© 2004 American Thoracic Society
Pediatrics, Surfactant, and Cystic Fibrosis in AJRCCM 2003Division of Pulmonary and Critical Care Medicine, Loyola University of Chicago Stritch School of Medicine and Hines Veterans Affairs Hospital, Hines, Illinois 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
Pediatrics (46) Pulmonary Function Testing and Diagnostic Techniques (4) Normative Values (2) Thoracoabdominal Compression (1) Respiratory Muscles and Mechanics (1) Mechanical Ventilation (3) Respiratory Syncytial Virus Bronchiolitis (4) Sleep and Control of Breathing (7) Pediatric Asthma (11) Epidemiology (3) Airway Inflammation (6) Treatment (2) Other Pediatric Issues (17) Air Pollution (2) In utero Exposure to Cigarette Smoke (4) Maternal Asthma (1) Lung Development (2) Bronchopulmonary Dysplasia (7) Infections and Sepsis (1) Surfactant Biology and Disorders (8) Pathophysiology (3) Deficiency (2) Treatment (3) Cystic Fibrosis (25) Genetics (3) Lung Inflammation (2) Microbiology (3) Pathophysiology and Exercise Performance (8) Treatment (9) Gene Therapy (2) Mucolytic Agents (1) Antibiotic Therapy (5) Outcome (1)
Pulmonary Function Testing and Diagnostic Techniques Normative values. Pulmonary function in children is commonly normalized for subject height, but height is an unreliable reference standard in children with neuromuscular weakness or spinal deformity. In 1,444 boys and 1,999 girls (ages 5.3 to 19.6 years), Gauld and coworkers (1) investigated the relationship between pulmonary function and limb length. Prediction equations that included both ulnar length and age were predictive of forced expiratory volume in one second (FEV1) (r2 = 0.86 for boys and 0.84 for girls) and forced vital capacity (FVC) (r2 = 0.86 for boys and 0.83 for girls). Precision was equivalent to that provided by height. The authors conclude that pulmonary function can be reliably predicted on the basis of ulnar length in children whose height is difficult to measure. Reported values for functional residual capacity (FRC) in infants have declined, for unexplained reasons, over the last 30 years. Hulskamp and coworkers (2) measured lung volume with a new plethysmograph in 32 healthy infants. Mean FRC was 19.6 ml per kg. Compared with recently collated data from the a task force of the American Thoracic Society, mean FRC was 7.0 ml per kg lower. A total of 66% of healthy infants had values for FRC below the normal range. The authors conclude that new reference standards for lung function in infants need to be established.
Thoracoabdominal compression.
Respiratory muscles and mechanics.
Mechanical Ventilation In a critical care perspective, Bollen and colleagues (7) present a meta-analysis on use of high-frequency and conventional ventilation in premature neonates.
Respiratory Syncytial Virus Bronchiolitis
In 88 babies who had at least one parent with atopy and asthma, Legg and coworkers (10) investigated the in vivo immune response to natural infection with RSV. Upper respiratory tract infection associated with RSV occurred in 28 infants, and 9 developed signs of acute bronchiolitis. Compared with infants with upper respiratory tract infection alone, the infants with acute bronchiolitis had an increased ratio of interleukin-4 to interferon-
Sleep and Control of Breathing To determine the characteristics of arousal from sleep in infants who eventually die from sudden infant death syndrome (SIDS), Kato and coworkers (13) analyzed recordings obtained in 16 infants who had been studied some days or weeks before dying from SIDS. Compared with a control group of infants, the infants who later died of SIDS had less frequent cortical arousals (complete arousals) during both REM sleep (14.3 versus 23.1 per hour of sleep) and non-REM sleep (3.1 versus 3.6 per hour of sleep). Compared with the control group, the infants who later died of SIDS had more frequent subcortical activations (body movement without EEG change) during REM sleep (4.0 versus 1.4 per hour of sleep). The duration of subcortical activations was greater in the infants who later died of SIDS than in the control group (median duration, 7 versus 5 seconds). Compared with the control group, the infants who later died of SIDS had more frequent subcortical activations in the first part of the night (from 9:00 P.M. to 12:00 A.M.) and fewer cortical arousals during the later part of the night (from 3:00 A.M. to 6:00 A.M.) The authors conclude that infants who die from SIDS exhibit incomplete arousal processes during sleep in the weeks or months before their death. An editorial commentary by Harper (14) accompanies this article. In 10 children with obstructive sleep apnea (apnea–hypopnea index, 8 events per hour) and 6 healthy children, Katz and White (15) studied genioglossus activity (intraoral surface electromyography) during wakefulness and sleep onset. During wakefulness, genioglossus activity was greater in patients than in control subjects (3.6 versus 1.6% of maximum). The decline in genioglossus activity during early and late sleep onset was greater in the patients. During stable non-REM sleep, activity of the genioglossus remained below the baseline value for wakefulness