Pediatrics, Surfactant, and Cystic Fibrosis in AJRCCM 2002

http://www.100md.com 《美国呼吸和危急护理医学》2003年第3期

     Division of Pulmonary and Critical Care Medicine, Loyola University of Chicago Stritch School of Medicine and Hines Veterans Affairs Hospital, Hines, Illinois0o, http://www.100md.com

    CONTENTS0o, http://www.100md.com

    Pediatrics (84)0o, http://www.100md.com

    Pulmonary Function Testing and Diagnostic Techniques (5)0o, http://www.100md.com

    Normative Values (1)0o, http://www.100md.com

    Exhaled Nitric Oxide (1)0o, http://www.100md.com

    Respiratory Muscles and Mechanics (2)0o, http://www.100md.com

    Lung Water (1)0o, http://www.100md.com

    Mechanical Ventilation (3)0o, http://www.100md.com

    Respiratory Syncytial Virus Bronchiolitis (2)0o, http://www.100md.com

    Active Infection (2)0o, http://www.100md.com

    Sleep and Control of Breathing (8)0o, http://www.100md.com

    Pediatric Asthma (17)0o, http://www.100md.com

    Genetics (2)0o, http://www.100md.com

    Epidemiology (7)0o, http://www.100md.com

    Risk Factors: Air Pollution (3)0o, http://www.100md.com

    Risk Factors: Aeroallergens (1)0o, http://www.100md.com

    Airway Inflammation (2)

    Treatment (2)ua9, 百拇医药

    Other Pediatric Issues (18)ua9, 百拇医药

    Air Pollution (1)ua9, 百拇医药

    Passive Smoking (3)ua9, 百拇医药

    Lung Development (2)ua9, 百拇医药

    Bronchopulmonary Dysplasia (2)ua9, 百拇医药

    Congenital Diaphragmatic Hernia (2)ua9, 百拇医药

    Infections (3)ua9, 百拇医药

    Pulmonary Hypertension (2)ua9, 百拇医药

    Interstitial Lung Disease (2)ua9, 百拇医药

    Gastroesophageal Reflux (1)ua9, 百拇医药

    Surfactant Biology and Disorders (5)ua9, 百拇医药

    Pathophysiology (3)ua9, 百拇医药

    Deficiency (1)ua9, 百拇医药

    Treatment (1)ua9, 百拇医药

    Cystic Fibrosis (26)ua9, 百拇医药

    Genetics (1)ua9, 百拇医药

    Lung Inflammation (5)ua9, 百拇医药

    Microbiology (5)ua9, 百拇医药

    Pathophysiology and Exercise Performance (9)ua9, 百拇医药

    Bone Demineralization and Metabolic Disorders (2)

    Treatment (4)@:, http://www.100md.com

    Mucolytic Agents (1)@:, http://www.100md.com

    Lung Transplantation (3)@:, http://www.100md.com

    PEDIATRICS@:, http://www.100md.com

    Pulmonary Function Testing and Diagnostic Techniques@:, http://www.100md.com

    Normative values.@:, http://www.100md.com

    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.\, 百拇医药

    In an occasional essay, Godfrey (2) discussed the ups and downs of nitric oxide in chesty children.\, 百拇医药

    Respiratory muscles and mechanics.\, 百拇医药

    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.81, 百拇医药

    Lung water.81, 百拇医药

    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 Ventilationa$)^.[, http://www.100md.com

    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.;3[w\, http://www.100md.com

    Respiratory Syncytial Virus Bronchiolitis

    Active infection.zn[99, http://www.100md.com

    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.zn[99, http://www.100md.com

    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|{w--48, http://www.100md.com

    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–area 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–hypopnea 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.d[&e%#a, 百拇医药

    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–hypopnea 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.[s[c4pm, 百拇医药

    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.xs^1j, 百拇医药

    Pediatric Asthmaxs^1j, 百拇医药

    Genetics.xs^1j, 百拇医药

    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.61z@f, 百拇医药

    Epidemiology.61z@f, 百拇医药

    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_25–75; 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.54osvl, 百拇医药

    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.^kn-jp%, 百拇医药

    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–response 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.11x*, 百拇医药

