© 2003 American Thoracic Society
Pediatrics, Surfactant, and Cystic Fibrosis in AJRCCM 2002Division 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 (84) Pulmonary Function Testing and Diagnostic Techniques (5) Normative Values (1) Exhaled Nitric Oxide (1) Respiratory Muscles and Mechanics (2) Lung Water (1) Mechanical Ventilation (3) Respiratory Syncytial Virus Bronchiolitis (2) Active Infection (2) Sleep and Control of Breathing (8) Pediatric Asthma (17) Genetics (2) Epidemiology (7) Risk Factors: Air Pollution (3) Risk Factors: Aeroallergens (1) Airway Inflammation (2) Treatment (2) Other Pediatric Issues (18) Air Pollution (1) Passive Smoking (3) Lung Development (2) Bronchopulmonary Dysplasia (2) Congenital Diaphragmatic Hernia (2) Infections (3) Pulmonary Hypertension (2) Interstitial Lung Disease (2) Gastroesophageal Reflux (1) Surfactant Biology and Disorders (5) Pathophysiology (3) Deficiency (1) Treatment (1) Cystic Fibrosis (26) Genetics (1) Lung Inflammation (5) Microbiology (5) Pathophysiology and Exercise Performance (9) Bone Demineralization and Metabolic Disorders (2) Treatment (4) Mucolytic Agents (1) Lung Transplantation (3)
Pulmonary Function Testing and Diagnostic Techniques Normative values. Maximal flow at functional residual capacity during a partial forced expiratory maneuver is the most popular test of lung function in infants and young children. Because appropriate reference data are lacking, Hoo and coworkers (1) collated data from 459 healthy infants tested on 654 occasions during the first 20 months of life. The most important predictors of maximal flow at functional residual capacity were sex, age, and length. Flow was 20% higher in girls than in boys during the first nine months of life. Models for predicting normal values are presented. The authors conclude that failure to include sex-specific data in prediction equations for maximum flow at functional residual capacity during a partial forced expiratory maneuver may miss significant problems in girls and lead to false diagnoses in boys.
Exhaled nitric oxide.
Respiratory muscles and mechanics. The interrupter technique provides a measure of respiratory resistance from recordings of flow and mouth pressure while the airways are occluded during tidal breathing. To characterize the values before and after administration of a bronchodilator in healthy children, Beydon and coworkers (4) studied 91 children (aged 2.9 to 7.9 years). Inspiratory resistance was higher than expiratory resistance before 5 years of age, and the opposite pattern was seen after 5 years. Both resistances decreased with height. Inhaled albuterol produced a 15% decrease in inspiratory resistance and a 12% decrease in expiratory resistance. Sex did not affect the prebronchodilator or postbronchodilator values. The authors conclude that the reported values for resistance measured by the interrupter technique may help in assessing lung function in children who are unable to perform a forced expiratory maneuver.
Lung water.
Mechanical Ventilation Most infants born before a gestational age of 30 weeks have been exposed to chorioamnionitis and aspiration of infected amniotic fluid. To simulate this situation and determine whether susceptibility to injury is related to gestational age, Kramer and coworkers (8) studied lambs delivered at 130 or 141 days of gestation (term is 146 days). In the preterm lambs, both a low and high dose of intratracheal endotoxin (0.1 or 10 mg per kg) caused impaired gas exchange and systemic inflammation. In the near-term lambs, a high dose of intratracheal endotoxin (10 mg per kg) caused lung inflammation without a systemic effect; systemic inflammation occurred when the intratracheal endotoxin was combined with ventilation at a high tidal volume or with intravenous endotoxin. The authors conclude that intratracheal endotoxin produces systemic inflammation in preterm lambs, but not in near-term lambs, unless it is combined with ventilation using high tidal volumes.