in all of the control children but increased above baseline in 4 of the 10 children with sleep apnea. The authors conclude that children with obstructive sleep apnea display increased activity of the genioglossus during wakefulness, probably as compensation for deficient pharyngeal anatomy. To determine whether snoring is associated with poor academic performance in third-grade school children (mostly 9-year-olds), Urschitz and coworkers (16) studied 1,444 children by questionnaire and nocturnal home oximetry. Poor academic performance was a score of 4 to 6 (lowest quintile) on a 6-point scale (1 for outstanding, and 6 for failed). Snoring reported as "always" was associated with poor performance in mathematics (odds ratio, 3.6), science (odds ratio, 4.3), and spelling (odds ratio, 3.5). Snoring reported as "frequent" was associated with poor performance in mathematics (odds ratio, 2.4) and spelling (odds ratio, 2.0). Intermittent hypoxia did not show an independent association with poor academic performance. The authors conclude that habitual snoring is associated with poor academic performance in third-grade school children To determine whether prenatal hypoxia leads to sustained modifications in ventilatory control and impairs the ability to learn a spatial task, Gozal and coworkers (17) exposed pregnant rats to intermittent hypoxia (10% oxygen concentration alternating with 21% oxygen every 90 seconds) or room air. At 5, 10, 15, and 30 days after delivery, newborn rats exposed to prenatal hypoxia had higher normoxic ventilation than did newborn rats exposed to prenatal room air. The peak ventilatory response to hypoxia at 5 days of age was depressed in rats exposed to prenatal hypoxia. Ventilatory equivalent (minute ventilation in relation to oxygen consumption) was decreased in rats exposed to prenatal hypoxia. The learning and memory of spatial tasks at one and four months was similar in rats exposed to prenatal hypoxia or normoxia. The authors conclude that gestational intermittent hypoxia leads to prolonged and irreversible alterations in respiratory control but does not produce obvious neurocognitive impairment. Exposing an adult rat to intermittent hypoxia results in neurobehavioral impairment and increased apoptosis in the hippocampal CA1 region and cortex. In adult rats, Row and coworkers (18) examined whether intermittent hypoxia induces lipid peroxidation in cortical tissue and whether the latter is associated with neurocognitive impairment. Exposing adult rats to intermittent hypoxia (alternating 90-second periods of 10% oxygen and 21% oxygen) caused impairment of the ability to learn a spatial task (in a water maze). Twice-daily treatment with an antioxidant (PNU-101033E) attenuated the impairment in spatial learning. The antioxidant also attenuated the increase in lipid peroxidation and isoprostane concentration associated with intermittent hypoxia. The authors conclude that exposure to intermittent hypoxia induces oxidative stress, which is associated with behavioral impairment.
Pediatric Asthma To determine whether parasitic infection decreases the risk of wheeze in young children, Dagoye and coworkers (20) did a nested case-control study based on data on 7,155 children aged 1 to 4 years living in urban and rural areas of Ethiopia. Infections with parasites was common: Trichuris (54%), Ascaris (38%), and hookworm (10%). Wheezing in the past year was more prevalent in urban children than in rural children (4.4% versus 2%), and was less prevalent in children infected with Ascaris (adjusted odds ratio, 0.5). A similar, although nonsignificant, association was found for hookworm (adjusted odds ratio, 0.6), but not for Trichuris. Skin sensitization with Dermatophagoides pteronyssinus and cockroach (Blattella germanica) was more prevalent in rural than in urban children, and unrelated to wheeze. The authors conclude that Ascaris infection protects against wheeze in young Ethiopian children and that this effect is not mediated by inhibition of allergen sensitization. Home dampness is associated with lower respiratory symptoms in children. To determine whether in-home fungal concentrations can predict lower respiratory illnesses (croup, pneumonia, bronchitis, and bronchiolitis) in the first year, Stark and coworkers (21) studied a prospective birth cohort of 499 children of parents with asthma/allergies. After controlling for sex, presence of water damage, presence of visible mold/mildew, a winter birth, breastfeeding, and exposure to other children (through siblings), multivariate analyses revealed significant associations between lower respiratory illnesses and high levels (more than 90th percentile) of airborne Penicillium (relative risk, 1.73), dust-borne Cladosporium (relative risk, 1.52), Zygomycetes (relative risk, 1.96), and Alternaria (relative risk, 1.51). On multivariate analysis, lower respiratory illnesses were associated with households that had any fungal level above the 90th percentile (relative risk, 1.86). The authors conclude that exposure to high levels of fungi in the home increase the risk of wheezing and nonwheezing lower respiratory illnesses during infancy.
