular mass index was 22% greater, and relative wall thickness was 24% greater in the children with obstructive sleep apnea than in the children with primary snoring. An apnea¨Chypopnea index of 10 or more events per hour was associated with a 6.7-fold increased risk of enlarged right-ventricular dimensions and 11.2-fold increased risk of an increased left-ventricular mass index. The authors conclude that obstructive sleep apnea leads to cardiac remodeling and hypertrophy of both the right and left ventricles in children and adolescents.

    Measurement of airflow at the nose with a thermistor or measurement of pressure at the nose with a cannula is used in the detection of apneas and hypopneas. Trang and coworkers (17) compared the accuracy of the two techniques in 14 infants (aged 2.6 months) and 16 children (aged 5.5 years) with suspected obstructive sleep apnea. All children tolerated the nasal cannula. An noninterpretable flow signal lasting more than 20% of total sleep time occurred in five children using a cannula versus only one child using the thermistor. A total of 465 obstructive apneas were identified: 43% of the apneas were detected by both techniques; 52% of the apneas missed by the thermistor were detected by nasal pressure monitoring; and only 5% of the apneas missed by nasal pressure were detected by the thermistor. A total of 159 obstructive hypopneas were detected: nasal pressure detected 100% of these events, whereas the thermistor detected only 14%. Esophageal pressure was recorded in six children; all events detected by nasal pressure were associated with increased airway resistance. The authors conclude that measurement of pressure at the nose with a nasal cannula is more reliable than measurement of flow with thermistors in detecting obstructive apneas and hypopneas in children.

    The cause of congenital central hypoventilation syndrome is unknown, although a genetic etiology is suspected. Sritippayawan and coworkers (18) described a 25-year-old woman with congenital central hypoventilation who gave birth to an infant with the same condition. The mother did not have worsening of symptoms during pregnancy, and her ventilatory response to hypercapnia was unchanged. The mother was managed by diaphragmatic pacing throughout pregnancy. The authors conclude that the presence of congenital central hypoventilation syndrome in both a mother and daughter supports a dominant mode of inheritance for the condition.

    Pediatric Asthma

    Genetics.

    Several members of the glutathione S-transferase superfamily function as enzymatic antioxidants and hydroperoxidases in the respiratory tract. To determine the association between GSTM1, GSTT1, and GSTP1 genotypes and acute respiratory illness, Gilliland and coworkers (19) studied 1,183 fourth-grade children (aged 9 to 11 years). Over a 6-month period, 29% of the children were absent from school at least once because of a respiratory illness. Children who were homozygous for the Val 105 variant of the GSTP1 genotypes experienced 40% fewer respiratory-related school absences than did children who were homozygous for the common Val 105 allele. Children with at least one Val 105 allele had a 20% lower rate of respiratory illness. Children with the GSTM1 null genotype had a slightly higher rate of respiratory-related school absences than did children with the GSTM1 present genotype. The authors conclude that the GSTP1 genotype influences the risk of respiratory infections in school children.

    Gilliland and coworkers (20) studied the effect of genotypes for glutathione-S-transferase M1, T1, and P1 on lung growth in 1,940 children, aged 8 to 11 years, who were followed annually for 4 years. GSTM1 null was associated with deficits in the annual growth rates in FVC (-0.21%) and FEV₁ (-0.27%). Compared with children who had one or more ile105 alleles, children who were homozygous for the GSTP1 val105 allele had a slower rate of growth in FVC (-0.35%) and FEV₁ (-0.34%). Compared with children free of asthma, children with asthma who were homozygous for the GSTP1 val105 allele had substantially larger deficits in FVC, FEV₁, and maximum mid-expiratory flow. The authors conclude that children who have the GSTM1 null genotype and children who are homozygous for the GSTP1 val105 variant allele have a lower growth in lung function than do children with more common alleles at these two loci.

    Epidemiology.

