Zhanhai Li

Reproducibility of a scoring system for computed tomography scanning in cystic fibrosis.

Introduction Computerized tomography (CT) scanning shows promise as an outcome surrogate for cystic fibrosis (CF) lung disease progression. The scoring system used to convert the CT image to numeric data is an essential determinant of the performance of CT scanning. Methods Three radiologists independently scored 16 high-resolution CT scans performed on children in the Wisconsin CF Neonatal Screening Project. The test scans were selected to provide a broad range of disease severity. The scoring system provided subscores for the presence and severity of 5 findings of CF lung disease. The sum of the subscores provided a total score. The CT scans were then read again by each of the radiologists at least 11 months later. Using Mixed Effects Linear Model Analysis, the sources of error (scan-to-scan variation, interrater variance, and intrarater variance) were calculated. Results For the total score, the scan-to-scan variation was 14.48, interrater variance was 0.28, and intrarater variance was 0.45, with an overall reproducibility of 95%. The square root of scan-to-scan variance, a measure of sensitivity, was 3.81. Evaluation of the subscores showed higher reproducibility for bronchiectasis and hyperinflation (95% and 88%, respectively). The bronchiectasis score was more sensitive than the air-trapping score (1.46 vs. 0.89). Discussion This system was developed to provide a reproducible method that could be used to evaluate the lobar location, severity, and extent of a broad spectrum of CT features of CF lung disease, especially in children. This study demonstrates that the overall score is both sensitive to variation in the severity of lung disease and reproducible.

Decreased energy expenditure is caused by abnormal body composition in infants with Prader-Willi Syndrome

OBJECTIVE Infants with Prader-Willi syndrome (PWS) are hypotonic and underweight before the onset of childhood obesity. This study evaluates body composition in the PWS infant and its relationship to energy expenditure. STUDY DESIGN Sixteen infants and toddlers with PWS (mean age, 12.4+/-6 months; eight female subjects) underwent analysis of body composition with dual-energy x-ray absorptiometry and deuterium dilution, and energy expenditure with both doubly labeled water and indirect calorimetry. RESULTS Percent body fat was significantly increased (male subjects, P<.001; female subjects, P<.001) and fat-free mass (FFM) was significantly decreased (male subjects, P<.001; female subjects, P=.04) in infants with PWS when compared with age-matched published data for normal infants. Meanwhile, total energy expenditure was significantly decreased (male subjects, P=.025; female subjects, P<.001) in infants with PWS when compared with published normative data. There was a normal relationship between FFM and total energy expenditure in infants with PWS. CONCLUSION Compared with published data for infants without PWS, infants with PWS demonstrate increased percent body fat, decreased FFM, and decreased energy expenditure. Importantly, total energy expenditure per kilogram of FFM appears similar in infants with and without PWS. We conclude that lower energy expenditure in infants with PWS is caused by decreased FFM.

Viral infections, cytokine dysregulation and the origins of childhood asthma and allergic diseases.

Background: The origins of asthma and allergic disease begin in early life for many individuals. It is vital to understand the factors and/or events leading to their development. Methods: The Childhood Origins of Asthma project evaluated children at high risk for asthma to study the relationships among viral infections, environmental factors, immune dysregulation, genetic factors, and the development of atopic diseases. Consequently wheezing illnesses, viral respiratory pathogen identification, and in vitro cytokine response profiles were comprehensively evaluated from birth to 3 years of age, and associations of the observed phenotypes with genetic polymorphisms were investigated. Results: For the entire cohort, cytokine responses did not develop according to a strict T helper cell 1 or T helper cell 2 polarization pattern during infancy. Increased cord blood mononuclear cell phytohemagglutin-induced interferon-γ responses of mononuclear cells were associated with decreased numbers of moderate to severe viral infections during infancy, especially among subjects with the greatest exposure to other children. In support of the hygiene hypothesis, an increased frequency of viral infections in infancy resulted in increased mitogen-induced interferon-γ responses at 1 year of age. First year wheezing illnesses caused by respiratory viral infection were the strongest predictor of subsequent third year wheezing. Also, genotypic variation interacting with environmental factors, including day care, was associated with clinical and immunologic phenotypes that may precede the development of asthma. Conclusions: Associations between clinical wheezing, viral identification, specific cytokine responses and genetic variation provide insight into the immunopathogenesis of childhood asthma and allergic diseases.

