American Journal of Respiratory and Critical Care Medicine

Pediatrics

  Pulmonary Function Testing and Diagnostic Techniques

    Normative Values (4)

    Thoracoabdominal Compression (3)

    Flow–Volume Loops (3)

    Forced Oscillation (3)

    Exhaled Nitric Oxide (2)

    Respiratory Muscles and Mechanics (2)

    Bronchoscopy (1)

    Aspiration of Milk (1)

  Mechanical Ventilation (9)

  Respiratory Syncytial Virus Bronchiolitis

    Active Infection (2)

    Long-Term Consequences (2)

  Sleep and Control of Breathing (5)

  Pediatric Asthma

    Genetics (2)

    Epidemiology (3)

    Risk Factors: Air Pollution (2)

    Risk Factors: City, Farm, and Home (3)

    Risk Factors: Aeroallergens (2)

    Risk Factors: Tobacco Smoke (2)

    Risk Factors: Parental Asthma (1)

    Airway Inflammation (3)

    Airway Hyperreactivity: Methacholine Challenge (3)

    Airway Hyperreactivity: Exercise Induced (1)

    Airway Hyperreactivity: Cold, Dry Air (1)

    Clinical Issues: Dyspnea (1)

    Clinical Issues: Quality of Life (1)

    Treatment (4)

  Other Pediatric Issues

    Air Pollution (1)

    Crohn's Disease (1)

    Lung Development (1)

Surfactant Biology and Disorders

  Pathophysiology (2)

  Deficiency (5)

  Treatment (5)

Cystic Fibrosis

  Genetics (3)

  Lung Inflammation (3)

  Exercise Performance (1)

  Bone Demineralization and Metabolic Disorders (4)

  Treatment

    Gene Therapy (2)

    Mucolytic Agents (2)

    Bronchodilator Therapy (1)

    Vitamin Supplements (1)

    Antibiotics (2)

    Lung Transplantation (1)

References

Pulmonary Function Testing and Diagnostic Techniques
Normative values

To establish reference values for forced expiratory flows and volumes in infants, Jones and coworkers (1) studied 153 healthy infants aged between 3 and 149 weeks. Forced vital capacity (FVC) was correlated with body length; after accounting for length, FVC was also correlated with age. Flow parameters were correlated with length, boys had lower flows than girls, and infants of mothers who smoked had lower flows. The authors conclude that their findings provide reference values and demonstrate that smoke-exposed infants and boys have lower forced expiratory flows.

To determine prediction equations for spirometry in Chinese children and adolescents, Ip and coworkers (2) studied 852 healthy students in Hong Kong aged 7 to 19 years. Prediction equations are presented. Between 1985 and 1995, significant increases in height-corrected FVC and FEV1 (forced expired volume in 1 second) were seen in both boys and girls. In boys, FVC was 9–10% lower than in whites, whereas girls showed little difference. The authors conclude that exogenous factors may significantly influence lung function.

To determine prediction equations for static lung volumes in Chinese children, Ip and coworkers (3) did body plethysmography in 551 subjects in Hong Kong aged 8 to 19 years. Standing height and sitting height were the best predictors of lung volumes. After allowing for height, age contributed to less than 1% of the variance in boys and to 3% in girls.

To determine the relationship between growth in height and growth in lung function, Xuan and coworkers (4) studied 557 children aged 8 to 10 years. Growth in height stopped between 17 and 19 years, but growth in FEV1 was still 200 ml per year in boys and 100 ml per year in girls. The peak growth in height was at age 13 in both boys and girls; growth in FEV1 peaked at the same time in girls and 1 year later in boys. Having wheeze or airway hyperresponsiveness during an earlier evaluation was associated with lower subsequent growth in FEV1, but not with subsequent growth in FVC. The authors conclude that growth in lung function continues after growth in height stops and that growth in FEV1 is decreased in children with airway hyperresponsiveness or recent wheezing.

Thoracoabdominal compression

In 41 infants (age 12.4 months), Platzker and coworkers (5) determined whether the thoracoabdominal compression maneuver would alter the mechanics of the respiratory system. Compression produced decreases in total thoracic compliance and the time constant of the respiratory system, with no change in resistance. Compression produced a greater fall in compliance and a rise in resistance in infants infected with the human immunodeficiency virus. The authors conclude that thoracoabdominal compression decreases thoracic compliance and time constant, and the results emphasize the need to maintain a fixed sequence when measuring pulmonary function in longitudinal studies.

In 17 infants with acute viral bronchiolitis, Modl and coworkers (6) compared two methods of assessing lung function. The end-tidal rapid thoracoabdominal compression technique involves measurement of maximum expiratory flow at functional residual capacity (FRC); the mean coefficient of variation within subjects was 14%. The raised volume rapid thoracoabdominal compression technique involves raising lung volume before the compression, and measuring FEV0.5, FEV0.75, and FEV1.0; the coefficient of variation within subjects was 5%. Albuterol caused an improvement in timed volumes in eight infants, whereas end-tidal maximum expiratory flow did not improve. The authors conclude that the raised volume rapid thoracoabdominal compression technique is more sensitive in detecting changes in airway function.

The raised volume rapid thoracoabdominal compression technique is discussed in a summary statement from an ATS–ERS workshop (7).

Flow–volume loops

In adults, the flow during a forced expiration is less when preceded by a partial rather than full inspiration. To determine the importance of volume history for epidemiologic research in children, O'Connor and coworkers (8) measured maximal forced expiratory flow–volume curves and partial forced expiratory flow–volume curves in 1,834 children aged 10–11 years. The ratio of V30 during a maximal expiratory maneuver and a partial expiratory maneuver was slightly higher in girls than boys (1.26 and 1.18), indicating a greater volume-history effect in girls. The ratio was related to neither a history of asthma nor maternal smoking, in contrast to most other spirometric indices. The authors conclude that measuring the effect of volume history offers no benefit in epidemiologic studies of respiratory disorders in children.

To evaluate the diagnostic value of flow–volume loops in infants or young children with noisy breathing, Filippone and coworkers (9) studied 113 consecutive children (aged 15 months to 4 years). Flexible bronchoscopy was performed to establish a conclusive diagnosis, and the physicians reading flow–volume curves of tidal breathing were blinded to the bronchoscopic findings and vice versa. Three abnormal patterns were seen. Inspiratory fluttering was seen in 44 children (39%), and bronchoscopy in the first 26 of these children always revealed isolated laryngomalacia. Expiratory limb flattening was seen in 41%, and all had an obstruction somewhere between the glottis and mainstem bronchi. A concave expiratory loop, with early expiratory peak flow and low flow at low volume, was seen in 18%, and invariably associated with peripheral obstruction. The authors conclude that flow–volume loops during tidal breathing are helpful in diagnosing the nature of airway obstruction in children with noisy breathing.

Forced expiratory flows by the rapid compression technique are used to assess airway function in infants, but it is not clear whether flow limitation is achieved. Jones and coworkers (10) determined whether the technique of negative expiratory pressure could be adapted to assess flow limitation in infants. In four infants, a negative pressure (−5 cm H2O) applied to the airway during a forced expiration produced increases in flow of less than 5%, which is consistent with flow limitation. The authors conclude that the negative expiratory pressure can be used in infants to detect flow limitation.

Forced oscillation

The forced oscillation method of measuring resistance of the total respiratory system is attractive because it requires only passive cooperation. In 313 children (aged 3 to 16 years) with asthma or nocturnal cough, Delacourt and coworkers (11) assessed the reliability of the method. In 181 children able to perform forced expiratory maneuvers, resistance (normalized for height and weight) was correlated with FEV1 and maximal expiratory flow at 50%. An optimal resistance value, derived from receiver operating characteristic curves, discriminated between FEV1 values of above and below 80% predicted with a sensitivity of 84% and a specificity of 73%. This optimal resistance detected reversibility to bronchodilator with 69% sensitivity and 78% specificity. The authors conclude that the forced oscillation technique provides reliable assessment of bronchial obstruction in asthmatic children older than 3 years.

In 37 healthy infants (aged 7 weeks to 2 years), Hall and coworkers (12) used a forced oscillation technique, superimposing a forcing signal of 0.5 to 21 Hz at a transpulmonary pressure of 20 cm H2O, to measure respiratory impedance. A model containing airway resistance, inertance, and elastance was fitted to the impedance values. Airway and tissue parameters showed a decreasing quadratic relationship with increasing body length. FEV0.5, determined by the raised volume rapid thoracic compression technique, showed an increasing cubic relationship with length.

Because the rapid thoracic compression technique cannot distinguish between changes in airway caliber and changes in airway wall mechanics, Frey and coworkers (13) developed a method for measuring airway wall compliance. Input impedance at frequencies up to 900 Hz was measured with a high-speed interrupter; the frequency at which the first antiresonant frequency occurs is a function of airway wall compliance. Measurements were obtained in 23 asymptomatic infants (aged 36 to 81 weeks) with a history of wheezing and 19 healthy controls. The frequency at which the first antiresonance occurred was lower in infants with wheezing disorders. The authors conclude that abnormalities in airway wall mechanics may be involved in the pathogenesis of wheezing disorders.

Exhaled nitric oxide

To determine the most appropriate flow rate for measuring exhaled nitric oxide in adolescents, Kissoon and coworkers (14) measured exhaled nitric oxide using a single-breath technique at eight flows (range, 2 to 46 ml per second) in 32 healthy adolescents (aged 15 to 18 years). Exhaled nitric oxide increased as flow rate decreased, with strong correlations between exhaled nitric oxide values and flow at the four highest flow rates (r = 0.85 to 0.93). Offline bag and online specimens showed good agreement. Multiple regression revealed that flow, body surface area, age, and FEF25–75 were significant predictors of exhaled nitric oxide. The authors provide normal values for exhaled nitric oxide in adolescents and propose that the ideal flow is between 30 and 50 ml per second.

Measurement of exhaled nitric oxide requires subjects to maintain a constant expiratory flow for several seconds, which many young children are unable to do. To avoid this requirement Baraldi and coworkers (15) developed an approach whereby an operator uses a flow regulator to keep the expiratory flow at 50 ml per second. In 74 children aged 4 to 8 years, 93% could perform the modified approach but only 49% were able to perform the standard approach. In 41 children aged 9 to 16 years, all could perform the modified approach and 96% were able to perform the standard approach. The values of exhaled nitric oxide with the two approaches showed good agreement (r = 0.99). The authors conclude that this modified method makes it easy to measure exhaled nitric oxide in children as young as 4 years.

Respiratory muscles and mechanics

The increase in transdiaphragmatic pressure achieved by transcutaneous stimulation of phrenic nerves has the advantage of being independent of a patient's volition. In 25 newborn infants, Rafferty and coworkers (16) compared two means of delivering a magnetic stimulus to the phrenic nerves. Stimulation of the phrenic nerve roots with a probe placed over the cervical spine produced a transdiaphragmatic pressure of 2.5 cm H2O. With probes over the anterolateral portion of the neck, stimulation produced a transdiaphragmatic pressure of 4.5 cm H2O. The authors conclude that stimulation of the phrenic nerves with anterolateral magnetic stimulation may provide a useful method of assessing diaphragmatic function in newborn infants.

To characterize the mechanical behavior of the lungs and chest wall, Ingimarsson and coworkers (17) measured pressure–volume curves in 17 anesthetized children (aged 3 months to 15 years). Esophageal pressure was the same in the supine and right lateral position (11 cm H2O) at an airway pressure of 30 cm H2O (inspiratory capacity), whereas it was 7 cm H2O in the supine position and almost 0 cm H2O in lateral position at end-expiration. Compliances of the lung and chest wall increased with growth. Elastance of the chest wall was 33% of the elastance of the total respiratory system in the lateral position and 12% in the supine position. The authors conclude that respiratory mechanics in children correlate closely with body size and show important differences between the supine and lateral positions.