    To determine whether stress in parents is associated with the development of wheeze in infants, Wright and coworkers (21) studied a genetically predisposed birth cohort of 496 infants and their caregivers. A greater level of stress in a caregiver (97% consisted of mothers) when a child was 2 to 3 months old was associated with an increased risk of wheezing during the first 14 months of life (relative risk, 1.6). The relationship was still significant after controlling for confounding factors (parental asthma, socioeconomic status, birth weight, maternal smoking, breastfeeding, indoor allergen exposure, and lower respiratory infections). Stress in the caregivers predicted subsequent wheeze in the infants, whereas wheeze in the infants did not predict subsequent stress in the caregivers. The authors conclude that an increase in the level of stress in parents of 2- to 3-month-old infants is associated with increased risk of recurrent wheeze over the first 14 months of life.

    In a longitudinal study of 243 infants, 23 subjects (9.4%) displayed flow limitation during tidal expiration at 4 weeks, which was associated with reduced lung function at 4 weeks and 6 months of age, and airway hyperresponsiveness at 12 months of age. To determine whether the flow-limited group would continue to display decreased lung function, Turner and coworkers (22) analyzed data between the ages of 3 and 11 years. Only at 4 years of age did the flow-limited group have increased wheeze as compared with other cohort members (odds ratio, 4.25). At 6 years of age, the flow-limited group has greater airway hyperresponsiveness and lower FEV₁ (131 ml) and forced expiratory flow (FEF_25¨C75; 0.28 liter per second). At 11 years of age, the flow-limited group had greater airway hyperresponsiveness. Atopy and parental asthma were not increased in the flow-limited group. The authors conclude that airflow limitation in early infancy identifies a group with increased risk for reduced lung function and greater airway hyperresponsiveness, but not asthma, in later life.

    Five retrospective studies have reported an association between use of antibiotics in early life and asthma in childhood. Celedon and coworkers (23) studied this relationship in 448 children with a parenteral history of asthma. After adjusting for potential confounders, the use of antibiotics in the first year of life was not associated with asthma, recurrent wheezing, allergic rhinitis, or wheezing at 5 years. The authors conclude that use of antibiotics in the first year of life is not associated with the subsequent development of asthma and atopy in childhood.

    It is traditionally thought that avoiding ownership of a pet protects against the development of allergy. To determine the effect that living with a cat or a dog has on the development of allergy and asthma, Perzanowski and coworkers (24) studied longitudinally a cohort of children living in three towns in northern Sweden. Data on the prevalence of asthma were obtained at ages 7 to 8 years, and incidence data were obtained over the subsequent three years. The strongest risk factor for incident cases of asthma was type 1 allergy (relative risk, 4.9), followed by a family history of asthma (relative risk, 2.83). Living with a cat was inversely related to a positive skin test to cat (relative risk, 0.62) and to the incidence of physician-diagnosed asthma (relative risk, 0.49). This effect on incident asthma was greatest among children with a family history of asthma (relative risk, 0.25). Weaker protective trends were seen with dog ownership. The authors conclude that avoiding ownership of a pet does not protect against the development of asthma or allergy.

    To determine whether the level of endotoxin in house dust is associated with allergic sensitization in children, Gehring and coworkers (25) studied 740 children, aged between 5 and 10 years. Dust from the floor of living rooms was collected from the homes of 454 of the children (61%). After adjusting for place of residence, sex, age, parental education, parental atopy, and pet ownership, exposure to endotoxin was associated with sensitization to one or more allergens (odds ratio, 0.95) and to two or more allergens (odds ratio, 0.80). The authors conclude that a higher level of endotoxin in house dust is associated with a lower prevalence of allergic sensitization in children.

    To determine the interrelationship between current and past infection with Ascaris lumbricoides and asthma and atopy, Palmer and coworkers (26) studied a cross-sectional sample of 2,164 children between the ages of 8 and 18 years from rural China. The prevalence of either a history or positive stool examination for Ascaris was 24.5%. Independent of other factors, infection with Ascaris was associated with increased risk of asthma (odds ratio, 1.85), an increased number of skin tests positive to aeroallergens (odds ratio, 1.25), and an increased slope of the dose¨Cresponse to methacholine. The authors conclude that infection with A. lumbricoides is associated with an increased risk of childhood asthma, increased airway hyperresponsiveness, and sensitization to common aeroallergens.

