Jeffrey S. Wagener

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.

Prospective, long-term study of fat-soluble vitamin status in children with cystic fibrosis identified by newborn screen☆☆☆★

OBJECTIVE To prospectively evaluate the biochemical status of vitamins A, D, and E in children with cystic fibrosis (CF). SUBJECTS A total of 127 infants identified by the Colorado CF newborn screening program. DESIGN Vitamin status (serum retinol, 25-hydroxy vitamin D, ratio of alpha-tocopherol/total lipids) and serum albumin were assessed at diagnosis (4 to 8 weeks), ages 6 months, 12 months, and yearly thereafter, to age 10 years. RESULTS Deficiency of 1 or more vitamins was present in 44 (45.8%) of 96 patients at age 4 to 8 weeks as follows: vitamin A 29.0%, vitamin D 22.5%, and vitamin E 22.8%. Of these patients with initial deficiency, the percent that was deficient at 1 or more subsequent time points, despite supplementation, was vitamin A 11.1%, vitamin D 12.5%, and vitamin E 57.1%. Of the initial patients with vitamin sufficiency, the percent who became deficient at any time during the 10-year period was as follows: vitamin A 4.5%, vitamin D 14.4%, and vitamin E 11.8%. The percent of patients deficient for 1 or more vitamins ranged from 4% to 45% for any given year. CONCLUSIONS Despite supplementation with standard multivitamins and pancreatic enzymes, the sporadic occurrence of fat-soluble vitamin deficiency and persistent deficiency is relatively common. Frequent and serial monitoring of the serum concentrations of these vitamins is therefore essential in children with CF.

Impact of Pseudomonas and Staphylococcus infection on inflammation and clinical status in young children with cystic fibrosis.

OBJECTIVE To assess the effects of Pseudomonas aeruginosa and Staphylococcus aureus infection on lower airway inflammation and clinical status in young children with cystic fibrosis (CF). STUDY DESIGN We studied 111 children age < 6 years who had 2 P aeruginosa-positive oropharyngeal cultures within 12 months. We examined bronchoalveolar lavage fluid (BALF) inflammatory markers (ie, cell count, differential, interleukin [IL]-8, IL-6, neutrophil elastase), CF-related bacterial pathogens, exotoxin A serology, and clinical indicators of disease severity. RESULTS Young children with CF with both upper and lower airway P aeruginosa infection had higher neutrophil counts, higher IL-8 and free neutrophil elastase levels, increased likelihood of positive exotoxin A titers, and lower Shwachman scores compared with those with positive upper airway cultures only. S aureus was associated with increased lower airway inflammation, and the presence of both P aeruginosa and S aureus had an additive effect on concentrations of lower airway inflammatory markers. BALF markers of inflammation were increased with the number of different bacterial pathogens detected. CONCLUSIONS Young children with CF who have upper and lower airway P aeruginosa infection have increased endobronchial inflammation and poorer clinical status compared with those with only upper airway P aeruginosa infection. The independent and additive effects of S aureus on inflammation support the significance of polymicrobial infection in early CF lung disease.

Sustained Benefit from Ivacaftor Demonstrated by Combining Clinical Trial and Cystic Fibrosis Patient Registry Data

RATIONALE In clinical trials, patients with cystic fibrosis and a G551D mutation who received ivacaftor experienced improvements in pulmonary and nutritional outcomes. However, whether these improvements reflect a change in disease trajectory cannot be determined without longer-term analyses with an appropriate comparator population. OBJECTIVES To examine, over a 3-year period, whether ivacaftor therapy affects pulmonary function and nutritional measures in patients with CF with a G551D mutation compared with patients with CF who are homozygous for the F508del mutation. METHODS A propensity score was used to match patients with CF greater than or equal to 6 years of age who have a G551D mutation and received ivacaftor in clinical trials for up to 144 weeks with data from patients in the U.S. Cystic Fibrosis Foundation Patient Registry who are homozygous for the F508del mutation. Matching was based on variables including age, sex, weight for age, height for age, body mass index for age, % predicted FEV1, and chronic therapies (dornase alfa, inhaled antibiotics, inhaled and oral corticosteroids). MEASUREMENTS AND MAIN RESULTS By calculating the annual estimated rate of decline in lung function for G551D patients receiving ivacaftor and comparing it with the rate of decline in lung function for matched F508del control patients, we show that the rate of lung function decline in G551D ivacaftor-treated patients was slower by nearly half. Moreover, treatment with ivacaftor is shown to improve body mass index and weight-for-age z scores for G551D patients over the 3-year analysis period. CONCLUSIONS These findings suggest that ivacaftor is a disease-modifying therapy for the treatment of cystic fibrosis.

Impact of socioeconomic status, race, and ethnicity on quality of life in patients with cystic fibrosis in the United States.

BACKGROUND Patient-reported outcomes are increasingly used in clinical trials to assess the natural history of chronic diseases and the efficacy of new treatments. Understanding the effects of socioeconomic and minority status on health-related quality of life (HRQOL) will facilitate interpretation of the results of clinical trials and suggest targets for interventions to improve patient care and outcomes. The objective of this study was to examine the effects of socioeconomic and minority status on HRQOL in patients with cystic fibrosis (CF) from childhood through adulthood in a large, comprehensive database containing medical and HRQOL data for patients with CF. METHODS A cross-sectional study was performed using data obtained from the Epidemiologic Study of Cystic Fibrosis on 4,751 patients and 1,826 parents who were non-Hispanic white, African-American, or Hispanic and who completed the Cystic Fibrosis Questionnaire-Revised (CFQ-R), a disease-specific HRQOL measure, during a stable clinic visit. RESULTS Multivariate models assessed the main effects of socioeconomic and minority status on clinical and HRQOL outcomes. Regression models that controlled for disease severity identified the contributions of these two variables to HRQOL. Low socioeconomic status was associated with significantly lower CFQ-R scores for children, parents, and adults on the majority of domains. After controlling for disease severity and socioeconomic status, African-American and Hispanic patients reported worse emotional and social functioning. CONCLUSIONS Low socioeconomic and minority status may affect important clinical and patient-reported outcomes for patients with CF across their life span.

