Christopher G. Green

Acceleration of lung disease in children with cystic fibrosis after Pseudomonas aeruginosa acquisition

As part of the ongoing Wisconsin Cystic Fibrosis (CF) Neonatal Screening Project, we had the unique opportunity to study the longitudinal relationship between Pseudomonas aeruginosa (Pa) acquisition and infection and developing lung disease in children with CF. The primary objective was to determine whether acquisition of Pa was associated with a measurable change in the progression of lung disease. Two outcome measures were used to study 56 patients who were diagnosed through newborn screening: 1) Wisconsin additive chest radiograph score (WCXR), based on the average of scores from a pulmonologist and a radiologist, and 2) the highest forced expired volume in 1 sec (FEV1)/forced vital capacity (FVC) ratio. We used two measures of Pa acquisition: 1) time of first positive protocol‐determined oropharyngeal (with cough) culture, and 2) the magnitude of antibody titer detected by ELISA assays, using as antigen a crude cell lysate, purified exotoxin A, or an elastase toxoid prepared from three Pa strains. Other predictor variables included age, pancreatic status, height‐for age, and weight‐for‐age‐percentiles.

Obstructive sleep apnea in Apert's and Pfeiffer's syndromes: more than a craniofacial abnormality.

Nine acrocephalosyndactyly type I patients (Aperts syndrome) and three acrocephalosyndactyly type V patients (Pfeiffers syndrome) were evaluated for the relative importance of upper and lower airway abnormalities in the generation of obstructive sleep apnea. All patients were found to have a combination of upper and lower abnormalities. The influence of lower pathology was greater in the infants, and the influence of upper airway, specifically pharyngeal, was greater in the adults. A comparison between preoperative and postoperative polysomnography revealed little improvement with standard craniofacial advancements. Furthermore, three patients are described who succumbed to pulmonary death despite tracheostomy. Conservative treatment with prone or lateral positioning and medical pulmonary regimens is advocated. Finally, the pathogenesis of this diffuse airway pathology is discussed.

Wisconsin cystic fibrosis chest radiograph scoring system: Validation and standardization for application to longitudinal studies †

This study was designed to achieve a final modeling, validation, and standardization plan for the Wisconsin cystic fibrosis (CF) chest radiographic scoring system. Sixty chest radiographs were selected to reflect a range of severity of lung pathology in children with CF. Seven experienced volunteer raters (three radiologists and four pediatric pulmonologists) from five institutions were recruited to evaluate and score the films. Analysis of scores revealed that the subcomponents of the Wisconsin system showed considerable variation from rater to rater, but reliability assessment indicated satisfactory Cronbachs alpha coefficients (0.83–0.90) among the seven raters. It was found that an additive method of total score computation is significantly more reliable (P < 0.05) than either the original multiplicative model or the traditional Brasfield scoring system. Comparison of radiologists and pulmonologists revealed a marked, systematic difference in scoring with the former group being more conservative in interpretation of abnormalities than the pulmonologists, and some of the raters showing very limited sensitivity.

Temporal Associations Among Energy Intake, Plasma Linoleic Acid, and Growth Improvement in Response to Treatment Initiation After Diagnosis of Cystic Fibrosis

OBJECTIVE. It is unclear why some patients with cystic fibrosis (CF) succeed (“responders”) in recovering from malnutrition and growth faltering after treatment initiation whereas others fail to do so (“nonresponders”). We conducted a study to test the hypothesis that sustained high energy intake (↑EN) and normal plasma essential fatty acid status are critical determinants of treatment responsiveness within 2 years after diagnosis of CF. METHODS. A total of 71 CF children who had pancreatic insufficiency but not meconium ileus and were enrolled in the Wisconsin CF Neonatal Screening Project were studied. Responders were defined by having achieved adequate weight gain, as indicated by a recovery of weight z score (Wtz) comparable to Wtz at birth (WtzBR) within 2 years of diagnosis. ↑EN and sustained normal plasma linoleic acid level (↑pLA) were defined by achieving energy intake ≥120% of estimated requirement for ≥75% of the time and maintaining plasma LA ≥26% of total fatty acids for ≥75% of the time, respectively. RESULTS. Thirty-two (68%) screened patients and 13 (54%) patients whose CF was diagnosed conventionally recovered WtzBR within 2 years of diagnosis. Screened patients responded at significantly younger ages (mean/median: 6.3/4.3 months) than patients whose CF was diagnosed conventionally (mean/median: 15.8/11.8 months). Proportionately fewer screened patients (33%) achieved ↑EN compared with patients whose CF was diagnosed conventionally (73%). However, more screened patients responded to ↑EN and recovered WtzBR (91%) than patients whose CF was diagnosed conventionally (56%), although this difference was of borderline significance. Compared with having neither ↑EN nor ↑pLA, the likelihood of being a responder was greatest with combined ↑EN and ↑pLA, followed by ↑EN only. The positive associations between ↑EN and ↑pLA to treatment responsiveness remained significant after adjustment for neonatal screening status, baseline height and weight status, and indices of pulmonary disease severity. CONCLUSION. ↑EN and ↑pLA are critical in promoting adequate weight gain in children with newly diagnosed CF.