Respiratory Syncytial Virus Bronchiolitis
Infection with respiratory syncytial virus causes inflammation of the airway mucosa associated with activation of nuclear factor-
Sleep and Control of Breathing Because avoiding the prone position is linked with a decrease in the incidence of sudden infant death syndrome, Ishikawa and coworkers (12) measured patency of the upper airway in 19 infants and small children (10 to 101 weeks old). The static pressure–area relationship of the passive pharynx was measured in three postures under general anesthesia. Maximum pharyngeal area was smaller in the prone position with the neck rotated than in the supine position: 0.44 versus 0.56 cm2. Pharyngeal closing pressure was lower in the supine position with the neck rotated (-2.83 cm H2O) than in the supine position with the face straight up (-4.45 cm H2O) and was further decreased in the prone position with the neck rotated (-0.27 cm H2O). Pharyngeal closing pressure was above atmospheric pressure in half the subjects in the prone position, whereas all subjects had a negative pharyngeal pressure in the supine position. The authors conclude that the prone position increases collapsibility of the upper airway of infants and young children. To determine the pattern of growth for tissues surrounding the upper airway, Arens and coworkers (13) did magnetic resonance imaging in 92 healthy children between 1 and 11 years of age. In the midsagittal plane, the distance between the mental spine (point that the genioglossus is inserted into the mandible) and the clivus (passing through the centroid of the soft palate) was related linearly to age (r = 0.86). The dimensions of the tongue, soft palate, nasopharyngeal airway, and adenoids increased with age and maintained a constant proportion to the distance between the mental spine and the clivus. In the axial plane, the transverse distance between the mandibles was related to age (r = 0.78). The width of the tonsils, intertonsillar region, parapharyngeal fat pads, and pterygoids maintained a constant proportion to the intermandibular width with age. The authors conclude that the skeleton of the lower face grows linearly along the sagittal and axial planes between the first and eleventh years of life. To determine the efficacy and tolerance of an oral jaw-positioning appliance in children with sleep apnea, Villa and coworkers (14) studied 32 patients (aged 4 to 10 years). Nineteen patients were randomized to 6 months treatment with the device, and 13 served as control subjects. Four treated patients and five untreated patients were lost to follow-up. Of the 14 treated patients, 9 (64%) showed a 50% or greater decrease in the apnea–hypopnea index. Symptoms of sleep apnea decreased in all treated patients and completely resolved in half. Untreated patients showed no change. The authors conclude that use of a jaw-positioning appliance is effective in treating sleep apnea in children and that the appliance is reasonably well tolerated. Harrington and coworkers (15) studied cardiovascular autonomic function in 10 infants who had experienced an apparent life-threatening event and 12 control infants. The studies were done during slow wave sleep and REM sleep. Five of the 10 infants who had experienced a life-threatening event had obstructive sleep apnea. Breathing during sleep was normal in the other five infants and in all of the control infants. In response to 45-degree head-up tilts, the infants with obstructive sleep apnea had a decreased heart rate response, and three developed marked hypotension. The infants with sleep apnea also had altered variability of heart rate and blood pressure and an increased threshold for arousal during REM sleep. The authors concluded that half of infants with an apparent life-threatening event have obstructive sleep apnea and that this subgroup also has abnormal autonomic cardiovascular control. To evaluate cardiac structure in children and adolescents with obstructive sleep apnea, Amin and coworkers (16) did echocardiography on 28 children with obstructive sleep apnea and 19 children with primary snoring. Left-ventricular mass index was 22% greater, and relative wall thickness was 24% greater in the children with obstructive sleep apnea than in the children with primary snoring. An apnea–hypopnea index of 10 or more events per hour was associated with a 6.7-fold increased risk of enlarged right-ventricular dimensions and 11.2-fold increased risk of an increased left-ventricular mass index. The authors conclude that obstructive sleep apnea leads to cardiac remodeling and hypertrophy of both the right and left ventricles in children and adolescents. Measurement of airflow at the nose with a thermistor or measurement of pressure at the nose with a cannula is used in the detection of apneas and hypopneas. Trang and coworkers (17) compared the accuracy of the two techniques in 14 infants (aged 2.6 months) and 16 children (aged 5.5 years) with suspected obstructive sleep apnea. All children tolerated the nasal cannula. An noninterpretable flow signal lasting more than 20% of total sleep time occurred in five children using a cannula versus only one child using the thermistor. A total of 465 obstructive apneas were identified: 43% of the apneas were detected by both techniques; 52% of the apneas missed by the thermistor were detected by nasal pressure monitoring; and only 5% of the apneas missed by nasal pressure were detected by the thermistor. A total of 159 obstructive hypopneas were detected: nasal pressure detected 100% of these events, whereas the thermistor detected only 14%. Esophageal pressure was recorded in six children; all events detected by nasal pressure were associated with increased airway resistance. The authors conclude that measurement of pressure at the nose with a nasal cannula is more reliable than measurement of flow with thermistors in detecting obstructive apneas and hypopneas in children. The cause of congenital central hypoventilation syndrome is unknown, although a genetic etiology is suspected. Sritippayawan and coworkers (18) described a 25-year-old woman with congenital central hypoventilation who gave birth to an infant with the same condition. The mother did not have worsening of symptoms during pregnancy, and her ventilatory response to hypercapnia was unchanged. The mother was managed by diaphragmatic pacing throughout pregnancy. The authors conclude that the presence of congenital central hypoventilation syndrome in both a mother and daughter supports a dominant mode of inheritance for the condition.
Pediatric Asthma Gilliland and coworkers (20) studied the effect of genotypes for glutathione-S-transferase M1, T1, and P1 on lung growth in 1,940 children, aged 8 to 11 years, who were followed annually for 4 years. GSTM1 null was associated with deficits in the annual growth rates in FVC (-0.21%) and FEV1 (-0.27%). Compared with children who had one or more ile105 alleles, children who were homozygous for the GSTP1 val105 allele had a slower rate of growth in FVC (-0.35%) and FEV1 (-0.34%). Compared with children free of asthma, children with asthma who were homozygous for the GSTP1 val105 allele had substantially larger deficits in FVC, FEV1, and maximum mid-expiratory flow. The authors conclude that children who have the GSTM1 null genotype and children who are homozygous for the GSTP1 val105 variant allele have a lower growth in lung function than do children with more common alleles at these two loci.