Bronchoscopy

In 156 infants and children undergoing fiberoptic bronchoscopy, Nielson and coworkers (18) determined whether topical lidocaine exaggerates laryngomalacia. During playback of video recordings, blinded observers assigned scores for laryngomalacia, based on magnitude of collapse of the arytenoids and folding of the epiglottis. The scores were higher after applying topical lidocaine. In 10 patients suspected of laryngomalacia, the score for laryngomalacia rose after instilling lidocaine but did not change with saline. The authors conclude that the larynx and contiguous structures should be examined before topical anesthesia is applied during fiberoptic bronchoscopy.

Aspiration of milk

Aspiration of milk is a common cause of acute and chronic lung disease in children, but techniques for its diagnosis are unsatisfactory. In a murine model of milk aspiration, Elidemir and coworkers (19) examined lung lavage fluid for two milk proteins, α-lactalbumin and β-lactoglobulin. After single and repeated aspiration, a large number of alveolar macrophages became positive for the proteins. The authors conclude that the immunocytochemical staining of milk proteins within alveolar macrophages is a sensitive and specific test for diagnosing milk aspiration in a murine model.

Mechanical Ventilation

The technique of continuous tracheal gas insufflation has been used in premature infants, but its usefulness in lowering ventilator pressure has not been examined. In 34 preterm infants receiving pressure-control ventilation, Dassieu and coworkers (20) did a randomized trial of the effect of adding or not adding continuous tracheal gas insufflation. At entry, both groups had equivalent alveolar ventilation, as reflected by transcutaneous PCO2 (40–46 mm Hg). Over the first 4 days, peak pressure was 18–35% lower in the infants receiving gas insufflation, with no difference in transcutaneous PCO2 or PO2. The duration of mechanical ventilation was shorter in infants receiving gas insufflation (3.6 and 15.6 days). The authors conclude that the addition of tracheal gas insufflation facilitates the use of lower volume ventilation and shortens the duration of ventilator support.

In 19 infants and children requiring conventional mechanical ventilation, Cannon and coworkers (21) compared tidal volume exhaled at the expiratory valve and displayed on the ventilator screen with tidal volume measured with a pneumotachometer at the endotracheal tube. For 70 infant circuits, displayed tidal volume was poorly correlated with the direct pneumotachographic measurement (r2 = 0.54). Estimated effective tidal volume (which corrects for compliance in the ventilator circuit, PEEP, and peak inspiratory pressure) was also poorly correlated with the direct measurement (r2 = 0.58). For 28 pediatric circuits, closer relationships were noted between the direct measurement and displayed tidal volume (r2 = 0.84) and effective tidal volume (r2 = 0.85). The authors conclude that a significant discrepancy exists between tidal volume displayed on a ventilator and the tidal volume measured at the tip of the endotracheal tube.

To understand the relationship between ventilator management of infant respiratory distress syndrome and the development of neonatal chronic lung disease, Yoder and coworkers (22) performed a randomized comparison of high-frequency oscillatory ventilation and positive-pressure ventilation using low tidal volume in premature baboons. After receiving prenatal glucocorticoids, 18 baboons were delivered 60 days before term, given exogenous surfactant, and placed on mechanical ventilation. From 12 hours through 10 days, baboons ventilated with high frequency oscillation had a higher arterial-to-alveolar PO2 ratio; this group also had better lung mechanics at almost every time point up to 28 days, and lower tracheal values of interleukin-8 and numbers of macrophages/ monocytes at 1 and 4 weeks. Pathologic lesions typical of those found in infants with immature lungs were seen in both groups. Although high-frequency oscillation did not enhance alveolization, the lungs displayed better inflation patterns on morphometry. The authors conclude that early and prolonged use of high-frequency oscillatory ventilation caused improvement in histopathology of neonatal chronic lung disease.

Concerns have been raised that extracorporeal membrane oxygenation (ECMO) might improve short-term survival in neonates with respiratory failure only to cause long-term disability. In infants who had received ECMO or conventional ventilation for respiratory distress, Beardsmore and coworkers (23) compared their lung function at age 1 year. Infants treated with conventional ventilation had lower specific conductance and higher lung volume and than those treated with ECMO. The authors conclude that ECMO did not cause worsening of lung function.

Because hyperoxia is important in the pathophysiology of bronchopulmonary dysplasia, Deng and coworkers (24) determined whether blockade of neutrophil chemokines decreases lung injury in newborn rats exposed to 95% oxygen for 8 days. In alveolar macrophages and alveolar epithelium, hyperoxia produced 10-fold increases in cytokine-induced neutrophil chemoattractant-1 (CINC-1) and macrophage inflammatory protein-1 (MIP-1). On the third and fourth day of hyperoxia, administration of antibodies to the two neutrophil cytokines produced a 90% decrease in neutrophils in bronchoalveolar fluid, and prevented thickening of the alveolar septum. The authors conclude that the neutrophil influx into the lungs of newborn rats exposed to hyperoxia is mediated by cytokine-induced neutrophil chemoattractant-1 and macrophage inflammatory protein-2.

In neonates with an uncuffed endotracheal tube, changing the position of the head may cause the distal orifice to abut against the tracheal wall, causing obstruction. In 11 preterm infants suspected of this problem, Jarreau and coworkers (25) used the acoustic reflection method to measure cross-sectional area. Beyond the tip of the tube, area increased by 49% in the absence of obstruction and it decreased by 38% in the presence of obstruction. The authors conclude that the acoustic reflection method is reliable for detecting obstruction of an endotracheal tube in infants.

With a goal of identifying ventilator-induced overdistension, Neve and coworkers (26) measured dynamic pressure–volume curves during regular constant flow ventilation with a Servo 300 ventilator in 20 ventilated children (aged 2 months to 14 years) and compared them with reference pressure–volume curves obtained with low-flow insufflation. Describing the shape of the curve by fitting the data to a second-order polynomial provided better detection of overdistension than taking the ratio of compliance of the last 20% of the curve to total compliance or by defining the upper inflection point graphically. The authors conclude that the low-flow inflation technique can be used to measure pressure–volume curves in children.

Pulmonary interstitial emphysema was found in 70% of preterm lambs delivered 24 hours after betamethasone compared with 5% of control animals. Willet and coworkers (27) found that the volume-dependent component of elastance, an index of overdistension, was lower in animals with interstitial emphysema. Alveolar architecture was distorted, and parenchymal collagen was decreased by 30% and elastin increased 120% in animals with interstitial emphysema but the alveolar walls were not thinned. The authors conclude that pulmonary interstitial emphysema results in structural abnormalities without overinflation.

Care of the child with a tracheostomy is discussed in an ATS statement (28).

Respiratory Syncytial Virus Bronchiolitis
Active infection

Because infants with respiratory syncytial virus (RSV) bronchiolitis are deficient in surfactant and because surfactant assists in keeping conducting airways patent, Tibby and coworkers (29) did a pilot randomized study of exogenous surfactant in 4-week-old infants receiving mechanical ventilation for RSV bronchiolitis. Static lung compliance and resistance worsened progressively over the first 30 hours in 10 infants receiving placebo, whereas 9 infants who received two doses of Survanta (100 mg/kg) showed rapid improvement in gas exchange. An index of surfactant maturity, the ratio of dipalmitoylphosphatidylcholine (the disaturated phospholipid species) to palmitoyloleoylphosphatidylcholine (the monounsaturated species), was positively correlated with lung compliance and inversely correlated with resistance; this ratio increased over time in the treated group and fell in the placebo group. The authors conclude that surfactant helps maintain airway patency in infants with RSV bronchiolitis and that an outcome trial of its value is warranted.

Schwarze and coworkers (30) determined the mechanism by which infection with RSV induces airway inflammation and hyperresponsiveness. In BALB/c mice, treatment with an antibody to interleukin-5 during RSV infection caused a decrease in lung eosinophilia and airway hyperresponsiveness during subsequent allergen exposure. Mice genetically deficient in interleukin-5 or -4 developed less lung eosinophilia and airway hyperresponsiveness after RSV infection and allergen exposure. Administration of interleukin-5 during RSV infection restored the responses to allergen in both sets of mice. Administration of interleukin-5 during sensitization, however, restored the responses only in mice deficient in interleukin-4, and not in those deficient in interleukin-5. In mice deficient in interferon-gamma, RSV enhanced the eosinophilia and airway hyperresponsiveness resulting from allergen. The authors conclude that both interleukin-5 and -4 are critical in mediating the effects of RSV infection on allergic airway sensitization, resulting in the development of lung eosinophilia and airway hyperresponsiveness.

Long-term consequences

In an earlier report, a group of 47 children hospitalized for RSV bronchiolitis in infancy had been shown to have an increased risk of bronchial obstructive disease and allergic sensitization up to 3 years of age. Sigurs and coworkers (31) did a follow-up study of these 47 children plus 93 matched controls at age 7.5 years. The cumulative prevalence of asthma was 30% in the RSV group and 3% in the control group. Multivariate analysis showed that the children who developed RSV bronchiolitis were 12.7 times more likely to have asthma and 2.4 times more likely to have allergic sensitization. The authors conclude that the data support the theory that RSV influences the mechanisms responsible for the development of asthma and allergy in children.

To determine whether cytokine responses to RSV bronchiolitis are associated with the development of recurrent wheezing, Bont and coworkers (32) studied 50 children during acute hospitalization, while convalescing 3–4 weeks later, and at 1 year. At 1 year, 58% of the children had recurrent wheezing, as documented by their parents in a diary. Interleukin-10 levels were normal during the acute phase, but higher during convalescence in children who developed wheezing during the ensuing year; the number of episodes of wheezing was correlated with the level of interleukin-10 during convalescence (r = 0.42). Wheezing was not correlated with interferon-gamma or interleukin-4. The authors conclude that interleukin-10 predicts the development of recurrent wheezing after RSV bronchiolitis, and that viral-induced responses of the type 2 helper T (Th2) cell can lead to asthmatic symptoms.

Sleep and Control of Breathing

Although configuration of the upper airway changes markedly during the first year of life, collapsibility of the pharynx has not been studied. To address this issue, Isono and coworkers (33) measured static pressure–area relationships of the passive pharynx in nine healthy infants (aged 2 to 12 months) during general anesthesia and paralysis. Maximal velopharyngeal area was related to age (r = 0.84), and velopharyngeal closing pressure decreased progressively with increasing age (r = −0.81). The slope of the pressure–area curves became steeper with age, indicating increased stiffness of the pharyngeal wall. The authors conclude that the anatomic properties of the pharynx in healthy infants become more stable and assist in maintaining a patent airway during development.

Because maternal smoking is a risk factor for the sudden infant death syndrome, Poole and coworkers (34) asked, “Do infants born to mothers who smoke have depressed ventilatory responses to hypoxia?” Smoking status of mothers was confirmed by urinary cotinine, and mother–infant pairs in the smoking group were matched for confounding variables with a nonsmoking group. At age 10 weeks, peripheral chemoreceptor function was studied by the alternating breath test in 40 infants (17 in the smoking group) during nighttime sleep. Responses in 10 variables, including respiratory drive and timing, were similar in the two groups. The authors conclude that maternal smoking does not influence the hypoxic ventilatory response of infants.