Airway inflammation. To characterize airway pathology in children with asthma, Barbato and coworkers (24) obtained bronchial biopsies in 9 children with asthma, 6 children with atopy and free of asthma, and 8 control children without asthma or atopy (ages ranged from 3 to 13 years). Thickness of the basement membrane and the number of eosinophils were increased in the children with asthma as compared with control subjects, but not when compared with atopic children. Children with asthma had decreased expression of receptor II for transforming growth factor-ß1 as compared with either the control children or atopic children. In the children with asthma, the number of eosinophils correlated negatively with receptor II for transforming growth factor-ß1 and positively with the duration of symptoms. The authors conclude that airway eosinophilia and thickening of the basement membrane are evident in children with mild asthma (and even in children with atopy but free of asthma), and that children with asthma (but not atopic children) exhibit downregulation of receptor II for transforming growth factor-ß1. Because an imbalance between oxidant and antioxidants is implicated in the pathogenesis of asthma, Corradi and coworkers (25) obtained exhaled breath condensates in 12 children with an exacerbation of asthma (mean, 11 years). Malondialdehyde, an oxidant, was higher in children with asthma than in control subjects, 30.2 versus 19.4 nM; malondialdehyde was reduced to 18.5 nM by 5 days of prednisone. Glutathione, an antioxidant, was lower in children with asthma than in control children, 6.0 versus 14.1 nM; glutathione was increased to 8.4 nM after treatment with oral prednisone. In the overall group (both patients and control subjects), glutathione and malondialdehyde were negatively correlated (r = -0.50). The authors conclude that aldehydes and glutathione are measurable in exhaled breath condensates in children with asthma, and are modified by an acute exacerbation and by treatment with prednisone. An editorial commentary by Gaston (26) accompanies this article. Remodeling of the airway wall occurs in adult patients with asthma and thickening of the reticular basement membrane is pathognomonic of asthma. Payne and coworkers (27) asked, "Do children with asthma display thickening of the reticular basement membrane?" They studied endobronchial biopsies from 19 children with difficult asthma, 10 children without asthma, 10 adults with mild asthma, 6 adults who had been intubated for life-threatening asthma, and 8 healthy adults. Thickness of the reticular basement membrane in children with asthma (median, 8.2 µm) was similar to that in adults with mild asthma (8.1 µm) and adults with life-threatening asthma (7.2 µm), and thicker than that in healthy children (4.4 µm) or healthy adults (4.9 µm). The authors conclude that thickening of the reticular basement membrane in children with difficult asthma is similar to that found in adults with asthma.
Treatment. To determine the magnitude and predictors for hospital readmission for childhood asthma, Bloomberg and coworkers (29) analyzed data from 8,761 children who experienced 14,905 admissions for asthma. During the 10-year period, 30% of children were admitted more than once. A multivariate model revealed that African-American children with Medicaid or no insurance had a higher rate of readmission than did African-American children with commercial insurance or white (or other ethnicity) children regardless of insurance (risk ratio 1.28). The probability of readmission increased from 30% after the first admission to 46% after a second admission and to 59% after a third admission. The authors conclude that prior admission is a more powerful predictor for readmission for childhood asthma than are ethnicity, insurance status, or their combination.
Other Pediatric Issues Nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase (NQO1) and glutathione S-transferase (GST) M1 are detoxifying enzymes induced in response to oxidative stress, as occurs during ozone exposure. To examine the relationship between significant polymorphisms in NQO1 and GSTM1 and risk of asthma, David and coworkers (31) studied 218 case-parent triads in children from Mexico City (which has the highest ozone levels in North America). The Pro187Ser polymorphism in NQO1 was not associated with risk of asthma. Among subjects with homozygous deletion of GSTM1, carriers of a serine allele were at reduced risk of asthma as compared with Pro/Pro homozygotes. The authors conclude that children who live in an area with high exposure to ozone and who carry at least one NQO1 Ser allele and are homozygous for the GSTM1 deletion are at a decreased risk of asthma.
