Pediatrics, Surfactant, and Cystic Fibrosis in AJRCCM 2001 

MARTIN J. TOBIN

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

	CONTENTS

TOP CONTENTS PEDIATRICS SURFACTANT BIOLOGY AND... CYSTIC FIBROSIS REFERENCES

Pediatrics (62)

    Pulmonary Function Testing and Diagnostic Techniques (13)

        Normative Values (1)

        Thoracoabdominal Compression (1)

        Spirometry (4)

        Forced Oscillation (3)

        Exhaled Nitric Oxide (1)

        Respiratory Muscles and Mechanics (3)

    Mechanical Ventilation (4)

    Respiratory Syncytial Virus Bronchiolitis (8)

    Sleep and Control of Breathing (5)

    Pediatric Asthma (23)

        Epidemiology (6)

        Risk Factors: Air Pollution (1)

        Risk Factors: Aeroallergens (2)

        Risk Factors: Parental Asthma and Exposure (1)

        Airway Inflammation (6)

        Airway Hyperreactivity (3)

        Clinical Issues (1)

        Treatment (3)

    Other Pediatric Issues (9)

        Passive Smoking (2)

        Lung Development (2)

        Bronchopulmonary Dysplasia (5)

Surfactant Biology and Disorders (11)

    Pathophysiology (7)

    Treatment (3)

    Workshop (1)

Cystic Fibrosis (12)

    Genetics (1)

    Lung Inflammation (2)

    Microbiology (1)

    Pathophysiology and Exercise Performance (3)

    Treatment (3)

        Gene Therapy (1)

        Lung Transplantation (2)

    Outcome (2)

	PEDIATRICS

TOP CONTENTS PEDIATRICS SURFACTANT BIOLOGY AND... CYSTIC FIBROSIS REFERENCES

Pulmonary Function Testing and Diagnostic Techniques

Normative values In 49 healthy infants, between one week and two years of age, Tepper and colleagues (1) recorded static pressure-volume curves. The respiratory system was inflated with an airway pressure of 30 cm H₂O, and static recoil pressure was measured during multiple brief occlusions as the system was deflated. Compliance and expired volume (between peak inflation and functional residual capacity) increased with increasing body length. After adjusting for length, compliance was higher in male as compared with female infants. Expired volume was smaller in female infants and in infants whose mothers had smoked during pregnancy. The authors conclude that compliance of the respiratory system increases with body length and is higher in male infants, and that maternal smoking during pregnancy may produce lung hypoplasia.

Thoracoabdominal compression To assess lung function in infants and children without HIV infection but born to mothers with HIV infection, Colin and coworkers (2) studied 285 children, aged 6 to 30 months. Using the rapid thoracic compression maneuver, the maximal expiratory flow at functional residual capacity (FRC) was positively correlated with height. The slope of the regression in exposed children did not differ from the slope in healthy children. The intercept in the exposed children was about 20% lower as compared with the healthy children. The authors conclude that maternal HIV infection has a modest effect on expiratory flow in uninfected children.

Spirometry To determine whether birth weight influences airway function, Lum and coworkers (3) did partial and raised volume forced expiratory maneuvers in 103 infants (gestation of more than 35 weeks) at about 6 to 7 weeks after birth. The infants had not been exposed to maternal smoking either before or after birth. The 38 infants with a low birth weight were shorter and lighter at testing as compared with the 65 infants with an appropriate birth weight. Compared with the infants of appropriate birth weight, the infants with a low birth weight had a lower forced vital capacity (FVC), 127 versus 143 ml, lower forced expiratory volume in 0.4 seconds (FEV_0.4), 112 versus 125 ml, and lower forced expired flow at 75% of FVC (FEF₇₅), 173 versus 203 ml per second. After correcting for sex and body size, the differences between the two groups were no longer significant. Boys had a lower FEF₇₅ as compared with girls: 177 versus 209 ml per second. The authors conclude that infants who are born small for gestational age have decreased airway function during the first few months of life, and that the decrease is mediated through impaired body growth rather than through a specific effect on lung growth.

Forced oscillation The forced oscillation technique and the interrupter technique are attractive for detecting airway obstruction in children because they require only passive cooperation. Delacourt and coworkers (7) compared the diagnostic accuracy of these two techniques in 118 children (ages 3 to 16 years) with asthma or chronic nocturnal cough. In 93 children able to perform forced expiratory maneuvers, R₀ on forced oscillation achieved the best discrimination between children with FEV₁ above and below 80% of predicted. (R₀ is the resistance extrapolated to 0 Hz, and is thought to reflect airway and tissue resistance plus delayed resistance secondary to gas redistribution.) At a specificity of 80%, R₀ yielded a sensitivity of 66% and resistance measured by the interrupter technique yielded a sensitivity of 33%. At a specificity of 80%, the change in R₀ after inhaling a bronchodilator yielded a sensitivity of 67% and the change in interrupter resistance after bronchodilator yielded a sensitivity of 58%. In 25 children unable to perform forced expiratory maneuvers, the oscillatory technique identified a subgroup of children with high values of resistance that fell to normal after bronchodilator therapy; similar discrimination was not achieved by the interrupter technique. The authors conclude that the forced oscillation technique provides a more reliable measure of bronchial obstruction and its reversibility in young children, as compared with the interrupter technique.