    To determine the relationship between exposure to microbial load during pregnancy and the development of allergic disease, McKeever and coworkers (27) analyzed data from a birth cohort of 24,690 children. Exposure to antibiotics in utero was associated with an increased risk of asthma in a dose-related manner. Compared with no antibiotics, more than two courses of antibiotics was associated with increased risk of asthma (hazard ratio, 1.68), eczema (hazard ratio, 1.17), and hay fever (hazard ratio, 1.56). Exposure to a range of infections in utero was associated with a small increased risk of developing allergic disease. The presence of an older sibling had a strong protective effect on the incidence of allergy. The authors conclude that exposure to antibiotics in utero is associated with a dose-related increase in the risk of allergic disease in children.

    Risk factors: air pollution.

    To determine whether antioxidant vitamins could modulate the adverse effect of air pollution on lung function in children, Romieu and coworkers (28) did a double-blind randomized study in 158 children with asthma who lived in Mexico City. During the 31-month study, the average maximum level of ozone was 102 parts per billion (ppb), and the mean 24-hour average level of particulates with a mass median diameter of less than 10 µm was 57 µg per m³. Pulmonary function was measured twice weekly. In the placebo group, the children with moderate and severe asthma showed an inverse relationship between the level of ozone (on the day before spirometry) and peak expiratory flow (-15 ml per second per 10 ppb), forced expiratory flow (FEF_25¨C75, -13.3 ml per second per 10 ppb), and FEV₁ (-4.6 ml per 10 ppb). In children treated with vitamin E (50 mg daily) and vitamin C (250 mg daily), no association was seen between ozone and lung function. The authors conclude that antioxidant supplements might modulate the impact of exposure to ozone on the small airways of children with moderate to severe asthma.

    To determine the relationship between exposure to air pollution related to traffic and the development of asthmatic symptoms, allergic diseases, and respiratory infections, Brauer and coworkers (29) studied a birth cohort of 4,146 children. Outdoor concentrations of traffic-related air pollutants were modeled for the home of each subject. Adjusted odds ratios for wheezing; physician-diagnosed asthma; infections of the ear, nose, or throat; and serious colds at 2 years of age were associated with air pollutants; some of the associations reached borderline statistical significance. The authors conclude that traffic-related air pollution may be associated with the prevalence of respiratory illness at 2 years of age.

    To determine whether the type of indoor heating systems have an influence on respiratory symptoms during the first year of life, Triche and coworkers (30) collected information on symptoms and type of indoor heating every 2 weeks during the first year of life in 890 infants. During the heating season, 88% of infants had at least one episode of cough, and 33% had at least one episode of wheeze. After adjusting for confounding influences, the use of a gas space heater was associated with episodes of wheeze and days of wheeze. The use of a wood stove was associated with total days of cough, and the use of a kerosene heater was associated with episodes of cough. The use of a fireplace was not associated with any respiratory symptoms. The authors conclude that use of some indoor heating sources are associated with the development of respiratory symptoms in the first year of life.

    Risk factors: aeroallergens.

    To determine whether avoiding exposure to house dust mite allergen influences the development of symptoms in the first two years of life, Koopman and coworkers (31) selected 1,282 pregnant women with allergy. Of the women, 416 were randomized to receive mattress covers that were impermeable to house-dust mite allergen for the beds of the children and the parents; 394 received placebo covers, and 472 received no intervention. Compared with individuals who received placebo covers, children in the group that received active covers had a lower prevalence of night cough without a cold in the second year of life (odds ratio, 0.65). The intervention had no effect on other respiratory symptoms, atopic dermatitis, and total and specific IgE. The authors conclude that applying a mattress cover that is impermeable to house-dust mite allergen on the beds of children and their parents reduces night cough in the second year of life.

    Airway inflammation.

    Asthma is associated with an imbalance between type 2 (Th2) helper T cells, which secrete interleukin-4, and type 1 (Th1) helper T cells, which secrete interferon-{gamma} . Shahid and coworkers (32) analyzed exhaled breath condensates in 14 children receiving glucocorticoids for asthma, 12 steroid-naive children with asthma, and 11 healthy children. The level of exhaled interferon- was lower in children with asthma receiving glucocorticoids (3.7 pg per ml) than in steroid-naive children with asthma (5.1 pg per ml) or healthy children (4.1 pg per ml). Exhaled interleukin-4 was higher in children with asthma than in healthy children: 54 versus 36 pg per ml. Exhaled interleukin-4 was lower in children receiving more than 600 µg of inhaled glucocorticoid a day. The ratio of interleukin-4 to interferon- was greater in children with asthma than in healthy children or in children receiving inhaled glucocorticoids. The authors conclude that interferon-{gamma} and interleukin-4 can be measured in exhaled breath condensates and that the increase in the ratio of interleukin-4 to interferon- is consistent with a predominance of type 2 (Th2) cells in the airways.

