The associations between pediatric weight status and cystic fibrosis-related diabetes status and health-related quality of life among children and young adults with cystic fibrosis: A systematic review.

BACKGROUND: Cystic fibrosis (CF) is a life-shortening genetic disease, yet life expectancy has recently increased, shifting the focus to disease management and health-related quality of life (HRQoL). Identification of clinical factors, such as weight status and CF-related diabetes (CFRD), that are associated with HRQoL can inform clinicians about the patient's health perception. The goal of this systematic review was two prong: identify the association of pediatric weight status and HRQoL and determine how CFRD status impacts HRQoL. METHODS: A systematic review of published research was conducted following the methodology in the Cochrane Handbook on Systematic Reviews for Interventional Studies. Results were reported according to the Preferred Reporting Items for Systematic Review and Meta-Analyses. Risk of bias was assessed using the National Heart Lung & Blood Institute tool. A meta-analysis was not performed due to variability of the inclusion/exclusion criteria, differences in outcome reporting, and insufficient primary outcome data to pool. RESULTS: Nine studies met inclusion criteria (n = 6 explored weight status and n = 3 studied CFRD), for a total of 1585 subjects (CFRD cases = 87). Pediatric weight status was positively associated with HRQoL, most commonly the Body Image and Eating Disturbance domains. CFRD was negatively associated with HRQoL, specifically the Treatment Burden and Weight domains. CONCLUSIONS: Based on the limited data available, improved pediatric weight status appears to increase HRQoL while a CFRD diagnosis appears to decrease HRQoL. More research is needed to fully understand the role of these clinical factors on HRQoL, especially with life expectancy increasing among those with CF.

Genetics of CFTR and male infertility.

Cystic fibrosis (CF) is a rare autosomal-recessive disorder manifested as multisystem organ dysfunction. The cystic fibrosis transmembrane conductance regulator (CFTR) protein functions as an ion transporter on the epithelium of exocrine glands, regulating secretion viscosity. The CFTR gene, encoded on chromosome 7, is required for the production and trafficking of the intact and functional CFTR protein. Literally thousands of human CFTR allelic mutations have been identified, each with varying impact on protein quality and quantity. As a result, individuals harboring CFTR mutations present with a spectrum of symptoms ranging from CF to normal phenotypes. Those with loss of function but without full CF may present with CFTR-related disorders (CFTR-RDs) including male infertility, sinusitis, pancreatitis, atypical asthma and bronchitis. Studies have demonstrated associations between higher rates of CFTR mutations and oligospermia, epididymal obstruction, congenital bilateral absence of the vas deferens (CBAVD), and idiopathic ejaculatory duct obstruction (EDO). Genetic variants are detected in over three-quarters of men with CBAVD, the reproductive abnormality most classically associated with CFTR aberrations. Likewise, nearly all men with clinical CF will have CBAVD. Current guidelines from multiple groups recommend CFTR screening in all men with clinical CF or CBAVD though a consensus on the minimum number of variants for which to test is lacking. CFTR testing is not recommended as routine screening for men with other categories of infertility. While available CFTR panels include 30 to 96 of the most common variants, complete gene sequencing should be considered if there is a high index of suspicion in a high-risk couple (e.g., partner is CFTR mutation carrier). CF treatments to date have largely targeted end-organ complications. Novel CFTR-modulator treatments aim to directly target CFTR protein dysfunction, effectively circumventing downstream complications, and possibly preventing symptoms like vasal atresia at a young age. Future gene therapies may also hold promise in preventing or reversing genetic changes that lead to CF and CFTR-RD.

Preventing asthma in high risk kids (PARK) with omalizumab: Design, rationale, methods, lessons learned and adaptation.

Asthma remains one of the most important challenges to pediatric public health in the US. A large majority of children with persistent and chronic asthma demonstrate aeroallergen sensitization, which remains a pivotal risk factor associated with the development of persistent, progressive asthma throughout life. In individuals with a tendency toward Type 2 inflammation, sensitization and exposure to high concentrations of offending allergens is associated with increased risk for development of, and impairment from, asthma. The cascade of biological responses to allergens is primarily mediated through IgE antibodies and their production is further stimulated by IgE responses to antigen exposure. In addition, circulating IgE impairs innate anti-viral immune responses. The latter effect could magnify the effects of another early life exposure associated with increased risk of the development of asthma - viral infections. Omalizumab binds to circulating IgE and thus ablates antigen signaling through IgE-related mechanisms. Further, it has been shown restore IFN-α response to rhinovirus and to reduce asthma exacerbations during the viral season. We therefore hypothesized that early blockade of IgE and IgE mediated responses with omalizumab would prevent the development and reduce the severity of asthma in those at high risk for developing asthma. Herein, we describe a double-blind, placebo-controlled trial of omalizumab in 2-3 year old children at high risk for development of asthma to prevent the development and reduce the severity of asthma. We describe the rationale, methods, and lessons learned in implementing this potentially transformative trial aimed at prevention of asthma.