In 20 children with sleep apnea and 10 healthy controls, Goh and coworkers (35) found that the distribution of sleep stages in the patients did not differ from the controls. Of obstructive apneas, 55% occurred during rapid eye movement (REM) sleep; apnea index, apnea duration, and desaturation were greater during REM than non-REM sleep. The number of apneas, irrespective of association with REM, more than doubled between the first and final third of the night. The authors conclude that children with sleep apnea have normal sleep architecture, and that apneas occur predominantly during REM sleep and worsen over the course of the night.

Peripheral chemoreceptor function is assessed in infants by measuring the percentage decrease in minute ventilation while inspiring 100% for 30 seconds. In 18 infants, Bouferrache and coworkers (36) compared the standard method, based on the change in mean ventilation, with a new approach, based on calculating the time to the first significant change in ventilation after commencing hyperoxia. The new method yielded greater decreases in minute ventilation and tidal volume than the old approach; reproducibility was also better. The authors conclude that a time-based approach to quantifying the ventilatory response to hyperoxia improves assessment of peripheral chemoreceptor function.

To determine whether passive movement of the feet would increase alveolar ventilation in children with congenital central hypoventilation syndrome, Gozal and Simakajornboon (37) studied six patients during non-REM sleep. The feet were moved at the ankles either manually or with a motor achieving 40–50 strokes per minute. In 74 trials not associated with change in sleep state, motion decreased end-tidal PCO2 from 59 to 41 torr and increased frequency from 10 to 21 breaths per minute. The authors conclude that the improvement in alveolar ventilation may result from activating mechanoreceptor pathways, rather than by respiratory entrainment.

Pediatric Asthma
Genetics

Polymorphisms in the genes for tumor necrosis factor-α (A-308G), interleukin-4 (C-589T), and the high-affinity IgE receptor (E-237G) have been associated with asthma and related phenotypes. (A polymorphism consists of an allele with a frequency in a population of least 1%.) To determine the predictive value of these polymorphisms, Zhu and coworkers (38) studied a high-risk infant population. In 373 infants and 572 parents, DNA was genotyped for each polymorphism. Phenotypic data for atopy and allergic diseases were collected at age 1 year. The prevalence of any phenotype was not different between genotypes of the tumor necrosis factor-α and high-affinity IgE receptor polymorphisms. The interleukin-4-589*T allele was associated with a 4-fold increased risk of probable asthma and homozygotes for that allele had a 2.4-fold increased risk of rhinitis. The authors conclude that the interleukin-4-589*T allele is a risk factor for the development of atopy, asthma, and rhinitis by 1 year of age.

Malerba and coworkers (39) investigated the linkage between 13 DNA markers on chromosome 12 with allergic asthma phenotypes in 116 Italian families (560 individuals). A suggestive linkage for asthma with markers on chromosome 12, centering around marker D12S390, was found. The authors conclude that their data provide further support for the location of asthma susceptibility factors on chromosome 12q.

Epidemiology

To develop an index for predicting the development of asthma among children having wheezing episodes during the first 3 years of life, Castro-Rodriguez and coworkers (40) analyzed data derived from a longitudinal study of 1,246 newborns. A stringent index consisted of frequent wheezing in the first 3 years plus either one major risk factor (parental history of asthma or eczema) or two minor risk factors (eosinophilia, wheezing without colds, or allergic rhinitis). A lax index consisted of any wheezing in the first 3 years plus one major risk factor or two minor risk factors. Children meeting the criteria of the stringent index were 4.3–9.8 times more likely to have active asthma between ages 6 and 13 years than children who did not meet either set of criteria; the risk was 2.6 to 5.5 times increased in children satisfying the criteria of the lax index. Of children not meeting the criteria of the lax index, over 95% remained free of asthma between ages 6 and 13 years. The authors conclude that the likelihood of developing asthma can be predicted with reasonable accuracy.

In investigating gender-specific patterns of lung function in children, Berhane and coworkers (41) analyzed data in a cohort of 2,277 fourth- and seventh-grade children over a 4-year period. A history of asthma was associated with a 4.9% deficit in maximum midexpiratory flow in boys and a 1.9% deficit in girls. When time from diagnosis exceeded 6 years, the deficit in maximum midexpiratory flow became even greater, 7.4% in boys and 9.3% in girls. Lung growth showed little evidence of catching up at older ages. The authors conclude that deficits of lung function in asthmatic children persist into adulthood.

A cohort of 378 asthmatic children was studied from ages 7 to 35 years at 7-year intervals. Wolfe and coworkers (42) found that the odds of more severe asthma in later life were increased 1.66-fold by the presence of eczema in childhood, 1.39-fold by hay fever, and 2.25-fold by a positive skin test. The odds of eczema and hay fever in later life increased with the severity of asthma in childhood. The authors conclude that increasingly severe asthma, as well as the presence of hay fever, eczema, or skin reactivity, indicates an increased risk of more severe asthma in adult years.

Risk factors: air pollution

To determine the effect of air pollution on respiratory symptoms, Heinrich and coworkers (43) studied children aged 5 to 14 years living in three areas of East Germany shortly after reunification; 2,470 children were studied in 1992–1993, and 2,814 were studied in 1995–1996. Over this 3-year period, total suspended particulates decreased from 44–65 to 36–44 μg/m3. The prevalence of bronchitis decreased by 45%, otitis media decreased by 17%, frequent colds decreased by 26%, and febrile infections decreased by 24%. The authors conclude that a reduction in air pollution decreased the prevalence of nonasthmatic respiratory symptoms.

To determine whether subgroups of asthmatic children are more susceptible to the effects of ozone, Mortimer and coworkers (44) analyzed data from a cohort of 846 inner-city asthmatic children (ages 4 to 9 years). Compared with full-term infants of normal birth weight, children born more that 3 weeks premature or weighing less that 5.5 pounds had a six times greater decline in morning PEFR and a 30% higher incidence of morning symptoms than children born at term with normal birth weight. Among children born premature with low birth weight, greater declines in peak expiratory flow rate (PEFR) were seen among those using steroids or no medications, as opposed to β-agonists, cromolyn, or xanthines. The authors conclude that asthmatic children who were born prematurely or underweight have greatest responses to ozone.

Risk factors: city, farm, and home

To determine the relative effects of race, poverty, and urban residence on the prevalence of childhood asthma, Aligne and coworkers (45) analyzed data on 17,110 children (aged 0 to 17 years). Black children had higher rates of asthma than white children, but after controlling for multiple factors, race was no longer a significant correlate. Compared with nonurban white children, urban black children had an increased risk of asthma (odds ratio [OR] 1.45), urban white children also had an increased risk (OR 1.22), whereas nonurban white and black children did not (OR 1.15). Compared with nonurban, nonpoor children, urban and poor children had an increased risk of asthma (OR 1.44), urban and nonpoor children had an increased risk of asthma (OR 1.22), whereas nonurban poor children did not (OR 1.03). The authors conclude that the high prevalence of asthma among black children is not due to race or poverty per se, and that all urban children are at increased risk.

Because children raised on a farm are exposed to large quantities of allergens, Ernst and Cormier (46) asked, “Does growing up on a farm influence the prevalence of allergic disease in adolescence?” The subjects were aged 12 to 19 years, 802 were raised on a farm and 397 were from a nonfarming environment. After adjusting for gender and smoking, adolescents raised on a farm were 30% less likely to wheeze, 41% less likely to have asthma (diagnosed by wheezing and methacholine provocation), and 42% less likely to have atopy (based on skin tests). The authors conclude that the prevalence of asthma and atopy is decreased in children who are raised on a farm.

Because formaldehyde has been implicated in occupational asthma, Franklin and coworkers (47) examined whether the levels typically found in a home would affect the airways. Formaldehyde was measured using a passive sampling technique in the homes of 224 healthy children (aged 11 to 13 years). Formaldehyde did not affect spirometry. Children living in homes with an average formaldehyde level of at least 50 ppb had higher expired nitric oxide levels than children exposed to a lower level of formaldehyde (15.5 and 8.7 ppb). The authors conclude that domestic levels of formaldehyde may invoke subclinical inflammation of the airways.

Risk factors: aeroallergens

To determine the influence of ambient aeroallergens on morbidity of childhood asthma, Dales and coworkers (48) analyzed data on 3,000 visits to an emergency department for asthma and the daily concentrations of pollen and fungal spores. Over 5 years, the daily number of asthma visits was 7.5. Fungal spores, but not pollen grains, were associated with visits, with an increase of 8.8% for all fungal spores combined. The authors conclude that fungal spores account for a significant proportion of the asthma exacerbations in children that prompt a visit to the emergency department.

Because epidemiologists have not investigated the relationship between exposure to microorganisms in the home environment and lung function, Douwes and coworkers (49) conducted such a study in 148 children (aged 7 to 11 years), half of whom had chronic respiratory symptoms. Over a 16-week period, the children monitored their PEFR twice daily, and dust samples were collected from mattresses and floors. Regression analysis revealed a relationship between variability in PEFR and the levels of endotoxin and a marker of fungal exposure, (1→ 3)-β-d-glucan, per square meter of living room floor, particularly in atopic children with symptoms of asthma. Adjusted analysis confirmed the association for (1→ 3)-β-d-glucan, but not for endotoxin. The authors conclude that variability of PEFR in children with chronic respiratory symptoms is related to the levels of (1→ 3)-β-d-glucan in dust from living room floors.

Risk factors: tobacco smoke

To assess the effect of environmental tobacco smoke on the health of children aged 7 to 12 years, Schwartz and coworkers (50) studied 74 children with asthma and 95 with cough. For 3 months, children kept a diary of smoking in the home, use of medications, and recorded PEFR twice daily. Exposure to smoke occurred in 11% of children with asthma and 14% of those with cough. Any exposure was associated with a decrease in morning PEFR of 42 liters per minute. If exposed to smoke during the preceding day, children were 10.3 times more likely to use a bronchodilator, 12.4 times more likely to cough, and 7.8 times more likely to produce phlegm. Exposure had little effect on children who coughed but did not have asthma. The authors conclude the exposure to environmental tobacco smoke was associated with worsening symptoms and airflow in asthmatic children.

Conflicting reports on the effect of in utero exposure to maternal smoking may have resulted from failing to control for gender and asthma status. To address this concern, Li and coworkers (51) analyzed data from 5,263 participants in the Children's Health Study. In utero exposure to maternal smoking resulted in deficits in FEV1/FVC and maximum midexpiratory flow (MMEF) in boys and girls. Compared with nonasthmatic children, boys with asthma who had in utero exposure had larger deficits in FVC, FEV1/FVC, and MMEF, and girls with asthma had larger deficits in FEV1/FVC. Current exposure to environmental tobacco smoke caused deficits in flows only in children without asthma. Past exposure to environmental tobacco smoke was associated with decreased FEV1, FEV1/FVC, and MMEF in boys with asthma, and with decreased flows in girls without asthma. The authors conclude that in utero exposure to maternal smoking resulted in persistent deficits in lung function, which were greatest in children with asthma.

Risk factors: parental asthma

To determine whether a parental history of allergy increases the rate of respiratory infections in infants, Bosken and coworkers (52) prospectively evaluated 1,193 infants from birth to 18 months of age using telephone surveillance. The rate of respiratory illnesses increased up to 10.6 per infant per year at 7–9 months, and then leveled off. The risk of respiratory illnesses in infants older than 7 months was increased 1.2-fold with a parental history of atopy. Occurrence of wheezing during a respiratory illness was increased 2.1-fold with a parental history of asthma. The authors conclude the respiratory illnesses are increased in infants with a parental history of asthma or atopy, whereas wheezing is related only to a parental history of asthma.

