Early pulmonary infection, inflammation, and clinical outcomes in infants with cystic fibrosis.

A thorough understanding of the early natural history of cystic fibrosis (CF) lung disease is critical for the development of effective interventions in the youngest patients. We assessed the evolution of pulmonary infection, inflammation, and clinical course among 40 infants over a 2-year period through annual bronchoalveolar lavage (BAL) for culture and measurements of pro- and anti-inflammatory cytokines, semiannual infant pulmonary function testing, and quarterly clinical evaluations. Both the prevalence of CF pathogens and their density in BAL fluid increased with age. Infants had neutrophilic lower airway inflammation and elevated IL-8 concentrations independent of whether CF pathogens were recovered. Total leukocyte and neutrophil densities and IL-8 concentrations increased with density of CF pathogens in BAL fluid, whether the isolated organism was P. aeruginosa or another pathogen. IL-10 concentrations were similar in CF subjects and non-CF historical controls. Infants generally had suboptimal growth (low weight and height percentiles) and obstructive lung disease (decreased expiratory flows and air trapping). Subjects from whom CF pathogens were isolated at > 10(5) cfu/mL had the worst air trapping and lowest Brasfield chest X-ray scores. Our findings provide a foundation for future studies of early intervention in CF lung disease, including antimicrobial and anti-inflammatory therapy.

Comparison of high-frequency chest wall oscillation and oscillating positive expiratory pressure in the home management of cystic fibrosis: a pilot study.

Enhanced airway clearance is thought to result in better-maintained pulmonary function in cystic fibrosis (CF). Postural drainage, percussion, and vibration (PDPV) have been the primary airway clearance technique (ACT) employed in CF for over 40 years. Two new airway clearance modalities are high-frequency chest wall oscillation (HFCWO) and oscillating positive expiratory pressure (OPEP). This pilot study was undertaken to evaluate the efficacy of these techniques during home use, assess patient satisfaction with them as compared to PDPV, and assess the feasibility of performing a definitive comparative trial. The prospective, randomized, multicenter crossover trial was conducted at three urban academic CF Care Centers. Twenty-nine CF patients, 9-39 years of age, participated. Subjects performed 4 weeks each of HFCWO and OPEP following 2-week lead-in/washout periods. Spirometry, lung volumes, National Institutes of Health and Petty Scores, and a satisfaction survey were performed at baseline and after each treatment period. An ACT preference survey was completed at the conclusion of the study. Twenty-four subjects completed both therapies. There were no statistically significant differences between therapies for spirometry, lung volumes, or clinical scores. No significant safety issues arose during the study period. Compliance between therapies was similar. Significant differences among therapies existed in patient satisfaction. Given a choice of therapy, 50% of subjects chose HFCWO, 37% OPEP, and 13% PDPV. This study suggests that HFCWO and OPEP are safe and as effective as patients' routine therapies when used for airway clearance in a home setting. Patient satisfaction and preference differ among ACTs and should be considered when prescribing home therapy. A definitive, multi-center, comparative study evaluating long-term efficacy of these techniques is feasible.

Lateral thoracic expansion for Jeune's syndrome: midterm results.

BACKGROUND: In 1995, we reported the use of lateral thoracic expansion in a patient with symptomatic Jeune's asphyxiating thoracic dystrophy. We have subsequently used lateral thoracic expansion 16 times on 10 patients during 7 years. This article reports our outcomes and provides surgical details. METHODS: Charts of all patients undergoing lateral thoracic expansion were reviewed. Eight of the 10 patients had symptomatic Jeune's syndrome. The other 2 had similar thoracic deformities limiting thoracic capacity. In half of the patients the procedures were performed bilaterally. RESULTS: All patients older than 1 year of age were symptomatically benefited by lateral thoracic expansion. Functional and anatomic measurements documented thoracic enlargement in several patients who had comparable preoperative and postoperative studies. However, 2 infants with significant underlying airway disease did not improve and went on to succumb to that aspect of their disease despite enlargement of the thorax. Fracture of the titanium ministruts has been a recurrent problem, and we now use larger struts. CONCLUSIONS: Lateral thoracic expansion is a safe and effective procedure in selected patients with Jeune's syndrome older than 1 year of age as judged by short-term and midterm follow-up. More experience and longer follow-up are required to discern the place of the lateral thoracic expansion in the overall management of these patients.

Bronchodilator responsiveness in normal infants and young children.