Epidemiology. In a longitudinal study of 243 infants, 23 subjects (9.4%) displayed flow limitation during tidal expiration at 4 weeks, which was associated with reduced lung function at 4 weeks and 6 months of age, and airway hyperresponsiveness at 12 months of age. To determine whether the flow-limited group would continue to display decreased lung function, Turner and coworkers (22) analyzed data between the ages of 3 and 11 years. Only at 4 years of age did the flow-limited group have increased wheeze as compared with other cohort members (odds ratio, 4.25). At 6 years of age, the flow-limited group has greater airway hyperresponsiveness and lower FEV1 (131 ml) and forced expiratory flow (FEF25–75; 0.28 liter per second). At 11 years of age, the flow-limited group had greater airway hyperresponsiveness. Atopy and parental asthma were not increased in the flow-limited group. The authors conclude that airflow limitation in early infancy identifies a group with increased risk for reduced lung function and greater airway hyperresponsiveness, but not asthma, in later life. Five retrospective studies have reported an association between use of antibiotics in early life and asthma in childhood. Celedon and coworkers (23) studied this relationship in 448 children with a parenteral history of asthma. After adjusting for potential confounders, the use of antibiotics in the first year of life was not associated with asthma, recurrent wheezing, allergic rhinitis, or wheezing at 5 years. The authors conclude that use of antibiotics in the first year of life is not associated with the subsequent development of asthma and atopy in childhood. It is traditionally thought that avoiding ownership of a pet protects against the development of allergy. To determine the effect that living with a cat or a dog has on the development of allergy and asthma, Perzanowski and coworkers (24) studied longitudinally a cohort of children living in three towns in northern Sweden. Data on the prevalence of asthma were obtained at ages 7 to 8 years, and incidence data were obtained over the subsequent three years. The strongest risk factor for incident cases of asthma was type 1 allergy (relative risk, 4.9), followed by a family history of asthma (relative risk, 2.83). Living with a cat was inversely related to a positive skin test to cat (relative risk, 0.62) and to the incidence of physician-diagnosed asthma (relative risk, 0.49). This effect on incident asthma was greatest among children with a family history of asthma (relative risk, 0.25). Weaker protective trends were seen with dog ownership. The authors conclude that avoiding ownership of a pet does not protect against the development of asthma or allergy. To determine whether the level of endotoxin in house dust is associated with allergic sensitization in children, Gehring and coworkers (25) studied 740 children, aged between 5 and 10 years. Dust from the floor of living rooms was collected from the homes of 454 of the children (61%). After adjusting for place of residence, sex, age, parental education, parental atopy, and pet ownership, exposure to endotoxin was associated with sensitization to one or more allergens (odds ratio, 0.95) and to two or more allergens (odds ratio, 0.80). The authors conclude that a higher level of endotoxin in house dust is associated with a lower prevalence of allergic sensitization in children. To determine the interrelationship between current and past infection with Ascaris lumbricoides and asthma and atopy, Palmer and coworkers (26) studied a cross-sectional sample of 2,164 children between the ages of 8 and 18 years from rural China. The prevalence of either a history or positive stool examination for Ascaris was 24.5%. Independent of other factors, infection with Ascaris was associated with increased risk of asthma (odds ratio, 1.85), an increased number of skin tests positive to aeroallergens (odds ratio, 1.25), and an increased slope of the dose–response to methacholine. The authors conclude that infection with A. lumbricoides is associated with an increased risk of childhood asthma, increased airway hyperresponsiveness, and sensitization to common aeroallergens. To determine the relationship between exposure to microbial load during pregnancy and the development of allergic disease, McKeever and coworkers (27) analyzed data from a birth cohort of 24,690 children. Exposure to antibiotics in utero was associated with an increased risk of asthma in a dose-related manner. Compared with no antibiotics, more than two courses of antibiotics was associated with increased risk of asthma (hazard ratio, 1.68), eczema (hazard ratio, 1.17), and hay fever (hazard ratio, 1.56). Exposure to a range of infections in utero was associated with a small increased risk of developing allergic disease. The presence of an older sibling had a strong protective effect on the incidence of allergy. The authors conclude that exposure to antibiotics in utero is associated with a dose-related increase in the risk of allergic disease in children.