Airway inflammation

In 38 children with acute severe asthma, Norzila and coworkers (53) characterized their airway inflammation. Sputum contained increased eosinophil and neutrophil counts. EG2-positive eosinophils were elevated and correlated with airflow limitation (r = −0.5). On resolution, eosinophilic cationic protein decreased from the acute phase (1,078 to 272 ng per ml), as did myeloperoxidase (220 to 1 ng per ml). Levels of interleukin-8 and -5 were elevated in the acute phase, and interleukin-8 decreased at resolution. The authors conclude that airway inflammation in children with acute severe asthma is characterized by activation of both eosinophils and neutrophils.

In 68 infants and children with various respiratory problems, Marguet and coworkers (54) assessed the role of intercellular adhesion molecule-1 and interferon-gamma in the recruitment of eosinophils and neutrophils. The level of intercellular adhesion molecule-1 was higher in children with asthma than in children with chronic cough or healthy children, and the level was correlated with symptom score and lymphocyte count. Children with asthma had higher levels of interferon-gamma than did children with chronic cough, but the levels did not correlate with disease activity. In infants with wheeze, the levels of intercellular adhesion molecule-1 were correlated with disease severity, lymphocyte count, and interferon-gamma. Children with chronic cough did not have a characteristic inflammatory profile. The authors conclude that intercellular adhesion molecule-1 and interferon-gamma contribute to the inflammatory process in children with asthma and possibly in some infants with wheezing.

A comprehensive series of review articles focusing on the measurement of airway inflammation in young children arose from a symposium on this topic (55-70). In addition to reviewing the current knowledge in the field, several articles deal with the research agenda for the near future.

Airway hyperreactivity: methacholine challenge.

Because dosages used for methacholine testing are similar in children and adults despite large variation in subject size, it is possible that reported decreases in airway hyperresponsiveness with age might be due to a relatively smaller dose in taller children. To address this issue, Ownby and coworkers (71) studied 471 children, aged 6 to 8 years, from a birth cohort. Stepwise regression analysis revealed no association between responsiveness to methacholine and either height or age. After controlling for other variables, FEF25–75 and FVC were related to airway hyperresponsiveness. The authors conclude that responsiveness to methacholine in children is not related to height.

Although airway hyperresponsiveness is a hallmark of asthma, the degree to which it predicts the severity of asthma in children is unknown. To address this issue, Weiss and coworkers (72) analyzed data on 1,041 children with mild to moderate asthma (aged 5 to 12 years) enrolled in the Childhood Asthma Management Program. Decreases in PC20 (the dose of methacholine causing a 20% fall in FEV1) were associated with lower FEV1 (r = 0.29), symptoms of chronic asthma, persistent wheezing (OR 1.7), and longer duration of asthma. The authors conclude that the degree of airway hyperresponsiveness is linked to the severity of disease in children with mild to moderate asthma.

In children unable to perform spirometry, the bronchoconstrictive response to methacholine can be quantified as the concentration at which wheezing becomes audible over the trachea or chest. Springer and coworkers (73) modified the test by adding oxygen desaturation and tachypnea as end points, and evaluated its efficacy and safety in 146 asthmatic children (aged 2 to 8 years). A positive response was observed in 96% of the children, and wheezes alone or in combination with other signs appeared in 81%. The mean oxygen desaturation at end-point was 5%; spirometry with provocation was used in a subgroup, and desaturation was 5% at PC20. The authors conclude that the modified auscultation method is an effective and safe method of assessing the bronchoconstrictive response to methacholine.

Airway hyperreactivity: exercise induced

To determine the involvement of nitric oxide in exercise-induced bronchoconstriction, Scollo and coworkers (74) had 24 asthmatic children (age 11.2 years) and 18 healthy controls (age 10.8 years) exercise on a treadmill. After exercise, 10 children developed bronchoconstriction (34% decrease in FEV1) and 14 did not. Exhaled nitric oxide did not change after exercise, although the baseline level was higher in asthmatic children developing bronchoconstriction (12.3 ppb). In the overall group of asthmatic children, the fall in FEV1 after exercise was correlated with baseline exhaled nitric oxide (r = 0.61). The authors conclude that asthmatic children develop exercise-induced bronchoconstriction without change in exhaled nitric oxide, although baseline nitric oxide predicts those who will develop bronchoconstriction.

Airway hyperreactivity: cold, dry air

Because exposure to cold, dry air relates more closely to the pathophysiology of asthma than does pharmacological provocation, Nielsen and Bisgaard (75) assessed the feasibility of performing cold, dry air challenges in children. The challenge was readily performed in 38 asthmatic and 29 healthy children (aged 2 to 5 years); specific airway resistance was measured with a body plethysmograph. Hyperresponsiveness, defined as an increase in resistance of more than 3 SDs, occurred in 68% of the asthmatic children and 7% of the controls. Hyperresponsiveness was detected in 32% of the asthmatic children by the interrupter technique, in 24% by measurement of reactance at 5 Hz using impulse oscillations, and in 18% by measuring resistance at 5 Hz using impulse oscillations. The authors conclude that a cold, dry air challenge may be used to diagnose asthma in young children.

Clinical issues: dyspnea.

An inspiratory effort against an occlusion elicits evoked potentials over the somatosensory cortex, and the first positive peak is thought to indicate afferent information arriving at the cortex. Davenport and coworkers (76) found that an inspiratory occlusion elicited a first peak on evoked potentials in all of 15 healthy children and 14 of 15 asthmatic children, but the peak was not found in 6 of 11 children with a high risk for life-threatening asthmatic attacks. The authors conclude that some children with life-threatening asthma have an abnormality in the neural processing of afferent information arising from an inspiratory stimulus.

Clinical issues: quality of life

The Child Health Questionnaire (CHQ-PFSO) was designed to measure quality of life in children, and has been extensively tested in healthy children. Asmussen and coworkers (77) investigated the psychometric performance of this instrument in 5 to 12 year-old children with asthma. The questionnaire was completed by 74 caregivers. Internal consistency reliability (ability of tested items to fit together as a single construct) was consistently high (intraclass correlation coefficients ranged from 0.37 to 0.84). The scales were better at distinguishing levels of disease severity based on symptoms than based on pulmonary function tests or medication use. In a sample of inner-city parents of low to moderate income, the instrument gave mixed results. The authors conclude that the questionnaire addresses a broad range of concepts.

Treatment

The efficacy of inhaled glucocorticoids in preschool children has been documented by improvement in symptom score and decrease in use of rescue treatment with β-agonists. In 38 asthmatic children aged 2 to 5 years, Nielsen and Bisgaard (78) assessed whether objective measures of lung function could serve as supplemental tools in assessing response to therapy. In a randomized, double-blind trial, inhaled budesonide (400 μg twice daily) produced a decrease in nighttime and daytime symptoms, and decreased daytime, but not nighttime, use of rescue medications. Budesonide also improved measurements of resistance and bronchial responsiveness to a cold air challenge (but not methacholine responsiveness). The authors conclude that inhaled budesonide decreases symptom scores and improves objective measures of lung function in preschool children.

In a randomized double-blind trial in 481 infants and young children with persistent asthma, nebulized budesonide was shown to be effective. Mellon and coworkers (79) analyzed the data from this trial to compare the efficacy of treatment with the suspension administered through a facemask or a mouthpiece. Both were equally effective.

To determine whether a leukotriene receptor antagonist provides bronchoprotection in preschool asthmatic children, Bisgaard and Nielsen (80) did a double-blind crossover study in 13 asthmatic children aged 3 to 5 years. Hyperventilation of cold, dry air produced a 46% decrease in specific airway resistance when the children took placebo, and a 17% decrease after 2 days of montelukast (5 mg per day). The benefit was seen irrespective of whether the children were receiving inhaled budesonide. The authors conclude that leukotriene receptor antagonists may be of value in treating preschool asthmatic children.

Because dosages of aerosolized medications are commonly adjusted to age or body weight, Onhoj and coworkers (81) compared plasma concentrations in three groups of subjects inhaling a fixed dose of budesonide (4000 μg) from an inhaler and spacer: 8 children aged 2–3 years; 8 children aged 4–6 years; and 10 adults aged 20–41 years. The dose delivered to the patient (estimated as the delivered dose of the batch measured in vitro minus drug recovered from equipment, face and mouth rinses) was similar for the three age groups. Systemic exposure, estimated as area under the plasma concentration plotted over time, and terminal half-life were also similar in the three age groups. That adults had the same plasma concentrations as children for the same dose, despite a larger body size, indicates that lung deposition increases with age. The authors conclude that the same nominal dose of budesonide can be used in children and adults without increased risk of systemic toxicity.

Other Pediatric Issues
Air pollution

To assess the relationship between air pollution and growth of lung function, Gauderman and coworkers (82) analyzed longitudinal data from 3,035 children living within 200 miles of Los Angeles. The average growth of lung function over 4 years was modeled as a function of average exposure to ambient air pollutants. For children in the fourth grade of school, significant deficits of lung function were associated with exposure to particles with aerodynamic diameter less than 10 μm (PM10), PM2.5, nitrogen dioxide, and inorganic acid vapor, but not with ozone. Over the 4-year period, children in the most polluted, as compared with the least polluted, communities were predicted to have a cumulative decrease of 3.4% in FEV1. The authors conclude that current levels of air pollutants impair the growth of lung function in children.

Crohn's disease

Abnormalities in pulmonary function and bronchoalveolar lavage have been reported in adults with Crohn's disease despite a lack of pulmonary symptoms. Mansi and coworkers (83) studied 14 children (aged 9 to 16 years) with Crohn's disease without clinical evidence of lung disease, 10 children with asthma (aged 8 to 13 years), and 10 healthy controls (aged 8 to 15 years). Bronchial hyperresponsiveness was found in 71% of the children with Crohn's disease, and the PD20 was seven times greater than in the asthmatic children. PD20 was not related to baseline FEV1, IgE, or eosinophil count. The authors speculate that the bronchial hyperresponsiveness seen in some children with Crohn's disease may be an expression of subclinical airway inflammation.

Lung development

Because impaired activity of the lung epithelial sodium channel causes neonatal respiratory distress, Smith and coworkers (84) investigated the ontogeny and cellular expression of the alpha subunit of this channel. They were surprised to find strong expression of this channel in human embryos aged 4–5 weeks. The channel was also significantly expressed in the lungs of preterm infants with the respiratory distress syndrome and in term infants with hypoplastic lungs. The authors conclude that mRNA of the epithelial sodium channel is constitutively expressed throughout lung development and is separate from the process of pulmonary epithelial maturation and differentiation.

Pathophysiology

Two methods are used to separate alveolar surfactant into subtypes: differential centrifugation separates bronchoalveolar fluid into large and small aggregates; equilibrium buoyant density gradient centrifugation separates bronchoalveolar fluid into three peaks, ultraheavy, heavy, and light. Using the same pool of mouse bronchoalveolar fluid, Gross and coworkers (85) examined whether the two methods provide similar proportions of surfactant subtypes. The amount of phospholipid in the large aggregate fraction on differential centrifugation was 33–43% less than that found in the ultraheavy and heavy peaks on gradient centrifugation. This discrepancy arose from the failure of differential centrifugation to sediment all of the phospholipid that banded as ultraheavy or heavy peaks. When purified heavy and light subtypes were subjected to differential centrifugation, 4 to 33% cross-contamination occurred. The authors conclude that the two methods for separating surfactant subtypes provide systematically different results.