UNLABELLED: Several studies have demonstrated that normal infants exhibit bronchoconstriction after inhalation of nonspecific agonists and that the induced airway narrowing can be reversed by the inhalation of a beta-agonist. However, there are very limited data on baseline airway tone and the airway response to a beta-agonist in this subject population. The purpose of our study was to evaluate in normal infants baseline airway responsiveness to the inhaled beta-agonist, albuterol, using changes in maximal expiratory flows. Forty-one healthy infant volunteers with no history of respiratory disease or recurrent wheezing (ages 5.4 to 141.4 wk) were studied. Maximal expiratory flow- volume curves were obtained at baseline and 10 min after inhalation of albuterol (n = 28) or placebo (n = 13) using a metered-dose inhaler with a spacer. The mean percent change was significantly greater (p < 0.05) in the albuterol versus placebo group for FEV(0.5) (2.2% versus -1.5%), FEF(75%) (10.6% versus -3.1%), and FEF(85%) (12.9% versus 0.5%). Six of 28 albuterol-treated infants demonstrated increases in FEF(75%) greater than two standard deviations from the mean change in FEF(75%) seen in the placebo group. These infants were younger and more frequently exposed to maternal smoking during pregnancy. We conclude that normal healthy infants have overall levels of baseline airway tone that are similar to that reported in adults and older children; however, among the infants we evaluated the response to an inhaled bronchodilator was greatest in the youngest infants and in those exposed to tobacco smoking. KEYWORDS: airway responsiveness; asthma; tobacco smoke; infant pulmonary function; bronchodilator

Static compliance of the respiratory system in healthy infants.

We recorded static deflation pressure-volume (PV) curves from near TLC to FRC in 49 healthy, sedated, spontaneously breathing infants of 1 to 104 wk of age. Respiratory activity was transiently inhibited by inflating the respiratory system several times to a volume at an airway pressure of 30 cm H2O (V30). Passive deflation from V30 to FRC was then interrupted by multiple brief occlusions at the airway opening, in order to measure static recoil pressures. The expired volume from V30 to FRC was defined as V30E. Compliance of the respiratory system (Crs) was calculated as the slope of the linear portion of the PV curve from 5 to 15 cm H2O. Crs and V30E increased with increasing body length (p < 0.001). After adjustment for body length, males had greater Crs values than did females (p < 0.01). V30E was smaller in female infants (p < 0.05) and in infants whose mothers smoked during pregnancy (p < 0.04). Specific compliance (Crs/V30E) declined with increasing age (p < 0.01), but there were no differences related to sex or maternal smoking. We conclude that static deflation PV curves can be recorded in the age range from 1 to 104 wk, and that maternal smoking may produce hypoplastic lungs.

Compression of the trachea by the innominate artery in a 2-month-old child.

SUMMARY. We utilized improved methods for assessing airway structure and function to define the clinical significance of the innominate artery syndrome. Both infant pulmonary function tests (IPFT) and noninvasive controlled ventilation computed tomography (CVCT) were used, along with traditional diagnostic techniques in a 2-month-old child with compression of the trachea by the innominate artery. These tests provided objective documentation of functional impairment before surgery and improvement postoperatively. These tests should aid in the understanding of this controversial syndrome and help to further define treatment options.

Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis.

Pseudomonas aeruginosa lung infection is an important cause of morbidity and mortality in cystic fibrosis (CF). Longitudinal assessment of the phenotypic changes in P. aeruginosa isolated from young children with CF is lacking. This study investigated genotypic and phenotypic changes in P. aeruginosa from oropharynx (OP) and bronchoalveolar lavage fluid (BALF) in a cohort of 40 CF patients during the first 3 years of life; antibody response was also examined. A high degree of genotypic variability was identified, and each patient had unique genotypes. Early isolates had a phenotype distinct from those of usual CF isolates: generally nonmucoid and antibiotic susceptible. Genotype and phenotype correlated between OP and BALF isolates. As determined by culture, 72.5% of patients demonstrated P. aeruginosa during their first 3 years. On the basis of combined culture and serologic results, 97.5% of patients had evidence of infection by age 3 years, which suggests that P. aeruginosa infection occurs early in CF and may be intermittent or undetectable by culture.

Forced expiratory flows and volumes in infants. Normative data and lung growth.