In utero exposure to cigarette smoke. To determine the independent and joint effects of in utero exposure to maternal smoking and age at diagnosis of asthma, Gilliland and coworkers (34) analyzed data on 5,933 participants in the Children's Health Study. Children exposed to cigarette smoke in utero, but without asthma, displayed decreases in FEV1/FVC, FEF25–75, and FEF25–75/FVC ratio. Among children exposed to smoke in utero, early onset of asthma was associated with larger decreases in FEV1, FEF25–75, and FEV1/FVC as compared with later diagnosed asthma. Children with both in utero exposure plus early onset asthma showed a 13.6% deficit in FEV1 and a 29.7% deficit in FEF25–75 among boys, and a 26.6% deficit in FEV1/FVC among girls. Exposure to environmental tobacco smoke alone had little effect. The authors conclude that deficits in lung function are greatest among children who are exposed to cigarette smoke in utero and who have an early onset of asthma. Epidemiologic studies indicate that in utero exposure to cigarette smoke increases the risk of asthma in childhood, but the mechanism is unclear. To address this issue, Singh and coworkers (35) studied the effects of in utero smoke in mice. Animals exposed to smoke prenatally, but not postnatally, exhibited increased airway hyperresponsiveness to a single intratracheal injection of Aspergillus fumigatus extract. The increase in airway hyperresponsiveness was related to increased enzymatic activity of phosphodiesterase-4 and increased lung expression of messenger RNA for the phosphodiesterase-4D isoform. Hyperresponsiveness was not associated with increased leukocyte migration or mucus production. Exposure of adult mice to cigarette smoke did not alter airway hyperresponsiveness, levels of cyclic adenosine monophosphate, or phosphodiesterase activity. The authors conclude that prenatal exposure to cigarette smoke increases airway hyperresponsiveness by modulating levels of cyclic adenosine monophosphate through changes in the activity of phosphodiesterase-4D, and that these effects are independent of mucus production or leukocyte recruitment.
Maternal asthma.
Lung development. In the developing cardiac, neural and mammary systems, differentiation induced by neuregulin-1 is based on cell-to-cell communication: the ligand neuregulin-1 is produced and secreted by one cell type (that does not express its receptors, erbB3 and erbB4) and acts on neighboring cell types (that do express these receptors). Dammann and coworkers (38) investigated the role of neuregulin-1 in fetal lung maturation. Immunostaining revealed increased neuregulin-1 in lung fibroblasts at the onset of surfactant synthesis. Neuregulin-1ß was secreted by fetal lung fibroblasts and stimulated synthesis of surfactant by type II cells. Neuregulin-1 and fetal lung fibroblast–conditioned media stimulated the phosphorylation of erbB2 receptor in type II cells. An antibody to neuregulin-1 blocked the effects of neuregulin-1 and fibroblast-conditioned media on both surfactant synthesis and phosphorylation of erbB2 receptor in type II cells. The authors conclude that neuregulin-1ß controls fetal lung maturation through mesenchymal–epithelial interactions in a paracrine mechanism.
