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1.  Lessons learned from a randomized trial of airway secretion clearance techniques in cystic fibrosis 
Pediatric pulmonology  2010;45(3):291-300.
Airway secretion clearance therapies are a cornerstone of cystic fibrosis care, however longitudinal comparative studies are rare. Our objectives were to compare three therapies [postural drainage and percussion: (postural drainage), flutter device, and high frequency chest wall oscillation: (vest)], by studying 1) change in pulmonary function; 2) time to need for IV antibiotics, 3) use of pulmonary therapies, 4) adherence to treatment, 5) treatment satisfaction, and 6) quality of life.
Participants were randomly assigned to one of three therapies twice daily. Clinical outcomes were assessed quarterly over 3 years.
Enrollment goals were not met, and withdrawal rates were high, especially in postural drainage (51%) and flutter device (26%), compared to vest (9%), resulting in early termination. FEV1 decline, time to need IV antibiotics, and other pulmonary therapies were not different. The annual FEF25–75% predicted rate of decline was greater in those using vest (p=0.02). Adherence was not significantly different (p=0.09). Overall treatment satisfaction was higher in vest and flutter device than in postural drainage (p<0.05). Health-related quality of life was not different. The rate of FEV1 decline was 1.23% predicted/year.
The study was ended early due to dropout and smaller than expected decline in FEV1. Patients were more satisfied with vest and flutter device. The longitudinal decline in FEF25–75% was faster in vest; we found no other difference in lung function decline, taken together this warrants further study. The slow decline in FEV1 illustrates the difficulty with FEV1 decline as a clinical trial outcome.
PMCID: PMC4163837  PMID: 20146387
cystic fibrosis; Chest Wall Oscillation; drainage, postural, Medication Adherence; patient dropouts
2.  Clinical Significance of a First Positive Nontuberculous Mycobacteria Culture in Cystic Fibrosis 
Rationale: Little is known about outcomes of infection with nontuberculous mycobacteria (NTM) in cystic fibrosis (CF) or about the significance of a positive NTM culture. Determining which patients are at risk for active NTM disease is clinically valuable.
Objectives: To examine the clinical course of subjects with CF with an initial positive NTM culture and identify characteristics associated with active NTM disease.
Methods: We performed a retrospective study of pediatric and adult subjects with CF with at least one positive NTM culture at the Colorado CF Center from 2000 to 2010.
Measurements and Main Results: Mycobacterium avium complex was the first identified NTM in the majority of subjects (73%). The frequency of growing a second NTM species was 26% at 5 years. Clinical characteristics and distribution of NTM species between pediatric and adult subjects were similar except for differences in baseline FEV1 (89% vs. 71%; P < 0.001) and coinfection with Pseudomonas aeruginosa (33% vs. 55%; P = 0.04). Over 60% of subjects had transient or persistent infection but not active NTM disease. Subjects who developed active NTM disease were distinguished from those with transient or persistent infection, respectively, by FEV1 at the time of first positive NTM culture (72% vs. 84 or 86%; P = 0.02) and FEV1 decline in the prior year (−5.8%/yr vs. −0.7%/yr [P = 0.009] or −0.4%/yr [P = 0.001]).
Conclusions: The majority of patients with CF with a first positive NTM culture do not progress to active disease. Lower lung function and accelerated lung function decline appear to be indicators of the significance of an initial positive NTM culture.
PMCID: PMC3972987  PMID: 24251858
nontuberculous mycobacteria; Mycobacterium avium complex; Mycobacterium abscessus
3.  Molecular Identification of Bacteria in Tracheal Aspirate Fluid from Mechanically Ventilated Preterm Infants 
PLoS ONE  2011;6(10):e25959.
Despite strong evidence linking infections to the pathogenesis of bronchopulmonary dysplasia (BPD), limitations of bacterial culture methods have precluded systematic studies of airway organisms relative to disease outcomes. Application of molecular bacterial identification strategies may provide new insight into the role of bacterial acquisition in the airways of preterm infants at risk for BPD.
Serial (within 72 hours, 7, 14, and 21 days of life) tracheal aspirate samples were collected from 10 preterm infants with gestational age ≤34 weeks at birth, and birth weight of 500–1250 g who required mechanical ventilation for at least 21 days. Samples were analyzed by quantitative real time PCR assays for total bacterial load and by pyrosequencing for bacterial identification.
Subjects were diagnosed with mild (1), moderate (3), or severe (5) BPD. One patient died prior to determination of disease severity. 107,487 sequences were analyzed, with mean of 3,359 (range 1,724–4,915) per sample. 2 of 10 samples collected <72 hours of life contained adequate bacterial DNA for successful sequence analysis, one of which was from a subject exposed to chorioamnionitis. All other samples exhibited bacterial loads >70copies/reaction. 72 organisms were observed in total. Seven organisms represented the dominant organism (>50% of total sequences) in 31/32 samples with positive sequences. A dominant organism represented>90% of total sequences in 13 samples. Staphylococcus, Ureaplasmaparvum, and Ureaplasmaurealyticum were the most frequently identified dominant organisms, but Pseudomonas, Enterococcus, and Escherichia were also identified.
