Late Diagnosis in the Era of Universal Newborn Screening Negatively Affects Short- and Long-Term Growth and Health Outcomes in Infants with Cystic Fibrosis.

Newborn screening for cystic fibrosis was fully implemented in the US by 2010, but delays in timeliness of evaluation for infants with positive newborn screening tests persist. Through evaluation of national patient registry data, we determined that late initiation of cystic fibrosis care is associated with poorer long-term nutritional outcomes.

Application of the New Centers for Disease Control and Prevention Surveillance Criteria for Ventilator-Associated Events to a Cohort of PICU Patients Identifies Different Patients Compared With the Previous Definition and Physician Diagnosis.

OBJECTIVES: We sought to compare the performance of the 2008 Centers for Disease Control and Prevention Pediatric criteria for ventilator-associated pneumonia, the 2013 Adult Ventilator-Associated Condition criteria, the new Draft Pediatric Ventilator-Associated Condition criteria, and physician-diagnosed ventilator-associated pneumonia in a cohort of PICU patients. DESIGN: Secondary analysis of a previously conducted prospective observational study. SETTING: PICU within a tertiary care children's hospital between April 1, 2010, and April 1, 2011. PATIENTS: Patients between 31 days and 18 years old, mechanically ventilated via endotracheal tube for more than 72 hours and no limitations of care. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Ventilator-associated pneumonia criteria applied in real time and ventilator-associated condition criteria applied retrospectively. Outcomes assessed between cases and noncases within criteria. Of the 133 eligible participants, 24 (18%) had ventilator-associated pneumonia by 2008 Pediatric criteria and 27 (20%) by physician diagnosis. Sixteen (12%) and 10 (8%) had ventilator-associated condition by 2013 Adult and Draft Pediatric criteria, respectively. We found significant overlap between cases identified with 2008 Pediatric criteria and physician diagnosis (p = 0.549), but comparisons between the other definitions revealed that the newer criteria identify different patients than previous Centers for Disease Control and Prevention ventilator-associated pneumonia criteria and physician diagnosis (p < 0.01). Although 20 participants were diagnosed with ventilator-associated pneumonia by 2008 Pediatric criteria and physician diagnosis, only three participants were identified by all four criteria. Three subjects uniquely identified by the Draft Pediatric criteria were noninfectious in etiology. Cases identified by all criteria except Draft Pediatric had higher ratios of actual ICU length of stay to Pediatric Risk of Mortality III-adjusted expected length of stay compared with noncases. CONCLUSIONS: The Draft Pediatric criteria identify fewer and different patients than previous ventilator-associated pneumonia criteria or physician diagnosis, potentially missing patients with preventable harms, but also identified patients with potentially preventable noninfectious respiratory deteriorations. Further investigations are required to maximize the identification of patients with preventable harms from mechanical ventilation.

Reliability of Echocardiographic Indicators of Pulmonary Vascular Disease in Preterm Infants at Risk for Bronchopulmonary Dysplasia.

OBJECTIVES: To determine the assessment and inter-rater reliability of echocardiographic evaluations of pulmonary vascular disease (PVD) in preterm infants at risk for bronchopulmonary dysplasia. STUDY DESIGN: We prospectively studied echocardiograms from preterm infants (birthweights 500-1250 g) at 7 days of age and 36 weeks postmenstrual age (PMA). Echocardiograms were assessed by both a cardiologist on clinical service and a single research cardiologist. Interpretations were reviewed for inclusion of determinants of PVD and assessed for inter-rater reliability using the Prevalence Adjusted Bias Adjusted Kappa Score (PABAK). RESULTS: One hundred eighty and 188 matching research and clinical echocardiogram reports were available for the 7-day and 36-week PMA studies. At least one of the specific qualitative measures of PVD was missing from 54% of the clinical reports. PVD was diagnosed at 7 days in 31% and 20% of research and clinical interpretations, respectively (PABAK score of 0.54). At 36 weeks, PH was diagnosed in 15.6% and 17.8% of research and clinical interpretations, respectively (PABAK score of 0.80). CONCLUSIONS: Although all qualitative variables of PVD are not consistently provided in echocardiogram reports, the inter-rater reliability of cardiologists evaluating measures of PVD revealed strong agreement, especially at 36 weeks PMA. We speculate that establishment of a protocol for echocardiographic evaluation may improve the identification of PVD in preterm infants.