Bronchopulmonary dysplasia. In newborn mice exposed to hyperoxia, Ahmed and coworkers (41) determined whether targeted overexpression of human extracellular superoxide dismutase would promote normal lung development. Newborn transgenic mice and wild-type mice were exposed to 95% oxygen or air for 7 days. Activity of extracellular superoxide dismutase was 2.5 times greater in the transgenic mice than in the control mice. At 7 days, the transgenic mice had less pulmonary neutrophil influx and oxidized glutathione than did the control mice. After 14 days of exposure to 60% oxygen, transgenic mice had greater preservation of alveolar surface and volume density than did the control mice. The authors conclude that overexpression of human extracellular superoxide dismutase protects newborn mice against hyperoxia-induced inflammation at 7 days and impairment of lung development at 21 days. To determine the role of fibroblast growth factor receptor-1 in compensatory lung growth after hyperoxic exposure, Jankov and coworkers (42) exposed neonatal rats to 95% oxygen for 7 days after birth. The rats showed inhibited lung growth, DNA synthesis, and secondary septation, all of which recovered during a period of air breathing. Expression of basic fibroblast growth factor was reduced at the end of 7 days of 95% oxygen; it increased after 3 days of recovery in air. Expression of fibroblast growth factor receptor-1 was not affected by hyperoxia or recovery in air. The role of fibroblast growth factor in the compensatory lung growth after discontinuation of hyperoxia was further evaluated by injecting (intraperitoneally) soluble truncated fibroblast growth factor receptor-1 at the onset of the recovery phase. (The truncated receptor acts as a decoy for the natural receptor ligands, which are then no longer available to bind to the endogenous receptor.) The truncated receptor arrested compensatory lung DNA synthesis and secondary septation. The authors conclude that the compensatory lung growth and septation in neonatal rats experiencing growth arrest secondary to hyperoxia is in part mediated by fibroblast growth factor receptor-1. Bombesin-like peptides are elevated in newborns that go on to develop bronchopulmonary dysplasia, and blocking these peptides abrogates bronchopulmonary dysplasia in baboons. Subramaniam and coworkers (43) determined whether bombesin-like peptides function postnatally as proinflammatory cytokines. In mice, intratracheal administration of bombesin induced increased numbers of mast cells after 48 hours. The mast cells revealed messenger RNAs encoding bombesin receptor subtype 3 and neuromedin-B receptor, but not gastrin-releasing peptide receptor. Only neuromedin-B receptor null mice accumulated fewer mast cells in the lungs after treatment with bombesin. In vitro studies revealed that bombesin, gastrin-releasing peptide, neuromedin-B receptor, and a bombesin receptor subtype 3–specific ligand induced proliferation of mast cells and chemotaxis. The authors conclude that multiple bombesin-like peptides promote mast cell responses and contribute to the development of bronchopulmonary dysplasia. The American Thoracic Society (44) presents a statement on care of the child with chronic lung disease of infancy and childhood. In a state of the art review article, Kinnula and Crapo (45) discuss superoxide dismutase in lung disease.
Infections and sepsis.
Pathophysiology Keratinocyte growth factor induces transient proliferation of alveolar type II cells associated with alterations of surfactant. To determine the effect of keratinocyte growth factor on homeostasis of surfactant, Fehrenbach and coworkers (47) studied lung tissue from adult rats after intratracheal instillation of recombinant human keratinocyte growth factor or phosphate-buffered saline. Compared with saline, keratinocyte growth factor produced a 3.6-fold increase in coverage of alveolar walls by type II cells, a 1.7-fold increase in the number of type II cells per ml of lung volume, a 44% decrease in the number of lamellar bodies per cell, and a 54% decrease in the volume of lamellar bodies per cell (although the total amount of lamellar bodies per ml of lung volume did not change). There was a parallel shift to larger lamellar bodies. Keratinocyte growth factor led to an increase in radiolabeled phospholipids in whole lung tissue (relative to lavage fluid), although less radiolabel was incorporated per cell. The authors conclude that proliferation of alveolar type II cells induced by keratinocyte growth factor is accompanied by a decrease in surfactant within a unit cell, although the amount of surfactant per unit lung volume remains constant.
The hydrophobic surfactant protein C binds to lipopolysaccharide (which is found in airborne particles) and one of its cellular receptors, CD14. Augusto and coworkers (48) investigated the influence of surfactant protein C on the responses of immunocompetent cells to lipopolysaccharide. When associated with vesicles of dipalmitoylphosphatidylcholine, surfactant protein C inhibited the mitogenic effect of lipopolysaccharide to a macrophage cell line (RAW 264.7). Under similar conditions, surfactant protein C inhibited the mitogenic effect of lipopolysaccharide on mouse splenocytes, inhibited the lipopolysaccharide-induced production of tumor necrosis factor-
Surfactant inhibits the synthesis of type IIA secretory phospholipase A2 by alveolar macrophages. Wu and coworkers (49) sought to determine the components of surfactant involved in this inhibition, and the associated signaling pathways. Expression of type IIA secretory phospholipase A2 by alveolar macrophages (stimulated by endotoxin) was inhibited by both surfactant protein-A and the surfactant phospholipid fraction. Expression of the enzyme was abolished by surfactant phospholipid dioleylphosphatidylglycerol, but not by dipalmitoylphosphatidylcholine. Phosphatidylglycerol was rapidly incorporated and metabolized by alveolar macrophages and its metabolites accumulated in the cytosol. Nuclear factor-
Deficiency To assess the postnatal profile of surfactant proteins, Ballard and coworkers (51) collected tracheal aspirates from 35 intubated infants of 23 to 31 weeks of gestation and between 8 and 80 days of age. In 71 large aggregate surfactant samples, the content of surfactant protein-A was 7.1% of phospholipids, content of surfactant protein-B was 1.8% of phospholipid, and content of surfactant protein-C was 4.6% of phospholipid. On the second day of life, content of surfactant protein-A was 13.4%, content of surfactant protein-B was 8.4%, and content of surfactant protein-C was 0.1% of the mean levels for the samples obtained between the eight to eightieth day. The major postnatal increases occurred during the first week for surfactant protein-A, the second week for surfactant protein-B, and third week for surfactant protein-C. The authors conclude that newborn premature infants of less than 32 weeks of gestation have low concentrations of surfactant protein-A and surfactant protein-B and extremely low values of surfactant protein-C, and that the three proteins have different postnatal development profiles.