Chest Computed Tomography Scores of Severity Are Associated with Future Lung Disease Progression in Children with Cystic Fibrosis

RATIONALE Most children with cystic fibrosis (CF) experience a slow decline in spirometry, although some children continue to be at risk for more significant lung disease progression. Chest computed tomography (CT) scans have been shown to be more sensitive to changes in lung disease than spirometry and may provide a means for predicting future lung disease progression. OBJECTIVES We hypothesized that Brody chest CT scan scores obtained in 2000 in a prospectively monitored cohort of children with CF would be associated with the most recent measures of lung disease severity. METHODS Brody chest CT scan scores were calculated for 81 children enrolled in the Wisconsin CF Neonatal Screening Project. Multivariable linear regression was used to determine associations between Brody scores and the most recent (age 21 yr or June 30, 2010, whichever was later) measures of CF lung disease. MEASUREMENTS AND MAIN RESULTS The mean observation time after the chest CT scan was 7.5 years. Brody chest CT scan scores were significantly associated with the most recent measures of spirometry (P < 0.001) and Wisconsin and Brasfield chest radiograph scores (P < 0.001). The strength of this association was much stronger than spirometry obtained near the time of the chest CT scan (P < 0.01) but not chest radiograph scores. CONCLUSIONS Chest CT scan scores are associated with future lung disease severity, and quantitative chest imaging(chest CT scan and chest radiograph scores) is more strongly associated with future lung disease severity than measures of spirometry. These findings may help clinicians identify patients at risk of future lung disease progression.

Association between Mucoid Pseudomonas Infection and Bronchiectasis in Children with Cystic Fibrosis

PURPOSE To correlate the severity of bronchiectasis in children with cystic fibrosis with clinical and microbiologic variables in order to clarify risk factors for the development of irreversible lung disease. MATERIALS AND METHODS After institutional review board approval and parental informed consents were obtained, a HIPAA-compliant longitudinal epidemiologic evaluation was performed in patients with cystic fibrosis who were enrolled in the Wisconsin trial of newborn screening from 1985 to 2009. Thin-section chest computed tomography (CT) was used in a prospective cross-sectional design to study patients ranging in age from 6.6 to 17.6 years (mean, 11.5 years). Thin-section CT scores were determined objectively on coded images by multiple raters in a standardized fashion. Microbiologic data were obtained by means of culture of respiratory secretions by using methods for differentiation of Pseudomonas aeruginosa (PA) as either nonmucoid or mucoid. RESULTS Eighty-three percent of patients (68 of 82) showed bronchiectasis of varying severity. Of 12 potential risk factors, only respiratory infection with mucoid PA correlated significantly with bronchiectasis (P = .041). CONCLUSION The severity of bronchiectasis in children with cystic fibrosis is significantly related to respiratory infection with mucoid PA; attempts to prevent bronchiectasis should include reducing exposure to and early eradication of PA.

A controlled, randomized, double-blind trial of prophylaxis against jaundice among breastfed newborns.

Objectives. Neonatal jaundice is a greater problem for infants fed breast milk, compared with formula. This study tested the hypotheses that feeding breastfed newborns β-glucuronidase inhibitors during the first week after birth would increase fecal bilirubin excretion and would reduce jaundice without affecting breastfeeding deleteriously. Methods. Sixty-four breastfed newborns were randomized to 4 groups, ie, control or receiving 6 doses per day (5 mL per dose) of l-aspartic acid, enzymatically hydrolyzed casein (EHC), or whey/casein (W/C) for the first week. l-Aspartic acid and EHC inhibit β-glucuronidase. Transcutaneous bilirubin levels (primary outcome) were measured daily (Jaundice Meter [Minolta/Air Shields, Hatboro, PA] and Bilicheck [Respironics, Pittsburgh, PA]). All stools were collected, and fecal bile pigments, including bilirubin diglucuronide, bilirubin monoglucuronides, and bilirubin, were analyzed with high-performance liquid chromatography. Follow-up assessments included day 7 body weight, day 6/7 prebreastfeeding/postbreastfeeding weights, maternal ratings, and ages at formula introduction and breastfeeding cessation. Results. The groups were comparable at entry. Overall, the l-aspartic acid, EHC, and W/C groups had significantly lower transcutaneous bilirubin levels than did the control group (75.8%, 69.6%, and 69.2%, respectively, of the control mean, 8.53 mg/dL, at the bilirubin peak on day 4). The l-aspartic acid, EHC, and W/C groups had significantly lower transcutaneous bilirubin levels on days 3 to 7. Fecal bile pigment excretion was greatest in the l-aspartic acid group, significantly greater than control values. There were no significant differences in dosages, follow-up measurements, and maternal ratings. Conclusions. Use of minimal aliquots of l-aspartic acid and EHC for β-glucuronidase inhibition results in increased fecal bilirubin excretion and less jaundice, without disruption of the breastfeeding experience. Decreased jaundice in the W/C group, which lacked a β-glucuronidase inhibitor, suggests a different mechanism.