Forced expiratory flows (FEF) can be measured in infants from lung volumes initiated near total lung capacity. In order to establish reference values and to evaluate lung growth, we obtained measurements in 155 healthy subjects between 3 and 149 wk of age. Forced vital capacity (FVC) was highly correlated with body length; however, after accounting for length, age was also significant. When subjects were divided at the median age (40 wk) younger compared with older subjects had a significantly larger slope for length (3.7 versus 2.8; p = 0.002). The flow parameters (FEF(50), FEF(75), FEF(85), and FEF(25-75)) were highly correlated with length, and those infants whose mothers smoked had lower flows. For FEF(75), male subjects had lower flows than female subjects. The relationship between FEF and volume was assessed using FEV(0.5)/FVC, which decreased with increasing length. Smaller subjects emptied their lung volume proportionately faster. We conclude that our study provides reference values for this age group and demonstrates that smoke-exposed infants and male subjects have decreased FEF. In addition, our findings indicate that lung volume increases most rapidly during the first year of life and that airways are large relative to lung volume very early in life.

Induction of interleukin-8 release by lung epithelium with cystic fibrosis epithelial lining fluid is marginally affected by inhibitors of interleukin-1beta.

Interleukin-1beta (IL-1beta) and neutrophil elastase (NE) are present in the epithelial lining fluid (ELF) of patients with cystic fibrosis (CF). Both factors activate surrounding cells including lung epithelial cells, causing release of IL-8, a potent chemoattractant for neutrophils. Previous studies showed up-regulation of IL-8 release by lung epithelial cells as a function of NE in CF; however, few studies addressed the relationship between IL-1beta and activation of lung epithelial cells in CF lungs. Confluent layers of A549 cells, a type II-like human lung epithelial cell line, were incubated overnight with IL-1beta (0-5 ng/ml) or NE (100 nM), and supernatants were analyzed for IL-8 by enzyme-linked immunosorbent assay (ELISA). Both IL-1beta and NE led to a significant increase in IL-8: 12.8 +/- 2.8 ng/ml and 0.8 +/- 0.3 ng/ml, respectively. Next, bronchoalveolar lavage (BAL) samples were obtained from one healthy adult volunteer and six patients with CF and measured for IL-8 and IL-1beta concentrations by ELISA. Both IL-8 (range 169.00 +/- 56.57 to 1742.04 +/- 338.98 pg/ml) and IL-1beta (range 0-24.26 +/- 0.52 pg/ml) were detected in CF specimens, whereas neither was detected in the volunteer's specimen. Normal and CF BALs then were incubated overnight at a 1:10 dilution with confluent A549 cells. Analysis by ELISA of cell-free supernatants revealed increased IL-8 production from cells stimulated with CF BALs only. Similar experiments were performed with BAL supernatants that had been incubated with soluble IL-1 type II receptor, soluble IL-1 receptor antagonist, or a peptide inhibitor of NE. Addition of IL-1 inhibitors had a marginal effect on the amount of IL-8 release after incubation with CF BAL samples, whereas inhibition of NE had no effect. Our results indicate that other factors present in ELF in CF account for IL-8 release from lung epithelial cells.

Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis.

The objective of this study was to assess the diagnostic accuracy of oropharyngeal (OP) cultures relative to simultaneous bronchoalveolar lavage (BAL) cultures in very young children with CF, and to examine the effects of bacterial density, age, and study cohort on diagnostic accuracy. Respiratory culture data were analyzed from three independent, prospective studies involving simultaneous collection of 286 OP and BAL cultures from 141 children with CF <5 years of age. For predicting any growth of Pseudomonas aeruginosa (Pa) from the lower airway in subjects /=10(3) or >/=10(5) cfu/mL. Specificity for Pa declined significantly with increasing age. In children with CF <5 years of age, the specificity and negative predictive value of OP cultures for Pa are high, while the sensitivity and positive predictive value are poor. Thus, in this age range, a negative throat culture is helpful in "ruling out" lower airway infection with Pa. However, a positive culture does not reliably "rule in" the presence of Pa in the lower respiratory tract. These findings may have implications for study design and interpretation as well as clinical management of young children with CF.

Passive respiratory mechanics in healthy infants. Effects of growth, gender, and smoking.

This investigation characterizes the normal growth, variability, and effects of gender and smoking on passive respiratory mechanics in healthy infants. Passive respiratory mechanics were assessed at 193 test sessions on 127 infants (55 boys, 72 girls) between 2 wk and 18 mo of age using the single-occlusion passive flow-volume technique. Respiratory compliance (Crs) increased significantly with increasing infant length, whereas respiratory resistance (Rrs) declined. No significant gender differences were apparent for Crs, although there was a tendency for this measure to be both lower at birth and increase at a slower rate in girls than in boys. Rrs was significantly higher at birth in infant boys than in infant girls, but the rate of the normal decline in Rrs during the first 18 mo also occurred at a significantly greater rate in boys. The passive respiratory time constant (Trs) overall showed little change over this age range, but it was both lower near birth and increased at a significantly greater rate versus infant length in girls than in boys. Maternal smoking during pregnancy was associated with lower levels of Rrs at birth, as well as with significantly slower growth of Crs and natural decline of Rrs in the first 18 mo of life. These data suggest that infant girls may have more mature respiratory mechanics at birth, but that postnatal growth/maturation may be faster in boys.