The specific contribution of phosphatidylglycerol and phosphatidylinositol, anionic phospholipids present in surfactant, to function is unknown. Ingenito and coworkers (86) employed pulsating bubble surfactometry to study the influence of anionic phospholipids on the stability and absorption of surfactant monolayer. Measurements made with native phospholipids and phospholipids devoid of anionic species had similar equilibrium and dynamic properties. By interacting with nonlipid surfactant components, anionic phospholipids were shown to play a critical role in promoting surface film stability during dynamic compression through interaction with nonlipid surfactant components, and to prevent destabilization of the surface film by cholesterol and other neutral lipids. The authors conclude that anionic phospholipids play an important role in determining the dynamic properties of lung surfactant, particularly in the presence of neutral lipids.

Deficiency

Cutz and coworkers (87) report a full-term infant who presented with severe respiratory distress shortly after birth and died after 23 days. Deficiency of surfactant proteins was excluded. Ultrastructural studies showed that cytoplasmic lamellar bodies were lacking in the alveolar type II cells, the principal storage site for pulmonary surfactant.

Inability to produce surfactant protein B causes fatal neonatal respiratory distress. A frame-shift mutation (121ins2) resulting in a net 2-base pair insertion into codon 121 of surfactant protein-B mRNA is the predominant but not only cause of the disease. To determine the range of mechanisms responsible for deficiency of surfactant protein B, Nogee and coworkers (88) characterized both alleles from 32 affected infants: 16 were homozygous for the 121ins2 mutation, 10 were heterozygous for 121ins2 and another mutation, and 6 were homozygous for other mutations. Investigation of surfactant protein expression revealed that nonsense and frame-shift mutations were associated with the absence of precursor protein and mature surfactant B; missense mutations or mutations causing in-frame deletions or insertions were associated with precursor protein expression; and four mutations were associated with low levels of mature surfactant B protein expression. The authors conclude the hereditary deficiency of surfactant protein B is caused by a variety of mutations in the governing gene, and may be associated with reduced, as well as absent, levels of mature surfactant, likely caused by impaired processing of precursor protein.

The effect of prenatal glucocorticoids on the synthesis of surfactant phosphatidylcholine in preterm infants with primary surfactant deficiency has not been studied. To address this issue, Bunt and coworkers (89) studied 27 preterm infants with respiratory distress syndrome: 4 infants received one dose, 12 infants received two doses of prenatal beclomethasone (12 mg intramuscularly), and 11 infants received none. Five hours after birth, a stable isotope, [U-13C] glucose, was infused for 24 hours. The incorporation of 13C into palmitic acid in surfactant phosphatidylcholine was measured in serial tracheal aspirates. Surfactant synthesis was increased 40% per dose of glucocorticoid. The authors conclude that prenatal glucocorticoid therapy stimulates surfactant synthesis in preterm human infants.

Antenatal exposure to glucocorticoids or endotoxin can improve the function of the lung after a preterm delivery. To better understand the mechanisms involved, Jobe and coworkers (90) injected endotoxin into the amniotic cavity of ewes 7 days before preterm delivery of fetal sheep (125-day gestation). Endotoxin produced increases in compliance, lung volumes, and alveolar saturated phosphatidylcholine, without increasing cord cortisol. The authors conclude that intraamniotic administration of endotoxin promoted early maturation of the lung by a mechanism independent of cortisol.

Avery (91) recalls the discovery of the deficiency of surfactant in infants with hyaline membrane disease.

Treatment

Since radioactive isotopes cannot be used to study surfactant metabolism in humans, Torresin and coworkers (92) used a new nonradioactive technique in eight preterm infants with the respiratory distress syndrome. A natural porcine surfactant was labeled with the stable nonradioactive isotope 13C as a tracer and infused intravenously. The trachea was aspirated sequentially and 13C enrichment of phosphatidylcholine was measured in the aspirates. The half-life was 34 hours, and the pool size was 5.8 mg per kg for the first dose and 17.3 ml per kg after two doses. The authors conclude that the nonradioactive isotope method allows the tracing of exogenous surfactant in infants receiving replacement therapy.

Bernhard and coworkers (93) compared the functional, biochemical, and morphological characteristics of four commercial surfactants with native bovine and porcine surfactant. To achieve a minimum surface tension of less than 5 mN/m during cyclic film compression, concentrations of Curosurf and Alveofact needed to be 6 to 12 times the concentration of native surfactants; neither Exosurf nor Survanta achieved a surface tension of less than 8 mN/m. Impaired surface activity in commercial surfactants corresponded to their lack of surfactant protein-A and to low levels of surfactant protein-B and -C. A lower concentration of dipalmitoylphosphatidylcholine (DPCC) also caused impairment of surface activity. The authors conclude that commercial surfactants need to be evaluated using a standardized protocol.

Almaas and coworkers (94) investigated the inhibitory action of meconium on three commercial surfactants. In a pulsating bubble system, meconium caused less inhibition of Alveofact than of Curosurf or Survanta. The prevention of effective spreading of surfactant and the reduction in the number of microbubbles with meconium were unexpectedly counteracted by the addition of ferric chloride. Additional studies showed that the beneficial action of ferric chloride was achieved by the lowering of pH. The authors conclude that the inhibition of surfactant by meconium in vitro is pH dependent, and can be abolished by adding ferric chloride or acetic acid.

Lu and coworkers (95) investigated whether polymers that prevent and reverse surfactant inactivation, such as polyethylene glycol, might enhance the action of surfactant in treating acute lung injury. Instillation of human meconium, which is known to interfere with surfactant, produced acute injury in the lungs of rats. Animals treated with the combination of Survanta and polyethylene glycol showed the greatest improvements in oxygenation, compliance, and histology, whereas use of surfactant on its own achieved little improvement. The authors conclude that adding polyethylene glycol to surfactant decreases the lung injury caused by meconium.

Because selective inhibition of phosphodiesterase-4 has antiinflammatory properties and attenuates activation of neutrophils, Hafner and Germann (96) determined whether the combination of a phosphodiesterase-4 inhibitor, roflumilast, and a protein C-based surfactant would act synergistically in a lung lavage model of acute lung injury. Separate administration of the surfactant and the phosphodiesterase inhibitor prevented hyaline membrane formation; the effect was greater when the agents were combined. Oxygenation was improved by the surfactant, and improved further by adding the phosphodiesterase inhibitor; the inhibitor on its own did not improve oxygenation. The authors conclude that a phosphodiesterase-4 inhibitor and surfactant act synergistically in acute lung injury.

Genetics

Over 500 mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been described. A 5T allele of the polythymidine tract in intron 8 (IVS8) results in a lower than normal level of full-length CFTR mRNA and a decrease in functional CFTR protein. Noone and coworkers (97) reported the first two patients with cystic fibrosis-like lung disease associated with the 5T sequence and no other cystic fibrosis gene mutation. In these two women, the levels of full-length CFTR mRNA in respiratory epithelia were low (6–11% of total CFTR mRNA expression). Both patients had defective CFTR-mediated chloride conductance in epithelia of the sweat ducts and airways. The authors conclude that the 5T polythymidine tract sequence on specific haplotype backgrounds may cause a low level of full-length functional CFTR protein and cystic fibrosis-like lung disease.

In 75 patients with cystic fibrosis, Grasemann and coworkers (98) examined the relationship between exhaled nitric oxide and the size of an AAT repeat polymorphism in intron 20 of the nitric oxide synthase 1 gene. Patients with a high number of AAT repeats (both alleles having at least 12 repeats) at this locus had higher concentrations of exhaled nitric oxide than did patients with a low number of repeats (at least one allele having less than 12 repeats): 4.0 and 6.4 ppb. The airways of patients with a high number of AAT repeats were more commonly colonized with Pseudomonas aeruginosa. The authors conclude that the gene for nitric oxide synthase 1 is associated not only with variability in the level of exhaled nitric oxide in patients with cystic fibrosis but also with P. aeruginosa colonization of the airways.

Aminoglycosides can increase the frequency of erroneous insertions of nonsense codons, thereby permitting the translation of CFTR (cystic fibrosis transmembrane conductance regulator) alleles carrying missense mutations to continue reading to the end of the gene. This leads to the appearance of functional CFTR channels at the apical plasma membrane. Wilschanski and coworkers (99) applied gentamicin to the nose of nine patients with cystic fibrosis (aged 12 to 46 years) carrying stop mutations. After 14 days, repolarization of the nasal epithelium increased from −1 to −10 mV, representing chloride transport. The authors conclude that gentamicin may influence the chloride channel abnormality in patients with cystic fibrosis carrying stop mutations.

Lung Inflammation

Because inflammation and angiogenesis are codependent phenomena, McColley and coworkers (100) measured vascular endothelial growth factor, a major mediator of angiogenesis and vascular permeability, in 38 patients with cystic fibrosis and 25 patients with other pulmonary disorders. Vascular endothelial growth factor was increased in both groups, but 58% higher in the patients with cystic fibrosis; in these patients the factor was correlated with FEV1 (r = 0.51). After intravenous antibiotic therapy for an exacerbation, levels fell by 52% in 10 patients with cystic fibrosis. The authors conclude that the increased level of vascular endothelial growth factor in patients with cystic fibrosis is related to airway infection.

Because weight loss in patients with cystic fibrosis could be caused by pulmonary inflammation or by impaired pulmonary function, van Heeckeren and coworkers (101) examined the relative contribution of each in an animal model. After infection with Pseudomonas, mice lost weight and developed increases in proinflammatory cytokines in bronchoalveolar fluid, but lung resistance and compliance did not change. Weight loss was correlated with the cytokine levels. The authors conclude that weight loss in Pseudomonas-infected mice results from an inflammatory process rather than abnormal lung mechanics.

Because oxidative stress is involved in the pathophysiology of cystic fibrosis, Paredi and coworkers (102) measured exhaled ethane, which is produced from lipid peroxidation, in 24 patients with cystic fibrosis. Patients not taking steroids had higher exhaled ethane levels (1.99 ppb) than patients on steroids (0.67 ppb) or healthy controls (0.82 ppb). In patients not taking steroids, ethane was correlated with the ratio of residual volume to total lung capacity (r = 0.66) and exhaled carbon monoxide (r = 0.65). Exhaled nitric oxide was not influenced by steroids, and was lower than in healthy controls (3.0 and 7.0 ppb). The authors conclude that exhaled ethane may be a useful noninvasive marker of oxidative stress in cystic fibrosis.

Exercise Performance

To determine whether a decrease in muscle mass accounts for diminished exercise performance in children with cystic fibrosis, Moser and coworkers (103) measured mid-thigh muscle cross-sectional area with magnetic resonance imaging in 22 patients with cystic fibrosis (aged 6 to 18 years) who also performed progressive cycle ergometry. Muscle cross-sectional area was not smaller in the patients. The patients had a 35% decrease in peak oxygen consumption, and a 30% decrease in peak oxygen consumption per cross-sectional area. The slope of oxygen consumption to work rate, a measure of aerobic function that is less dependent on effort, was 68% of predicted. The authors conclude that impaired exercise performance in patients with cystic fibrosis is not due to decreased muscle mass, and that the patients have a muscle-related abnormality in oxygen metabolism.

Bone Demineralization and Metabolic Disorders

Because inflammatory cytokines activate osteoclasts and promote bone resorption, Aris and coworkers (104) studied the dynamic interactions between inflammatory cytokines and bone metabolic markers in 17 adults with cystic fibrosis (aged 18 to 41 years) at the start and end of treatment for an acute infective exacerbation. Treatment produced a 25% decrease in urinary N-telopeptides of type 1 collagen (a marker of bone breakdown), a 19% decrease in urinary free deoxypyridinoline (another marker of bone breakdown), a 55% decrease in serum interleukin-1β, a 51% decrease in interleukin-6, and a 47% decrease in C-reactive protein; osteoclastin, a marker of bone formation, increased by 55%. Three weeks later, the changes in the N-telopeptides and osteocalcin were still evident. The authors conclude that the elaboration of inflammatory cytokines during pulmonary infection may be linked to increased bone resorption and diminished bone formation.