    Risk factors: air pollution.11x*, 百拇医药

    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_25–75, -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.t{h+iun, 百拇医药

    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.w):+0k, 百拇医药

    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.w):+0k, 百拇医药

    Airway inflammation.[qk.{y, 百拇医药

    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.!jqz, 百拇医药

    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.&vy, 百拇医药

    Other Pediatric Issues&vy, 百拇医药

    Air pollution.&vy, 百拇医药

    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.2]$q, 百拇医药

    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.2]$q, 百拇医药

    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.*'!z, http://www.100md.com

    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.1h/c+g!, 百拇医药

    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 2–6 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.6k, 百拇医药

    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.6k, 百拇医药

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

    Infections.6, http://www.100md.com

    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.k'\:, 百拇医药

    Pulmonary hypertension.k'\:, 百拇医药

    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.*c)l2}(, http://www.100md.com

    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.2f..$o, 百拇医药

    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.2f..$o, 百拇医药

    SURFACTANT BIOLOGY AND DISORDERS

    Pathophysiology;v\y$, http://www.100md.com

    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–perfusion 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.)62t.nu, 百拇医药

    Deficiency)62t.nu, 百拇医药

    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]oq@|, 百拇医药

    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.]oq@|, 百拇医药

    CYSTIC FIBROSIS]oq@|, 百拇医药

    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 chloride was higher in these children than in subjects without the mutation (39 versus 35 mM), and five had an abnormal nasal potential difference. The authors conclude that 23% of children displaying an intermediate level of sweat chloride carry a putative mutation on both CFTR genes.'j^z, 百拇医药

    Lung Inflammation'j^z, 百拇医药

    In 22 children with CF (aged 7 to 44 months), Dakin and coworkers (60) assessed the interrelationship between inflammation, infection, and pulmonary function. The presence of pathogens in the lower airways was associated with a prior respiratory admission (relative risk, 3.60), a history of asthma (relative risk, 1.75), and wheeze (relative risk, 1.88). Lower respiratory pathogens were found in 14 of the 22 children, and the concentration exceeded 10⁵ colony forming units per ml in eight children. The level of pathogens explained 78% of the variance in percent neutrophils and 34% of the variance in level of interleukin-8. The level of pathogens correlated with specific respiratory system compliance (r = -0.49) and the ratio of functional residual capacity to total lung capacity (r = 0.49). The authors conclude that the presence of pathogens in the lower airways was associated with the level of inflammation, respiratory compliance, and gas trapping. An editorial commentary by Berger (61) accompanies this article.

    To determine the role of endotoxin in airway inflammation in CF, Muhlebach and Noah (62) did bronchoalveolar lavage in 55 patients with CF and 56 patients without CF (age, 0.04 to 13.3 years). Infection, defined as a bacterial count above 50,000 colony forming units per ml, was present in 49% of the patients with CF and in 45% of the patients without CF. The level of endotoxin was equivalent in the patients with and without CF, irrespective of whether they were infected (75 versus 51 EU per ml) or uninfected (6 versus 11 EU per ml). The level of endotoxin activity was correlated with the number of Gram-negative organisms in both groups. Interleukin-8 and neutrophils were correlated with the level of endotoxin in both groups, although the slope was shifted to a higher level of inflammation in the patients with CF. The authors conclude that the inflammatory response in patients with CF is not explained by higher levels of endotoxin independently of the effect of infection. An editorial commentary by Berger (61) accompanies this article.

    Because patients with CF appear to have decreased levels of interleukin-10 in their airways, Chmiel and coworkers (63) investigated the role of interleukin-10 in the inflammatory response to infection with Pseudomonas aeruginosa. After transient challenge with P. aeruginosa, both wild-type mice and interleukin-10 knockout mice cleared the infection within 6 days. The interleukin-10 knockout mice had higher levels of neutrophils and proinflammatory cytokines in bronchoalveolar fluid. The interleukin-10 knockout mice failed to regenerate the inhibitor of nuclear factor-{kappa} B activation once degraded, and the mice subsequently had prolonged activation of nuclear factor-{kappa} B. The authors conclude that deficiency of interleukin-10 contributes to prolongation of the inflammatory response to an acute challenge with P. aeruginosa in mice.{w--48, http://www.100md.com