Relationships Among Health-Related Quality of Life, Pulmonary Health, and Newborn Screening for Cystic Fibrosis

BACKGROUND The objective of this study was to examine relationships between pulmonary health and health-related quality of life (HRQOL) in patients with cystic fibrosis (CF) evaluated longitudinally in the Wisconsin Newborn Screening Project. METHODS Patients aged 8 to 18 years (mean ± SD, 13.5 ± 2.8) in early diagnosis (n = 45) and control (n = 50) groups completed Cystic Fibrosis Questionnaires (CFQs) to measure HRQOL at three data points over a 2-year period. Pulmonary health was evaluated concurrently by the Wisconsin chest x-ray scoring system (WCXR) and pulmonary function tests (PFTs). RESULTS WCXR showed significant group differences (P ≤ .023), with the early diagnosis group showing more-severe lung disease. When adjusted for group differences in mucoid Pseudomonas aeruginosa status and pancreatic status, however, WCXR differences and PFT data were not significant. Most patients (74%) had FEV(1) values ≥ 80% predicted (within normal range). For patients aged < 14 years, as WCXR scores worsened CFQ respiratory and physical domain scores decreased (both P ≤ .007). FEV(1)/FVC showed a positive relationship with the respiratory and physical domains (both P ≤ .006). WCXR scores for patients aged ≥ 14 years were associated with CFQ weight, respiratory, and health domains (all P ≤ .011). FEV(1) was associated with CFQ weight, respiratory, health, and physical domains (all P ≤ .003). Changes in pulmonary health were not associated with changes in CFQ over time. Significant group differences on the CFQ-Child social functioning domain favored the control group. CONCLUSIONS To our knowledge, this study is the first to compare pulmonary outcomes with HRQOL indicators assessed by serial, standardized, patient-reported outcome measures for patients with CF identified either through newborn screening or diagnosed by use of traditional methods. This study found no benefits of newborn screening for pulmonary health or HRQOL after controlling for risk factors. Using WCXR and PFT data collectively helped to identify associations between pulmonary health and HRQOL.

Regional differences in the evolution of lung disease in children with cystic fibrosis

Progression of lung disease is a major event in children with cystic fibrosis (CF), but regional differences in its evolution are unclear. We hypothesized that regional differences occur beginning in early childhood. We examined this issue by evaluating 132 patients followed in the Wisconsin Neonatal Screening Project between 1985 and 2010. We scored chest X‐rays obtained every 1–2 years with the Wisconsin chest X‐ray system, in which we divided the lungs into quadrants, and gave special attention to ratings for bronchiectasis (BX) and nodular/branching opacities. We compared the upper and lower quadrant scores, and upper right and left quadrant scores, as patients aged using a multivariable generalized estimation equation (GEE) model. We did a confirmatory analysis for a subset of 81 patients with chest computerized tomography (CT) images obtained in 2000 and scored using the Brody scoring system. The chest X‐ray analysis shows that the upper quadrants have higher BX (P < 0.001) and nodular/branching opacities (P < 0.001) scores than the lower quadrants. CT analysis likewise reveals that the upper quadrants have more BX (P = 0.02). Patients positive for mucoid PA showed significantly higher BX scores than patients with non‐mucoid PA (P = 0.001). Chest X‐ray scoring also revealed that the upper right quadrant has more BX (P < 0.001) than the upper left quadrant, and CT analysis was again confirmatory (P < 0.001). We conclude that pediatric patients with CF develop more severe lung disease in the upper lobes than the lower lobes in association with mucoid PA infections and also have more severe lung disease on the right side than on the left side in the upper quadrants. A variety of potential explanations such as aspiration episodes may be clinically relevant and provide insights regarding therapies. Pediatr Pulmonol. 2012; 47:635–640.

Exploration of the contribution of biobehavioral variables to the energy expenditure of preterm infants.

Variation in energy expended by preterm infants may be due to infant maturity and history of resolved acute lung disease (respiratory distress syndrome [RDS]) as well as growth, caloric intake, and activity. Indirect calorimetry was used in this exploratory, short-term longitudinal study to estimate energy expenditure (EE) from measures of inspired and expired O2 and CO2.The sample included 35 assessments for 10 preterm infants (5 with and 5 without RDS history). Lung disease history (resolved RDS, no RDS diagnosis), weight gain (g/d) from the day on which birth weight had been regained to the study day, mean activity level, the number of the assessment (1 6), and the interaction of lung disease history and time were included in a linear mixed model for repeated measures. Time was an index of postconceptional and postnatal age; all 3 were highly correlated. Because of high correlation with weight gain, caloric intake was not included in the analytic model. Lung disease history, mean activity level, and time were significant contributors to EE. A more precise measure of medical status than absence or presence of lung disease history, evenly spaced repetitions of EE assessment, and exploration of contexts in which the infants exhibit a higher activity level are needed in a replication study with a larger sample.

A survey of training in pediatric flexible bronchoscopy

There is currently no evidence‐based method for defining competency in pediatric flexible bronchoscopy (FB). Based on expert opinion, guidelines using numbers of procedures have been published in defining competency for pediatric FB. The purpose of this study was to formally survey the opinion of USA pediatric pulmonology training directors about the assessment of competency and training experiences in pediatric FB in their programs.

Rapid Methylprednisolone Clearance in a Patient with Cystic Fibrosis

A pharmacokinetic investigation of administered corticosteroids was conducted in a 16-year-old girl with cystic fibrosis (CF). Equivalent doses of methylprednisolone were given orally and intravenously on consecutive days. Oral bioavailability was essentially 100 percent, ruling out impaired absorption. Drug half-life was shorter and both clearance and volume of distribution were greater in this patient than in normal young adults. From one patient it is impossible to conclude that this unusual disposition of corticosteroids is characteristic of CF. Given the interest in use of corticosteroids in this population, and the examples of other drugs with altered pharmacokinetics in patients with CF, further investigation is warranted.