Urinary metabolomics reveals unique metabolic signatures in infants with cystic fibrosis.

BACKGROUND: Biologic pathways and metabolic mechanisms underpinning early systemic disease in cystic fibrosis (CF) are poorly understood. The Baby Observational and Nutrition Study (BONUS) was a prospective multi-center study of infants with CF with a primary aim to examine the current state of nutrition in the first year of life. Its secondary aim was to prospectively explore concurrent nutritional, metabolic, respiratory, infectious, and inflammatory characteristics associated with early CF anthropometric measurements. We report here metabolomics differences within the urine of these infants as compared to infants without CF. METHODS: Urine metabolomics was performed for 85 infants with predefined clinical phenotypes at approximately one year of age enrolled in BONUS via Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS). Samples were stratified by disease status (non-CF controls (n = 22); CF (n = 63, All-CF)) and CF clinical phenotype: respiratory hospitalization (CF Resp, n = 22), low length (CF LL, n = 23), and low weight (CF LW, n = 15). RESULTS: Global urine metabolomics profiles in CF were heterogeneous, however there were distinct metabolic differences between the CF and non-CF groups. Top pathways altered in CF included tRNA charging and methionine degradation. ADCYAP1 and huntingtin were identified as predicted unique regulators of altered metabolic pathways in CF compared to non-CF. Infants with CF displayed alterations in metabolites associated with bile acid homeostasis, pentose sugars, and vitamins. CONCLUSIONS: Predicted metabolic pathways and regulators were identified in CF infants compared to non-CF, but metabolic profiles were unable to discriminate between CF phenotypes. Targeted metabolomics provides an opportunity for further understanding of early CF disease. TRIAL REGISTRATION: United States ClinicalTrials.Gov registry NCT01424696 (clinicaltrials.gov).

Beyond the expected: Identifying broad research priorities of researchers and the cystic fibrosis community.

The Cystic Fibrosis Foundation (CFF) supports research programs aimed at improving care and building a successful drug development pipeline. To ensure its research agenda meets the needs of the community it serves, the CFF sought community input into clinical research prioritization for topics not well-known as already being addressed by CFF-funded research. In 2018, clinical researchers, adults with CF, and family members were surveyed about a broad range of research topics that are perceived to receive less attention. We compared responses from researchers (n = 19) and community members (n = 135) and found groups aligned on their top three research priorities: 1) respiratory microorganism detection and treatment, 2) mental health, and 3) reducing treatment burden. We also explored whether or not those priorities align with the CFF research portfolio. Cognizance of researcher and community priorities can help inform clinical research endeavors to improve the health and well-being of people affected by CF.

An update on the screening, diagnosis, management, and treatment of vitamin D deficiency in individuals with cystic fibrosis: evidence-based recommendations from the Cystic Fibrosis Foundation.

OBJECTIVE: The objective was to develop evidence-based clinical care guidelines for the screening, diagnosis, management, and treatment of vitamin D deficiency in individuals with cystic fibrosis (CF). PARTICIPANTS: The guidelines committee was comprised of physicians, registered dietitians, a pharmacist, a nurse, a parent of an individual with CF, and a health scientist, all with experience in CF. PROCESS: Committee members developed questions specific to vitamin D health in individuals with CF. Systematic reviews were completed for each question. The committee reviewed and graded the available evidence and developed evidence-based recommendations and consensus recommendations when insufficient evidence was available. Each consensus recommendation was voted upon by an anonymous process. CONCLUSIONS: Vitamin D deficiency is common in CF. Given the limited evidence specific to CF, the committee provided consensus recommendations for most of the recommendations. The committee recommends yearly screening for vitamin D status, preferably at the end of winter, using the serum 25-hydroxyvitamin D measurement, with a minimal 25-hydroxyvitamin D concentration of 30 ng/ml (75 nmol/liter) considered vitamin D sufficient in individuals with CF. Recommendations for age-specific vitamin D intake for all individuals with CF, form of vitamin D, and a stepwise approach to increase vitamin D intake when optimal vitamin D status is not achieved are delineated.

Serum and lower respiratory tract drug concentrations after tobramycin inhalation in young children with cystic fibrosis.