    Aldallal and coworkers (64) determined whether inflammatory gene expression is altered in airway epithelial cells from patients with CF. The release of interleukin-8 in response to several inflammatory stimuli was much greater in CF epithelial cell lines than in control cell lines that contained the CFTR. The level of interleukin-8 became moderately elevated after infection with P. aeruginosa. In CF cells that released a high level of interleukin-8, the use of an adenoviral vector to cause transient expression of the CF transmembrane conductance regulator did not alter the constitutive or inducible levels of interleukin-8 or intercellular adhesion molecule-1. The authors conclude that some CF airway epithelial cells display increased expression of intercellular adhesion molecule-1 and interleukin-8 but that many cells do not exhibit dysregulation of these inflammatory genes.

    Microbiology|%m0, http://www.100md.com

    Cross-infection by P. aeruginosa between unrelated patients with CF is believed to be uncommon. Prompted by the finding of a genotypically identical strain of P. aeruginosa in five unrelated children who had CF and had died from severe lung disease, Armstrong and coworkers (65) determined the distribution of the clonal strain within their patient population using pulsed-field gel electrophoresis and random amplified polymorphic DNA assays. Over a four-month period, 152 patients provided sputum for culture. P. aeruginosa was detected in 118 patients (78%). The genotyping techniques were concordant, showing that 65 of 118 infected patients (55%) carried an indistinguishable or closely related strain. Patients with the clonal strain were more likely to have required admission to hospital for a respiratory exacerbation over the preceding 12 months than were patients with unrelated isolates. The authors conclude that molecular typing techniques made it possible to demonstrate extensive spread of a single clonal strain of P. aeruginosa in a large CF clinic. An editorial commentary by Ramsey (66) accompanies this article.

    To determine the frequency of patient-to-patient spread of P. aeruginosa, Speert and coworkers (67) did genetic fingerprinting on isolates collected from 174 patients over a 20-year span. A total of 157 genetic types of P. aeruginosa were identified, and 123 were unique to individual patients. A total of 34 types were shared by more than one patient; epidemiologic evidence linked these individuals only in the cases of 10 sibships and in one pair of unrelated patients. The authors conclude that the risk of patients with CF acquiring P. aeruginosa from other patients is extremely low and appears to require prolonged close contact as occurs between siblings. An editorial commentary by Ramsey (66) accompanies this article.5, 百拇医药

    Allergic bronchopulmonary aspergillosis can cause irreversible damage in patients with CF. To assess the reliability of intracutaneous testing with recombinant Aspergillus fumigatus in the diagnosis of allergic bronchopulmonary aspergillosis, Nikolaizik and coworkers (68) studied 50 patients with CF (mean age 22 years). Twelve patients had allergic bronchopulmonary aspergillosis, and all of these patients reacted to at least one of the two A. fumigatus allergens, rAsp f4 or rAsp f6, at a concentration of 10^-2 µg/ml. The tests were negative or only marginally positive in 21 patients who displayed allergy to A. fumigatus but who did not have allergic bronchopulmonary aspergillosis. The tests were completely negative in 17 patients with CF who were not sensitized to A. fumigatus. The authors conclude that intracutaneous tests with two recombinant A. fumigatus allergens are specific markers for allergic bronchopulmonary aspergillosis.

    The Gram-negative bacterium Stenotrophomonas maltophilia (formerly Pseudomonas and Xanthomonas maltophilia) has been cultured with increasing frequency in patients with CF. To determine the clinical characteristics of patients who acquire S. maltophilia and its effect on survival, Goss and coworkers (69) analyzed data on all patients who were included in the Cystic Fibrosis Foundation Registry between 1991 and 1997. The sample was confined to patients who were older than 6 years of age and who had been negative for S. maltophilia in the first year of enrollment. Data on a total of 19,255 patients followed for a median of 3 years were available for analysis. Of these, 1,673 (8.7%) had at least one sputum positive for S. maltophilia. Compared with sputum-negative patients, the patients with a positive sputum culture had a lower FEV₁, were older, were more likely to be female, had more pulmonary exacerbations, had more clinic visits, and had more hospitalizations. After controlling for confounding variables, detection of S. maltophilia was not associated with worse survival. The authors conclude that patients with CF who acquire S. maltophilia have more advanced disease but that detection of the organism does not independently influence survival.