In 22 adults with cystic fibrosis (mean age 24 years), Ionescu and coworkers (105) studied weight loss and bone demineralization. Compared with 22 age-matched controls, patients had a 19% decrease in fat-free mass, had negative nitrogen balance, and all but two had bone mineral density Z scores below 1 SD (13 below 2.5 SDs). Bone mineral density was related to FEV1 (r = 0.44), interleukin-6 (r = −0.60), and tumor necrosis factor receptors (r = −0.42). The authors conclude that chronic pulmonary infection contributes to the weight loss and bone disease in patients with cystic fibrosis.

Because loss of bone mineral density is common in patients with cystic fibrosis undergoing lung transplantation, Aris and coworkers (106) did a randomized controlled trial of pamidronate, a second-generation biphosphonate, in 34 patients with CF after lung transplantation. All patients received vitamin D (800 IU per day) and calcium (1 g per day), and 16 also received pamidronate (30 mg IV every 3 months) for 2 years. Compared with the control group, patients receiving pamidronate developed greater bone mineral density of the spine (8.8 versus 2.6%) and femur (8.2 versus 3.2%). Six fractures occurred in the pamidronate group and seven in the control group. Bone resorption was highest immediately after transplantation, and improved with both pamidronate and time. Bone formation was very poor immediately after transplantation and improved over the first year in both groups. The authors conclude that pamidronate improves bone mineral density in patients with cystic fibrosis undergoing lung transplantation.

To evaluate whether glucose intolerance influences outcome in patients with cystic fibrosis, Milla and coworkers (107) prospectively followed 152 patients for 4 years. At baseline 52% had normal glucose tolerance, 39% had impaired glucose tolerance, and 16% had diabetes without fasting hyperglycemia. Spirometry and body mass index were comparable in the groups. The rate of decline in FEV1 and FVC over 4 years correlated with glucose tolerance, and the greatest decline occurred in patients with diabetes without fasting hyperglycemia. The authors conclude that the degree of glucose intolerance predicts decline in pulmonary function in patients with cystic fibrosis.

Treatment
Gene therapy

To reach the submucosal glandular cells and epithelial cells of the small airways in patients with cystic fibrosis, a gene transfection system must permeate the overlying tenacious mucous layer. To determine the influence of particle size and sputum viscoelasticity, Sanders and coworkers (108) used inert fluorescence-labeled polystyrene nanospheres of a size comparable to those in transfection systems under current evaluation. After 150 minutes, less than 0.3% of nanospheres had moved through a 200-μm-thick layer of cystic fibrosis sputum. The largest nanospheres (560 mm) were almost completely blocked, and the smaller nanospheres (124 mm) were retarded by a factor of 1.3 compared with buffer. Nanospheres moved more easily through sputum of increased viscoelasticity, possibly because an increase in viscoelasticity causes the network structure to become more macroporous. The addition of DNase I moderately facilitated transport. Transport was retarded in the same manner in sputum from one patient with COPD. The authors conclude that cystic fibrosis sputum offers a size-dependent barrier to the transport of nanospheres.

Ferkol and coworkers (109) developed a strategy for delivering α1-antitrypsin to inaccessible cystic fibrosis airways by targeting the respiratory epithelium via the polymeric immunoglobulin receptor. A fusion protein, consisting of a single-chain Fv protein directed against human secretory component and linked to human α1-antitrypsin, was used for transport. Transport was achieved in a basolateral-to-apical direction across in vitro model systems of polarized respiratory epithelium consisting of cells that overexpress the receptor and human respiratory epithelial cells grown in primary culture at the air–liquid interface. When applied to the basolateral surface, the fusion protein penetrated the respiratory epithelia, with transcytosis of the fusion protein being proportional to the amount of secretory protein detected at the apical surface. The authors conclude that this system is capable of concentrating the antiproteases of the fusion protein in the thin film of epithelial surface fluid to a level expected to be therapeutic in the airways of many patients with cystic fibrosis.

Mucolytic agents

During an infective exacerbation of cystic fibrosis, the release of interleukin-8 mediates the neutrophil inflammatory response. The release of the anionic polymers, DNA and actin, from necrosing neutrophils increases the viscoelasticity of airway secretions. Gelsolin, which cleaves actin polymers, and DNase I decrease the viscosity of cystic fibrosis sputum in vitro. Perks and Shute (110) found that DNA and actin bind and mask the immunologic recognition of the basic peptide, interleukin-8, and prevent this chemokine from binding to neutrophil receptors. The decrease in viscosity of cystic fibrosis sputum by DNase or gelsolin in vitro was accompanied by increases in free interleukin-8 and by interleukin-8-dependent neutrophil chemotactic activity of sputum. The authors conclude that an electrostatic interaction between polymers (DNA and actin) and chemokines (interleukin-8) may limit the inflammatory potential of the chemokines, but that this interaction is weakened by depolymerization; they caution that use of these mucolytic agents may pose a risk of causing increased inflammation.

Dextran, an oligosaccharide with mucolytic properties, is being considered for use in the treatment of cystic fibrosis. To determine whether dextran can be delivered successfully to the lung as an inhaled aerosol, Finlay and coworkers (111) assessed delivery during breath simulation with four nebulizer systems (Pari LC STAR, Hudson T-Updraft II, Acorn II, and Sonix 2000). The high viscosity of dextran (seven times that of water) interfered with nebulization and most of the systems performed poorly. In a model of the airway mucosa, only one system, the Pari LC STAR nebulizer, produced satisfactory concentrations.

Bronchodilator therapy

In 18 patients with stable cystic fibrosis (aged 6–21 years), Fauroux and coworkers (112) asked, “Would using pressure support increase the deposition of a nebulized aerosol in the lungs?” Coupling a breath-actuated nebulizer to a pressure-support ventilator achieved 30% greater deposition of a radioactive aerosol. Deposition efficacy, the percentage of nebulizer output, was greater after pressure support than with the control session (15.3 versus 11.5%). The authors conclude that driving the delivery of nebulized aerosol with pressure support improves lung deposition.

Vitamin supplements

Pulmonary inflammation in cystic fibrosis is associated with oxidative stress and amplified by deficiencies of antioxidants (especially vitamin E) due to exocrine pancreatic insufficiency. In 36 patients with cystic fibrosis (aged 6–44 years), Ciabattoni and coworkers (113) found that urinary excretion of immunoreactive 8-iso-prostaglandin F, an index of lipid peroxidation in vivo, was 3.7 times higher than in healthy controls. Urinary excretion of immunoreactive 11-dehydrothomboxane B2, an index of platelet activation in vivo, was 7.6 times higher in the patients than in the controls. The prostaglandin level was correlated with the level of the thromboxane (r = 0.51) and FEV1 (r = −0.40). Excretion of the prostaglandin did not change with administration of cyclooxygenase inhibitors, supporting a noncyclooxygenase mechanism of F2-isoprostane formation in cystic fibrosis. Vitamin E supplementation achieved a 42% decrease in the prostaglandin and a 29% decrease in the thromboxane. The authors conclude that increased lipid peroxidation may contribute to the pulmonary and platelet dysfunction in patients with cystic fibrosis, and that the approach to vitamin E supplementation merits reassessment.

Antibiotics

Because many isolates of Pseudomonas aeruginosa are resistant to multiple antibiotics, Lang and coworkers (114) developed an in vitro method of testing bacterial isolates against multiple combinations of antibiotics to determine sensitivity patterns. In 75 multiresistant isolates of P. aeruginosa, referred from 44 patients with cystic fibrosis, monotherapy with meropenem was bactericidal against 44% of isolates, and high-dose tobramycin was bactericidal against 72%. Adding a second antibiotic improved bactericidal activity; high-dose tobramycin plus meropenem, piperacillin plus tazobactam, or ciprofloxacin were bactericidal against 88–94% of isolates. Adding a third antibiotic did not improve inhibition. The authors conclude that double-antibiotic combinations, containing meropenem or high-dose tobramycin, show the best bactericidal activity in vitro against multiresistant strains of P. aeruginosa.

Selection of the appropriate antibiotic to treat Burkholderia cepacia in patients with cystic fibrosis is difficult because most strains are resistant to many commonly used agents. Aaron and coworkers (115) tested multiple combinations of 10 to 15 antibiotics in vitro against 119 isolates of B. cepacia that were resistant to multiple drugs. Of the 119 isolates, 50% were resistant to all single antibiotics, 8% were resistant to two-drug combinations, but all were inhibited by at least one triple-drug regimen. Bactericidal activity varied among single agents: meropenem (47%), ceftazidine (15%), and tobramycin (14%). While double-drug combinations improved bactericidal activity, 47% of isolates showed antagonism—growth of an organism when a second drug was added to a single bactericidal agent. Triple-agent regimens containing tobramycin, meropenem, and an additional agent were most effective, being bactericidal against 81 to 93% of isolates. The authors conclude that triple-antibiotic regimens are more likely than single-agent or double-drug combinations to be bactericidal against Burkholderia cepacia in vitro.

Lung transplantation

In patients waiting for lung transplantation, donor lungs are allocated according to seniority (accrued time on the waiting list). To determine the outcome in patients with cystic fibrosis awaiting transplantation, Vizza and coworkers (116) analyzed data of a consecutive cohort. Of 146 patients, 52% underwent transplantation, 23% were alive and waiting, and 25% died while waiting. Actuarial survival for the entire cohort was 81% at 1 year, 67% at 2 years, and 59% at 3 years. Risk factors for dying on the waiting list were: shorter 6-minute walking distance, elevated systolic pulmonary artery pressure, and diabetes mellitus. These factors, however, were also common in survivors. The authors conclude that the lack of reliable predictors for survival hinders the ability to allocate donor lungs according to medical urgency.

Supported by a Merit Review grant from the Veterans Affairs Research Service.