Exhaled nitric oxide Buchvald and Bisgaard (10) described a new method for measuring exhaled nitric oxide during controlled tidal breathing in 67 children, aged 2 to 14 years. While continuously adjusting an expiratory resistance, the operator targeted the child's exhaled flow within preset limits of 0.4 to 0.6 liters per second. The new method showed good agreement against the reference method of a single breath maneuver performed online, and performed better than measuring nitric oxide in exhaled air collected in a bag. With the new technique, the fraction of nitric oxide was higher in asthmatic children as compared with the healthy children (4-8 versus 2-4 parts per billion). Tapering a maintenance dose of budesonide in nine children caused exhaled nitric oxide to increase from 4 to 13 ppb. The authors conclude that exhaled nitric oxide can be measured online at a fixed exhalation rate in children as young as 2 years, and that the concentration covaries with asthma severity and the dosage of glucocorticoids.

Respiratory muscles and mechanics To determine the effect of maturation on diaphragmatic function, Dimitriou and coworkers (11) studied 28 infants with a post-conceptional age of 37.6 weeks (range, 25 to 44 weeks). Transdiaphragmatic pressure during crying was 16% lower in 12 infants who were preterm (post-conceptional age of 37 weeks or lower); the pressure was correlated with post-conceptional age (r = 0.44). In 14 infants, transdiaphragmatic pressure during crying was correlated with maximum inspiratory pressure (r = 0.79). The authors conclude that maturation affects diaphragmatic function.

Mechanical Ventilation

In 11 piglets with acute lung injury created by saline lavage, Katz and coworkers (14) assessed whether a helium oxygen mixture would enhance gas exchange during high-frequency oscillatory ventilation. Compared with 40% nitrogen and 60% oxygen, a mixture of 40% helium and 60% oxygen decreased PCO₂ by 11%, and a mixture of 60% helium and 40% oxygen reduced PCO₂ by 20%. The mixture of 40% helium and 60% oxygen produced 21% higher oxygenation as compared with the mixture of 40% nitrogen and 60% oxygen. In a test lung, tidal volume increased by 66% when the ventilator was operated with 60% helium and 40% oxygen. The authors conclude that a a mixture of helium and oxygen improves oxygenation and the removal of carbon dioxide during high-frequency oscillatory ventilation, but the associated increase in tidal volume may counteract the benefit.

Unlike the adult lung, the fetal lung contains almost no neutrophils or macrophages. To determine whether mechanical ventilation produces an inflammatory response in the preterm lung, Naik and coworkers (15) studied lambs delivered 21 days before term. Before the first breath, each animal received recombinant human surfactant protein-C. Compared with unventilated animals, the ventilated animals had increases in alveolar protein, activated neutrophils, and expression of messenger RNAs for interleukin-1, interleukin-6, interleukin-8, and tumor necrosis factor- in their lung tissue. Animals ventilated with PEEP of 4 cm H₂O had lower levels of alveolar protein and neutrophils as compared with the animals ventilated with a PEEP of 0 or 7 cm H₂O, and lower levels of messenger RNAs for interleukin-1, interleukin-6, and interleukin-8 as compared with the animals ventilated with a PEEP of 0 cm H₂O. On morphometry, the fractional area of collapsed alveoli was higher in animals ventilated with ZEEP versus PEEP of 4 or 7 cm H₂O. The authors conclude that mechanical ventilation causes injury of the preterm lung and the release of proinflammatory mediators and that the response is lessened with use of PEEP of 4 cm H₂O.

To determine the incidence, cost, and outcome of the use of mechanical ventilation in newborn infants requiring mechanical ventilation, Angus and coworkers (16) analyzed discharge data on 16,405 newborns receiving mechanical ventilation in California and New York in 1994. Compared with infants of normal birth weight (at least 2,500 g), the rate of mechanical ventilation was 16 times higher in infants with a low birth weight (1,500 to 2,499 g) and 69 times higher in infants with a very low birth weight (less than 1,500 g). Of all infants receiving mechanical ventilation, 38% had normal birth weight. The incidence of mechanical ventilation was 28% higher in boys than in girls, and 74% higher in black than in white infants. Hospital mortality was 11%, length of stay 31 days, and hospital costs $51,700. The authors estimate that 80,000 neonates receive mechanical ventilation every year in the United States, with total annual cost of $4.4 billion. The authors conclude that neonatal respiratory failure is common, expensive, and frequently lethal.

Laryngomalacia accounts for more than 75% of cases of congenital stridor, and some infants require a tracheostomy. Fauroux and coworkers (17) studied five children with chronic stridor caused by laryngomalacia. Compared with spontaneous breathing, noninvasive ventilation produced a 33% increase in tidal volume, a 53% decrease in respiratory rate, and a 60% decrease in diaphragmatic effort. A total of 12 children with laryngomalacia received long-term noninvasive ventilation in the home, and they experienced improvements in sleep and growth. The authors conclude that noninvasive ventilation can decrease the increased respiratory load in children with laryngomalacia and contribute to improved clinical status on long-term follow-up.