Clarification of Laboratory and Clinical Variables That Influence Cystic Fibrosis Newborn Screening With Initial Analysis of Immunoreactive Trypsinogen

OBJECTIVES. To ensure that each newborn receives an equitable test of the highest possible sensitivity, we recognized the necessity to reassess immunoreactive trypsinogen and DNA issues in cystic fibrosis newborn screening algorithms. Our objectives included clarification of various factors that influence immunoreactive trypsinogen concentrations and resolution of long-standing questions about variations in immunoreactive trypsinogen levels among newborns. METHODS. Immunoreactive trypsinogen data on 660443 newborns who were born between July 1, 1994, and June 30, 2004, were abstracted from the Wisconsin State Laboratory of Hygiene databases and deidentified for analysis. Using a compiled data set, we analyzed various demographic characteristics to determine their role, if any, in immunoreactive trypsinogen variation. Specifically, season of birth, reagent lot, and birth weight were examined. Sensitivities of the most common cystic fibrosis newborn screening protocols, namely immunoreactive trypsinogen/immunoreactive trypsinogen and immunoreactive trypsinogen/DNA, were also investigated. RESULTS. Mean and 95th percentile immunoreactive trypsinogen levels were shown to vary by both season and reagent lot number and affect sensitivity of the assay. Low birth weight infants had significantly higher immunoreactive trypsinogen values than normal birth weight infants. Sensitivities were also found to vary on the basis of the algorithm used, with the highest sensitivity of 96.2% calculated for an immunoreactive trypsinogen/DNA protocol with 23 cystic fibrosis transmembrane conductance regulator mutation analyses compared with 80.2% with the immunoreactive trypsinogen/immunoreactive trypsinogen method used in 9 states. CONCLUSIONS. Floating, rather than fixed, cutoff values for the initial immunoreactive trypsinogen portion of any cystic fibrosis newborn screening protocol are generally necessary on the basis of the seasonal and reagent lot variations observed. Because of its lower sensitivity, immunoreactive trypsinogen/immunoreactive trypsinogen does not optimize detection of patients with cystic fibrosis.

Early Immune Response to the Components of the Type III System of Pseudomonas aeruginosa in Children with Cystic Fibrosis

ABSTRACT The lungs of patients with cystic fibrosis (CF) are colonized initially by Pseudomonas aeruginosa, which is associated with progressive lung destruction and increased mortality. The pathogenicity of P. aeruginosa is caused by a number of virulence factors, including exotoxin A (ETA) and the type III cytotoxins (ExoS, ExoT, ExoU, and ExoY). P. aeruginosa contacts the plasma membrane to deliver type III cytotoxins through a channel formed by PopB, PopD, and PcrV; ETA enters mammalian cells via receptor-mediated endocytosis. The Wisconsin CF Neonatal Screening Project is a longitudinal investigation to assess the potential benefits and risks of newborn screening for CF; the project was the source of serum samples used in this study. Past studies evaluated the longitudinal appearance of antibodies to ETA and elastase and P. aeruginosa infections in patients with CF. The current study characterized the longitudinal appearance of antibodies to components of the type III system in children with CF. Western blot analyses showed that serum antibodies to PopB, PcrV, and ExoS were common. Longitudinal enzyme-linked immunosorbent assays determined that the first detection of antibodies to pooled ExoS/PopB occurred at a time similar to those of detection of antibodies to a P. aeruginosa cell lysate and the identification of oropharyngeal cultures positive for P. aeruginosa. This indicates that children with CF are colonized early with P. aeruginosa expressing the type III system, implicating it in early pathogenesis, and implies that surveillance of clinical symptoms, oropharyngeal cultures, and seroconversion to type III antigens may facilitate early detection of P. aeruginosa infections.

Risk factors for the progression of cystic fibrosis lung disease throughout childhood.

RATIONALE Previous studies of risk factors for progression of lung disease in cystic fibrosis (CF) have suffered from limitations that preclude a comprehensive understanding of the determinants of CF lung disease throughout childhood. The epidemiologic component of the 27-year Wisconsin Randomized Clinical Trial of CF Neonatal Screening Project (WI RCT) afforded us a unique opportunity to evaluate the significance of potential intrinsic and extrinsic risk factors for lung disease in children with CF. OBJECTIVES Describe the most important intrinsic and extrinsic risk factors for progression of lung disease in children with CF. METHODS Variables hypothesized at the onset of the WI RCT study to be determinants of the progression of lung disease and potential risk factors previously identified in the WI RCT study were assessed with multivariable generalized estimating equation models for repeated measures of chest radiograph scores and pulmonary function tests in the WI RCT cohort. MEASUREMENTS AND MAIN RESULTS Combining all patients in the WI RCT, 132 subjects were observed for a mean of 16 years and contributed 1,579 chest radiographs, and 1,792 pulmonary function tests. The significant determinants of lung disease include genotype, poor growth, hospitalizations, meconium ileus, and infection with mucoid Pseudomonas aeruginosa. The previously described negative effect of female sex was not seen. CONCLUSIONS Modifiable extrinsic risk factors are the major determinants of progression of lung disease in children with CF. Better interventions to prevent or treat these risk factors may lead to improvements in lung health for children with CF.

The Need for Quality Improvement in Sweat Testing Infants after Newborn Screening for Cystic Fibrosis

The proportion of insufficient sweat tests after positive newborn screening for cystic fibrosis was determined. Infants ≤ 3 months old had a mean (± standard deviation) rate of 7.2% (± 7.6) (range, 0% to 40%). Collection methods did not affect the rates. The high and variable rates indicate a need for quality improvement.