    Pathophysiology and Exercise Performance[s[c4pm, 百拇医药

    Genetic mutations that disrupt the CFTR protein are divided into five classes. To examine the relationship between genotype with fitness and nutrition in children, Selvadurai and coworkers (70) studied 97 children with both CF and at least one copy of the {Delta}[s[c4pm, 百拇医药

    F508 mutation. Peak aerobic capacity was lower in children with defective CFTR production (class I; 29 ml per kg per minute) and defective CFTR processing (class II; 32 ml per kg per minute) than in children with defective regulation of CFTR (class III; 44 ml per kg per minute). Peak anaerobic power was higher in children with mutation inducing decreased CFTR conduction (class IV; 11.4 watts per kg) or CFTR messenger RNA (class V; 11.6 watts per kg) than in children with class I (9.7 watts per kg), class II (9.8 watts per kg), or class III (10.5 watts per kg) mutations. Lung function did not differ among the groups. The authors conclude that the class of the second CFTR mutation is related to aerobic and anaerobic fitness in patients with CF who are heterogeneous for the {Delta}

    F508 mutation.xs^1j, 百拇医药

    The exhaled concentration of nitric oxide is used to monitor inflammatory lung disease. Although the plateau concentration has been used, it requires a constant flow rate during exhalation. Shin and coworkers (71) examined the ability of a number of flow-independent variables to discriminate between nine children with CF and nine healthy children (ages, 10 to 14 years). The diffusing capacity of nitric oxide in the airways was higher in the patients than in the control subjects: 17.6 versus 4.8 pl second^-1 ppb^-1. Compared with the control subjects, the patients had a lower steady-state alveolar concentration of nitric oxide, 1.96 versus 4.63 ppb, and a lower mean tissue concentration of nitric oxide in the airways, 38 versus 198 ppb. The plateau concentration of exhaled nitric oxide did not differ between the groups. The authors concluded that the flow-independent variables derived from exhaled nitric oxide discriminate between children with CF and healthy subjects.

    Gaston and coworkers (72) determined whether bacteria that colonize the airways of patients with CF alter the balance between oxidized and reduced forms of nitrogen. The airway concentration of ammonium was higher in 13 children with stable CF who were colonized with P. aeruginosa than in 13 children with neurogenic respiratory failure: 1.6 versus 0.46 mM. Antimicrobial therapy produced a 27% decrease in ammonium concentration in the sputum. Nitric oxide reductase was present in strains of P. aeruginosa, which produced ammonium and consumed nitric oxide. The consumption of nitric oxide was inhibited by antimicrobial therapy ex vivo. The authors conclude that treating children with CF whose airways are colonized with P. aeruginosa causes a decrease in the concentration of ammonium in the airway.61z@f, 百拇医药

    S-nitrosoglutathione is a naturally occurring constituent of airway lining fluid that enhances ciliary motility, relaxes smooth muscle, inhibits amiloride-sensitive transport of sodium in the airway epithelium, and prevents pathogen replication. Because levels of S-nitrosoglutathione are low in the airways of patients with CF, Snyder and coworkers (73) studied its effect on gas exchange in a double-blind study in 20 patients with CF. Aerosolized S-nitrosoglutathione produced an increase in oxygen saturation over a 30-minute period. The breakdown product of S-nitrosoglutathione, nitric oxide, also rose in expired air. There were no adverse effects. The authors conclude that aerosolized S-nitrosoglutathione increases oxygen saturation in patients with CF and is well tolerated.