Respiratory Syncytial Virus

To determine whether nebulized epinephrine alters lung mechanics, Numa and coworkers (18) studied 15 infants (median age, 2 months) with RSV-positive bronchiolitis. Lung mechanics were evaluated using a two-compartment model of the flow-volume curve. Epinephrine produced a 54% decrease in resistance of the slow compartment and a 31% decrease in resistance of the fast compartment, with no change in compliance or oxygenation. The authors conclude that nebulized epinephrine decreases respiratory system resistance in infants with RSV-positive bronchiolitis.

Kao and colleagues (19) investigated whether infection with respiratory syncytial virus (RSV) alters the production of nitric oxide by airway epithelial cells. RSV infection increased the release of nitrites in monolayers of human epithelial cells (A549), in human small-airway epithelial cells, and in bronchoalveolar fluid of BALB/c mice. The increase in nitrite was associated with activation of inducible nitric oxide synthase. The increase in nitric oxide production was not affected by interferon- or interleukin-13, whereas production was decreased by interleukin-4 (a Th2-type cytokine) and dexamethasone. The authors conclude that RSV infection enhances the production of nitric oxide by activating inducible nitric oxide synthase within the airway epithelium.

A series of review articles focusing on the link between respiratory syncytial virus and reactive airways disease (20) arose from a symposium on this topic.

Sleep and Control of Breathing

Over an 18-month period, Katz and coworkers (26) saw three neonates with flutter of the diaphragm and intercostal muscles. The infants presented with respiratory failure shortly after birth. The breathing pattern was dirhythmic: a regular underlying rate of 60 breaths per minute, and a superimposed fast rate of 300 flutters per minute limited to inspiration. The infants had associated dysphagia, laryngomalacia, and gastroesophageal reflux. All had a favorable response to continuous positive airway pressure (CPAP). Chlorpromazine terminated the flutter and permitted weaning from ventilator support within a few hours. The children were developmentally normal at 8, 10, and 26 months of age. The authors conclude that the syndrome of respiratory flutter may be more common than is commonly suspected.

In 18 children with obstructive sleep apnea (aged 2 to 9 years and with an apnea-hypopnea index of 11.2), Arens and coworkers (27) assessed the structure of the upper airway using magnetic resonance imaging under sedation. Compared with control subjects, the volume of the upper airway was 40% smaller, the adenoids 55% larger, and the tonsils 57% larger in the patients. The volume of the mandible and tongue were similar in the two groups. The apnea-hypopnea index was correlated with the volume of the tonsils and adenoids (r = 0.51). The authors conclude that the upper airway is smaller in children with obstructive sleep apnea because the adenoids, tonsils, and soft palate are enlarged.

In a state of the art review article, Marcus (28) discusses sleep-disordered breathing in children.

In a state of the art review article, Hunt (29) discusses the mechanisms, risks, and diagnosis of the sudden infant death syndrome (SIDS).

In a pulmonary perspective, Gozal and Gaultier (30) discuss evolving concepts on the maturation of central pathways involved in the ventilatory response to hypoxia.

Pediatric Asthma

Epidemiology The recent increases in both obesity and asthma raise the possibility that the two are related. To evaluate the interaction, Castro-Rodriguez and colleagues (31) assessed changes in body mass index between early school years and early adolescence in children enrolled in a longitudinal study of asthma. Body mass index at six years of age was not related to the prevalence of wheezing at any age. Girls, but not boys, who were overweight at 11 years were more likely to have current wheezing at ages of 11 and 13 but not at ages of 6 or 8 years. Girls who became overweight between 6 and 11 years were seven times more likely to develop new symptoms of asthma at ages 11 or 13; at age 11, variability of PEFR and bronchodilator responsiveness were increased. The authors conclude that girls who become overweight between 6 and 11 years of age have an increased risk of developing new asthma symptoms and increased bronchial responsiveness during early adolescence.

Risk factors: air pollution The primary exhaust pollutants from motor vehicles are increased up to a distance of 150 m from a main road. To determine the relationship between wheezing in children and proximity of the home to the nearest main road, Venn and coworkers (40) analyzed data from a case-control study of 6,147 children aged 4 to 11 years, and from a random cross-sectional sample of 3,709 children aged 11 to 16 years. Among children living within 150 m of a main road, the risk of wheezing increased with increasing proximity: the odds ratio per 30-m distance was 1.08 in the 4- to 11-year-old children and 1.16 in the 11- to 16-year-old children. Most of the increased risk was localized to within 90 m of the roadside, and the effects were stronger in girls than in boys. The authors conclude that the risk of wheezing is increased in children who live within 90 m of a main road.

Risk factors: aeroallergens Almquist and colleagues (41) asked, "Do children with asthma who are allergic to cats suffer exacerbations on exposure to cat allergen at school?" From a total of 410 children (aged 6 to 12 years) with asthma, cat allergy, and without a cat at home, the authors selected 92 children reporting no contact with furred pets. During the second and third weeks of the new school year after summer vacation, children attending classes that had more than the median number of cat owners experienced a fall in PEFR, more days with asthma symptoms, and increased use of medications. Children in classes with many cat owners had a 9-fold increased risk of exacerbated asthma after recommencing school. The authors conclude that indirect exposure to cats at school may cause worsening of asthma in children sensitized to cats.

