Validation of an omega-3 substrate challenge absorption test as an indicator of global fat lipolysis.

INTRODUCTION: The coefficient of fat absorption (CFA) quantifies fat that remains in stool after digestion and is not a direct measure of lipolysis. CFA has been used to assess treatment of pancreatic insufficiency but does not correlate with pancreatic enzyme replacement therapy dose. We explored use of an omega-3 substrate absorption challenge test as a sensitive test of lipolysis and absorption. METHODS: We studied a novel microbially-derived lipase (SNSP003) employing an established surgical model commonly used to study the uptake of macronutrients, the exocrine pancreatic insufficient pig. Pigs were fed a high-fat diet and given a standardized omega-3 substrate challenge to test the effect of lipolysis on its absorption. Blood was drawn at 0, 1, 2, 4, 6, 8, 12, and 24 hours following the substrate challenge and was analyzed for omega-3 and total fat levels (c14:c24). SNSP003 was also compard to porcine pancrelipase. RESULTS: The absorption of omega-3 fats was significantly increased following administration of 40, 80 and 120 mg SNSP003 lipase by 51% (p = 0.02), 89%, (p = 0.001) and 64% (p = 0.01), respectively, compared to that observed when no lipase was administered to the pigs, with Tmax at 4 hours. The two highest SNSP003 doses were compared to porcine pancrelipase and no significant differences were observed. Both doses increased plasma total fatty acids (141% for the 80 mg dose (p = 0.001) and 133% for the 120 mg dose (p = 0.006), compared to no lipase) and no significant differences were observed between the SNSP003 lipase doses and porcine pancrelipase. CONCLUSION: The omega-3 substrate absorption challenge test differentiates among different doses of a novel microbially-derived lipase and correlates with global fat lipolysis and absorption in exocrine pancreatic insufficient pigs. No significant differences were observed between the two highest novel lipase doses and porcine pancrelipase. Studies in humans should be designed to support the evidence presented here that suggests the omega-3 substrate absorption challenge test has advantages over the coefficient of fat absorption test to study lipase activity.

Reduction of Recurrence Risk of Pancreatitis in Cystic Fibrosis With Ivacaftor: Case Series.

The effect of ivacaftor in patients with cystic fibrosis (CF) with recurrent pancreatitis is unknown. We conducted a multicenter retrospective study of patients with CF taking ivacaftor who had a history of recurrent pancreatitis. During the first 3 months of therapy, only 1 of the 6 patients had an episode of pancreatitis, which was managed on an outpatient basis. Between 3 and 12 months on ivacaftor therapy, none of the patients had recurrence of pancreatitis or required hospitalization. The use of ivacaftor was associated with a reduced frequency and recurrence rate of pancreatitis in patients with CF.

Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome and Cystic Fibrosis Screen Positive, Inconclusive Diagnosis.

OBJECTIVE: An unintended consequence of cystic fibrosis (CF) newborn screening (NBS) is the identification of infants with a positive NBS test but inconclusive diagnostic testing. These infants are classified as CF transmembrane conductance regulator-related metabolic syndrome (CRMS) in the US and CF screen positive, inconclusive diagnosis (CFSPID) in other countries. Diagnostic and management decisions of these infants are challenges for CF healthcare professionals and stressful situations for families. As CF NBS has become more widespread across the world, increased information about the epidemiology and outcomes of these infants is becoming available. These data were reviewed at the 2015 CF Foundation Diagnosis Consensus Conference, and a harmonized definition of CRMS and CFSPID was developed. STUDY DESIGN: At the consensus conference, participants reviewed published and unpublished studies of CRMS/CFSPID and used a modified Delphi methodology to develop a harmonized approach to the definition of CRMS/CFSPID. RESULTS: Several studies of CRMS/CFSPID from populations around the world have been published in the past year. Although the studies vary in the number of infants studied, study design, and outcome measures, there have been some consistent findings. CRMS/CFSPID occurs relatively frequently, with CF:CRMS that ranges from 3 to 5 cases of CF for every 1 case of CRMS/CFSPID in regions where gene sequencing is not used. The incidence varies by NBS protocol used, and in some regions more cases of CRMS/CFSPID are detected than cases of CF. The majority of individuals with CRMS/CFSPID do not develop CF disease or progress to a diagnosis of CF. However, between 10% and 20% of asymptomatic infants can develop clinical features concerning for CF, such as a respiratory culture positive for Pseudomonas aeruginosa. Most studies have only reported short-term outcomes in the first 1-3 years of life; the long-term outcomes of CRMS/CFSPID remain unknown. The European CF Society definition of CFSPID and the CF Foundation definition of CRMS differ only slightly, and the consensus conference was able to create a unified definition of CRMS/CFSPID. CONCLUSIONS: CRMS/CFSPID is a relatively common outcome of CF NBS, and clinicians need to be prepared to counsel families whose NBS test falls into this classification. The vast majority of infants with CRMS/CFSPID will remain free from disease manifestations early in life. However, a small proportion may develop clinical features concerning for CF or demonstrate progression to a clinical phenotype compatible with a CF diagnosis, and their long-term outcomes are not known. A consistent international definition of CRMS/CFSPID will allow for better data collection for study of outcomes and result in improved patient care.