1. Jones M, Castile R, Davis S, Kisling J, Filbrun D, Flucke R, Goldstein A, Emsley C, Ambrosius W, Tepper RSForced expiratory flows and volumes in infants. Normative data and lung growth. Am J Respir Crit Care Med1612000353359
2. Ip MS, Karlberg EM, Karlberg JP, Luk KD, Leong JCLung function reference values in Chinese children and adolescents in Hong Kong. I. Spirometric values and comparison with other populations. Am J Respir Crit Care Med1622000424429
3. Ip MS, Karlberg EM, Chan KN, Karlberg JP, Luk KD, Leong JCLung function reference values in Chinese children and adolescents in Hong Kong. II. Prediction equations for plethysmographic lung volumes. Am J Respir Crit Care Med1622000430435
4. Xuan W, Peat JK, Toelle BG, Marks GB, Berry G, Woolcock AJLung function growth and its relation to airway hyperresponsiveness and recent wheeze. Results from a longitudinal population study. Am J Respir Crit Care Med161200018201824
5. Platzker AC, Colin AA, Chen XC, Hiatt P, Hunter J, Koumbourlis AC, Schluchter MD, Ting A, Wohl METhoracoabdominal compression and respiratory system compliance in HIV-infected infants. Am J Respir Crit Care Med161200015671571
6. Modl M, Eber E, Weinhandl E, Gruber W, Zach MSAssessment of bronchodilator responsiveness in infants with bronchiolitis. A comparison of the tidal and the raised volume rapid thoracoabdominal compression technique. Am J Respir Crit Care Med1612000763768
7. Joint American Thoracic Society/European Respiratory Society Working Group on Infant Lung Function. The raised volume rapid thoracoabdominal compression technique. Am J Respir Crit Care Med 2000;161:1760–1762.
8. O'Connor GT, Sparrow D, Demolles D, Dockery D, Raizenne M, Fay M, Ingram RH, Speizer FEMaximal and partial expiratory flow rates in a population sample of 10- to 11-yr-old schoolchildren. Effect of volume history and relation to asthma and maternal smoking. Am J Respir Crit Care Med1622000436439
9. Filippone M, Narne S, Pettenazzo A, Zacchello F, Baraldi EFunctional approach to infants and young children with noisy breathing: validation of pneumotachography by blinded comparison with bronchoscopy. Am J Respir Crit Care Med162200017951800
10. Jones MH, Davis SD, Kisling JA, Howard JM, Castile R, Tepper RSFlow limitation in infants assessed by negative expiratory pressure. Am J Respir Crit Care Med1612000713717
11. Delacourt C, Lorino H, Herve-Guillot M, Reinert P, Harf A, Housset BUse of the forced oscillation technique to assess airway obstruction and reversibility in children. Am J Respir Crit Care Med1612000730736
12. Hall GL, Hantos Z, Petak F, Wildhaber JH, Tiller K, Burton PR, Sly PDAirway and respiratory tissue mechanics in normal infants. Am J Respir Crit Care Med162200013971402
13. Frey U, Makkonen K, Wellman T, Beardsmore C, Silverman MAlterations in airway wall properties in infants with a history of wheezing disorders. Am J Respir Crit Care Med161200018251829
14. Kissoon N, Duckworth LJ, Blake KV, Murphy SP, Taylor CL, Silkoff PEFeNO: relationship to exhalation rates and online versus bag collection in healthy adolescents. Am J Respir Crit Care Med1622000539545
15. Baraldi E, Scollo M, Zaramella C, Zanconato S, Zacchello FA simple flow-driven method for online measurement of exhaled NO starting at the age of 4 to 5 years. Am J Respir Crit Care Med162200018281832
16. Rafferty GF, Greenough A, Dimitriou G, Kavadia V, Laubscher B, Polkey MI, Harris ML, Moxham JAssessment of neonatal diaphragm function using magnetic stimulation of the phrenic nerves. Am J Respir Crit Care Med162200023372340
17. Ingimarsson J, Thorsteinsson A, Larsson A, Werner OLung and chest wall mechanics in anesthetized children. Influence of body position. Am J Respir Crit Care Med1622000412417
18. Nielson DW, Ku PL, Egger MTopical lidocaine exaggerates laryngomalacia during flexible bronchoscopy. Am J Respir Crit Care Med1612000147151
19. Elidemir O, Fan LL, Colasurdo GNA novel diagnostic method for pulmonary aspiration in a murine model. Immunocytochemical staining of milk proteins in alveolar macrophages. Am J Respir Crit Care Med1612000622626
20. Dassieu G, Brochard L, Benani M, Avenel S, Danan CContinuous tracheal gas insufflation in preterm infants with hyaline membrane disease. A prospective randomized trial. Am J Respir Crit Care Med1622000826831
21. Cannon ML, Cornell J, Tripp-Hamel DS, Gentile MA, Hubble CL, Meliones JN, Cheifetz IMTidal volumes for ventilated infants should be determined with a pneumotachometer placed at the endotracheal tube. Am J Respir Crit Care Med162200021092112
22. Yoder BA, Siler-Khodr T, Winter VT, Coalson JJHigh-frequency oscillatory ventilation: effects on lung function, mechanics, and airway cytokines in the immature baboon model for neonatal chronic lung disease. Am J Respir Crit Care Med162200018671876
23. Beardsmore C, Dundas I, Poole K, Enock K, Stocks JRespiratory function in survivors of the United Kingdom Extracorporeal Membrane Oxygenation Trial. Am J Respir Crit Care Med161200011291135
24. Deng H, Mason SN, Auten RLLung inflammation in hyperoxia can be prevented by antichemokine treatment in newborn rats. Am J Respir Crit Care Med162200023162323
25. Jarreau PH, Louis B, Desfrere L, Blanchard PW, Isabey D, Harf A, Moriette GDetection of positional airway obstruction in neonates by acoustic reflection. Am J Respir Crit Care Med161200017541756
26. Neve V, de la Roque ED, Leclerc F, Leteurtre S, Dorkenoo A, Sadik A, Cremer R, Logier RVentilator-induced overdistension in children: dynamic versus low-flow inflation volume–pressure curves. Am J Respir Crit Care Med1622000139147
27. Willet KE, Jobe AH, Ikegami M, Newnham J, Sly PDPulmonary interstitial emphysema 24 hours after antenatal betamethasone treatment in preterm sheep. Am J Respir Crit Care Med162200010871094
28. Sherman JM, Davis S, Albamonte-Petrick S, Chatburn RL, Fitton C, Green C, Johnston J, Lyrene RK, Myer C, Othersen HB, Wood R, Zach M, Zander J, Zinman RCare of the child with a chronic tracheostomy. Official statement of the American Thoracic Society (adopted by the ATS Board of Directors, July 1999). Am J Respir Crit Care Med1612000297308
29. Tibby SM, Hatherill M, Wright SM, Wilson P, Postle AD, Murdoch IAExogenous surfactant supplementation in infants with respiratory syncytial virus bronchiolitis. Am J Respir Crit Care Med162200012511256
30. Schwarze J, Cieslewicz G, Joetham A, Ikemura T, Makela MJ, Dakhama A, Shultz LD, Lamers MC, Gelfand EWCritical roles for interleukin-4 and interleukin-5 during respiratory syncytial virus infection in the development of airway hyperresponsiveness after airway sensitization. Am J Respir Crit Care Med1622000380386
31. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman BRespiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med161200015011507
32. Bont L, Heijnen CJ, Kavelaars A, van Aalderen WM, Brus F, Draaisma JT, Geelen SM, Kimpen JLMonocyte IL-10 production during respiratory syncytial virus bronchiolitis is associated with recurrent wheezing in a one-year follow-up study. Am J Respir Crit Care Med161200015181523
33. Isono S, Tanaka A, Ishikawa T, Nishino TDevelopmental changes in collapsibility of the passive pharynx during infancy. Am J Respir Crit Care Med1622000832836
34. Poole KA, Hallinan H, Beardsmore CS, Thompson JREffect of maternal smoking on ventilatory responses to changes in inspired oxygen levels in infants. Am J Respir Crit Care Med1622000801807
35. Goh DY, Galster P, Marcus CLSleep architecture and respiratory disturbances in children with obstructive sleep apnea. Am J Respir Crit Care Med1622000682686
36. Bouferrache B, Filtchev S, Leke A, Marbaix-Li Q, Freville M, Gaultier CThe hyperoxic test in infants reinvestigated. Am J Respir Crit Care Med1612000160165
37. Gozal D, Simakajornboon NPassive motion of the extremities modifies alveolar ventilation during sleep in patients with congenital central hypoventilation syndrome. Am J Respir Crit Care Med162200017471751
38. Zhu S, Chan-Yeung M, Becker AB, Dimich-Ward H, Ferguson AC, Manfreda J, Watson WT, Pare PD, Sandford AJPolymorphisms of the IL-4, TNF-α, and Fcα RIβ genes and the risk of allergic disorders in at-risk infants. Am J Respir Crit Care Med161200016551659
39. Malerba G, Lauciello MC, Scherpbier T, Trabetti E, Galavotti R, Cusin V, Pescollderungg L, Zanoni G, Martinati LC, Boner AL, Levitt RC, Pignatti PFLinkage analysis of chromosome 12 markers in Italian families with atopic asthmatic children. Am J Respir Crit Care Med162200015871590
40. Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FDA clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med162200014031406
41. Berhane K, McConnell R, Gilliland F, Islam T, Gauderman WJ, Avol E, London SJ, Rappaport E, Margolis HG, Peters JMSex-specific effects of asthma on pulmonary function in children. Am J Respir Crit Care Med162200017231730
42. Wolfe R, Carlin JB, Oswald H, Olinsky A, Phelan PD, Robertson CFAssociation between allergy and asthma from childhood to middle adulthood in an Australian cohort study. Am J Respir Crit Care Med162200021772181
43. Heinrich J, Hoelscher B, Wichmann HEDecline of ambient air pollution and respiratory symptoms in children. Am J Respir Crit Care Med161200019301936
44. Mortimer KM, Tager IB, Dockery DW, Neas LM, Redline SThe effect of ozone on inner-city children with asthma: identification of susceptible subgroups. Am J Respir Crit Care Med162200018381845
45. Aligne CA, Auinger P, Byrd RS, Weitzman MRisk factors for pediatric asthma. Contributions of poverty, race, and urban residence. Am J Respir Crit Care Med1622000873877
46. Ernst P, Cormier YRelative scarcity of asthma and atopy among rural adolescents raised on a farm. Am J Respir Crit Care Med161200015631566
47. Franklin P, Dingle P, Stick SRaised exhaled nitric oxide in healthy children is associated with domestic formaldehyde levels. Am J Respir Crit Care Med161200017571759
48. Dales RE, Cakmak S, Burnett RT, Judek S, Coates F, Brook JRInfluence of ambient fungal spores on emergency visits for asthma to a regional children's hospital. Am J Respir Crit Care Med162200020872090
49. Douwes J, Zuidhof A, Doekes G, van der Zee SC, Wouters I, Boezen MH, Brunekreef B(1→ 3)-β-d-glucan and endotoxin in house dust and peak flow variability in children. Am J Respir Crit Care Med162200013481354
50. Schwartz J, Timonen KL, Pekkanen JRespiratory effects of environmental tobacco smoke in a panel study of asthmatic and symptomatic children. Am J Respir Crit Care Med1612000802806
51. Li YF, Gilliland FD, Berhane K, McConnell R, Gauderman WJ, Rappaport EB, Peters JMEffects of in utero and environmental tobacco smoke exposure on lung function in boys and girls with and without asthma. Am J Respir Crit Care Med162200020972104
52. Bosken CH, Hunt WC, Lambert WE, Samet JMA parental history of asthma is a risk factor for wheezing and nonwheezing respiratory illnesses in infants younger than 18 months of age. Am J Respir Crit Care Med161200018101815
53. Norzila MZ, Fakes K, Henry RL, Simpson J, Gibson PGInterleukin-8 secretion and neutrophil recruitment accompanies induced sputum eosinophil activation in children with acute asthma. Am J Respir Crit Care Med1612000769774
54. Marguet C, Dean TP, Warner JOSoluble intercellular adhesion molecule-1 (sICAM-1) and interferon-γ in bronchoalveolar lavage fluid from children with airway diseases. Am J Respir Crit Care Med162200010161022