Early bacterial colonization with diverse species occursafter the first 3 days of life in the airways of intubated preterm infants, and can be characterized by bacterial load and marked species diversity. Molecular identification of bacteria in the lower airways of preterm infants has the potential to yield further insight into the pathogenesis of BPD.
PMCID: PMC3189942  PMID: 22016793
4.  Effects of Gender and Age at Diagnosis on Disease Progression in Long-term Survivors of Cystic Fibrosis 
Rationale: Long-term survivors of cystic fibrosis (CF) (age > 40 yr) are a growing population comprising both patients diagnosed with classic manifestations in childhood, and nonclassic phenotypes typically diagnosed as adults. Little is known concerning disease progression and outcomes in these cohorts.
Objectives: Examine effects of age at diagnosis and gender on disease progression, setting of care, response to treatment, and mortality in long-term survivors of CF.
Methods: Retrospective analysis of the Colorado CF Database (1992–2008), CF Foundation Registry (1992–2007), and Multiple Cause of Death Index (1992–2005).
Measurements and Main Results: Patients with CF diagnosed in childhood and who survive to age 40 years have more severe CFTR genotypes and phenotypes compared with adult-diagnosed patients. However, past the age of 40 years the rate of FEV1 decline and death from respiratory complications were not different between these cohorts. Compared with males, childhood-diagnosed females were less likely to reach age 40 years, experienced faster FEV1 declines, and no survival advantage. Females comprised the majority of adult-diagnosed patients, and demonstrated equal FEV1 decline and longer survival than males, despite a later age at diagnosis. Most adult-diagnosed patients were not followed at CF centers, and with increasing age a smaller percentage of CF deaths appeared in the Cystic Fibrosis Foundation Registry. However, newly diagnosed adults demonstrated sustained FEV1 improvement in response to CF center care.
Conclusions: For patients with CF older than 40 years, the adult diagnosis correlates with delayed but equally severe pulmonary disease. A gender-associated disadvantage remains for females diagnosed in childhood, but is not present for adult-diagnosed females.
PMCID: PMC2937235  PMID: 20448091
cystic fibrosis; middle aged; aged; gender; outcome assessment
5.  The Scope and Impact of Early and Late Preterm Infants Admitted to the PICU with Respiratory Illness 
The Journal of pediatrics  2010;157(2):209-214.e1.
To determine the clinical course and outcomes of children born early preterm (EPT, <32 weeks), late preterm (LPT, 32-35 weeks), and full term (FT, ≥36 weeks) who were subsequently admitted to the pediatric intensive care unit (PICU) with respiratory illness.
Study design
Retrospective chart review of patients less than 2 years old admitted to a tertiary PICU with respiratory illness.
271 patients met inclusion criteria: 17.3% were EPT, 12.2% were LPT, and 70.5% were FT. Lower respiratory tract infection was the most common diagnosis (55%) for all groups., Median PICU length of stay was longer for EPT (6.3 days) and LPT infants (7.1 days) compared with FT infants (3.7 days; p <0.03 for both comparisons). EPT and LPT infants had longer hospital stays (median, 11.7 and 13.8 days, respectively) compared with FT infants (median, 7.1 days; p < 0.03 and p = 0.004, respectively). Median hospital charges were also greater for EPT ($85,151) and LPT ($83,576) groups compared with FT group ($55,122; p < 0.01 and p < 0.02, respectively).
EPT and LPT infants comprise a considerable proportion of PICU admissions for respiratory illness and have greater resource utilization than FT infants.
PMCID: PMC2892737  PMID: 20338574
pediatric intensive care; preterm birth; respiratory illness; resource utilization
6.  Clinical Utility of Echocardiography for the Diagnosis and Management of Pulmonary Vascular Disease in Young Children With Chronic Lung Disease 
Pediatrics  2008;121(2):317-325.
The goal was to determine the clinical utility of Doppler echocardiography in predicting the presence and severity of pulmonary hypertension in patients with chronic lung disease who subsequently underwent cardiac catheterization.
A retrospective review of data for all patients <2 years of age with a diagnosis of bronchopulmonary dysplasia, congenital diaphragmatic hernia, or lung hypoplasia who underwent echocardiography and subsequently underwent cardiac catheterization for evaluation of pulmonary hypertension was performed. The accuracy of echocardiography in diagnosing pulmonary hypertension, on the basis of estimated systolic pulmonary artery pressure, was compared with the detection of pulmonary hypertension with the standard method of cardiac catheterization.