Risk factors: air pollution. To determine the relationship between exposure to air pollution related to traffic and the development of asthmatic symptoms, allergic diseases, and respiratory infections, Brauer and coworkers (29) studied a birth cohort of 4,146 children. Outdoor concentrations of traffic-related air pollutants were modeled for the home of each subject. Adjusted odds ratios for wheezing; physician-diagnosed asthma; infections of the ear, nose, or throat; and serious colds at 2 years of age were associated with air pollutants; some of the associations reached borderline statistical significance. The authors conclude that traffic-related air pollution may be associated with the prevalence of respiratory illness at 2 years of age. To determine whether the type of indoor heating systems have an influence on respiratory symptoms during the first year of life, Triche and coworkers (30) collected information on symptoms and type of indoor heating every 2 weeks during the first year of life in 890 infants. During the heating season, 88% of infants had at least one episode of cough, and 33% had at least one episode of wheeze. After adjusting for confounding influences, the use of a gas space heater was associated with episodes of wheeze and days of wheeze. The use of a wood stove was associated with total days of cough, and the use of a kerosene heater was associated with episodes of cough. The use of a fireplace was not associated with any respiratory symptoms. The authors conclude that use of some indoor heating sources are associated with the development of respiratory symptoms in the first year of life.
Risk factors: aeroallergens.
Airway inflammation. Cysteinyl leukotrienes are primarily generated by mast cells and eosinophils and induce smooth muscle contraction, microvascular leakage, and mucous hypersecretion; leukotriene B4 is a potent chemoattractant of neutrophils. To determine whether the level of these substances in exhaled breath condensates reflect the severity of asthma, Csoma and coworkers (33) studied four groups of children aged between 7 and 14 years. The level of cysteinyl leukotrienes in 11 children with mild intermittent asthma (19.9 pg per ml) was equivalent to the level in 11 healthy children (18.5 pg per ml), but the level was higher in 13 children with mild persistent asthma (27.9 pg per ml) and in 13 children with moderate-to-severe asthma (31.5 pg per ml). The level of leukotriene B4 was 47.9 pg per ml in the normal children, 52.7 pg per ml in the children with mild intermittent asthma, 126.0 pg per ml in the children with mild persistent asthma, and 131.9 pg per ml in the children with moderate-to-severe persistent asthma. The level of leukotriene B4 was inversely correlated with the levels of cysteinyl leukotrienes (r = -0.76) in children with mild persistent asthma. The authors conclude that monitoring of exhaled breath condensates of cysteinyl leukotrienes and leukotriene B4 may be noninvasive markers of airway inflammation in children with asthma.
Treatment. Because the benefit of inhaled glucocorticoids in preschool children with intermittent wheeze is unproven, Pao and McKenzie (35) did a 6-week randomized crossover trial of fluticasone propionate (100 µg twice daily) versus placebo in 61 children aged 2 to 5 years of age. Compared with placebo, the geometric change in interrupter resistance was -7.6% in the fluticasone group. The change in resistance was -16% in children with positive skin prick tests and -3.5% in children with negative prick tests. Changes in resistance were not related to IgE. Resistance returned to baseline at 16 weeks after stopping fluticasone. The authors conclude that fluticasone propionate has a beneficial effect on intermittent wheezing in preschool children, especially in those who are sensitized to aeroallergens.
Other Pediatric Issues
Passive smoking. Maternal smoking is a major risk factor for late fetal death and the sudden infant death syndrome. To determine the effect of prenatal exposure to nicotine on postnatal defense against hypoxia, Hafstrom and coworkers (38) exposed 7 lambs to nicotine during the last trimester of pregnancy. At 5 days after birth, lambs with prenatal exposure to nicotine had a lower ventilatory response to hypoxia during quiet sleep than had control lambs. The time to arouse from sleep after exposure to hypoxia was more than twice as long in the nicotine-exposed lambs. The heart rate response to hypoxia was lower during both sleep and wakefulness in the lambs than had been exposed to prenatal nicotine. During wakefulness, the ventilatory response to hypoxia was equivalent in the two groups. The ventilatory response to hyperoxia was lower in the nicotine-exposed lambs during both wakefulness and sleep. The transition from wakefulness to sleep was associated with a decrease in ventilation in the control lambs but not in the nicotine-exposed lambs. The authors conclude that exposure to a low dose of nicotine during the last trimester of pregnancy blunts the ventilatory, heart rate, and arousal responses to hypoxia in newborn lambs. An editorial commentary by Nattie and Kinney (39) accompanies this article.
Lung development.
Bronchopulmonary dysplasia. By preventing injury to the epithelium and enhancing its repair, keratinocyte growth factor may reduce the risk of bronchopulmonary dysplasia. To determine whether a high level of keratinocyte growth factor would predict a lower likelihood of subsequent bronchopulmonary dysplasia, Danan and coworkers (43) obtained 114 tracheal aspirates within 3 hours of birth from 91 intubated neonates with a gestational age of 30 weeks or less. Keratinocyte growth factor was detected in all but six neonates. In 42 infants, a second sample obtained after 2–6 days revealed an 80% increase in keratinocyte growth factor. Fourteen infants developed bronchopulmonary dysplasia (defined as the need for supplemental oxygen at a postconceptional age of 36 weeks), and these infants had lower levels of keratinocyte growth factor. On a receiver operating characteristic curve, the best discriminator was the highest value of keratinocyte growth factor within 5 days after birth. The positive predictive value for not developing bronchopulmonary dysplasia was 95% for a keratinocyte growth factor exceeding 110 pg per ml. The authors conclude that high levels of keratinocyte growth factor in the airspaces after premature birth limit the risk of developing bronchopulmonary dysplasia.