Treatment In 40 patients with ARDS, Spragg and coworkers (54) did a phase I/Phase II randomized trial of a recombinant surfactant protein C–based surfactant (Venticute). Patients received one or two doses of exogenous surfactant on four occasions over 24 hours. Treatment was well tolerated. No benefit was noted. At 48 hours, bronchoalveolar lavage reflected exogenous surfactant components, did not show improvement in lowering of surface tension, and had lower level of interleukin-6 than did the control group. Exogenous surfactant was not detected in lavage fluid at 120 hours. The authors conclude that a recombinant protein C–based surfactant can be safely administered to patients with acute lung injury.
Genetics To determine whether polymorphisms of certain inflammatory mediator and regulatory genes influence organ damage in patients with cystic fibrosis (CF), Arkwright and coworkers (55) studied 261 patients. Ultrasound features of hepatic cirrhosis were more frequent in the high-producer (DD) than in the low-producer (II) genotype for angiotensin I–converting enzyme. The age at which FEV1 reached below 50% of predicted was associated with the high-producer DD genotype (odds ratio, 2.3), transforming growth factor-ß1 genotype (odds ratio, 2.6), and the age at which Pseudomonas aeruginosa first colonized the sputum (odds ratio, 9.1). The authors conclude that the high-producer genotype (DD) for angiotensin I–converting enzyme is associated with portal hypertension and early onset of pulmonary dysfunction in patients with CF. An editorial commentary by Accurso and Sontag (56) accompanies this article. In 70 patients with CF (aged 4 to 40 years with an FEV1 of 69% of predicted), Grasemann and coworkers (57) determined whether the 894G/T variant in exon 7 of the gene for endothelial nitric oxide synthase was related to exhaled nitric oxide and lung function. Exhaled nitric oxide was higher in female patients with an 894T mutant allele than in female patients who were homozygous for the 894G wild-type allele (7.0 versus 3.6 parts per billion); no such association was seen in male patients. Among female patients, colonization of the airways with Pseudomonas aeruginosa was more frequent among homozygotes with the 894G wild-type allele than among carriers of the 894T mutant allele: 69 versus 31%. The authors conclude that the 894T variant in the gene for endothelial nitric oxide synthase is associated with increased formation of nitric oxide in female patients with CF, possibly influencing airway colonization with Pseudomonas aeruginosa. An editorial commentary by Accurso and Sontag (56) accompanies this article.
Lung Inflammation The collectins, surfactant protein-A and surfactant protein-D, enhance opsonization of microbes and limit the lung inflammatory response. To assess the relationship between collectins, bacteria, and inflammation, Noah and coworkers (59) performed bronchoalveolar lavage in 46 children with CF and 31 patients without CF. Children with CF had more neutrophils relative to bacteria than did the control group. Surfactant protein-A tended to be lower in the patients with CF, although the decrease was significant only when bacterial infection was present. The concentration of surfactant protein-A was inversely related to inflammation, number of bacterial colony-forming units, and age. Children with CF had decreased levels of surfactant protein-D, and the levels were rarely detectable when infection was present. Autopsy specimens also revealed a paucity of surfactant protein-A and surfactant protein-D at sites of infection and inflammation. The authors conclude that inflammation induced by chronic infection in relatively young children with CF is linked to a marked deficiency of surfactant protein-D and age-related decline of surfactant protein-A.