Improving the Sensitivity and Positive Predictive Value in a Cystic Fibrosis Newborn Screening Program Using a Repeat Immunoreactive Trypsinogen and Genetic Analysis.

OBJECTIVE: To evaluate the performance of a new cystic fibrosis (CF) newborn screening algorithm, comprised of immunoreactive trypsinogen (IRT) in first (24-48 hours of life) and second (7-14 days of life) dried blood spot plus DNA on second dried blood spot, over existing algorithms. STUDY DESIGN: A retrospective review of the IRT/IRT/DNA algorithm implemented in Colorado, Wyoming, and Texas. RESULTS: A total of 1 520 079 newborns were screened, 32 557 (2.1%) had abnormal first IRT; 8794 (0.54%) on second. Furthermore, 14 653 mutation analyses were performed; 1391 newborns were referred for diagnostic testing; 274 newborns were diagnosed; and 201/274 (73%) of newborns had 2 mutations on the newborn screening CFTR panel. Sensitivity was 96.2%, compared with sensitivity of 76.1% observed with IRT/IRT (105 ng/mL cut-offs, P < .0001). The ratio of newborns with CF to heterozygote carriers was 1:2.5, and newborns with CF to newborns with CFTR-related metabolic syndrome was 10.8:1. The overall positive predictive value was 20%. The median age of diagnosis was 28, 30, and 39.5 days in the 3 states. CONCLUSIONS: IRT/IRT/DNA is more sensitive than IRT/IRT because of lower cut-offs (∼97 percentile or 60 ng/mL); higher cut-offs in IRT/IRT programs (>99 percentile, 105 ng/mL) would not achieve sufficient sensitivity. Carrier identification and identification of newborns with CFTR-related metabolic syndrome is less common in IRT/IRT/DNA compared with IRT/DNA. The time to diagnosis is nominally longer, but diagnosis can be achieved in the neonatal period and opportunities to further improve timeliness have been enacted. IRT/IRT/DNA algorithm should be considered by programs with 2 routine screens.

Variants in Solute Carrier SLC26A9 Modify Prenatal Exocrine Pancreatic Damage in Cystic Fibrosis.

OBJECTIVES: To test the hypothesis that multiple constituents of the apical plasma membrane residing alongside the causal cystic fibrosis (CF) transmembrane conductance regulator protein, including known CF modifiers SLC26A9, SLC6A14, and SLC9A3, would be associated with prenatal exocrine pancreatic damage as measured by newborn screened (NBS) immunoreactive trypsinogen (IRT) levels. STUDY DESIGN: NBS IRT measures and genome-wide genotype data were available on 111 subjects from Colorado, 37 subjects from Wisconsin, and 80 subjects from France. Multiple linear regression was used to determine whether any of 8 single nucleotide polymorphisms (SNPs) in SLC26A9, SLC6A14, and SLC9A3 were associated with IRT and whether other constituents of the apical plasma membrane contributed to IRT. RESULTS: In the Colorado sample, 3 SLC26A9 SNPs were associated with NBS IRT (min P=1.16×10(-3); rs7512462), but no SLC6A14 or SLC9A3 SNPs were associated (P>.05). The rs7512462 association replicated in the Wisconsin sample (P=.03) but not in the French sample (P=.76). Furthermore, rs7512462 was the top-ranked apical membrane constituent in the combined Colorado and Wisconsin sample. CONCLUSIONS: NBS IRT is a biomarker of prenatal exocrine pancreatic disease in patients with CF, and a SNP in SLC26A9 accounts for significant IRT variability. This work suggests SLC26A9 as a potential therapeutic target to ameliorate exocrine pancreatic disease.

A comparison of characteristics and outcomes in severe human metapneumovirus and respiratory syncytial virus infections in children treated in an intensive care unit.