    Cysteinyl leukotrienes are primarily generated by mast cells and eosinophils and induce smooth muscle contraction, microvascular leakage, and mucous hypersecretion; leukotriene B₄ is a potent chemoattractant of neutrophils. To determine whether the level of these substances in exhaled breath condensates reflect the severity of asthma, Csoma and coworkers (33) studied four groups of children aged between 7 and 14 years. The level of cysteinyl leukotrienes in 11 children with mild intermittent asthma (19.9 pg per ml) was equivalent to the level in 11 healthy children (18.5 pg per ml), but the level was higher in 13 children with mild persistent asthma (27.9 pg per ml) and in 13 children with moderate-to-severe asthma (31.5 pg per ml). The level of leukotriene B₄ was 47.9 pg per ml in the normal children, 52.7 pg per ml in the children with mild intermittent asthma, 126.0 pg per ml in the children with mild persistent asthma, and 131.9 pg per ml in the children with moderate-to-severe persistent asthma. The level of leukotriene B₄ was inversely correlated with the levels of cysteinyl leukotrienes (r = -0.76) in children with mild persistent asthma. The authors conclude that monitoring of exhaled breath condensates of cysteinyl leukotrienes and leukotriene B₄ may be noninvasive markers of airway inflammation in children with asthma.

    Treatment.

    To determine whether the improvement in bronchial hyperreactivity with inhaled glucocorticoids is related to a family history of bronchial hyperreactivity, Koh and coworkers (34) studied 121 children (aged 11 years) with atopic asthma. The dose of methacholine producing a 20% fall in FEV₁ was measured before and after 3 and 6 months of treatment with inhaled budesonide (800 µg daily). The prevalence of bronchial hyperreactivity was greater among parents of 40 children showing a small improvement in bronchial hyperreactivity after budesonide than among the parents of 40 children showing a large improvement: 29 versus 6%. The magnitude of improvement in bronchial hyperreactivity after budesonide therapy was 34% less in children who had at least one parent with bronchial hyperactivity than in children of parents without bronchial hyperreactivity. The authors conclude that the improvement in bronchial hyperreactivity in children treated with inhaled glucocorticoids is related to a family history of bronchial hyperreactivity.

    Because the benefit of inhaled glucocorticoids in preschool children with intermittent wheeze is unproven, Pao and McKenzie (35) did a 6-week randomized crossover trial of fluticasone propionate (100 µg twice daily) versus placebo in 61 children aged 2 to 5 years of age. Compared with placebo, the geometric change in interrupter resistance was -7.6% in the fluticasone group. The change in resistance was -16% in children with positive skin prick tests and -3.5% in children with negative prick tests. Changes in resistance were not related to IgE. Resistance returned to baseline at 16 weeks after stopping fluticasone. The authors conclude that fluticasone propionate has a beneficial effect on intermittent wheezing in preschool children, especially in those who are sensitized to aeroallergens.

    Other Pediatric Issues

    Air pollution.

    To determine whether exposure to ambient air pollutants affects the growth of lung function in children, Gauderman and coworkers (36) studied 2,081 fourth-grade children (average age, 9.9 years). Exposure to acid vapor, nitrogen dioxide, particles with an aerodynamic diameter of less than 2.5 µm, and elemental carbon were associated with significant deficits in the growth of lung function. Across the range of acid exposure, for example, the average annual growth rates of maximum mid-expiratory flow and FEV₁ were reduced by 11% and 5%, respectively. Exposure to acid vapor was associated with a decrease in the ratio of maximum mid-expiratory flow to FVC, whereas exposure to ozone was associated with a reduced rate of growth in peak expiratory flow. Children spending more time outdoors experienced greater deficits in lung function. The authors conclude that exposure to ambient levels of air pollutants has a detrimental effect on growth of lung function in children.