Congenital diaphragmatic hernia. In a clinical commentary, Bohn (45) discusses congenital diaphragmatic hernia.
Infections. Angiotensin-converting enzyme participates in inflammatory responses, and deletion (D) of a 284 base-pair marker in the gene for the enzyme causes the enzyme to be increased in plasma and tissue. To determine whether the DD genotype alters the outcome of a uniform infectious disease, Harding and coworkers (47) studied 110 children, aged 49 months, with meningococcal disease. Compared with children who had at least one insertion allele (ID, II), the 34 children with the DD genotype had a 14% higher mortality, a 22% higher meningococcal septicemia score, a greater prevalence of inotropic support (76 versus 55%), a greater prevalence of mechanical ventilation (82 versus 63%), and a longer intensive care unit stay (5.8 versus 3.9 days). The frequency of the DD genotype was 45% for children who died, 33% for children admitted to the intensive care unit who survived, and 6% for children not requiring admission to the intensive care unit. The authors conclude that the DD variant of the gene for angiotensin-converting enzyme is associated with increased severity of illness in children with meningococcal disease.
To assess the reproducibility of blind protected bronchoalveolar lavage in the diagnosis of ventilator-associated pneumonia, Gauvin and coworkers (48) did two blind lavages at a two-hour interval in 30 mechanically ventilated children (age, 52 months). Bacterial growth was present in 43% of the 60 lavages. Reproducibility for the presence of bacteria on quantitative cultures was excellent: concordance 93% and
Pulmonary hypertension. The development of pulmonary hypertension in newborn rats exposed to 60% oxygen for 14 days is mediated by endothelin-1. Jankov and coworkers (50) assessed whether activation of the receptor for thromboxane A2 is involved in the development of pulmonary hypertension in this model. Newborn rats were exposed to 60% oxygen or air for 14 days and received daily injections of either a competitive antagonist of the thromboxane A2 receptor, L670596, or an inhibitor of cyclooxygenase-2, DFU. The antagonist of thromboxane A2 prevented the development of right-ventricular hypertrophy and smooth muscle hypertrophy in small pulmonary vessels in the rats exposed to hyperoxia; the inhibitor of cyclooxygenase-2 did not prevent these developments. The antagonist of the thromboxane A2 receptor decreased the content of endothelin-1 in the lungs of the hyperoxic rats. The level of 8-isoprostane, a product of lipid peroxidation, was elevated in both groups exposed to hypercapnia as compared with control animals exposed to air. The authors conclude that upregulation of endothelin-1 and the development of pulmonary hypertension in newborn rats exposed to 60% oxygen for 14 days are mediated by activation of the thromboxane A2 receptor.
Interstitial lung disease.
Gastroesophageal reflux.
Pathophysiology To identify the precise sequence of events that produce endotoxin-induced lung injury, Davidson and coworkers (54) infused endotoxin (Salmonella abortus equi) intravenously into spontaneously breathing rats. The animals developed an early marked fall in arterial PO2 and a progressive deterioration in airway resistance, tissue resistance, and lung elastance; these changes occurred despite a 1.7-fold increase in minute ventilation and fivefold increase in the number of sighs. The changes occurred before changes in alveolar neutrophils, macrophages, albumin flux, or edema; the latter changes were increased appreciably only at 8.5 hours. The increase in elastance preceded the increase in resistance, indicating that the change in elastance arose within the lung tissue rather than reflecting a fall in lung volume. Despite a dramatic increase in the synthesis and turnover of 3H-disaturated phosphatidylcholine, the subcellular and alveolar content of surfactant protein A, surfactant protein B, cholesterol, disaturated phospholipids, and phospholipid classes remained normal; the increased turnover in surfactant disaturated phospholipid was attributed to the increase in the number of sighs. The authors conclude that the initial respiratory failure caused by endotoxin is the result of ventilation–perfusion mismatch and not alveolar edema per se and that endotoxin has effects on lung elastance and resistance that are independent of surfactant composition.