BACKGROUND: Human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) are among the leading causes of respiratory tract infections requiring admission to the pediatric intensive care unit (PICU). We evaluated the risk factors, clinical courses and outcomes of severe HMPV disease relative to severe RSV in children admitted to the PICU. METHODS: Retrospective chart review of children ≤18 years old admitted to a tertiary PICU between October 2008 through July 2010 with acute respiratory tract infection and positive direct antigen stain or polymerase chain reaction for RSV or HMPV. RESULTS: One hundred thirty-three patients met inclusion criteria: 107 (80.5%) with RSV and 26 (19.5%) with HMPV. HMPV-infected patients were older than RSV children (3.4 vs. 1.5 years, P = 0.002) and more likely to have congenital heart disease (34.6% vs. 10.3%, P = 0.002). Although HMPV children required longer duration of mechanical ventilation (11 vs. 7 days, P = 0.01), there were no other differences in hospital course. HMPV patients were more likely to be discharged receiving inhaled steroids (53.8% vs. 30.8%, P = 0.03), but there were no differences in other outcome assessments. CONCLUSIONS: Children admitted to the PICU with HMPV are significantly older and more likely to have congenital heart disease than those with RSV. The course of illness was similar between the 2 groups, but HMPV-infected children were more likely to be discharged with inhaled steroid therapy.

Scope and impact of early and late preterm infants admitted to the PICU with respiratory illness.

OBJECTIVE: To determine the clinical course and outcomes of children born early preterm (EPT, <32 weeks), late preterm (LPT, 32 to 35 weeks), and full term (FT, >or=36 weeks) who were subsequently admitted to the pediatric intensive care unit (PICU) with respiratory illness. STUDY DESIGN: Retrospective chart review of patients <2 years old admitted to a tertiary PICU with respiratory illness. RESULTS: Two hundred seventy-one 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 < .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 < .03 and P = .004, respectively). Median hospital charges were also greater for EPT ($85 151) and LPT ($83 576) groups compared with FT group ($55 122; P < .01 and P < .02, respectively). CONCLUSIONS: EPT and LPT infants comprise a considerable proportion of PICU admissions for respiratory illness and have greater resource utilization than FT infants.

Cystic Fibrosis Foundation practice guidelines for the management of infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome during the first two years of life and beyond.

Through early detection, newborn screening (NBS)(1) for cystic fibrosis (CF) offers the opportunity for early intervention and improved outcomes. NBS programs screen for hypertrypsinogenemia, and most also identify mutations in the CF transmembrane conductance regulator (CFTR) gene. Individuals identified by NBS are diagnosed with CF if they have an elevated sweat chloride level or if they have inherited 2 disease-causing mutations in the CFTR gene. Mutations in the CFTR gene can cause CF, but not all CFTR mutations are disease-causing. The term CFTR-related metabolic syndrome (CRMS) is proposed to describe infants identified by hypertrypsinogenemia on NBS who have sweat chloride values <60 mmol/L and up to 2 CFTR mutations, at least 1 of which is not clearly categorized as a "CF-causing mutation," thus they do not meet CF Foundation guidelines for the diagnosis of CF. With what is now near-universal CF NBS in the United States, an increasing number of infants with CRMS are being identified. Given our inadequate knowledge of the natural history of CRMS, standards for diagnosis, monitoring, and treatment are absent. This document aims to help guide the monitoring and care of individuals with CRMS while our knowledge base on appropriate management evolves.

A new cystic fibrosis newborn screening algorithm: IRT/IRT1 upward arrow/DNA.

OBJECTIVE: To evaluate an immunoreactive trypsinogen (IRT) IRT/IRT1 upward arrow/DNA algorithm, aimed at improving sensitivity while decreasing cystic fibrosis (CF) carrier identification. STUDY DESIGN: New technologies allow the measurement of the second IRT level solely in infants with an elevated first IRT level. Specimens with an elevated second IRT level undergo mutation analysis. We tested the projected efficacy with retrospective data from Colorado. RESULTS: All known infants with CF would have been identified with our proposed IRT cutoff points, and 3 would have been missed with our mutation panel. Two of 3 missed cases would have been identified by using a failsafe method (IRT >99.9th percentile), yielding a sensitivity rate of 99.7% (95% CI, 98.4-99.9). Estimated reduction in carrier detection was 80% compared with IRT/DNA. CONCLUSION: IRT/IRT1 upward arrow/DNA appears to improve cystic fibrosis newborn screen sensitivity while decreasing carrier identification, providing an alternative to IRT/IRT in states that obtain 2 blood spots.