    Passive smoking.

    Exposure to maternal smoking during pregnancy is a risk factor for sudden infant death, but the relative contributions of nicotine and other substances in cigarette smoke to this effect are not clear. Hafstrom and coworkers (37) exposed fetal lambs to nicotine at a dosage comparable to mild-to-moderate cigarette smoking. At 5 and 21 days after delivery, the nicotine-exposed lambs had a lower tidal volume and higher respiratory rate than did nonexposed control lambs. Nicotine-exposed lambs had a higher airway occlusion pressure and higher effective impedance on the fifth day after delivery. The authors conclude that in utero exposure to nicotine results in postnatal abnormalities in the control of breathing, most likely because of increased impedance in the respiratory system.

    Maternal smoking is a major risk factor for late fetal death and the sudden infant death syndrome. To determine the effect of prenatal exposure to nicotine on postnatal defense against hypoxia, Hafstrom and coworkers (38) exposed 7 lambs to nicotine during the last trimester of pregnancy. At 5 days after birth, lambs with prenatal exposure to nicotine had a lower ventilatory response to hypoxia during quiet sleep than had control lambs. The time to arouse from sleep after exposure to hypoxia was more than twice as long in the nicotine-exposed lambs. The heart rate response to hypoxia was lower during both sleep and wakefulness in the lambs than had been exposed to prenatal nicotine. During wakefulness, the ventilatory response to hypoxia was equivalent in the two groups. The ventilatory response to hyperoxia was lower in the nicotine-exposed lambs during both wakefulness and sleep. The transition from wakefulness to sleep was associated with a decrease in ventilation in the control lambs but not in the nicotine-exposed lambs. The authors conclude that exposure to a low dose of nicotine during the last trimester of pregnancy blunts the ventilatory, heart rate, and arousal responses to hypoxia in newborn lambs. An editorial commentary by Nattie and Kinney (39) accompanies this article.

    Lung development.

    In preterm lambs, Moss and coworkers (40) studied the effect of intrauterine inflammation at different gestational ages. Pregnant ewes received intra-amniotic endotoxin at five different times of gestation: 60, 80, 100, 60 plus 100, or 80 to 108 days. Compared with a saline-treated control group, all of the endotoxin groups showed improved lung function at 125 days. Marked increases in saturated phosphatidylcholine in lung tissues were seen in all the endotoxin groups, with the exception of the group receiving endotoxin at both 60 and 100 days. All endotoxin groups displayed large increases in mature surfactant protein B in alveolar lavage. Messenger RNA for surfactant protein and the size of the protein pool differed among the groups. Preterm lambs exposed to endotoxin between 80 and 108 days displayed decreases in the ratio of lung weight to body weight, total surface area, and thickness of the alveolar well. The authors conclude that intrauterine inflammation in early gestation alters the surfactant system and the structure and function of the lung. An editorial commentary by Warburton (41) accompanies this article.

    Bronchopulmonary dysplasia.

    Bombesin-like peptide represents a family of neuropeptides derived from the pulmonary neuroendocrine cells, which plays a critical role in normal lung growth and development. Because infants dying of bronchopulmonary dysplasia have an increase in the number of neuroendocrine cells containing bombesin-like peptide, Cullen and coworkers (42) studied 132 infants with a gestation of 28 weeks or less to determine whether urinary levels of the peptide would predict the development of bronchopulmonary dysplasia. Between the first and fourth postnatal day, a urinary level of bombesin-like peptide of greater than 20,000 pg per mg creatinine was found in 54% of infants who later developed bronchopulmonary dysplasia as compared with 10% of infants who did not (specificity, 90%). (Bronchopulmonary dysplasia was defined as dependence on oxygen at 36-weeks postmenstrual age.) After adjusting for other variables, an elevated urinary bombesin-like peptide was associated with bronchopulmonary dysplasia (odds ratio, 9.9). The authors conclude that infants with increased urinary levels of bombesin-like peptide within the first four days of birth have a tenfold increased risk of developing bronchopulmonary dysplasia.