Weight Gain and Growth After Fundoplication in the Pediatric Patient: A Case Report in the Pediatric Patient With Cystic Fibrosis and Literature Review.

Gastroesophageal reflux (GER) is common among infants, but when symptoms become troublesome, that is defined as gastroesophageal reflux disease (GERD). Making a diagnosis of GERD is difficult because there is no gold standard. GERD can be especially problematic for infants with cystic fibrosis (CF). There are signs and symptoms (ie, malnutrition, recurring aspiration pneumonias, refusal to eat, wheezing, coughing, and asthma) in addition to invasive and noninvasive methods used to determine a diagnosis. The treatments for GERD span from nonpharmacological to surgical, with a laparoscopic Nissen fundoplication being the gold standard of surgical intervention. Although surgical interventions have been demonstrated to reduce symptoms associated with GERD, there is little known about the weight/growth-related outcomes. This case report discusses an infant with CF and GERD requiring multiple interventions and ultimately a laparoscopic Nissen fundoplication and the weight changes from presurgery to postsurgery. The case report is expanded upon with a structured literature review of fundoplication and growth studies. There were 4 available studies that assessed changes in weight/growth before and after fundoplication among children with GERD. Because of the heterogeneity of the nutrition outcomes used, the weight/growth benefits after fundoplication are unclear at this time. Further research in needed to assess the nutrition outcomes among patients with GERD requiring fundoplication.

Meropenem time above the MIC exposure is predictive of response in cystic fibrosis children with acute pulmonary exacerbations.

Meropenem exposures from 15 children (8-17 years old) with cystic fibrosis (CF) acute pulmonary exacerbation were analyzed to define the pharmacodynamic threshold required for a positive response. The primary endpoint was the relative increase in forced expiratory volume in 1 s (↑FEV1) between pre- and posttreatment. Meropenem pharmacodynamic indices (fT > MIC, fAUC/MIC, fCmin/MIC) over the first 24 h were estimated for each participant based on their individual parameter estimates and the isolated pathogen with the highest meropenem MIC. Pseudomonas aeruginosa was the most common pathogen (n = 11/15). The mean ± SD ↑FEV1 was 18.8% ± 11.3% posttreatment. The mean (range) fT > MIC exposure was 63% (0-100%). An Emax model determined a significant relationship between fT > MIC and ↑FEV1 (r2 = 0.8, P < 0.0004). 65% fT > MIC was a significant predictor of response; the median (25th, 75th %) ↑FEV1 was 28.5% (22.2%, 31.7%) in those patients who achieved above 65% fT > MIC and 7.8% (1.1%, 12.6%) in those at or below 65% fT > MIC (P = 0.001). This is the first study in CF children to link meropenem exposure with a positive response as measured by ↑FEV1. Larger studies are required to confirm this exposure threshold.

Population pharmacokinetics of meropenem administered as a prolonged infusion in children with cystic fibrosis.

OBJECTIVES: Meropenem is frequently used to treat pulmonary exacerbations in children with cystic fibrosis (CF) in the USA. Prolonged-infusion meropenem improves the time that free drug concentrations remain above the MIC (fT> MIC) in adults, but data in CF children are sparse. We describe the population pharmacokinetics, tolerability and treatment burden of prolonged-infusion meropenem in CF children. METHODS: Thirty children aged 6-17 years with a pulmonary exacerbation received 40 mg/kg meropenem every 8 h; each dose was administered as a 3 h infusion. Pharmacokinetics were determined using population methods in Pmetrics. Monte Carlo simulation was employed to compare 0.5 with 3 h infusions to estimate the probability of pharmacodynamic target attainment (PTA) at 40% fT> MIC. NCT#01429259. RESULTS: A two-compartment model fitted the data best with clearance and volume predicted by body weight. Clearance and volume of the central compartment were 0.41 ±â€Š0.23 L/h/kg and 0.30 ±â€Š0.17 L/kg, respectively. Half-life was 1.11 ±â€Š0.38 h. At MICs of 1, 2 and 4 mg/L, PTAs for the 0.5 h infusion were 87.6%, 70.1% and 35.4%, respectively. The prolonged infusion increased PTAs to >99% for these MICs and achieved 82.8% at 8 mg/L. Of the 30 children, 18 (60%) completed treatment with prolonged infusion; 5 did so at home without any reported burden. Nine patients were changed to a 0.5 h infusion when discharged home. CONCLUSIONS: In these CF children, meropenem clearance was greater compared with published values from non-CF children. Prolonged infusion provided an exposure benefit against pathogens with MICs ≥1 mg/L, was well tolerated and was feasible to administer in the hospital and home settings, the latter depending on perception and family schedule.