Thirty-one linked measurements for 25 children were analyzed. Systolic pulmonary artery pressure could be estimated in 61% of studies, but there was poor correlation between echocardiography and cardiac catheterization measures of systolic pulmonary artery pressure in these infants. Compared with cardiac catheterization measurements, echocardiographic estimates of systolic pulmonary artery pressure diagnosed correctly the presence or absence of pulmonary hypertension in 79% of the studies in which systolic pulmonary artery pressure was estimated but determined the severity of pulmonary hypertension (severe pulmonary hypertension was defined as pulmonary/systemic pressure ratio of ≥0.67) correctly in only 47% of those studies. Seven (58%) of 12 children without estimated systolic pulmonary artery pressure demonstrated pulmonary hypertension during subsequent cardiac catheterization. In the absence of estimated systolic pulmonary artery pressure, qualitative echocardiographic findings, either alone or in combination, had worse predictive value for the diagnosis of pulmonary hypertension.
As used in clinical practice, echocardiography often identifies pulmonary hypertension in young children with chronic lung disease; however, estimates of systolic pulmonary artery pressure were not obtained consistently and were not reliable for determining the severity of pulmonary hypertension.
PMCID: PMC3121163  PMID: 18245423
chronic lung disease; bronchopulmonary dysplasia; pulmonary hypertension; echocardiography; cardiac catheterization
7.  Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results 
Human genetics  2009;126(6):763-778.
Cystic fibrosis (CF) is a monogenic disease due to mutations in the CFTR gene. Yet, variability in CF disease presentation is presumed to be affected by modifier genes, such as those recently demonstrated for the pulmonary aspect. Here, we conduct a modifier gene study for meconium ileus (MI), an intestinal obstruction that occurs in 16–20% of CF newborns, providing linkage and association results from large family and case–control samples. Linkage analysis of modifier traits is different than linkage analysis of primary traits on which a sample was ascertained. Here, we articulate a source of confounding unique to modifier gene studies and provide an example of how one might overcome the confounding in the context of linkage studies. Our linkage analysis provided evidence of a MI locus on chromosome 12p13.3, which was segregating in up to 80% of MI families with at least one affected offspring (HLOD = 2.9). Fine mapping of the 12p13.3 region in a large case–control sample of pancreatic insufficient Canadian CF patients with and without MI pointed to the involvement of ADIPOR2 in MI (p = 0.002). This marker was substantially out of Hardy–Weinberg equilibrium in the cases only, and provided evidence of a cohort effect. The association with rs9300298 in the ADIPOR2 gene at the 12p13.3 locus was replicated in an independent sample of CF families. A protective locus, using the phenotype of no-MI, mapped to 4q13.3 (HLOD = 3.19), with substantial heterogeneity. A candidate gene in the region, SLC4A4, provided preliminary evidence of association (p = 0.002), warranting further follow-up studies. Our linkage approach was used to direct our fine-mapping studies, which uncovered two potential modifier genes worthy of follow-up.
PMCID: PMC2888886  PMID: 19662435
8.  Effects of Long-term Sildenafil Treatment for Pulmonary Hypertension in Infants with Chronic Lung Disease 
The Journal of pediatrics  2008;154(3):379-384.e2.
To determine the clinical course and outcomes of infants with chronic lung disease (CLD) and pulmonary hypertension (PH) who received prolonged sildenafil therapy.
Study design
Retrospective review of 25 patients < 2 years of age with CLD in whom sildenafil was initiated for the treatment of PH while hospitalized from January 2004 – October 2007. Hemodynamic improvement was defined by a 20% decrease in the ratio of pulmonary to systemic systolic arterial pressure or improvement in the degree of ventricular septal flattening by serial echocardiograms.
Chronic sildenafil therapy (dose range: 1.5-8 mg/kg/d) was initiated at a median of 171 days of age (range: 14-673) for a median duration of 241 days (range: 28-950). Twenty-two patients (88%) achieved hemodynamic improvement after a median treatment duration of 40 days (range: 6-600). Eleven of the 13 patients with interval estimates of systolic pulmonary artery pressure by echocardiogram showed clinically significant reductions in PH. Five patients (20%) died during the follow up period. Adverse events leading to cessation or interruption of therapy occurred in 2 patients, one for recurrent erections, and the other had the medication held briefly due to intestinal pneumatosis.
These data suggest that chronic sildenafil therapy is well-tolerated, safe and effective for infants with PH and CLD.
PMCID: PMC2783835  PMID: 18950791
phosphodiesterase inhibitors; pediatrics; bronchopulmonary dysplasia; congenital diaphragmatic hernia; lung hypoplasia; chronic mechanical ventilation
9.  Gene modifiers in cystic fibrosis 
Studies of modifier genes in cystic fibrosis (CF) have often been performed in small or narrowly defined populations, leading to conflicting results. In this issue of the JCI, Dorfman et al. demonstrate in a large, population-based study that two previously studied modifier genes, coding for mannose-binding lectin 2 and TGF-β1, influence pulmonary outcome in pediatric CF patients (see the related article beginning on page 1040). They further show gene-gene interaction between the two, underscoring the complexity of CF lung disease. Their findings provide further impetus to study these molecules and associated signaling pathways in CF. In addition, these findings argue strongly for collecting genotypes of known modifiers prospectively in CF clinical trials as well as in longitudinal studies of infants identified through newborn screening, where the full impact of such modifiers can be defined more precisely.
PMCID: PMC2248430  PMID: 18292812

Results 1-9 (9)