Effects of long-term sildenafil treatment for pulmonary hypertension in infants with chronic lung disease.

OBJECTIVE: 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: We conducted a retrospective review of 25 patients <2 years of age with CLD in whom sildenafil was initiated for the treatment of PH while they were hospitalized from January 2004 to 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 with serial echocardiograms. RESULTS: Chronic sildenafil therapy (dose range, 1.5-8.0 mg/kg/d) was initiated at a median of 171 days of age (range, 14-673 days of age) for a median duration of 241 days (range, 28-950 days). Twenty-two patients (88%) achieved hemodynamic improvement after a median treatment duration of 40 days (range, 6-600 days). Eleven of the 13 patients with interval estimates of systolic pulmonary artery pressure with 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, 1 for recurrent erections, and the other had the medication held briefly because of intestinal pneumatosis. CONCLUSION: These data suggest that chronic sildenafil therapy is well-tolerated, safe, and effective for infants with PH and CLD.

Decreased total serum coenzyme-Q10 concentrations: a longitudinal study in children with cystic fibrosis.

OBJECTIVE: To assess total serum levels of coenzyme Q(10) (Co-Q(10)), an important antioxidant, in children with cystic fibrosis (CF) and to investigate an association between Co-Q(10) level and clinical outcome. STUDY DESIGN: Co-Q(10) levels were measured annually in a prospective cohort study of 381 children with CF. A total of 1092 serum levels of total Co-Q(10) were obtained by high-performance liquid chromatography and ultraviolet light detection. Associations of Co-Q(10) with demographic variables and clinical outcomes were investigated. RESULTS: Of the 381 initial total serum Co-Q(10) measurements, 188 were in the deficient range. Low Co-Q(10) was significantly more prevalent in patients with pancreatic insufficiency (PI) (55%) compared with patients with pancreatic sufficiency (PS) (3%); 22% of the patients with PI exhibited persistently low Co-Q(10) levels. Low Co-Q(10) levels were significantly associated with Pseudomonas aeruginosa colonization in patients with PI and CF under age 24 months, but not with subsequent lung function or hospitalization rates. Low Co-Q(10) levels were related to other markers of nutritional status, including total lipids, beta-carotene, and alpha-tocopherol. CONCLUSIONS: Persistently low total serum Co-Q(10) levels are common in children with CF and PI. A prospective study is indicated to determine whether Co-Q(10) supplementation in CF is beneficial.

The clinical course of a Mexican female with cystic fibrosis and the novel genotype S531P/S531P.

The case of a 16 year-old Mexican female with cystic fibrosis and the novel genotype S531P/S531P is presented. Her clinical course has consisted of recurrent pancreatitis and rapidly progressive lung disease complicated by Mycobacterium kansasii and Penicillium infection. This report illustrates the need for better characterization of CFTR mutations in a Hispanic population to aid in clinical care.

Genetic and physiologic correlates of longitudinal immunoreactive trypsinogen decline in infants with cystic fibrosis identified through newborn screening.

OBJECTIVES: To characterize the time course and physiologic significance of decline in serum immunoreactive trypsinogen (IRT) levels in infants with cystic fibrosis (CF) by mode of diagnosis and genotype, and to examine IRT heritability. STUDY DESIGN: We studied longitudinal IRT measurements in 317 children with CF. We developed statistical models to describe IRT decline. Pancreatic disease severity (Mild or Severe) was assigned using CF genotype and was confirmed in 47 infants through fat malabsorption studies. RESULTS: Infants with severe disease exhibited IRT decline with non-detectable levels typically seen by 5 years of age. Infants with mild disease exhibited a decline in the first 2 years, asymptomatically approaching a level greater than published norms. IRT and fecal fat were inversely correlated. IRT values in infants with meconium ileus (MI) were significantly lower than newborn-screened infants at birth. The high proportion of shared variation in predicted IRT values among sibling pairs with severe disease suggests that IRT is heritable. CONCLUSIONS: IRT declines characteristically in infants with CF. Lower IRT values in newborns with MI suggest increased pancreatic injury. Furthermore, IRT is heritable among patients with severe disease suggesting genetic modifiers of early CF pancreatic injury. This study demonstrates heritability of a statistically modeled quantitative phenotype.