    By preventing injury to the epithelium and enhancing its repair, keratinocyte growth factor may reduce the risk of bronchopulmonary dysplasia. To determine whether a high level of keratinocyte growth factor would predict a lower likelihood of subsequent bronchopulmonary dysplasia, Danan and coworkers (43) obtained 114 tracheal aspirates within 3 hours of birth from 91 intubated neonates with a gestational age of 30 weeks or less. Keratinocyte growth factor was detected in all but six neonates. In 42 infants, a second sample obtained after 2¨C6 days revealed an 80% increase in keratinocyte growth factor. Fourteen infants developed bronchopulmonary dysplasia (defined as the need for supplemental oxygen at a postconceptional age of 36 weeks), and these infants had lower levels of keratinocyte growth factor. On a receiver operating characteristic curve, the best discriminator was the highest value of keratinocyte growth factor within 5 days after birth. The positive predictive value for not developing bronchopulmonary dysplasia was 95% for a keratinocyte growth factor exceeding 110 pg per ml. The authors conclude that high levels of keratinocyte growth factor in the airspaces after premature birth limit the risk of developing bronchopulmonary dysplasia.

    Congenital diaphragmatic hernia.

    Experiments in animals suggest that surfactant deficiency contributes to the pathophysiology of congenital diaphragmatic hernia, but data in humans are limited. Using a stable-isotope method, Cogo and coworkers (44) studied 14 infants with congenital diaphragmatic hernia and 8 infants with normal lungs. The level of surfactant disaturated phosphatidylcholine in epithelial lining fluid was lower in the patients than in the control subjects: 2.3 versus 4.6 mg per ml. The level of surfactant protein A was also lower in the patients than in the control subjects: 16 versus 62 µg per ml. The kinetics of disaturated phosphatidylcholine synthesis did not differ between the two groups. The authors conclude that infants with congenital diaphragmatic hernia have reduced levels of surfactant disaturated phosphatidylcholine and surfactant protein A, but the rate of synthesis of disaturated phosphatidylcholine is normal.

    In a clinical commentary, Bohn (45) discusses congenital diaphragmatic hernia.

    Infections.

    Two families of antimicrobial peptides, human ß-defensin 1 and 2 and cathelicidin LL-37/hCAP-18, are effector molecules of the innate respiratory immune system and are expressed in the epithelium of the adult lung. To determine whether these molecules are produced in the respiratory tracts of newborns, Schaller-Bals and coworkers (46) obtained tracheal aspirates from 45 mechanically ventilated infants. All three peptides were found in the airway lining fluid, and the levels were equivalent in term and preterm infants. The concentrations of the peptides correlated with each other and with the levels of interleukin-8 and tumor necrosis factor-{alpha} in bronchoalveolar fluid. The levels of the three peptides were increased in children with pulmonary or systemic infections. The authors conclude that the antimicrobial peptides, human ß-defensin 1 and 2 and cathelicidan LL-37/hCAP-18, are present in lung secretions of premature and mature infants and that the peptides are upregulated in response to infection and inflammation.

    Angiotensin-converting enzyme participates in inflammatory responses, and deletion (D) of a 284 base-pair marker in the gene for the enzyme causes the enzyme to be increased in plasma and tissue. To determine whether the DD genotype alters the outcome of a uniform infectious disease, Harding and coworkers (47) studied 110 children, aged 49 months, with meningococcal disease. Compared with children who had at least one insertion allele (ID, II), the 34 children with the DD genotype had a 14% higher mortality, a 22% higher meningococcal septicemia score, a greater prevalence of inotropic support (76 versus 55%), a greater prevalence of mechanical ventilation (82 versus 63%), and a longer intensive care unit stay (5.8 versus 3.9 days). The frequency of the DD genotype was 45% for children who died, 33% for children admitted to the intensive care unit who survived, and 6% for children not requiring admission to the intensive care unit. The authors conclude that the DD variant of the gene for angiotensin-converting enzyme is associated with increased severity of illness in children with meningococcal disease.

    To assess the reproducibility of blind protected bronchoalveolar lavage in the diagnosis of ventilator-associated pneumonia, Gauvin and coworkers (48) did two blind lavages at a two-hour interval in 30 mechanically ventilated children (age, 52 months). Bacterial growth was present in 43% of the 60 lavages. Reproducibility for the presence of bacteria on quantitative cultures was excellent: concordance 93% and {kappa} 0.86. Concordance was 86% for the type of bacteria and 79% for the number of bacteria. Reproducibility for the presence of neutrophils containing bacteria was perfect (concordance 100%, 1.0). One child developed a pneumothorax, and one child experienced a significant increase in intracranial pressure; complications were otherwise benign and transitory. The authors conclude that blind protected bronchoalveolar lavage is a feasible and reproducible test in mechanically ventilated children.