Microbiological activity of ceftolozane/tazobactam, ceftazidime, meropenem, and piperacillin/tazobactam against Pseudomonas aeruginosa isolated from children with cystic fibrosis.

The activity of ceftolozane/tazobactam was tested against 50 nonduplicate Pseudomonas aeruginosa from 18 cystic fibrosis children collected in 2012-2014. These isolates were multidrug resistant with susceptibility to meropenem, ceftazidime, and piperacillin/tazobactam of 46%, 58%, and 50%, respectively. Ceftolozane/tazobactam was the most active with MIC50, MIC90, and percent susceptibility of 2mg/L, 8 mg/L, and 86%.

Improved pulmonary and growth outcomes in cystic fibrosis by newborn screening.

BACKGROUND: Newborn screening for cystic fibrosis (CF) is effective in improving long-term growth outcomes. However, there is conflicting evidence that early diagnosis maintains normal pulmonary function. Our goal was to determine if newborn screening results in improved longitudinal growth and maintenance of normal pulmonary function. METHODS: A retrospective study of individuals with CF born in Connecticut between 1983 and 1997 was conducted by medical record and CF Foundation Registry review. Growth, pulmonary function and bacterial acquisition/colonization data, from diagnosis through July 1, 2005, were compared in those diagnosed by newborn screen (n = 34) to those diagnosed by sweat test after symptom appearance (n = 21). RESULTS: Screened individuals demonstrated greater weight and height for age at diagnosis (P = 0.01 and 0.01) and through 15 years of age (P = 0.0002 and 0.01). Body mass index was higher in screened individuals (21 vs. 18 kg/m(2)) at 15 years of age (P = 0.01). At 15 years of age, screened individuals had a clinically higher forced expiratory volume in 1 second (FEV(1)) and forced vital capacity (FVC; 90% and 104% predicted) than non-screened individuals (74% and 91% predicted; P = 0.08 and 0.10). Over a 9-year period, from ages 6 to 15, percent predicted FEV(1) and FVC increased by 4% and 13% in screened individuals; and declined by 14% and 5% respectively in non-screened individuals (P = 0.01 and 0.02). Acquisition/colonization of Pseudomonas aeruginosa was similar between groups (P = 0.23). CONCLUSIONS: In this CF cohort, individuals diagnosed by newborn screening have improved growth and preservation of normal pulmonary function without increased risk of Pseudomonas aeruginosa colonization.

The influence of pulmonary function testing on the management of asthma in children.

OBJECTIVE: To assess how often in a single encounter that pulmonary function tests (PFTs) influenced management decisions in children with asthma, beyond what was obtained from history and physical examination alone. STUDY DESIGN: Children with asthma (n = 367, age 4 to 18 years) performed spirometry before clinical evaluation. Physicians and nurse practitioners in the outpatient pulmonary office evaluated the children and made initial treatment recommendations before reviewing the spirometry results. Any changes based on the test results were documented. RESULTS: Spirometry was abnormal in 45% of the visits, related to underlying asthma severity but not to clinical findings. PFT results changed management decisions in 15% of visits. This frequency was not affected by the patient's age, disease severity, symptom control, or exam findings. When spirometry did not change treatment decisions, the provider was more likely to maintain therapy (58%) than to increase (17%) or decrease (24%) therapy. In contrast, when spirometry did change treatment decisions, the provider was more likely to increase therapy (75%) than to maintain (20%) or decrease (5%) therapy. CONCLUSION: Without PFTs, providers often overestimated the degree of asthma control. This incorrect assessment could have resulted in suboptimal therapy.

Airway physiology, autogenic drainage, and active cycle of breathing.

Airway clearance techniques are used to aid in mucus clearance in a variety of disease states. Autogenic drainage and active-cycle-of-breathing technique are 2 such modalities that rely heavily on basic airway physiology to enhance clearance. In this review I discuss the equal pressure point, huffing, and asynchronous and collateral ventilation, and review the literature and theory regarding autogenic drainage and active cycle of breathing. Selection of airway clearance techniques is discussed in the light of evidence-based medicine.