Risk factors: parental asthma and exposure To determine whether prenatal exposure to indoor antigens predisposes to sensitization in infants, Miller and coworkers (43) studied 167 pregnant African American or Dominican women. Dust samples revealed increased levels of cockroach and mouse antigen, but not of mouse dust antigen, in the kitchens and beds of the women. Proliferation of mononuclear cells in response to an antigen was used as a surrogate for sensitization. Cord blood revealed increased proliferation of mononuclear cells in response to cockroach in 54%, to the dust mite Dermatophagoides pteronyssinus in 25%, to the dust mite D. farinae in 40%, and to mouse protein extract in 34%. Maternal blood revealed increased proliferation of mononuclear cells in response to cockroach in 43%, to D. pteronyssinus in 60%, to D. farinae in 65%, and to mouse protein extract in 30%. Proliferation of mononuclear cells in response to antigens occurred in the blood of some infants without it occurring in the mother. Proliferation in response to antigen did not correlate with IgE levels, but proliferation in response to D. pteronyssinus extract was correlated with production of interleukin-5 in cord blood (r = 0.41). The authors conclude that in utero sensitization to indoor antigens is common in a population with a high prevalence of asthma morbidity.

Airway inflammation To determine the nature of airway inflammation in very young wheezing children, Krawiec and colleagues (44) did bronchoalveolar lavage in 20 wheezing children (median age, 15 months) and in six healthy controls. The total number of bronchoalveolar cells was three times higher in the wheezing children. Similar to adults with asthma, the number of lymphocytes and epithelial cells were increased. Unlike adults or older children, the number of macrophages and neutrophils was increased but the increase in eosinophils was more modest. Wheezing children had increased levels of prostaglandin E_2, 15-hydroxyeicosatetraenoic acid, leukotriene E₄, and leukotriene B₄, but not of prostaglandin D₂ or -tryptase. The authors conclude that inflammatory cells and mediators are found in the airways at a very early age in children with wheezing, and that the inflammation does not have a specific cellular pattern. An editorial commentary by Bisgaard (45) accompanies this article.

Airway hyperreactivity Because of evidence that abnormalities early in life are important in causing childhood asthma, Palmer and colleagues (50) determined whether airway hyperresponsiveness at one month predicts asthma at six years of age. Airway hyperresponsiveness to histamine at one month was associated with decreases in FEV₁ and FVC, and with increases in physician-diagnosed asthma and lower respiratory tract symptoms at six years of age. Skin reactivity to common allergies at one month and serum IgE did not predict clinical and physiologic outcomes at six years. The authors conclude that airway hyperresponsiveness at one month predicts abnormal lung function and the emergence of asthma by six years of age.

Clinical issues Gibson and coworkers (53) studied the role of eosinophilic airway inflammation in children with the variant asthma syndromes of chronic cough and recurrent wheeze. Of 28 children with wheeze, aged 8 to 11 years, 45% had eosinophilic bronchitis (sputum eosinophils greater than 2.5%) as compared with 9.4% of 26 healthy children. The children with wheeze had 12% lower PEFR as compared with the control children. Twelve children with chronic cough and 17 children with recurrent colds did not have an increased frequency of eosinophilic bronchitis and their PEFR was normal. Chronic cough and chest colds were associated with exposure to cigarette smoke in the home. The authors conclude that wheeze is a good predictor of eosinophilic bronchitis and that persistent cough and recurrent colds should not be considered a variant of asthma.

Treatment When instituting inhaled glucocorticoids in children with asthma, it is common to start with a high dose with the intent of aggressively decreasing airway inflammation and to then decrease the dose in a stepwise fashion. To test the efficacy of this strategy, Visser and coworkers (54) entered 55 children with mild-to-moderate asthma, aged 6 to 10 years, into a one-year double-blind trial of inhaled fluticasone proprionate delivered as a constant dose (200 µg daily) or using stepdown approach (starting at 1,000 µg daily for 2 months, and then 500 µg daily for 2 months, 200 µg daily for 2 months, and 100 µg daily for 6 months). The PD₂₀ for methacholine improved with both treatment strategies, and was superior for the stepdown approach at four months. At 1 year, airway hyperresponsiveness, lung function, exhaled nitric oxide, and standing height were equivalent in the two groups. The authors conclude that use of a stepdown approach to the dosing of an inhaled glucocorticoid is not superior to the use of a constant dose in children with mild to moderate asthma.

Other Pediatric Issues

Passive smoking Maternal smoking during pregnancy causes reduced expiratory flow and increased airway responsiveness in newborn infants. To investigate the mechanisms by which this occurs, Elliot and colleagues (57) exposed pregnant guinea pigs to cigarette smoke for 40 days before term. Newborn animals, studied 21 days after delivery, had heightened airway responsiveness, and the distance between alveolar attachments was greater because of fewer attachments and an increase in the perimeter of the outer wall of the airway. The authors conclude that in utero exposure to cigarette smoke causes increased airway responsiveness in newborn animals as a result of decreased alveolar attachments and changes in airway dimensions.