Outcomes of infants with indeterminate diagnosis detected by cystic fibrosis newborn screening.

BACKGROUND AND OBJECTIVES: Cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS) describes asymptomatic infants with a positive cystic fibrosis (CF) newborn screen (NBS) but inconclusive diagnostic testing for CF. Little is known about the epidemiology and outcomes of CRMS. The goal of this study was to determine the prevalence, clinical features, and short-term outcomes of infants with CRMS. METHODS: We analyzed data from the US CF Foundation Patient Registry (CFFPR) from 2010 to 2012. We compared demographic, diagnostic, anthropometric, health care utilization, microbiology, and treatment characteristics between infants with CF and infants with CRMS. RESULTS: There were 1983 infants diagnosed via NBS between 2010 and 2012 reported to the CFFPR. By using the CF Foundation guideline definitions, 1540 and 309 infants met the criteria for CF and CRMS, respectively (CF:CRMS ratio = 5.0:1.0). Of note, 40.8% of infants with CRMS were entered into the registry with a clinical diagnosis of CF. Infants with CRMS tended to have normal nutritional indices. However, 11% of infants with CRMS had a positive Pseudomonas aeruginosa respiratory tract culture in the first year of life. CONCLUSIONS: CRMS is a common outcome of CF NBS, and some infants with CRMS may develop features concerning for CF disease. A substantial proportion of infants with CRMS were assigned a clinical diagnosis of CF, which may reflect misclassification or clinical features not collected in the CFFPR.

Early attained weight and length predict growth faltering better than velocity measures in infants with CF.

BACKGROUND: CF infants often do not grow as expected which adversely affects later clinical outcomes, thus sensitive early measures of growth deficiency are important. This study compared attained growth for age with velocity standards to determine which better predicts growth deficits at 24 months of age. METHODS: Growth deficiency in infancy based on weight and length velocity, and attained growth was calculated for 1992 infants in the US CF Foundation National Registry using the World Health Organization (WHO) and US growth standards. One, two and three month increments were used for calculating velocity and pooled for each age interval. Sensitivity and specificity of early indicators to predict growth deficiency at 24 months were calculated. RESULTS: Observed prevalence of weight deficiency (<10th percentile) during the first year of life was 26.8% higher (95% CI=(25.6, 28.1%), p<0.001) on average when measured by attained weight for age than velocity. Attained weight for age at four months was a more sensitive predictor of diminished weight for age (<10th percentile) at 24 months (sensitivity=100%, 95% CI=(87, 100%)) than weight velocity (sensitivity=40%, 95% CI=(23, 59%)). Attained length at four months was more sensitive to detecting subsequent stunting (<10th percentile length for age) (77%, 95% CI=(62, 87%)) than length velocity (30%, 95% CI=(19, 45%)). CONCLUSIONS: In CF infancy, attained weight or length is more sensitive than velocity-based definitions for predicting subsequent diminished growth.

Progress in cystic fibrosis and the CF Therapeutics Development Network.

Cystic fibrosis (CF), the most common life-shortening genetic disorder in Caucasians, affects approximately 70 000 individuals worldwide. In 1998, the Cystic Fibrosis Foundation (CFF) launched the CF Therapeutics Development Network (CF-TDN) as a central element of its Therapeutics Development Programme. Designed to accelerate the clinical evaluation of new therapies needed to fulfil the CFF mission to control and cure CF, the CF-TDN has conducted 75 clinical trials since its inception, and has contributed to studies as varied as initial safety and proof of concept trials to pivotal programmes required for regulatory approval. This review highlights recent and significant research efforts of the CF-TDN, including a summary of contributions to studies involving CF transmembrane conductance regulator (CFTR) modulators, airway surface liquid hydrators and mucus modifiers, anti-infectives, anti-inflammatories, and nutritional therapies. Efforts to advance CF biomarkers, necessary to accelerate the therapeutic goals of the network, are also summarised.

A review of pathophysiology and management of fetuses and neonates with meconium ileus for the pediatric surgeon.