55. Silverman M, Pedersen S, Grigg JMeasurement of airway inflammation in children. Introduction. Am J Respir Crit Care Med1622000S1
56. Larsen GL, Holt PGThe concept of airway inflammation. Am J Respir Crit Care Med1622000S2S6
57. Tiddens H, Silverman M, Bush AThe role of inflammation in airway disease: remodeling. Am J Respir Crit Care Med1622000S7S10
58. Bush A, Tiddens H, Silverman MClinical implications of inflammation in young children. Am J Respir Crit Care Med1622000S11S14
59. Shields MD, Riedler JBronchoalveolar lavage and tracheal aspirate for assessing airway inflammation in children. Am J Respir Crit Care Med1622000S15S17
60. Bush A, Pohunek PBrush biopsy and mucosal biopsy. Am J Respir Crit Care Med1622000S18S22
61. de Jongste JC, Alving KGas analysis. Am J Respir Crit Care Med1622000S23S27
62. Frischer T, Baraldi EUpper airway sampling. Am J Respir Crit Care Med1622000S28S30
63. Koller DYSampling methods: urine/blood analysis. Am J Respir Crit Care Med1622000S31S33
64. Von Mutius EStatistical/design methods. Am J Respir Crit Care Med1622000S34S35
65. Jones CA, Holt PGImmunopathology of allergy and asthma in childhood. Am J Respir Crit Care Med1622000S36S39
66. Openshaw PJ, Hewitt CProtective and harmful effects of viral infections in childhood on wheezing disorders and asthma. Am J Respir Crit Care Med1622000S40S43
67. Stone VEnvironmental air pollution. Am J Respir Crit Care Med1622000S44S47
68. Wilson N, Pedersen SInflammatory markers in clinical practice. Am J Respir Crit Care Med1622000S48S51
69. Grigg J, Riedler JDevelopmental airway cell biology. The “normal” young child. Am J Respir Crit Care Med1622000S52S55
70. Martinez FDContext dependency of markers of disease. Am J Respir Crit Care Med1622000S56S57
71. Ownby DR, Peterson EL, Johnson CCFactors related to methacholine airway responsiveness in children. Am J Respir Crit Care Med161200015781583
72. Weiss ST, Van Natta ML, Zeiger RSRelationship between increased airway responsiveness and asthma severity in the Childhood Asthma Management Program. Am J Respir Crit Care Med16220005056
73. Springer C, Godfrey S, Picard E, Uwyyed K, Rotschild M, Hananya S, Noviski N, Avital AEfficacy and safety of methacholine bronchial challenge performed by auscultation in young asthmatic children. Am J Respir Crit Care Med1622000857860
74. Scollo M, Zanconato S, Ongaro R, Zaramella C, Zacchello F, Baraldi EExhaled nitric oxide and exercise-induced bronchoconstriction in asthmatic children. Am J Respir Crit Care Med161200010471050
75. Nielsen KG, Bisgaard HLung function response to cold air challenge in asthmatic and healthy children of 2–5 years of age. Am J Respir Crit Care Med161200018051809
76. Davenport PW, Cruz M, Stecenko AA, Kifle YRespiratory-related evoked potentials in children with life-threatening asthma. Am J Respir Crit Care Med161200018301835
77. Asmussen L, Olson LM, Grant EN, Landgraf JM, Fagan J, Weiss KBUse of the child health questionnaire in a sample of moderate and low-income inner-city children with asthma. Am J Respir Crit Care Med162200012151221
78. Nielsen KG, Bisgaard HThe effect of inhaled budesonide on symptoms, lung function, and cold air and methacholine responsiveness. Am J Respir Crit Care Med162200015001506
79. Mellon M, Leflein J, Walton-Bowen K, Cruz-Rivera M, Fitzpatrick S, Smith JAComparable efficacy of administration with face mask or mouthpiece of nebulized budesonide inhalation suspension for infants and young children with persistent asthma. Am J Respir Crit Care Med1622000593598
80. Bisgaard H, Nielsen KGBronchoprotection with a leukotriene receptor antagonist in asthmatic preschool children. Am J Respir Crit Care Med1622000187190
81. Onhoj J, Thorsson L, Bisgaard HLung deposition of inhaled drugs increases with age. Am J Respir Crit Care Med162200018191822
82. Gauderman WJ, McConnell R, Gilliland F, London S, Thomas D, Avol E, Vora H, Berhane K, Rappaport EB, Lurmann F, Margolis HG, Peters JAssociation between air pollution and lung function growth in southern California children. Am J Respir Crit Care Med162200013831390
83. Mansi A, Cucchiara S, Greco L, Sarnelli P, Pisanti C, Franco MT, Santamaria FBronchial hyperresponsiveness in children and adolescents with Crohn's disease. Am J Respir Crit Care Med161200010511054
84. Smith DE, Otulakowski G, Yeger H, Post M, Cutz E, O'Brodovich HMEpithelial Na+ channel (ENaC) expression in the developing normal and abnormal human perinatal lung. Am J Respir Crit Care Med161200013221331
85. Gross NJ, Kellam M, Young J, Krishnasamy S, Dhand RSeparation of alveolar surfactant into subtypes. A comparison of methods. Am J Respir Crit Care Med1622000617622
86. Ingenito EP, Mora R, Mark LPivotal role of anionic phospholipids in determining dynamic behavior of lung surfactant. Am J Respir Crit Care Med1612000831838
87. Cutz E, Wert SE, Nogee LM, Moore AMDeficiency of lamellar bodies in alveolar type II cells associated with fatal respiratory disease in a full-term infant. Am J Respir Crit Care Med1612000608614
88. Nogee LM, Wert SE, Proffit SA, Hull WM, Whitsett JAAllelic heterogeneity in hereditary surfactant protein B (SP-B) deficiency. Am J Respir Crit Care Med1612000973981
89. Bunt JE, Carnielli VP, Darcos Wattimena JL, Hop WC, Sauer PJ, Zimmermann LJ. The effect in premature infants of prenatal corticosteroids on endogenous surfactant synthesis as measured with stable isotopes. Am J Respir Crit Care Med 2000;162:844–849.
90. Jobe AH, Newnham JP, Willet KE, Moss TJ, Gore EM, Padbury JF, Sly P, Ikegami MEndotoxin-induced lung maturation in preterm lambs is not mediated by cortisol. Am J Respir Crit Care Med162200016561661
91. Avery MESurfactant deficiency in hyaline membrane disease: the story of discovery. Am J Respir Crit Care Med161200010741075
92. Torresin M, Zimmermann LJ, Cogo PE, Cavicchioli P, Badon T, Giordano G, Zacchello F, Sauer PJ, Carnielli VPExogenous surfactant kinetics in infant respiratory distress syndrome: a novel method with stable isotopes. Am J Respir Crit Care Med161200015841589
93. Bernhard W, Mottaghian J, Gebert A, Rau GA, von der Hard H, Poets CFCommercial versus native surfactants: surface activity, molecular components, and the effect of calcium. Am J Respir Crit Care Med162200015241533
94. Almaas R, Robertson B, Linderholm B, Lundberg E, Saugstad OD, Moen AReversal of meconium inhibition of pulmonary surfactant by ferric chloride, copper chloride, and acetic acid. Am J Respir Crit Care Med162200017891794
95. Lu KW, William TH, Robertson B, Goerke J, Clements JAPolymer-surfactant treatment of meconium-induced acute lung injury. Am J Respir Crit Care Med1622000623628
96. Hafner D, Germann PGAdditive effects of phosphodiesterase-4 inhibition on effects of rSP-C surfactant. Am J Respir Crit Care Med161200014951500
97. Noone PG, Pue CA, Zhou Z, Friedman KJ, Wakeling EL, Ganeshananthan M, Simon RH, Silverman LM, Knowles MRLung disease associated with the IVS8 5T allele of the CFTR gene. Am J Respir Crit Care Med162200019191924
98. Grasemann H, Knauer N, Buscher R, Hubner K, Drazen JM, Ratjen FAirway nitric oxide levels in cystic fibrosis patients are related to a polymorphism in the neuronal nitric oxide synthase gene. Am J Respir Crit Care Med162200021722176
99. Wilschanski M, Famini C, Blau H, Rivlin J, Augarten A, Avital A, Kerem B, Kerem EA pilot study of the effect of gentamicin on nasal potential difference measurements in cystic fibrosis patients carrying stop mutations. Am J Respir Crit Care Med1612000860865
100. McColley SA, Stellmach V, Boas SR, Jain M, Crawford SESerum vascular endothelial growth factor is elevated in cystic fibrosis and decreases with treatment of acute pulmonary exacerbation. Am J Respir Crit Care Med161200018771880
101. van Heeckeren AM, Tscheikuna J, Walenga RW, Konstan MW, Davis PB, Erokwu B, Haxhiu MA, Ferkol TWEffect of Pseudomonas infection on weight loss, lung mechanics, and cytokines in mice. Am J Respir Crit Care Med1612000271279
102. Paredi P, Kharitonov SA, Leak D, Shah PL, Cramer D, Hodson ME, Barnes PJExhaled ethane is elevated in cystic fibrosis and correlates with carbon monoxide levels and airway obstruction. Am J Respir Crit Care Med161200012471251
103. Moser C, Tirakitsoontorn P, Nussbaum E, Newcomb R, Cooper DMMuscle size and cardiorespiratory response to exercise in cystic fibrosis. Am J Respir Crit Care Med162200018231827
104. Aris RM, Stephens AR, Ontjes DA, Denene BA, Lark RK, Hensler MB, Neuringer IP, Lester GEAdverse alterations in bone metabolism are associated with lung infection in adults with cystic fibrosis. Am J Respir Crit Care Med162200016741678
105. Ionescu AA, Nixon LS, Evans WD, Stone MD, Lewis-Jenkins V, Chatham K, Shale DJBone density, body composition, and inflammatory status in cystic fibrosis. Am J Respir Crit Care Med1622000789794
106. Aris RM, Lester GE, Renner JB, Winders A, Denene BA, Lark RK, Ontjes DAEfficacy of pamidronate for osteoporosis in patients with cystic fibrosis following lung transplantation. Am J Respir Crit Care Med1622000941946
107. Milla CE, Warwick WJ, Moran ATrends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline. Am J Respir Crit Care Med1622000891895
108. Sanders NN, De Smedt SC, Van Rompaey E, Simoens P, De Baets F, Demeester JCystic fibrosis sputum: a barrier to the transport of nanospheres. Am J Respir Crit Care Med162200019051911
109. Ferkol T, Eckman E, Swaidani S, Silski C, Davis PTransport of bifunctional proteins across respiratory epithelial cells via the polymeric immunoglobulin receptor. Am J Respir Crit Care Med1612000944951
110. Perks B, Shute JKDNA and actin bind and inhibit interleukin-8 function in cystic fibrosis sputa: in vitro effects of mucolytics. Am J Respir Crit Care Med162200017671772
111. Finlay WH, Lange CF, King M, Speert DPLung delivery of aerosolized dextran. Am J Respir Crit Care Med16120009197
112. Fauroux B, Itti E, Pigeot J, Isabey D, Meignan M, Ferry G, Lofaso F, Willemot JM, Clement A, Harf AOptimization of aerosol deposition by pressure support in children with cystic fibrosis: an experimental and clinical study. Am J Respir Crit Care Med162200022652271
113. Ciabattoni G, Davi G, Collura M, Iapichino L, Pardo F, Ganci A, Romagnoli R, Maclouf J, Patrono CIn vivo lipid peroxidation and platelet activation in cystic fibrosis. Am J Respir Crit Care Med162200011951201
114. Lang BJ, Aaron SD, Ferris W, Hebert PC, MacDonald NEMultiple combination bactericidal antibiotic testing for patients with cystic fibrosis infected with multiresistant strains of Pseudomonas aeruginosa. Am J Respir Crit Care Med162200022412245
115. Aaron SD, Ferris W, Henry DA, Speert DP, MacDonald NEMultiple combination bactericidal antibiotic testing for patients with cystic fibrosis infected with Burkholderia cepacia. Am J Respir Crit Care Med161200012061212
116. Vizza CD, Yusen RD, Lynch JP, Fedele F, Alexander PG, Trulock EPOutcome of patients with cystic fibrosis awaiting lung transplantation. Am J Respir Crit Care Med1622000819825
Correspondence and requests for reprints should be addressed to Martin J. Tobin, M.D., Division of Pulmonary and Critical Care Medicine, Hines Veterans Affairs Hospital, Route 111N, Hines, IL 60141. E-mail:

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