Effect of maternal smoking during pregnancy on passive respiratory mechanics in early infancy.

We studied the effect of prenatal maternal cigarette smoking on passive expiratory mechanics in 53 healthy infants tested early in infancy (mean +/- SD, 5.1 +/- 1.5 weeks). Maternal smoking was measured by: 1) questionnaire reports of the number of cigarettes smoked per day; and 2) urine cotinine concentrations (corrected for creatinine) at each visit. Respiratory system mechanics were assessed by the single-breath occlusion-passive-flow-volume maneuver. In ten infants born to smoking mothers the time constant of the respiratory system was 23% reduced [0.34 vs. 0.44 s; 95% confidence interval (CI), -45% + 1%; P = 0.06]. This was related to an estimated 13% decrease in respiratory system compliance (4.86 vs. 5.62 mL/cmH2O; 95%CI, -33% + 6%; P = 0.18) and a 10% reduction in respiratory system resistance (0.073 vs. 0.081 cm H2O/mL/s; 95%CI, -42% + 22%; P = 0.56). Functional residual capacity (FRC), measured by helium-dilution, was also decreased by 13% (78 vs. 90 mL; 95%CI, -27% + 0.3%; P = 0.06) in smoke-exposed infants. Forced expiratory flow rates at FRC obtained by thoraco-abdominal compression were reduced by 28% in infants of smoking mothers (VFRC, 99 vs. 138 mL/s; 95%CI, -54% + 2%; P = 0.04) as reported previously in a larger sample from this population. This study was limited by small numbers of infants exposed to smoking during pregnancy and by ethnic imbalance among the smoking-exposed and unexposed groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Lung function, pre- and post-natal smoke exposure, and wheezing in the first year of life.

The relationship between initial level of lung function and subsequent wheezing, lower respiratory illness (LRI) was studied in 97 infants in whom the first measurement of pulmonary function (PFT) was made before 6 months of age. Occurrence of LRI was evaluated by standardized questionnaires at each well-baby visit, biweekly telephone calls to mothers, and review of all visits to physicians. Infant PFT was assessed by partial expiratory flow-volume curves and helium-dilution measurement of functional residual capacity (FRC). Maternal, prenatal smoking was assessed by urine cotinine and standard questionnaires. Infants who developed an LRI during the first year of life had lower preillness length-corrected forced expiratory flow at FRC (VFRC) than those who did not experience an LRI (males, 2.06 +/- 0.20 versus 2.32 +/- 0.29 ml/s/cm; females, 2.38 +/- 0.20 versus 2.91 +/- 0.26 ml/s/cm). Similar results were observed with FRC-corrected VFRC. No differences were observed for FRC. Differences in lung function were greatest in female infants whose mothers did not smoke during pregnancy (VFRC 2.67 +/- 0.25 versus 3.49 +/- 0.26 ml/s/cm for those with and without LRI, respectively; p = 0.03). History of maternal wheezing was more common in infants who experience an LRI, independent of maternal smoking. The results were not influenced by exposure to nonmaternal sources of environmental tobacco smoke in the postnatal period. Regression analyses that included data for multiple measurements of VFRC over the first year and took account of duration of follow-up demonstrated that lower levels of VFRC were associated with an increased frequency of LRI, especially in female infants.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of maternal smoking during pregnancy on early infant lung function.