Longitudinal Assessment of Health-Related Quality of Life in an Observational Cohort of Patients With Cystic Fibrosis

Patient‐reported outcomes (PROs) are increasingly used to evaluate the efficacy of new treatments and the progression of chronic diseases. The Cystic Fibrosis Questionnaire‐Revised (CFQ‐R) is a disease‐specific, PRO measure of health‐related quality of life (HRQOL). We evaluated associations between changes in health status over time and HRQOL in a national CF database.

Newborn screening for cystic fibrosis.

Purpose of review Newborn screening for cystic fibrosis (CF) is now universal in the US and many other countries. The rapid expansion of screening has resulted in numerous publications identifying new challenges for healthcare providers. This review provides an overview of these publications and includes ideas on managing these challenges. Recent findings Most CF newborn screening algorithms involve DNA mutation analysis. As screening has expanded, new challenges have been identified related to carrier detection and inconclusive diagnoses. Early descriptions of infants with CF-related metabolic syndrome (CRMS) indicate that the natural history of this condition cannot be predicted. Early identification has also provided an opportunity to better understand the pathophysiology of CF. However, few studies have been conducted in infants with CF to determine optimal therapy and recommendations are largely anecdotal. Summary Newborn screening provides an opportunity to identify and begin treatment early in individuals with CF. Whereas a single, optimal approach to screening does not exist, all programs can benefit from new findings regarding sweat testing, carrier detection, early pathophysiology, and clinical outcomes.PURPOSE OF REVIEW Newborn screening for cystic fibrosis (CF) is now universal in the US and many other countries. The rapid expansion of screening has resulted in numerous publications identifying new challenges for healthcare providers. This review provides an overview of these publications and includes ideas on managing these challenges. RECENT FINDINGS Most CF newborn screening algorithms involve DNA mutation analysis. As screening has expanded, new challenges have been identified related to carrier detection and inconclusive diagnoses. Early descriptions of infants with CF-related metabolic syndrome (CRMS) indicate that the natural history of this condition cannot be predicted. Early identification has also provided an opportunity to better understand the pathophysiology of CF. However, few studies have been conducted in infants with CF to determine optimal therapy and recommendations are largely anecdotal. SUMMARY Newborn screening provides an opportunity to identify and begin treatment early in individuals with CF. Whereas a single, optimal approach to screening does not exist, all programs can benefit from new findings regarding sweat testing, carrier detection, early pathophysiology, and clinical outcomes.

Year-to-year changes in lung function in individuals with cystic fibrosis

BACKGROUND We examined the year-to-year change in FEV(1) for individuals and the overall cystic fibrosis population to better understand how individual trends may differ from population trends. METHODS We calculated individual yearly changes using the largest annual FEV(1) percent predicted (FEV(1)%) measurement in 20,644 patients (6-45years old) included in the Epidemiologic Study of Cystic Fibrosis. We calculated yearly population changes using age-specific medians. RESULTS FEV(1)% predicted decreased 1-3 points per year for individuals, with maximal decreases in 14-15year olds. Population changes agreed with individual changes up to age 15; however after age 30, yearly population change approximated zero while individual FEV(1)% predicted decreases were 1-2 points per year. CONCLUSIONS Adolescents have the greatest FEV(1)% predicted decreases; however, loss of FEV(1) is a persistent risk in 6-45year old CF patients. Recognizing individual year-to-year changes may improve patient-specific care and may suggest new methods for measuring program quality.

The impact of incident methicillin resistant Staphylococcus aureus detection on pulmonary function in cystic fibrosis

The incidence of methicillin resistant Staphylococcus aureus (MRSA) infection is increasing in cystic fibrosis (CF), but the impact of MRSA detection on clinical outcomes is unclear. Our objective was to determine whether incident detection of MRSA is associated with a change in pulmonary function over time in CF patients. We analyzed data from the Epidemiologic Study of Cystic Fibrosis (ESCF), a prospective observational study of CF patients in North America. Multivariable piecewise linear regression was used to model the impact of incident detection of MRSA on pulmonary function over time, measured by percent predicted forced expiratory volume in one second (FEV1% predicted), adjusting for potential confounders. There were 5,090 patients ≥6 years old who were MRSA negative for at least 2 calendar years. Five hundred ninety‐three (12%) of these patients acquired MRSA during the years 2001–2003, with detection rates of MRSA during those years rising from 4.4% to 6.9%. MRSA positive patients had a lower FEV1% predicted and received more antibiotic and other therapies than patients who remained MRSA negative. After adjusting for antibiotic therapy and other potential confounders, MRSA positive patients also had a higher rate of decline in FEV1% predicted both before and after the incident culture, although the rate of FEV1% predicted decline did not change significantly after MRSA detection. In conclusion, although MRSA in CF was a marker for more aggressive therapy and may reflect increased disease severity, incident MRSA detection was not associated with a changing rate of FEV1% predicted decline. Pediatr. Pulmonol. 2008; 43:1117–1123.

A comparison of the efficacy and tolerance of pancrelipase and placebo in the treatment of steatorrhea in cystic fibrosis patients with clinical exocrine pancreatic insufficiency

A comparison of the efficacy and tolerance of pancrelipase and placebo in the treatment of steatorrhea in cystic fibrosis patients with clinical exocrine pancreatic insufficiency