Complications associated with symptomatic diagnosis in infants with cystic fibrosis.

OBJECTIVE: To determine the complication and hospitalization rates in children with cystic fibrosis (CF) by mode of diagnosis. STUDY DESIGN: Newly diagnosed cases of CF were identified from the Cystic Fibrosis Foundation National Patient Registry for 2000 through 2002. Cases were categorized as symptomatic diagnosis (SYMP; n = 1760), prenatal diagnosis (PRE; n = 66), diagnosis by means of newborn screening (NBS; n = 256), or presentation with meconium ileus (MI; n = 484). Complications were defined for the calendar year of diagnosis as stunting (length <3rd percentile), wasting (weight <3rd percentile), positive Pseudomonas aeruginosa culture results, and hypoelectrolytemia or edema and hypoproteinemia. RESULTS: For infants (age <12 months), 70% of patients with SYMP had at least 1 complication or hospitalization, compared with 29% for patients with NBS diagnosis (P < .0001). Cross-sectional data for 2002 showed that patients with SYMP had significantly more complications compared with patients with NBS diagnosis as old as 20 years. When compared with patients with NBS diagnosis, patients with SYMP had increased mucoid P aeruginosa (P < .05) and decreased pulmonary function as assessed by means of forced expiratory volume in 1 second (P < .01). CONCLUSIONS: SYMP of CF is associated with increased complication rates throughout infancy, childhood, and adolescence when compared with NBS diagnosis.

Two-tiered immunoreactive trypsinogen-based newborn screening for cystic fibrosis in Colorado: screening efficacy and diagnostic outcomes.

OBJECTIVE: To examine immunoreactive trypsinogen (IRT)-based screening for cystic fibrosis (CF) for recall rate, genotype distribution, and "borderline" sweat test results. STUDY DESIGN: CF newborn screening in Colorado began in 1982, and >1,153,000 infants were screened through 2002 with an IRT-based screen (IRT/IRT). RESULTS: We have identified 313 infants with CF, giving an overall incidence of 1 in 3684 and a Hispanic incidence of 1 in 6495. Fifty-five infants with meconium ileus (17.6%) were excluded from analysis. Fourteen infants with false-negative results were identified (5.4%). The average recall rate was 0.6%, with a positive predictive value of 4.7%. Ninety-three percent of the infants had at least 1 DeltaF508 mutation, and 98% of the infants had at least 1 mutation from the American College of Medical Genetics recommended panel. Six infants had hypertrypsinogenemia and borderline results on sweat tests (30-60 mmol/L). Increased variability in sweat chloride levels were seen in these infants compared with infants with homozygous DeltaF508. Three children with initial borderline results on sweat tests had CF diagnosed. CONCLUSIONS: The recall and false-negative rates of our IRT/IRT CF screening program are reported. Additionally, genotypes of the patients identified mirror the CF population genotypes, reflecting similar disease severity in the screened population. Finally, infants with persistent hypertrypsinogenemia and borderline sweat test results need long-term follow-up.

Induced sputum inflammatory measures correlate with lung function in children with cystic fibrosis.

OBJECTIVE: To validate a sputum induction technique in cystic fibrosis (CF), we examined the relation between airway inflammation and pulmonary function in children with CF by correlating inflammatory indexes in induced sputum with FEV(1). STUDY DESIGN: We measured baseline spirometry and oxygen saturations and then performed sputum inductions with 3% hypertonic saline in 20 clinically stable children with CF (11 girls). We examined the relation of airway inflammation and lung function in the 19 individuals (95%) who expectorated an adequate sputum sample. Measures of airway inflammation in induced sputum included total cell counts, neutrophil (PMN) counts, interleukin-8 levels, and free neutrophil elastase activity. RESULTS: There were significant inverse relations between FEV(1) and total cell counts and PMN counts (r = -0.57, P <.01 for both), interleukin-8 (r = -0.72, P =.002), and elastase (r = -0.75, P =.001). Airway infection, as assessed by bacterial density in induced sputum, did not correlate with lung function or indexes of inflammation. CONCLUSIONS: We conclude that measures of inflammation in induced sputum correlate with FEV(1) in clinically stable children with CF with normal to mildly abnormal lung function and that they may be useful as surrogate outcome measures in clinical trials.