    Pulmonary hypertension.

    In a model of neonatal pulmonary hypertension in piglets, Shekerdemian and coworkers (49) studied the effect of intravenous sildenafil, a phosphodiesterase-5 inhibitor. Instilling human meconium into the trachea of piglets produced a 70% increase in pulmonary vascular resistance and a 100% increase in oxygenation index. Within one hour of commencing the infusion of sildenafil, pulmonary vascular resistance was reversed completely as compared with a 40% decrease in resistance after treatment with inhaled nitric oxide for two hours. Sildenafil also increased cardiac output by 30% without an adverse effect on oxygenation. The authors conclude that intravenous sildenafil is a selective and highly effective pulmonary vasodilator in piglets that have neonatal pulmonary hypertension.

    The development of pulmonary hypertension in newborn rats exposed to 60% oxygen for 14 days is mediated by endothelin-1. Jankov and coworkers (50) assessed whether activation of the receptor for thromboxane A₂ is involved in the development of pulmonary hypertension in this model. Newborn rats were exposed to 60% oxygen or air for 14 days and received daily injections of either a competitive antagonist of the thromboxane A₂ receptor, L670596, or an inhibitor of cyclooxygenase-2, DFU. The antagonist of thromboxane A₂ prevented the development of right-ventricular hypertrophy and smooth muscle hypertrophy in small pulmonary vessels in the rats exposed to hyperoxia; the inhibitor of cyclooxygenase-2 did not prevent these developments. The antagonist of the thromboxane A2 receptor decreased the content of endothelin-1 in the lungs of the hyperoxic rats. The level of 8-isoprostane, a product of lipid peroxidation, was elevated in both groups exposed to hypercapnia as compared with control animals exposed to air. The authors conclude that upregulation of endothelin-1 and the development of pulmonary hypertension in newborn rats exposed to 60% oxygen for 14 days are mediated by activation of the thromboxane A₂ receptor.

    Interstitial lung disease.

    Canakis and coworkers (51) described a new clinical entity, pulmonary interstitial glycogenosis, in seven infants. Within the first month of birth, the infants presented with tachypnea, hypoxemia, diffuse interstitial infiltrates, and radiologic hyperinflation. Lung biopsies revealed expansion of the interstitium by spindle-shaped cells containing material consistent with glycogen and positive for vimentin. Electron microscopy revealed primitive interstitial mesenchymal cells with few cytoplasmic organelles and abundant monoparticulate glycogen. Five cases were treated with pulse glucocorticoids, and hydroxychloroquine was added in one case. One infant died, and the other six have a favorable outcome. Three cases followed for at least six years have resolved clinically and have shown radiographic improvement. The authors conclude that pulmonary interstitial glycogenosis is a new developmental disorder that needs to be differentiated from other forms of interstitial lung disease in neonates. An editorial commentary by Fan and Langston (52) accompanies this article.

    Gastroesophageal reflux.

    Children with gastroesophageal reflux suffer from recurrent pulmonary infections. To determine whether reflux-induced lung disease is associated with alterations in surfactant protein, Griese and coworkers (53) did bronchoalveolar lavage in 20 children with gastroesophageal reflux disease and 20 control children without respiratory disease (mean age, 5 years). Compared with control group, the children with reflux had lower surfactant protein A, 362 versus 867 ng/ml, and lower surfactant protein D, 174 versus 518 ng/ml. The more active, higher molecular weight oligomers of surfactant protein A and D were decreased, and the smaller sized forms of surfactant protein D were increased. The authors conclude that children with gastroesophageal reflux disease have reduced amounts of surfactant protein A and surfactant protein D, and the surfactant protein oligomers have a disorganized structure.