PURPOSE: Meconium ileus (MI) is the earliest clinical manifestation of cystic fibrosis (CF), occurring in up to 20% of patients with CF. Our aim was to review and integrate current knowledge about the diagnosis and management of fetuses and neonates with MI that may aid the pediatric surgeon in caring for these patients. METHODS: We identified areas of interest including pathophysiology, prenatal diagnosis, nonoperative and operative management, postoperative management, and prognosis. We performed a Medline search using the search term meconium ileus for English language articles published in the last 20 years. We reviewed reference lists to identify other articles of historical significance. RESULTS: Meconium ileus is primarily associated with CF transmembrane (conductance) regulator mutations F508del, G542X, W1282X, R553X, and G551D, and modifier genes have been found to explain approximately 17% of the phenotypic variability. Mouse, pig, and ferret models for CF demonstrate neonatal bowel obstruction mimicking MI. Sonographic findings of hyperechoic masses and dilated bowel in a high-risk fetus are suggestive of MI. Less than 7% of low-risk fetuses with hyperechoic bowel will have MI. Contemporary series of noninvasive management with Gastrografin enema report success rates of 36% to 39%, significantly lower than historical values. The optimal surgical technique remains controversial, although primary anastomosis results in surgical complication rates between 21% and 31%, higher than those noted with delayed anastomosis. Pulmonary function for patients with CF and MI at 15 and 25 years old is similar to those without MI, although height and weight percentiles may be lower. CONCLUSIONS: This review for pediatric surgeons presents an examination of the literature and synthesizes current information about the pathophysiology, prenatal diagnosis, nonoperative and operative management, postoperative management, and prognosis of the patient with CF and MI.

Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation.

BACKGROUND: Ivacaftor (VX-770) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that was approved in the United States for the treatment of cystic fibrosis (CF) in patients ≥ 6 years of age who have a G551D mutation; however, the most prevalent disease-causing CFTR mutation, F508del, causes a different functional defect. The objectives of this study were to evaluate the safety of ivacaftor in a larger population and for a longer time period than tested previously and to assess the efficacy of ivacaftor in subjects with CF who are homozygous for F508del-CFTR. METHODS: This was a phase 2 study with a 16-week randomized (4:1), double-blind, placebo-controlled period (part A) and an open-label extension (part B) for subjects who met prespecified criteria. RESULTS: Part A: The safety profile of ivacaftor was comparable to that of the placebo. The overall adverse event frequency was similar in the ivacaftor (87.5%) and placebo (89.3%) groups through 16 weeks. The difference in the change of FEV1 % predicted from baseline through week 16 (primary end point) between the ivacaftor and placebo groups was 1.7% (P = .15). Sweat chloride, a biomarker of CFTR activity, showed a small reduction in the ivacaftor vs placebo groups of -2.9 mmol/L (P = .04) from baseline through week 16. Part B: No new safety signals were identified. The changes in FEV1 or sweat chloride in part A were not sustained with ivacaftor treatment from week 16 to week 40. CONCLUSIONS: These results expand the safety information for ivacaftor and support its continued evaluation. Lack of a clinical effect suggests that a CFTR potentiator alone is not an effective therapeutic approach for patients who have CF and are homozygous for F508del-CFTR. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00953706; URL: www.clinicaltrials.gov.

Guide to bone health and disease in cystic fibrosis.

Cystic fibrosis (CF) is the most common genetic disease within the Caucasian population and leads to premature respiratory failure. Approximately 60,000 individuals are currently living with CF in North America and Europe, 40% of whom are adults. The life span of these patients has increased from approximately 2 to 32 yr of age over the last three decades. Bone disease has emerged as a common complication in long-term survivors of CF. Some studies have observed that 50-75% of adults have low bone density and increased rates of fractures. Prevention and treatment of CF-related bone disease must address the myriad risk factors (decreased absorption of fat-soluble vitamins due to pancreatic insufficiency, altered sex hormone production, chronic lung infection with increased levels of bone-active cytokines, physical inactivity, and glucocorticoid therapy) for poor bone health. This review is a condensed and updated summary of the Guide to Bone Health and Disease in Cystic Fibrosis: A Consensus Conference, a statement that evolved from a meeting convened by the Cystic Fibrosis Foundation in May 2002 to address the pathogenesis, diagnosis, and treatment of bone disease in CF. The goal of this conference was to develop practice guidelines for optimizing bone health in patients with CF.

Congenital pancreatic cysts in children.

The authors report a case of an 11-year-old girl with a solitary, congenital pancreatic cyst and review the literature. Such cysts are very rare and typically are diagnosed in childhood. As a neonate, this patient's paternal half brother also had undergone resection of a congenital pancreatic cyst. The authors believe this is the first documented familial incidence of a congenital pancreatic cyst.