Mutations in the gene for surfactant protein C (SFTPC) are associated with familial interstitial pneumonitis. In a kindred of 97 members that included 11 adults and 3 children with pulmonary fibrosis, Thomas and coworkers (55) used a candidate gene approach. A heterozygous exon 5 + 128 T
Deficiency
Treatment
Genetics To determine the incidence of mutations of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene in children with intermediate levels of sweat chloride, Lebecque and coworkers (59) reviewed 2,349 consecutive first sweat tests. An intermediate level of chloride, 30 to 60 mM, was found in 98 subjects (4.2%); 43 of these children could be traced. A total of 24 putative CFTR mutations were found. Ten children, with mean age 8.9 years, who harbored one mutation on both CFTR genes were investigated in detail. Seven of the children had clinical features suggestive of CF. Sweat chloride was higher in these children than in subjects without the mutation (39 versus 35 mM), and five had an abnormal nasal potential difference. The authors conclude that 23% of children displaying an intermediate level of sweat chloride carry a putative mutation on both CFTR genes.
Lung Inflammation To determine the role of endotoxin in airway inflammation in CF, Muhlebach and Noah (62) did bronchoalveolar lavage in 55 patients with CF and 56 patients without CF (age, 0.04 to 13.3 years). Infection, defined as a bacterial count above 50,000 colony forming units per ml, was present in 49% of the patients with CF and in 45% of the patients without CF. The level of endotoxin was equivalent in the patients with and without CF, irrespective of whether they were infected (75 versus 51 EU per ml) or uninfected (6 versus 11 EU per ml). The level of endotoxin activity was correlated with the number of Gram-negative organisms in both groups. Interleukin-8 and neutrophils were correlated with the level of endotoxin in both groups, although the slope was shifted to a higher level of inflammation in the patients with CF. The authors conclude that the inflammatory response in patients with CF is not explained by higher levels of endotoxin independently of the effect of infection. An editorial commentary by Berger (61) accompanies this article.
Because patients with CF appear to have decreased levels of interleukin-10 in their airways, Chmiel and coworkers (63) investigated the role of interleukin-10 in the inflammatory response to infection with Pseudomonas aeruginosa. After transient challenge with P. aeruginosa, both wild-type mice and interleukin-10 knockout mice cleared the infection within 6 days. The interleukin-10 knockout mice had higher levels of neutrophils and proinflammatory cytokines in bronchoalveolar fluid. The interleukin-10 knockout mice failed to regenerate the inhibitor of nuclear factor- Aldallal and coworkers (64) determined whether inflammatory gene expression is altered in airway epithelial cells from patients with CF. The release of interleukin-8 in response to several inflammatory stimuli was much greater in CF epithelial cell lines than in control cell lines that contained the CFTR. The level of interleukin-8 became moderately elevated after infection with P. aeruginosa. In CF cells that released a high level of interleukin-8, the use of an adenoviral vector to cause transient expression of the CF transmembrane conductance regulator did not alter the constitutive or inducible levels of interleukin-8 or intercellular adhesion molecule-1. The authors conclude that some CF airway epithelial cells display increased expression of intercellular adhesion molecule-1 and interleukin-8 but that many cells do not exhibit dysregulation of these inflammatory genes.
Microbiology To determine the frequency of patient-to-patient spread of P. aeruginosa, Speert and coworkers (67) did genetic fingerprinting on isolates collected from 174 patients over a 20-year span. A total of 157 genetic types of P. aeruginosa were identified, and 123 were unique to individual patients. A total of 34 types were shared by more than one patient; epidemiologic evidence linked these individuals only in the cases of 10 sibships and in one pair of unrelated patients. The authors conclude that the risk of patients with CF acquiring P. aeruginosa from other patients is extremely low and appears to require prolonged close contact as occurs between siblings. An editorial commentary by Ramsey (66) accompanies this article. Allergic bronchopulmonary aspergillosis can cause irreversible damage in patients with CF. To assess the reliability of intracutaneous testing with recombinant Aspergillus fumigatus in the diagnosis of allergic bronchopulmonary aspergillosis, Nikolaizik and coworkers (68) studied 50 patients with CF (mean age 22 years). Twelve patients had allergic bronchopulmonary aspergillosis, and all of these patients reacted to at least one of the two A. fumigatus allergens, rAsp f4 or rAsp f6, at a concentration of 10-2 µg/ml. The tests were negative or only marginally positive in 21 patients who displayed allergy to A. fumigatus but who did not have allergic bronchopulmonary aspergillosis. The tests were completely negative in 17 patients with CF who were not sensitized to A. fumigatus. The authors conclude that intracutaneous tests with two recombinant A. fumigatus allergens are specific markers for allergic bronchopulmonary aspergillosis. The Gram-negative bacterium Stenotrophomonas maltophilia (formerly Pseudomonas and Xanthomonas maltophilia) has been cultured with increasing frequency in patients with CF. To determine the clinical characteristics of patients who acquire S. maltophilia and its effect on survival, Goss and coworkers (69) analyzed data on all patients who were included in the Cystic Fibrosis Foundation Registry between 1991 and 1997. The sample was confined to patients who were older than 6 years of age and who had been negative for S. maltophilia in the first year of enrollment. Data on a total of 19,255 patients followed for a median of 3 years were available for analysis. Of these, 1,673 (8.7%) had at least one sputum positive for S. maltophilia. Compared with sputum-negative patients, the patients with a positive sputum culture had a lower FEV1, were older, were more likely to be female, had more pulmonary exacerbations, had more clinic visits, and had more hospitalizations. After controlling for confounding variables, detection of S. maltophilia was not associated with worse survival. The authors conclude that patients with CF who acquire S. maltophilia have more advanced disease but that detection of the organism does not independently influence survival.