Lung development To determine whether systemic or local inflammation in amniotic fluid is required for subsequent lung maturation, Kramer and coworkers (59) injected various doses of endotoxin into the amniotic cavity of pregnant sheep 7 days before preterm delivery at a gestation of 125 days. Both 4 and 10 mg of endotoxin produced similar degrees of inflammation in the chorioamnion and lung, and similar lung maturation. Both 0.1 mg and 1 mg of endotoxin caused chorioamnionitis and lung and systemic inflammation, but did not induce lung maturation. These findings indicate that some inflammation can occur without subsequent lung maturation. Five hours after injecting 4 mg of endotoxin into the amniotic cavity, inflammatory cells were found in the airways and the levels of interleukin-6 and -8 were increased in cord blood, indicating both a pulmonary and a systemic response. Cells recruited into the amniotic fluid produced proinflammatory cytokine messenger RNA for 7 days; cytokine messenger RNA was absent from the chorioamnion, lung, and spleen after 72 hours. The authors conclude that exposing the fetus to inflammation above a certain threshold induces lung maturation.

Bronchopulmonary dysplasia Bronchopulmonary dysplasia appears to evolve from an early inflammatory response, which has been associated with oxidation of lung proteins. To determine whether specific protein oxidations in the first week of life help in predicting which infants will subsequently develop bronchopulmonary dysplasia, Ramsay and coworkers (61) obtained tracheal aspirates on the first, third, and sixth day of life in infants born after a gestation of 29 weeks or less. Of 45 infants, 19 developed bronchopulmonary dysplasia, 16 did not, and 10 died before the 28th day of postnatal life. The level of Clara cell secretory protein was twice as high on the first day of life in the infants who did not develop bronchopulmonary dysplasia as in the other two groups. Infants who died had higher levels of a protein that reacted with DNPH (2,4-dinitrophenylhydrazinea substance that reacts with aldehydes, ketones, and other products of protein oxidation) than the other two groups. The authors conclude that the levels of Clara cell secretory protein in tracheal aspirates are decreased in infants who subsequently develop bronchopulmonary dysplasia.

	SURFACTANT BIOLOGY AND DISORDERS

TOP CONTENTS PEDIATRICS SURFACTANT BIOLOGY AND... CYSTIC FIBROSIS REFERENCES

Pathophysiology

Surfactant function is impaired in patients with the acute respiratory distress syndrome, but the underlying mechanism is not known. Schmidt and colleagues (66) did bronchoalveolar lavage in 39 mechanically ventilated patients with ARDS, pneumonia, or both. The percentage of palmitic acid in phosphatidylcholine was 80% in eight healthy subjects, and it was about 15% lower in the patients. The concentration of unsaturated species in phosphatidylcholine was increased in the patients. The patients had only minor changes in the fatty acid pattern of sphingomyelin and phosphatidylethanolomine. The minimal surface tension of large surfactant aggregates was increased from near zero in the control subjects to about 16 mN per m in the patients, and it was inversely correlated with the percentage of palmitic acid in phosphatidylcholine (r = 0.68). Adding dipalmitoylated phosphatidylcholine to achieve control values of large surfactant aggregates improved minimal surface tension. The authors conclude that the fatty acid composition of surfactant is altered in patients with ARDS, and that the marked loss in the fraction of palmitic acid may contribute to impaired surfactant function.

In rabbits with acute lung injury, Kerr and coworkers (67) compared the effects of high-frequency oscillation versus controlled mechanical ventilation on lung function and surfactant kinetics. High-frequency ventilation achieved better oxygenation as compared with conventional ventilation. The percentage of surfactant recovered in large aggregate forms was greater with high-frequency oscillation. The conversion of surfactant from large aggregate forms that are functionally active to small aggregate forms of inferior function was less with high-frequency ventilation. The authors conclude that high-frequency oscillation achieved better oxygenation and surfactant kinetics as compared with conventional ventilation in a rabbit model of acute lung injury.

Unlike the adult lung, the preterm lung contains virtually no granulocytes or mature macrophages. Kramer and colleagues (68) asked, "Does surfactant protein A alter the proinflammatory response of the preterm lung to mechanical ventilation?" Lambs delivered after 20 days before term were ventilated for 15 minutes to initiate an inflammatory response and were then treated with recombinant human surfactant protein C, with or without ovine surfactant protein A. After six hours, animals receiving the surfactant protein A supplement had five times more cells, mainly granulocytes, in alveolar washes. The cells were not activated, however, and they produced two-thirds less hydrogen peroxide as compared with the cells of animals receiving surfactant protein C alone. The surfactant protein A supplement produced an increase in messenger RNAs for interleukin-1, interleukin-6, and interleukin-8, but it had no effect on lung function, protein leakage, or messenger RNA for surfactant protein. The authors conclude that supplementing surfactant protein C treatment with surfactant protein A may overcome deficiencies in the recruitment of neutrophils for clearing bacteria from the airway of preterm infants.