    To determine the relationship between pulmonary function and radiographic abnormalities with airway inflammation and fibrosis, Hamutcu and coworkers (74) studied 21 patients with CF who had undergone lung transplantation. FEV₁ was 26% of predicted. Residual volume was 342% of predicted, and PO₂ was 64 mm Hg; 24% had a PCO₂ above 50 mm Hg. The density of small airways (less than 2 mm per cm²) decreased with increasing age. The proportion of small airways less than 0.35 mm in diameter was lower in hypercapnic patients than in normocapnic patients: 26% versus 37%. The authors conclude that airway pathology in patients with CF is correlated with age and hypercapnia.^istrx], http://www.100md.com

    To determine the effect of a low FEV₁ on pulmonary mechanics in children and adolescents with CF, Hart and coworkers (75) studied 32 children with CF. The mean age was 14 years, and FEV₁ ranged from 12 to 49% of the predicted normal value. FEV₁ was correlated with arterial PO₂ (r = 0.76), arterial PCO₂ (r = -0.70), ratio of respiratory frequency to tidal volume (r = -0.41), dynamic lung compliance (r = 0.64), total work of breathing (r = -0.52), and elastic work of breathing (r = -0.60). FEV₁ was not correlated with sniff esophageal pressure, minute ventilation, total pulmonary resistance, intrinsic positive end-expiratory pressure, or resistive work of breathing. The authors conclude that a decline in FEV₁ in patients with CF is accompanied by an increase in elastic work of breathing, total work of breathing, rapid shallow breathing, and impaired gas exchange.

    To quantify the spectrum of airway disease in clinically stable patients with CF, Marostica and coworkers (76) studied 36 children who were able to perform two or three technically acceptable spirometric maneuvers. Compared with normative data for healthy children, the children with CF had abnormalities, expressed as Z scores (number of SDs that a value deviated from the predicted mean value): FEV₁, -1.23; FVC, -0.75; FEV₁/FVC, -0.87; and FEF_25–75, -0.74. The Brasfield radiologic score was correlated with the Z scores for FEV₁ (r² = 0.24) and FVC (r² = 0.26). Compared with heterozygous children, children who were homozygous for the {Delta}54osvl, 百拇医药

    F508 mutation had lower Z scores for FEV₁ (-1.38 versus 0.21) and FVC (-1.21 versus 0.47). Of 14 children who underwent full spirometry during infancy, 10 had Z scores for FEF_25–75 that were more negative than -2 on both evaluations. The authors conclude that spirometry can be used to evaluate lung function in preschool children with CF and detect airway obstruction.

    To characterize pulmonary function in preschool children with CF, Beydon and coworkers (77) studied 39 children with CF (age 3 to 8.2 years) and 79 healthy children (3 to 7.9 years). Compared with the healthy children, the children with CF had a 31% higher resistance on expiration (measured by the interrupter technique) and a 21% lower specific conductance on expiration. Children with CF who had a history of respiratory symptoms had a higher functional residual capacity (by helium dilution technique) and lower expiratory conductance. The response to albuterol did not differ between the children with CF and the control children. The authors conclude that tests of pulmonary function that do not require patient cooperation can reveal airway obstruction and hyperinflation in preschool children with CF.^kn-jp%, 百拇医药

    In 47 newly diagnosed infants with CF, Ranganathan and coworkers (78) compared the ability of variables derived from the tidal and raised volume rapid thoracoabdominal compression techniques in detecting impaired airway function. Measurements were compared against a reference group of 187 healthy infants. FEV_0.5 from the raised volume technique of rapid thoracoabdominal compression identified impaired airway function in 31% of infants with CF. FEV_0.5 was decreased by 42.5% in 35 infants with a previous lower respiratory illness and by 41.0% in 12 infants without a previous lower respiratory illness. Only one infant with CF had a maximal flow at functional residual capacity that was below the normal range. The authors conclude that FEV_0.5 is diminished in infants with CF more than any other variable and that the raised volume technique of rapid thoracoabdominal compression identified impaired airway function more frequently than did the tidal technique.