Pathophysiology and Exercise Performance The exhaled concentration of nitric oxide is used to monitor inflammatory lung disease. Although the plateau concentration has been used, it requires a constant flow rate during exhalation. Shin and coworkers (71) examined the ability of a number of flow-independent variables to discriminate between nine children with CF and nine healthy children (ages, 10 to 14 years). The diffusing capacity of nitric oxide in the airways was higher in the patients than in the control subjects: 17.6 versus 4.8 pl second-1 ppb-1. Compared with the control subjects, the patients had a lower steady-state alveolar concentration of nitric oxide, 1.96 versus 4.63 ppb, and a lower mean tissue concentration of nitric oxide in the airways, 38 versus 198 ppb. The plateau concentration of exhaled nitric oxide did not differ between the groups. The authors concluded that the flow-independent variables derived from exhaled nitric oxide discriminate between children with CF and healthy subjects. Gaston and coworkers (72) determined whether bacteria that colonize the airways of patients with CF alter the balance between oxidized and reduced forms of nitrogen. The airway concentration of ammonium was higher in 13 children with stable CF who were colonized with P. aeruginosa than in 13 children with neurogenic respiratory failure: 1.6 versus 0.46 mM. Antimicrobial therapy produced a 27% decrease in ammonium concentration in the sputum. Nitric oxide reductase was present in strains of P. aeruginosa, which produced ammonium and consumed nitric oxide. The consumption of nitric oxide was inhibited by antimicrobial therapy ex vivo. The authors conclude that treating children with CF whose airways are colonized with P. aeruginosa causes a decrease in the concentration of ammonium in the airway. S-nitrosoglutathione is a naturally occurring constituent of airway lining fluid that enhances ciliary motility, relaxes smooth muscle, inhibits amiloride-sensitive transport of sodium in the airway epithelium, and prevents pathogen replication. Because levels of S-nitrosoglutathione are low in the airways of patients with CF, Snyder and coworkers (73) studied its effect on gas exchange in a double-blind study in 20 patients with CF. Aerosolized S-nitrosoglutathione produced an increase in oxygen saturation over a 30-minute period. The breakdown product of S-nitrosoglutathione, nitric oxide, also rose in expired air. There were no adverse effects. The authors conclude that aerosolized S-nitrosoglutathione increases oxygen saturation in patients with CF and is well tolerated. To determine the relationship between pulmonary function and radiographic abnormalities with airway inflammation and fibrosis, Hamutcu and coworkers (74) studied 21 patients with CF who had undergone lung transplantation. FEV1 was 26% of predicted. Residual volume was 342% of predicted, and PO2 was 64 mm Hg; 24% had a PCO2 above 50 mm Hg. The density of small airways (less than 2 mm per cm2) decreased with increasing age. The proportion of small airways less than 0.35 mm in diameter was lower in hypercapnic patients than in normocapnic patients: 26% versus 37%. The authors conclude that airway pathology in patients with CF is correlated with age and hypercapnia. To determine the effect of a low FEV1 on pulmonary mechanics in children and adolescents with CF, Hart and coworkers (75) studied 32 children with CF. The mean age was 14 years, and FEV1 ranged from 12 to 49% of the predicted normal value. FEV1 was correlated with arterial PO2 (r = 0.76), arterial PCO2 (r = -0.70), ratio of respiratory frequency to tidal volume (r = -0.41), dynamic lung compliance (r = 0.64), total work of breathing (r = -0.52), and elastic work of breathing (r = -0.60). FEV1 was not correlated with sniff esophageal pressure, minute ventilation, total pulmonary resistance, intrinsic positive end-expiratory pressure, or resistive work of breathing. The authors conclude that a decline in FEV1 in patients with CF is accompanied by an increase in elastic work of breathing, total work of breathing, rapid shallow breathing, and impaired gas exchange.