Willet and colleagues (69) compared the effect of a single dose of betamethasone versus three doses at weekly intervals in pregnant ewes. Repetitive injections produced more pronounced structural changes as compared with a single injection: alveolar volume increased by 50 to 80%, numerical density of alveoli decreased by 30 to 40%, and pleural and interlobular septal volumes decreased by as much as 70%. The structural effect was the same when the treatment was given to either the mother or directly to the fetus. When delivery was delayed to term in animals receiving repetitive treatment, morphometry did not differ from that in untreated animals, indicating that the changes induced by betamethasone are reversible. The authors conclude that antenatal glucocorticoids promote functional maturation through effects on the parenchymal and nonparenchymal compartments, and that the changes are more pronounced with repetitive administration.

Deficiency of surfactant in premature infants may result from immaturity or from chronic lung disease, and the deficiency may predispose to lung infection. To investigate these issues, Awasthi and colleagues (70) studied two groups of baboons delivered prematurely at 68% of term. When animals were ventilated for up to two weeks without clinical incident, tissue pools of surfactant proteins A and D were equal to or exceeded those of adults, and the lavage pool of surfactant protein A increased progressively to about 35% of the adult level by 14 days. Animals that were ventilated for one to two months developed chronic lung disease complicated by infection; most of these animals had lavage pools of surfactant protein A of less than 20% of the adult level. A low level of lavage surfactant protein A was correlated with an index of infection (based on clinical, microbiologic, and histologic features) and release of interleukin-8. The authors conclude that the amounts of surfactant proteins A and D in lavage fluid predict the risk of infection in the evolution of neonatal chronic lung disease in premature baboons.

Infants with congenital diaphragmatic hernia have hypoplastic lungs and evidence of surfactant deficiency. To determine whether antenatal treatment with vitamin A would stimulate lung synthesis, Thébaud and coworkers (71) induced congenital diaphragmatic hernia in newborn rats by administering the herbicide, nitrofen, on Day 12 of gestation to pregnant rats. With this model, about 65% of exposed fetuses develop a right-sided congenital diaphragmatic hernia. When delivered on Day 21, fetuses with a congenital diaphragmatic hernia had reduced DNA content in their lungs, decreased surfactant disaturated phosphatidylcholine, decreased expression of surfactant protein-A and -C, and decreased type II cells. These abnormalities were reduced or returned to control values by treatment with vitamin A on Day 14. The authors conclude that antenatal treatment with vitamin A restores lung maturation in a rat model of congenital diaphragmatic hernia in terms of surfactant storage and expression.

The glucagon-like peptide 1 receptor is a member of the G-protein-linked receptors that mediate increases in cyclic AMP by activating adenyl cyclase. Vara and colleagues (72) studied the effect of an agonist and antagonist of this receptor on the secretion of surfactant by human type II pneumocytes. A truncated and amidated form of the peptide, glucagon-like peptide-1 (7) amide, and exendin-4 produced dose-dependent increases in cyclic AMP and secretion of phosphatidylcholine; these effects were reversed by exendin (9). Agents that inhibit protein kinase A reduced the secretion of surfactant by type II pneumocytes. An inhibitor of protein kinase C blocked most of the increase in phosphatidylcholine achieved by glucagon-like peptide 1 (7) amide. A calcium ionophore had an additive effect with glucagon-like peptide 1 (7) amide, and an inhibitor of calcium-calmodulin-dependent protein kinase inhibited the effect of the calcium ionophore but not the stimulatory effect of glucagon-like peptide 1 (7) amide. The authors conclude that both protein kinase A and C are involved in the stimulatory action of glucagon-like peptide-1 (7) amide on secretion of phosphatidylcholine, whereas this peptide has no effect on the secretion of phosphatidylcholine mediated by calcium-calmodulin-dependent protein kinase.

Treatment

In 17 preterm infants, Cavicchioli and colleagues (73) studied surfactant kinetics by infusing an isotope of labeled palmitic and linoleic acid. The fractional synthesis rate of phosphatidylcholine-linoleic acid was 1.9 times higher as compared with that of phosphatidylcholine-palmitic acid, whereas its half-life was 50% shorter. Six infants receiving exogenous surfactant for respiratory distress syndrome had longer secretion times and delayed peak times, but the fractional secretion rate and half-life were unaffected. The authors conclude that infants treated with exogenous surfactant had a fractional synthesis rate and half-life similar to those of untreated infants.

In a rabbit model of gastric acid aspiration, Brackenbury and colleagues (74) evaluated the actions of three surfactant preparations (natural ovine, modified natural, and a synthetic preparation) and two delivery methods (lung lavage and instillation). Over the hour following administration, none of the regimens achieved sustained improvement in oxygenation, possibly because protein leakage inhibited the surfactant. High-frequency oscillation produced better oxygenation as compared with conventional ventilation. The authors conclude that various strategies of surfactant treatment were not effective in a model of gastric acid aspiration, although high-frequency oscillation produced improved oxygenation.