    SURFACTANT BIOLOGY AND DISORDERS

    Pathophysiology

    To identify the precise sequence of events that produce endotoxin-induced lung injury, Davidson and coworkers (54) infused endotoxin (Salmonella abortus equi) intravenously into spontaneously breathing rats. The animals developed an early marked fall in arterial PO₂ and a progressive deterioration in airway resistance, tissue resistance, and lung elastance; these changes occurred despite a 1.7-fold increase in minute ventilation and fivefold increase in the number of sighs. The changes occurred before changes in alveolar neutrophils, macrophages, albumin flux, or edema; the latter changes were increased appreciably only at 8.5 hours. The increase in elastance preceded the increase in resistance, indicating that the change in elastance arose within the lung tissue rather than reflecting a fall in lung volume. Despite a dramatic increase in the synthesis and turnover of ³H-disaturated phosphatidylcholine, the subcellular and alveolar content of surfactant protein A, surfactant protein B, cholesterol, disaturated phospholipids, and phospholipid classes remained normal; the increased turnover in surfactant disaturated phospholipid was attributed to the increase in the number of sighs. The authors conclude that the initial respiratory failure caused by endotoxin is the result of ventilation¨Cperfusion mismatch and not alveolar edema per se and that endotoxin has effects on lung elastance and resistance that are independent of surfactant composition.

    Mutations in the gene for surfactant protein C (SFTPC) are associated with familial interstitial pneumonitis. In a kindred of 97 members that included 11 adults and 3 children with pulmonary fibrosis, Thomas and coworkers (55) used a candidate gene approach. A heterozygous exon 5 + 128 T"->" A transversion of the gene for surfactant protein C was found (the abnormality may hinder processing of the precursor protein for surfactant protein C). Immunostaining of lung tissue revealed aberrant subcellular localization of the precursor protein. Electron microscopy revealed atypical alveolar type II cells, with numerous abnormal lamellar bodies. The authors conclude that a large kindred of familial pulmonary fibrosis displayed a mutation in the gene for surfactant protein C and that damage to type II cells may underlie the pulmonary fibrosis associated with this mutation. An editorial commentary by Whitsett (56) accompanies this article.

    Deficiency

    It has not been possible to quantify surfactant apoprotein C by immunologic methods because of its hydrophobic nature. Schmidt and coworkers (57) assessed the usefulness of an ELISA (enzyme-linked immunosorbent assay) method based on a recently developed polyclonal antibody raised against recombinant human surfactant apoprotein C in rabbits. The method was able to detect surfactant apoprotein C in samples from humans, rabbits, pigs, and cows. Measurements did not cross-react with human surfactant apoprotein A or surfactant apoprotein B. The mean value of surfactant apoprotein C was 580 ng per ml in bronchoalveolar samples from healthy subjects, and 287 ng per ml in samples from patients with ARDS. The detection limit ranged below 3 ng per ml, and the coefficient of variation was 3.5% within an assay and 5.3% between assays. The authors conclude that an ELISA technique permits the quantification of surfactant apoprotein C in bronchoalveolar lavage with high specificity, sensitivity, and reproducibility.

    Treatment

    Recent studies have suggested that certain polymers, such as polyethylene glycol, improve the function of surfactant. In a model of acute lung injury in adult rabbits induced by lung lavage and mechanical ventilation, Campbell and coworkers (58) assessed the effect of adding polyethylene glycol to an exogenous surfactant preparation. Compared with animals treated with surfactant alone, the animals treated with the combination of surfactant and polyethylene glycol had a lower PO₂, higher PCO₂, and higher peak inspiratory pressures at three hours after treatment. Lavage samples revealed that the animals receiving polyethylene glycol had smaller pool sizes of total and large aggregate surfactant. The authors conclude that polyethylene glycol hindered rather than helped the response to exogenous surfactant in a rabbit model of acute lung injury.

    CYSTIC FIBROSIS

    Genetics

    To determine the incidence of mutations of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene in children with intermediate levels of sweat chloride, Lebecque and coworkers (59) reviewed 2,349 consecutive first sweat tests. An intermediate level of chloride, 30 to 60 mM, was found in 98 subjects (4.2%); 43 of these children could be traced. A total of 24 putative CFTR mutations were found. Ten children, with mean age 8.9 years, who harbored one mutation on both CFTR genes were investigated in detail. Seven of the children had clinical features suggestive of CF. Sweat chlo

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