To quantify the spectrum of airway disease in clinically stable patients with CF, Marostica and coworkers (76) studied 36 children who were able to perform two or three technically acceptable spirometric maneuvers. Compared with normative data for healthy children, the children with CF had abnormalities, expressed as Z scores (number of SDs that a value deviated from the predicted mean value): FEV1, -1.23; FVC, -0.75; FEV1/FVC, -0.87; and FEF25–75, -0.74. The Brasfield radiologic score was correlated with the Z scores for FEV1 (r2 = 0.24) and FVC (r2 = 0.26). Compared with heterozygous children, children who were homozygous for the To characterize pulmonary function in preschool children with CF, Beydon and coworkers (77) studied 39 children with CF (age 3 to 8.2 years) and 79 healthy children (3 to 7.9 years). Compared with the healthy children, the children with CF had a 31% higher resistance on expiration (measured by the interrupter technique) and a 21% lower specific conductance on expiration. Children with CF who had a history of respiratory symptoms had a higher functional residual capacity (by helium dilution technique) and lower expiratory conductance. The response to albuterol did not differ between the children with CF and the control children. The authors conclude that tests of pulmonary function that do not require patient cooperation can reveal airway obstruction and hyperinflation in preschool children with CF. In 47 newly diagnosed infants with CF, Ranganathan and coworkers (78) compared the ability of variables derived from the tidal and raised volume rapid thoracoabdominal compression techniques in detecting impaired airway function. Measurements were compared against a reference group of 187 healthy infants. FEV0.5 from the raised volume technique of rapid thoracoabdominal compression identified impaired airway function in 31% of infants with CF. FEV0.5 was decreased by 42.5% in 35 infants with a previous lower respiratory illness and by 41.0% in 12 infants without a previous lower respiratory illness. Only one infant with CF had a maximal flow at functional residual capacity that was below the normal range. The authors conclude that FEV0.5 is diminished in infants with CF more than any other variable and that the raised volume technique of rapid thoracoabdominal compression identified impaired airway function more frequently than did the tidal technique.
Bone Demineralization and Metabolic Disorders Patients with CF have a low bone mineral density, but the mechanism is not known. To investigate this issue, Elkin and coworkers (80) did bone biopsies after tetracycline labeling in 20 patients with CF (average age, 30 years). Compared with 18 healthy subjects, the patients had a lower cancellous bone area, a lower rate of bone formation at the tissue level, a smaller wall width (amount of bone formed within individual remodeling units), a lower rate of mineral apposition, and a lower mineralizing perimeter. Resorption cavities were smaller in the patients than in the control subjects, and osteoclasts were rarely seen. One patient had osteomalacia. The authors conclude that the low volume of cancellous bone in adult patients with CF results from low bone turnover and reduced bone formation at a tissue and cellular level rather than from an increase in active bone resorption.
Treatment
Lung transplantation. Deciding the right time to undertake lung transplantation in patients with CF is difficult, and the criteria used in guiding the decision are controversial. Mayer-Hamblett and coworkers (83) developed a mathematical model for predicting 2-year mortality using data on 14,572 patients in the National Patient Registry of the Cystic Fibrosis Foundation who were 6 years of age or older in 1996. Multivariate logistic regression revealed that age, height, FEV1, respiratory microbiology, number of hospitalizations for pulmonary exacerbations, and number of course of intravenous antibiotics in the home were significant predictors of 2-year mortality. When compared with the widely used criterion of an FEV1 of less than 30% of predicted, the mathematical model did not prove superior. The negative predictive value was 98% for the model and 97% for FEV1. The positive predictive value was 33% for the model and 28% for FEV1. Both the model and the FEV1 criterion will result in high rates of premature referral for lung transplantation. The authors conclude that a well-fitting mathematical model based on data from 14,572 patients with CF was not superior to the usual criterion of a FEV1 of less than 30% predicted in guiding decision on the best time to do lung transplantation. An editorial commentary by Noone and Egan (84) accompanies this article.
Supported by a merit review grant from the Veterans Affairs Research Service
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CONTENTS
PEDIATRICS
B. Compared with control mice, Haeberle and coworkers (
, macrophage inflammatory protein-1ß, and macrophage inflammatory protein-2 were decreased in the treated mice. Perflubron markedly decreased the activation of nuclear factor-
. Shahid and coworkers (
A transversion of the gene for surfactant protein C was found (the abnormality may hinder processing of the precursor protein for surfactant protein C). Immunostaining of lung tissue revealed aberrant subcellular localization of the precursor protein. Electron microscopy revealed atypical alveolar type II cells, with numerous abnormal lamellar bodies. The authors conclude that a large kindred of familial pulmonary fibrosis displayed a mutation in the gene for surfactant protein C and that damage to type II cells may underlie the pulmonary fibrosis associated with this mutation. An editorial commentary by Whitsett (
F508 mutation. Peak aerobic capacity was lower in children with defective CFTR production (class I; 29 ml per kg per minute) and defective CFTR processing (class II; 32 ml per kg per minute) than in children with defective regulation of CFTR (class III; 44 ml per kg per minute). Peak anaerobic power was higher in children with mutation inducing decreased CFTR conduction (class IV; 11.4 watts per kg) or CFTR messenger RNA (class V; 11.6 watts per kg) than in children with class I (9.7 watts per kg), class II (9.8 watts per kg), or class III (10.5 watts per kg) mutations. Lung function did not differ among the groups. The authors conclude that the class of the second CFTR mutation is related to aerobic and anaerobic fitness in patients with CF who are heterogeneous for the