    Bone Demineralization and Metabolic Disorders11x*, 百拇医药

    To determine the interrelationship between severity of lung disease and protein catabolism, Ionescu and coworkers (79) studied 40 adults with stable CF (age, 23 years) and 22 age-matched control subjects. A marker of protein breakdown, urinary pseudouridine, was higher in the patients than in the healthy subjects: 25.1 versus 14.0 mmol per mmol creatinine. Pseudouridine was also correlated with FEV₁ (r = -0.53). A marker of connective tissue breakdown, crossed-linked N-telopeptides of type I collagen, was higher in the patients than in the healthy subjects: 2.36 versus 0.69 mmol per mmol per kg. N-telopeptides were also correlated with FEV₁ (r = -0.43). The patients had higher levels of interleukin-6 and tumor necrosis factor-{alpha} and their soluble receptors. The authors conclude that stable patients with CF are catabolic and that breakdown of protein and connective tissue is proportional to the severity of underlying lung disease.

    Patients with CF have a low bone mineral density, but the mechanism is not known. To investigate this issue, Elkin and coworkers (80) did bone biopsies after tetracycline labeling in 20 patients with CF (average age, 30 years). Compared with 18 healthy subjects, the patients had a lower cancellous bone area, a lower rate of bone formation at the tissue level, a smaller wall width (amount of bone formed within individual remodeling units), a lower rate of mineral apposition, and a lower mineralizing perimeter. Resorption cavities were smaller in the patients than in the control subjects, and osteoclasts were rarely seen. One patient had osteomalacia. The authors conclude that the low volume of cancellous bone in adult patients with CF results from low bone turnover and reduced bone formation at a tissue and cellular level rather than from an increase in active bone resorption.t{h+iun, 百拇医药

    Treatmentt{h+iun, 百拇医药

    Mucolytic agents.t{h+iun, 百拇医药

    Because recombinant human DNase may liberate cationic mediators bound to DNA in the airways, Suri and coworkers (81) did a randomized crossover trial in 48 children (aged, 5 to 18 years) with CF. The children were allocated to DNase 2.5 mg daily, DNase 2.5 mg every alternate day, and 7% hypertonic saline twice daily for 12 weeks. Daily DNase and hypertonic saline caused no changes in sputum levels of total interleukin-8, free interleukin-8, myeloperoxidase, eosinophil cationic protein, and neutrophil elastase activity. Alternate-day DNase caused an increase in free interleukin-8. Change in neutrophil elastase activity was correlated with the change in FEV₁ (r = -0.25). The authors concluded that daily treatment with recombinant human DNase or hypertonic saline does not increase airway inflammation.

    Lung transplantation.w):+0k, 百拇医药

    The breathing reserve index is the minute ventilation at the lactate threshold during incremental exercise divided by maximal voluntary ventilation. To determine whether this index would predict mortality in patients with CF on a waiting list for lung transplantation, Tantisira and coworkers (82) did exercise testing in 45 consecutive patients with CF as part of their pretransplant assessment. Fifteen patients died. Twenty-one patients were transplanted, and 9 patients were still on the waiting list. In a multivariate model, the relative risk of mortality was 17.52 for the breathing reserve index, 1.29 for resting PCO₂, 0.97 for resting PO₂, and 1.19 for FEV₁. The authors concluded that the breathing reserve index provided the highest point estimate of mortality in patients with CF waiting for lung transplantation.w):+0k, 百拇医药

    Deciding the right time to undertake lung transplantation in patients with CF is difficult, and the criteria used in guiding the decision are controversial. Mayer-Hamblett and coworkers (83) developed a mathematical model for predicting 2-year mortality using data on 14,572 patients in the National Patient Registry of the Cystic Fibrosis Foundation who were 6 years of age or older in 1996. Multivariate logistic regression revealed that age, height, FEV₁, respiratory microbiology, number of hospitalizations for pulmonary exacerbations, and number of course of intravenous antibiotics in the home were significant predictors of 2-year mortality. When compared with the widely used criterion of an FEV₁ of less than 30% of predicted, the mathematical model did not prove superior. The negative predictive value was 98% for the model and 97% for FEV₁. The positive predictive value was 33% for the model and 28% for FEV₁. Both the model and the FEV₁ criterion will result in high rates of premature referral for lung transplantation. The authors conclude that a well-fitting mathematical model based on data from 14,572 patients with CF was not superior to the usual criterion of a FEV₁ of less than 30% predicted in guiding decision on the best time to do lung transplantation. An editorial commentary by Noone and Egan (84) accompanies this article.

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