OBJECTIVES: To assess the serum and lower respiratory tract tobramycin concentrations (C(T)) produced by a single dose of tobramycin for inhalation delivered by a nebulizer and a compressor in patients with cystic fibrosis (CF) 6 months to 6 years of age. STUDY DESIGN: We performed a dose escalation study of serum C(T) measured before and 0.5, 1, 2, and 4 hours after a single dose of inhaled tobramycin, either 180 mg (10 patients) or 300 mg (19 patients). In a separate group of 12 patients, epithelial lining fluid (ELF) C(T) was measured by bronchoalveolar lavage 30 to 45 minutes after a 300-mg dose. RESULTS: A 180-mg dose of inhaled tobramycin produced a mean peak serum C(T) of 0.5 microg/mL (SD 0.4; range, <0.2 to 1.4 microg/mL). A 300-mg dose produced a mean peak serum C(T) of 0.6 microg/mL (SD 0.5; range, <0.2 to 1.2 microg/mL). These peak values are well below the accepted maximum trough concentration with parenteral dosing (2 microg/mL). The target ELF C(T) was 20 microg/mL, 10-fold greater than the minimal inhibitory concentration for most Pseudomonas aeruginosa isolates from very young patients with CF (2 microg/mL). Mean ELF C(T) was 90 microg/mL (SD 54; range, 16 to 204 microg/mL) and exceeded the target concentration in 11 patients. CONCLUSION: In patients with CF ages 6 months to 6 years, a single 300-mg dose of inhaled tobramycin appears to produce safe peak serum concentrations and drug concentrations in the bactericidal range in the lower respiratory tract.

Relief of central airways obstruction following spinal release in a patient with idiopathic scoliosis.

SUMMARY. Patients with idiopathic scoliosis are reported to have a restrictive pattern on pulmonary function tests. A case is presented of a teenage girl with juvenile idiopathic scoliosis who had evidence of airways obstruction in addition to restriction on pulmonary function tests (PFT). Examination of flow-volume loops suggested central airways obstruction. At the time of induction of anesthesia for the initial spinal release surgery, a double-lumen endotracheal tube could not be passed, despite fiberoptic visualization, because of extreme deviation of the left main-stem bronchus. Postoperatively, PFT demonstrated improved flows at high lung volumes and normalization of the shape of the flow volume loop. We suggest that preoperative PFT may be used to predict which patients have central airways obstruction. This may lessen unanticipated problems with intubation at the time of surgery and may identify patients who may expect immediate improvement in lung function after scoliosis repair.

Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group.

BACKGROUND AND METHODS: We conducted two multicenter, double-blind, placebo-controlled trials of intermittent administration of inhaled tobramycin in patients with cystic fibrosis and Pseudomonas aeruginosa infection. A total of 520 patients (mean age, 21 years) were randomly assigned to receive either 300 mg of inhaled tobramycin or placebo twice daily for four weeks, followed by four weeks with no study drug. Patients received treatment or placebo in three on-off cycles for a total of 24 weeks. The end points included pulmonary function, the density of P. aeruginosa in sputum, and hospitalization. RESULTS: The patients treated with inhaled tobramycin had an average increase in forced expiratory volume in one second (FEV1) of 10 percent at week 20 as compared with week 0, whereas the patients receiving placebo had a 2 percent decline in FEV1 (P<0.001). In the tobramycin group, the density of P. aeruginosa decreased by an average of 0.8 log10 colony-forming units (CFU) per gram of expectorated sputum from week 0 to week 20, as compared with an increase of 0.3 log10 CFU per gram in the placebo group (P<0.001). The patients in the tobramycin group were 26 percent (95 percent confidence interval, 2 to 43 percent) less likely to be hospitalized than those in the placebo group. Inhaled tobramycin was not associated with detectable ototoxic or nephrotoxic effects or with accumulation of the drug in serum. The proportion of patients with P. aeruginosa isolates for which the minimal inhibitory concentration of tobramycin was 8 microg per milliliter or higher increased from 25 percent at week 0 to 32 percent at week 24 in the tobramycin group, as compared with a decrease from 20 percent at week 0 to 17 percent at week 24 in the placebo group. CONCLUSIONS: In a 24-week study of patients with cystic fibrosis, intermittent administration of inhaled tobramycin was well tolerated and improved pulmonary function, decreased the density of P. aeruginosa in sputum, and decreased the risk of hospitalization.

Prenatal diagnosis of the fetus with cystic fibrosis and meconium ileus.