Microbiology To determine the short-term effect of nontuberculous mycobacteria on the clinical course of patients with CF, Olivier and coworkers (62) followed 60 incident-positive and 99 culture-negative patients for 15 months. The annual rate of decline in FEV1 was 5% in patients who met ATS criteria for nontuberculous mycobacteria disease, 3% in culture-positive patients not meeting the ATS criteria, and 3% in control subjects. Two or more characteristic findings on high-resolution computed tomography were seen in 60% patients with three or more positive cultures, in 32% of patients two or fewer positive cultures, and in 19% of patients with negative cultures. Progression of changes on computed tomography was seen in all of the patients with three or more positive cultures. The authors conclude that multiple positive cultures for nontuberculous mycobacteria in patients with CF predict progressive changes on computed tomography without affecting FEV1. An editorial commentary by Griffith (61) accompanies this article.
Pathophysiology and Exercise Performance To determine the pathophysiology of impaired exercise tolerance in patients with CF, Selvadurai and coworkers (65) studied 16 girls with mild CF (age 15 years) participating in elite sports and a control group of 16 female teammates without CF; FEV1 was respectively 96% and 98% of predicted. Compared with the control group, resting energy expenditure was 7.6% higher and habitual daily activity was 15% higher in the CF group. Peak aerobic capacity was equivalent in the two groups. Peak anaerobic power was 20% lower in the CF Group. 31P magnetic resonance spectroscopy revealed no difference between the groups at rest. At 25% of total work output, the CF group was less acidotic than was the control group (pH 6.99 versus 6.90) and had a lower ratio of inorganic phosphorus to phosphocreatine (0.34 versus 0.41). The differences between the groups continued to increase until maximum exercise. The authors conclude that girls with mild CF who are exercising on a treadmill have intrinsic metabolic defects in skeletal muscle, decreased anaerobic power, and leg strength despite having normal lung function and good nutritional status. To determine whether quantification of aerobic fitness is helpful in predicting disability, Frangolias and coworkers (66) studied 73 patients with CF (aged 30 years). Disability was associated with FEV1, maximal oxygen consumption, Schwachman-Kulczycki clinical score, Brasfield radiology score, and frequency of exacerbations. Disability was not associated with change in FEV1 over 2 years or with oxygen saturation at rest or during exertion. The best independent predictors of disability were FEV1 and the Schwachman-Kulczycki score. The authors conclude that FEV1 and the Schwachman-Kulczycki score predict limitation of patients with CF in a work or school environment, and that other physiological and clinical measures do not predict limitation. In 25 children with CF randomized to one-year treatment with daily dornase alfa (Pulmozyme) or normal saline, Robinson and coworkers (67) investigated the relative ability of variables derived from pulmonary function measurements and high-resolution computed tomography in detecting an intervention effect. At 12 months, the greatest change from baseline was obtained with a composite total computed tomography score that also incorporated pulmonary function (35.4%) and a composite maximal computed tomography score that incorporated pulmonary function (30.4%). These changes are contrasted with the change in FEF25–75% (13.0%), total global computed tomography (6.2%), and maximal global computed tomography (7.2%). The authors conclude that composite scores that incorporate both pulmonary function and high-resolution computed tomography are superior to other measures for detecting a treatment effect with dornase alfa in children with CF.
Abnormal ion transport is a fundamental defect in cystic fibrosis. To determine whether airway ion transport is related to severity of lung disease, Wallace and coworkers (68) measured nasal potential difference in 51 patients with CF (age range, 5.9 to 17.7 years). No correlation was observed between any measurement of ion transport and several measures of clinical status. Of 30 patients homozygous for the The response of nasal potential difference to perfusion solutions provides a convenient surrogate marker of the defect in movement of chloride across the epithelium, a characteristic abnormality in CF. In seven patients with CF, Middleton and coworkers (69) did sequential perfusions (on different days) with amiloride, low chloride, and isoproterenol, with diluents containing different concentrations of calcium and magnesium. With diluents nominally free of calcium, the low-chloride responses were 8.0, 8.6, and 9.6 millivolts at magnesium concentrations of 0, 1, and 3 mM, respectively; these responses were significantly different from the responses in the presence of divalent ions. The subsequent response to isoproterenol did not differ between the presence or absence of divalent ions. The authors conclude that perfusion of the CF airway with nominally calcium-free solutions reduces tonic inhibition of chloride secretion. In 20 patients with stable CF (aged 13.5 years) and 33 healthy subjects, Terheggen-Lagro and coworkers (70) investigated the relationship between measurements of end-tidal carbon monoxide and lung volume. End-tidal carbon monoxide did not differ between the patients and the control group: 1.2 versus 1.3 ppm. In the control group, end-tidal carbon monoxide was correlated with lung volume (r = 0.64) and with diffusing capacity for carbon monoxide (r = 0.48). When corrected for differences in total lung capacity, the level of end-tidal carbon monoxide was higher in the patients than in the control group: 143 versus 100%. The authors conclude that the level of end-tidal carbon monoxide is equivalent in patients with CF and healthy subjects but higher in the patients when the level is corrected for lung volume.