We studied the effect of prenatal maternal cigarette smoking on the pulmonary function (PF) of 80 healthy infants tested shortly after birth (mean, 4.2 +/- 1.9 wk). Mothers' prenatal smoking was measured by: (1) questionnaire reports at each prenatal visit of the number of cigarettes smoked per day, and (2) urine cotinine concentrations (corrected for creatinine) obtained at each visit. Infant PF was assessed by partial expiratory flow-volume curves and helium-dilution measurement of FRC. Forced expiratory flow rates were significantly lower in infants born to smoking mothers, both when unadjusted and after controlling for infant size, age, sex, and passive exposure to environmental tobacco smoke (ETS) between birth and the time of PF testing. Flow at functional residual capacity (VFRC) in infants born to smoking mothers was lower than that found in infants whose mothers did not smoke during pregnancy (74.3 +/- 15.9 versus 150.4 +/- 8.9 ml/s; p = 0.0007). Differences remained significant when flow was corrected for lung size (VFRC/FRC: 0.87 +/- 0.26 versus 1.77 +/- 0.12 s-1; p = 0.013). No differences in pulmonary function were evident among infants exposed and unexposed to ETS in the home after stratifying by prenatal exposure status. We conclude that maternal smoking during pregnancy is associated with significant reductions in forced expiratory flow rates in young infants. The results suggest that maternal smoking during pregnancy may impair in utero airway development and/or alter lung elastic properties. We speculate that these effects of maternal prenatal smoking on early levels of forced expiratory flow may be an important factor predisposing infants to the occurrence of wheezing illness later in childhood.

Assessment of the usefulness of helium-oxygen maximal expiratory flow curves in epidemiologic studies of lung disease in children.

Density dependence of maximal expiratory air flow (DD) has been used in adults as a test of early obstructive airway disease (OAD). Whether DD is useful as an epidemiologic tool to identify childhood risk factors for OAD is not known. In a population-based sample of 133 children 8 to 23 yr of age, we calculated density dependence at 50 and 25% of vital capacity (DD50 and DD25) (the ratios between maximal expiratory flow rates breathing helium-oxygen and air gas mixtures at each of these lung volumes), and the volume of isoflow (VisoV) (the lung volume, expressed as a percentage of vital capacity, at which maximal flow rates when breathing each gas mixture are equal), measured airway responsiveness using eucapnic hyperventilation with cold air, and obtained health and household information with questionnaires. Mean levels (+/- SD) of DD50, DD25, and VisoV were: 1.49 +/- 0.14, 1.37 +/- 0.18, and 10.7 +/- 10%. The DD50 significantly increased with age in these growing children (p less than 0.05), but DD50 was found to be significantly lower (1.42 +/- 0.14 versus 1.52 +/- 0.13; p less than 0.01) among children with nonspecific bronchial hyperresponsiveness. The DD50 also was significantly reduced among children with a history of a recent upper respiratory tract illness (URI) (p less than 0.01). There were no significant associations of DD with history of asthma, personal smoking, parental smoking, or respiratory illness during infancy. The reproducibility of DD50 was assessed on a subsample of 90 subjects in whom DD was measured during 2 surveys 1 yr apart.(ABSTRACT TRUNCATED AT 250 WORDS)

Secondary (AA) amyloidosis in cystic fibrosis. A report of three cases.

The authors report the pathologic features of three cases of amyloidosis associated with cystic fibrosis. Renal biopsy led to the diagnosis (case 1) or suspicion (case 2) of amyloidosis in patients who were 23 and 21 years old, respectively. The third patient died at age 22 years, and amyloidosis was not discovered until autopsy. Immunohistochemical staining and potassium-permanganate pretreatment of histologic sections in all three cases provided evidence that the amyloid seen in these patients is of the secondary (AA) type. Congo red staining in each case and electron microscopy in case 1 confirmed the initial diagnosis of amyloidosis. A markedly elevated serum amyloid A protein (160 micrograms/mL; normal less than 1 microgram/mL) in case 1 indicated the presence of large quantities of the precursor protein from which the AA fibrils of secondary amyloid are derived. The kidneys, spleen, and liver contained amyloid deposits in autopsy material from all three cases. Involvement of other organs by amyloid was variable. Review of autopsy material in Boston from 23 additional cystic fibrosis patients with long-term survival did not reveal any evidence of amyloidosis. It appears that secondary amyloidosis is emerging as a significant, although rare, complication of cystic fibrosis as greater numbers of these patients survive into adulthood.

Amyloidosis as a complication of cystic fibrosis.

Amyloidosis appears to be a rare complication of cystic fibrosis. We discuss three patients with amyloidosis complicating cystic fibrosis to add to the six patients previously recorded. The presenting problem was proteinuria in five patients, thyromegaly in three patients, and hepatosplenomegaly in one patient. The progression of proteinuria to nephrotic syndrome and edema occurred in eight of nine patients and portended a very poor prognosis. The kidneys, adrenal glands, spleen, thyroid gland, liver, heart, and bowel were most frequently involved. Renal involvement is a frequent and devastating complication of amyloidosis in patients with cystic fibrosis.