The addition of nonionic polymers, such as polyethylene glycol and dextran, can prevent and reverse some forms of surfactant inactivation in vitro. In rats with acute lung injury caused by either lipopolysaccharide or hydrochloric acid, Lu and coworkers (75) found that the addition of polyethylene glycol to Survanta produced improvements in serial measurements of PO₂ as compared with Survanta alone. Lung compliance on postmortem pressure-volume curves was higher in animals treated with the combination of the polymer and Survanta. Samples of tracheal fluid revealed lower dynamic surface tension in the animals treated with the combination. The authors conclude that the addition of polyethylene glycol to Survanta produced improved oxygenation and mechanical properties in animals with lung injuries caused by lipopolysaccharide or hydrochloric acid.

Workshop

The pathology of the surfactant system of the mature lung is discussed in the summary of an NHLBI workshop by Spragg and Lewis (76).

	CYSTIC FIBROSIS

TOP CONTENTS PEDIATRICS SURFACTANT BIOLOGY AND... CYSTIC FIBROSIS REFERENCES

Genetics

Premature stop mutations occur in about 10% of patients with cystic fibrosis. Because aminoglycosides can suppress stop mutations within the cystic fibrosis transmembrane conductance regulator (CFTR) gene, Clancy and coworkers (77) administered parenteral gentamicin for one week to 10 patients with cystic fibrosis (five with and five without stop mutations). On measuring nasal potential difference in the patients with stop mutations, gentamicin caused a threefold increase in the incidence of readings in the direction of chloride secretion. Four of the five patients had at least one reading during treatment in which the chloride secretory response was more than -5 mV (hyperpolarized); a response of this magnitude was not seen in any control patient. In 58 healthy subjects, 71% of readings were more than -5 mV. The authors conclude that gentamicin can suppress premature stop mutations in airway cells from patients with cystic fibrosis, and produce small increases in chloride conductance.

Lung Inflammation

Actin, on release from inflammatory cells, not only contributes to the increased viscosity of airway secretions but also inhibits the action of recombinant human DNase (DNase). Zahm and coworkers (78) compared the activity of wild-type DNase with a variant DNase resistant to actin. Mucus samples from patients with cystic fibrosis were frozen and thawed, a procedure that lyses cells in the manner of a severe infection. Both forms of DNase decreased the viscosity of airway secretions. The actin-resistant variant decreased the airway secretion contact angle and increased cough transport, as compared with the wild-type DNase. The authors conclude that the actin-resistant variant of recombinant human DNase has increased capacity to improve the physical properties of airway mucus from patients with cystic fibrosis.

To compare indices of airway inflammation in induced sputum versus spontaneously expectorated sputum, Sagel and coworkers (79) studied 7 patients with cystic fibrosis capable of producing sputum, 13 patients not capable of producing sputum, and 11 healthy subjects. Indices of airway inflammation, including total cell counts, absolute neutrophil counts, interleukin-8 levels, and elastase activity were increased in the patients as compared with the healthy subjects. The levels of total cells (r = 0.90) and interleukin-8 (r = 0.92) in induced and spontaneously expectorated sputum were correlated. Quantitative counts of bacterial pathogens were higher in the patients, and the same pathogens were found in both the induced and spontaneously expectorated samples. The authors conclude that indices of airway inflammation and infection are increased in children with cystic fibrosis, and that the values are similar in induced and spontaneously expectorated samples.

Microbiology

Several distinct species, termed genomovars, comprise bacteria identified as Burkholderia cepacia. LiPuma and coworkers (80) determined the species within the B. cepacia complex recovered in sputum from 606 patients with cystic fibrosis. Of patients infected with B. cepacia complex, 50% were infected with genomovar III, 38% with B. multivorans (formerly genomovar II), 5% with B. vietnamiensis (formerly genomovar V), and fewer than 5% were infected with genomovar I, B. stabilis (formerly genomovar IV), genomovar VI, or genomovar VII. The putative transmissibility factor, BCESM (the B. cepacia epidemic strain marker) was found in 46% of genomovar III isolates and not in any other species. The cblA gene, encoding the cable pilin subunit, was found in only one isolate. The authors conclude that closely related species of the Burkholderia cepacia complex differ in their capacity to cause infection, and neither BCESM nor cblA are sufficient as markers of transmissibility or virulence because of their low frequency.

Pathophysiology and Exercise Performance

Many patients with cystic fibrosis report benefit from regular exercise, but the mechanism of benefit is not known. To determine whether a single bout of exercise has an effect on activity of ion channels in the respiratory epithelium, Hebestreit and coworkers (81) measured the potential difference in the nasal epithelium of nine patients with cystic fibrosis and nine healthy subjects. The resting potential difference was 34 mV in the patients and -7 mV in the control subjects. Exercise caused the potential difference to become less negative in both the patients (7 mV) and the control subjects (0.1 mV). The addition of amiloride, which blocks amiloride-sensitive sodium channels, caused the potential difference to increase by 26 mV in the patients at rest and by 16 mV during exercise. In the healthy subjects, amiloride caused the potential difference to increase by 10 mV at rest and by 6 mV during exercise. Exercise had no effect on chloride conductance in either group. The authors conclude that exercise blocks amiloride-sensitive sodium conductance in the respiratory epithelium of patients with cystic fibrosis, and that the resulting increase in water content of mucus may explain the beneficial effects of exercise.