The sonographic finding of hyperechoic or dilated fetal bowel raises suspicion of a number of prenatal disorders including meconium ileus (MI), meconium peritonitis, congenital infection, neoplasm, or chromosomal trisomy. These findings may also represent transient normal variants. The following case report details the evaluation of one pregnancy with abnormal intestinal echogenic findings on serial sonograms (US), to demonstrate inherent diagnostic difficulties in such a case. A diagnostic algorithm is presented to aid in the proper use of US and DNA mutation analysis for cystic fibrosis (CF), so that the cause of an abnormal abdominal US can be established earlier and more accurately than suggested by previous management schemes. Earlier fetal diagnosis may help to anticipate postnatal problems associated with CF/MI, and therefore provide more optimal clinical management of the affected fetus.

High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis.

BACKGROUND: Fibrosing colonopathy has been reported in young children with cystic fibrosis, the majority of whom take high-strength pancreatic-enzyme supplements to control intestinal malabsorption. We conducted a case-control study in the United States to investigate the relation between dose and type of pancreatic-enzyme supplement and fibrosing colonopathy. METHODS: Children with histopathologically confirmed cases of fibrosing colonopathy who required colectomy for colonic strictures from January 1, 1990, through December 31, 1994, were identified. Each of these patients was matched according to age at the time of surgery and medical center with up to four controls with cystic fibrosis who did not have fibrosing colonopathy. RESULTS: We studied 29 patients (mean age, 5.0 years) with fibrosing colonopathy (case patients) and 105 controls (mean age, 5.2 years). The mean dose of pancreatic-enzyme supplement was 50,046 units of lipase per kilogram of body weight per day for the case patients and 18,985 units per kilogram per day for the controls. A history of gastrointestinal complications attributed to cystic fibrosis and the use of histamine H2-receptor blockers, corticosteroids, or recombinant human DNase (dornase alfa) were associated with a higher incidence of fibrosing colonopathy. After adjustment for a history of such complications and the use of these medicines, the relative risk of fibrosing colonopathy that was associated with a dose of 24,001 to 50,000 units of lipase per kilogram per day, as compared with a dose of 0 to 24,000 units per kilogram per day, was 10.9 (95 percent confidence interval, 1.6 to 71.8), and that associated with a dose of more than 50,000 units per kilogram per day was 199.5 (95 percent confidence interval, 9.9 to 4026.0). The strength, coating, and manufacturer of the products used were not associated with the risk of fibrosing colonopathy. CONCLUSIONS: In young children with cystic fibrosis, we found a strong relation between high daily doses of pancreatic-enzyme supplements and the development of fibrosing colonopathy. Our findings support recommendations that the daily dose of pancreatic enzymes for most patients should remain below 10,000 units of lipase per kilogram.

Cystic fibrosis mutation frequencies in upstate New York.

Upstate New York patients (100) with cystic fibrosis (i.e., 200 CF chromosomes), 72 from the CF center in Syracuse and 28 from a Buffalo CF center, were analyzed for their CF-causing mutations using restriction enzyme digest, single-strand conformation analysis (SSCA), and Heteroduplex (HA) analysis. Polymerase chain reaction (PCR) amplified products from all 27 CFTR exons using primers that included flanking intron junction sequence were investigated. More than 120 known cystic fibrosis transmembrane conductance regulator (CFTR) disease-causing mutations were screened. Four novel CFTR disease-causing mutations were identified (N287Y in exon 6b, 1259insA in exon 8, R1070P in exon 17b, and CF?20kbdel14b-18). A detection rate of 96% of the combined Syracuse and Buffalo population CF chromosomes was obtained.

The interrelationship of nutrition and pulmonary function in patients with cystic fibrosis.

This paper reviews recent publications on the interrelationship of nutrition and pulmonary function in patients with cystic fibrosis. It is unclear whether low weight is a cause or an effect of declining pulmonary status in patients with cystic fibrosis. Epidemiologic studies suggest that low weight may be an independent predictor of mortality. Elevations in energy expenditure are not seen in presymptomatic infants. The elevations in energy expenditure seen in those with lung disease are not totally explained by increased oxygen cost of breathing and can be decreased by improving lung function. Although circulating levels of natural antioxidants and inflammation-modulating nutrients are low in patients with cystic fibrosis and can be increased with supplements, there are no recent data on their clinical effects. Nutritional intervention for patients with chronic illness needs to take into account psychosocial and adherence factors as well as nutritional prescriptions. Pancreatic enzyme supplementation should be limited to no greater than 2500 lipase units per kilogram per meal to decrease the risk of developing dose-related fibrosing colonopathy.

Preventive care for patients with chronic illness. Multivitamin use in patients with cystic fibrosis.