Treatment Richard and coworkers (72) investigated the reliability of positron emission tomographic imaging in detecting the expression of genes delivered to the lungs by viral vectors. The study was conducted in normal rats and an enhanced mutant herpes simplex virus-1 thymidine kinase was used as the reporter gene. Rats were studied 3 days after the intratracheal administration of a replication-incompetent adenovirus containing a fusion gene for the mutant kinase and green fluorescent protein. The rats were injected with an imaging substance for the viral kinase, 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine; images were obtained one hour later. Measurements derived from imaging were linearly correlated with measures of thymidine kinase activity and green fluorescent protein levels in tissue (r2 = 0.96). Imaging detected expression of thymidine kinase in 15 of 16 rats, even at low viral doses. Imaging for the viral kinase was correlated with in vitro assays for both kinase activity (r2 = 0.48) and fluorescent protein (r2 = 0.46). The authors conclude that positron emission tomographic imaging is a sensitive and quantitative method for noninvasive detection of pulmonary reporter gene expression.
Mucolytic agents.
Antibiotic therapy. To assess the usefulness of markers of infection and inflammation in assessing the response to antibiotic therapy in CF, Ordonez and coworkers (75) obtained induced sputum in 55 patients with CF before and after treatment with intravenous antibiotics. Antibiotic therapy produced decreases in the density of Pseudomonas aeruginosa (by 2.4 log10 cfu per gram), and Staphylococcus aureus (by 4.0 log10 cfu per gram), decrease in neutrophil count (by 0.4 log10 cells per ml), decrease in interleukin-8 (by 0.5 log10 pg per ml), decrease in neutrophil elastase (by 0.4 log10 µg per ml), and an increase in FEV1 (by 0.3 liter). Of the 127 sputum induction procedures, 7 (6%) were accompanied by a decrease in FEV1 of 20% or more. The authors conclude that antibiotic treatment of a pulmonary exacerbation of CF results in improvements in FEV1 and several markers in induced sputum (namely, decreases in P. aeruginosa and S. aureus density, neutrophil count, interleukin-8 concentration, and neutrophil elastase activity). An editorial commentary by Armstrong (76) accompanies this article. In a state of the art review article, Gibson and colleagues (77) discusses the pathophysiology and management of infections in CF. In a clinical commentary, Tan and colleagues (78) discuss the use of aminoglycosides in the management of patients with CF.
Outcome.
Supported by a Merit Review grant from the Veterans Affairs Research Service. Conflict of Interest Statement: M.J.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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CONTENTS
PEDIATRICS
in nasal lavage fluid on Days 1 and 2 and Days 5 to 7 of the illness; infants with acute bronchiolitis also had a higher ratio of interleukin-10 to interleukin-12 on days 1 and 2. Stimulated peripheral blood mononuclear cells revealed a decrease in messenger RNA levels for interleukin-18 and an increase in the ratio of interleukin-4 to interferon-
B subunit and phosphorylated IkB
expression were greater in children with moderate asthma than in children with intermittent asthma or control children. Exhaled nitric oxide was equivalent in the three groups. Exacerbations were more frequent in children who were high producers of granulocyte/macrophage colony-stimulating factor, interleukin-8, and exhaled nitric oxide than in low producers. The authors conclude that several markers of inflammation are elevated in children with asthma. An editorial commentary by Warner (
F508 mutation, ion transport variables did not differ between patients whose pulmonary function was above or below the average level of function. Ten patients had significant hyperpolarization (greater than 5 mV) after perfusion with a zero chloride solution; chloride secretory capacity did not correlate with above average lung function. The authors conclude that the degree of abnormal ion transport in patients with CF is not correlated with severity of lung disease.