To determine the anabolic and catabolic mediator response to exercise in patients with cystic fibrosis, Tirakitsoontorn and coworkers (82) studied 14 patients with cystic fibrosis (9 of whom were receiving ibuprofen) and 14 healthy subjects. Compared with the control subjects, insulin-like growth factor-I, an anabolic growth hormone, was 47% lower in the patients, and interleukin-6, a catabolic inflammatory cytokine, was 79% greater in the patients at rest. The level of insulin-like growth factor was correlated with peak oxygen consumption during exercise in the control subjects (r = 0.68) but not in the patients. Exercise produced increases in interleukin-6 and tumor necrosis factor-, and the increases were greatest in patients not receiving ibuprofen, lower in patients receiving ibuprofen, and lowest in the control subjects. The authors conclude that a brief bout of exercise causes an increase in inflammatory mediators in patients with cystic fibrosis and that the response may be attenuated by ibuprofen.

To determine whether patients with cystic fibrosis have subclinical right-ventricular dysfunction, Ionesco and coworkers (83) did tissue Doppler echocardiography in 21 clinically stable patients (aged 23 years), five patients with severe disease (aged 24 years), and 23 healthy subjects. The mean systolic velocity of the free wall of the right ventricle was decreased by 18% in the stable patients and by 19% in the patients with severe disease. The stable patients had a 63% increase in isovolumic relaxation time, indicating diastolic dysfunction of the right ventricle. The right ventricular free wall was 33% thicker in the patients. The peak systolic velocity of the right ventricle was correlated with FEV₁ (r = 0.62). The authors conclude that patients with cystic fibrosis have subclinical dysfunction of the right ventricle that correlates with the severity of lung disease.

Treatment

Gene therapy One method of delivering gene therapy is to form a complex of a gene with a cationic liposome (a lipoplex). Sanders and coworkers (84) determined the extent to which components of the sputum of patients with cystic fibrosis cause destruction of lipoplexes. Adding linear DNA in amounts found in sputum altered the surface charge and size of the lipoplexes, and liberated plasmid DNA from the lipoplexes. Pretreatment with human recombinant DNase fragmented the linear DNA and prevented the release of plasmid DNA. Adding albumin and mucin also changed the surface charge of the lipoplexes, but they did not cause release of plasmid DNA. Dipalmitoylglycerophosphocholine and dipalmitoylglycerophosphoglycerol did not cause any change in properties of lipoplexes. Native cystic fibrosis sputum caused dissociation of lipoplexes when the DNA concentration exceeded 2.7 mg per ml. The authors conclude that high DNA concentrations in sputum of patients with cystic fibrosis patients can cause disintegration of lipoplexes used in gene therapy.

Lung transplantation Patients with cystic fibrosis who are infected with Burkholderia cepacia complex have a high mortality, and are excluded from lung transplantation at some centers. To determine the influence of genomovar type on outcome, Aris and coworkers (85) studied 121 patients with cystic fibrosis undergoing lung transplantation. Three patients were infected with B. cepacia complex after surgery and all were treated successfully. Six-month mortality was 33% among 21 patients infected preoperatively as compared with a mortality of 12% in patients without infection. The increase in mortality was completely attributable to genomovar III of the B. cepacia complex, and five of the 12 patients with this genomovar died. The authors conclude that more than 40% of patients with cystic fibrosis who are infected with genomovar III of the Burkholderia cepacia complex before transplantation die in the early postoperative period.

Outcome

To assess the effect of socioeconomic status on outcome in patients with cystic fibrosis, Schechter and coworkers (87) analyzed data on 20,390 patients under 20 years of age entered in the national registry. Medicaid eligibility, which is tied to family income, was used as a proxy for low socioeconomic status. Of the total group, 9% had always received Medicaid and 66% had never received Medicaid. Patients receiving Medicaid had a 3.7-fold higher mortality, a 9% lower predicted FEV₁, and were 2.2 times more likely to be below the fifth percentile for weight and 1.6 times more likely to require treatment for an exacerbation as compared with the patients who never received Medicaid. The number of outpatient visits did not differ between the groups, suggesting that access to specialty care did not explain the different outcomes. The authors conclude that children from poor families suffer more serious consequences from cystic fibrosis.

Sood and colleagues (88) determined the outcome in 76 patients with cystic fibrosis (aged 17 to 45 years) admitted to an intensive care unit. Reasons for 136 admissions were respiratory failure (65), hemoptysis (33), antibiotic desensitization (30), pneumothorax (3), and other reasons (5). All patients with pneumothorax and antibiotic desensitization, and 86% of the patients with hemoptysis, were alive one year after discharge. Of 42 patients with respiratory failure, 37 (88%) required mechanical ventilation and 23 survived to discharge. Of the 23 patients surviving respiratory failure, 17 underwent lung transplantation (14 were alive at one year), three died, and three others were alive at one year. The authors conclude that admission to an intensive care unit and the delivery of mechanical ventilation is appropriate in patients with cystic fibrosis who have reversible complications. An editorial commentary by Wallick and colleagues (89) accompanies this article.

	Footnotes

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: mtobin2{at}lumc.edu

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

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