Routine supplementation with multivitamins is recommended for all patients with cystic fibrosis (CF). The purpose of this study was to investigate how well patients at a large CF clinic follow recommendations for taking multivitamins and what factors affect use. A questionnaire was developed and sent to the 150 patients actively followed at our center. Of the 80 patients who returned the survey, only 47% followed clinic recommendations. Of those patients not taking extra supplements, serum vitamin A and E levels varied widely, although most were within the normal range (vitamin A 11-87 micrograms/dL, tocopherol 0.4-2.3 mg/dL, tocopherol/cholesterol 3.0-9.6 mg/g). Only 25% of respondents had known insurance coverage for vitamins. Gender or educational level did not affect adherence; however, those with minimal pulmonary disease (forced vital capacity [FVC] greater than 70% of predicted) were more likely to take vitamins than those with moderate or severe disease (P < .05). In addition to malabsorption, poor adherence should be considered by both CF specialists and primary-care providers as a cause of low serum vitamin A and E levels, especially in patients with moderate to severe lung disease.

Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group.

BACKGROUND: Respiratory disease in patients with cystic fibrosis is characterized by airway obstruction caused by the accumulation of thick, purulent secretions, which results in recurrent, symptomatic exacerbations. The viscoelasticity of the secretions can be reduced in vitro by recombinant human deoxyribonuclease I (rhDNase), a bioengineered copy of the human enzyme. METHODS: We performed a randomized, double-blind, placebo-controlled study to determine the effects of once-daily and twice-daily administration of rhDNase on exacerbations of respiratory symptoms requiring parenteral antibiotics and on pulmonary function. A total of 968 adults and children with cystic fibrosis were treated for 24 weeks as outpatients. RESULTS: One or more exacerbations occurred in 27 percent of the patients given placebo, 22 percent of those treated with rhDNase once daily, and 19 percent of those treated with rhDNase twice daily. As compared with placebo, the administration of rhDNase once daily and twice daily reduced the age-adjusted risk of respiratory exacerbations by 28 percent (P = 0.04) and 37 percent (P < 0.01), respectively. The administration of rhDNase once daily and twice daily improved forced expiratory volume in one second during the study by a mean (+/- SD) of 5.8 +/- 0.7 and 5.6 +/- 0.7 percent, respectively. None of the patients had anaphylaxis. Voice alteration and laryngitis were more frequent in the rhDNase-treated patients than in those receiving placebo but were rarely severe and resolved within 21 days of onset. CONCLUSIONS: In patients with cystic fibrosis, the administration of rhDNase reduced but did not eliminate exacerbations of respiratory symptoms, resulted in slight improvement in pulmonary function, and was well tolerated.

Are bioelectric impedance measurements valid in patients with cystic fibrosis?

This pilot study compared the use of bioelectric impedance analysis (BIA), a rapid, portable, and painless method of measuring body composition, to isotope dilution in patients with and without cystic fibrosis (CF). Many methods exist for measuring body composition but these measures can be difficult to use in the clinical setting. BIA has been validated as a tool for nutritional assessment in healthy adults, but it must be validated in patient populations with specific disease-related nutritional problems, such as CF. Ten ambulatory patients with CF were selected along with ten controls matched for age, sex, and body mass index (BMI; wt/ht2). Total body water (TBW) was determined using isotoperatio mass spectrometry on urine specimens before and after patients consumed 0.2 g/kg deuterium-rich water. BIA was performed using a tetrapolar technique; 500 microA of current at 50 kHz was introduced and the voltage drop measured. Seven men and three women were studied in each group. Median age was 27 (range, 18-39) and median BMI was 19.2 (range, 16.7-30.1) in CF adults. Median age was 27.5 (range, 15-43) and median BMI was 20.7 (range, 19.4-31.6) in controls. The resistance index (RI; ht2/resistance) correlated strongly with TBW in patients with CF (r = 0.88; y = 0.482x + 11.138; p < 0.05) as well as in controls (r = 0.87; y = 0.661x + 1.299; p < 0.05). We conclude that BIA is a rapid, portable, and painless method for measuring body composition that correlates well with the deuterium-dilution method.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic intestinal pseudo-obstruction with meconium ileus at onset.

Cystic fibrosis is most often the underlying cause of meconium ileus. We describe the diagnosis and treatment of a patient with chronic intestinal pseudo-obstruction, and not with cystic fibrosis, whose initial manifestation was meconium ileus.