Cystic fibrosis screening, evaluation, and management of hepatobiliary disease consensus recommendations.

Cystic fibrosis (CF) may cause a spectrum of hepatobiliary complications, including portal hypertension, multilobular cirrhosis, and liver failure. Current guidelines on the detection and monitoring of hepatobiliary complications in CF were published in 1999. The CF Foundation assembled a committee to evaluate research advances and formulate revised guidelines for CF-associated liver disease. A committee of hepatologists, gastroenterologists, pulmonologists, pharmacists, nurses, dietitians, individuals with CF, and the parents of a child with CF devised "population, intervention, comparison, and outcome" questions regarding hepatobiliary disease in CF. PubMed literature searches were performed for each population, intervention, comparison, and outcome question. Recommendations were voted on with 80% agreement required to approve a recommendation. Public comment on initial recommendations was solicited prior to the formulation of final recommendations. Thirty-one population, intervention, comparison, and outcome questions were assembled, 6401 manuscripts were title screened for relevance, with 1053 manuscripts undergoing detailed full-text review. Seven recommendations were approved for screening, 13 for monitoring of existing disease, and 14 for treatment of CF-associated hepatobiliary involvement or advanced liver disease. One recommendation on liver biopsy did not meet the 80% threshold. One recommendation on screening ultrasound was revised and re-voted on. Through a multidisciplinary committee and public engagement, we have assembled updated recommendations and guidance on screening, monitoring, and treatment of CF-associated hepatobiliary involvement and advanced liver disease. While research gaps remain, we anticipate that these recommendations will lead to improvements in CF outcomes through earlier detection and increased evidence-based approaches to monitoring and treatment.

Heterogeneous liver on research ultrasound identifies children with cystic fibrosis at high risk of advanced liver disease.

BACKGROUND: This study examines whether heterogeneous (HTG) pattern on liver ultrasound (US) identifies children at risk for advanced cystic fibrosis liver disease (aCFLD). METHODS: Prospective 6-year multicenter case-controlled cohort study. Children with pancreatic insufficient cystic fibrosis (CF) aged 3-12 years without known cirrhosis underwent screening US. Participants with HTG were matched (by age, Pseudomonas infection status and center) 1:2 with participants with normal (NL) US pattern. Clinical status and laboratory data were obtained annually and US bi-annually for 6 years. Primary endpoint was development of nodular (NOD) US pattern consistent with aCFLD. RESULTS: 722 participants underwent screening US, with 65 HTG and 592 NL. Final cohort included 55 HTG and 116 NL with ≥ 1 follow-up US. ALT, AST, GGTP, FIB-4, GPR and APRI were higher, and platelets were lower in HTG compared to NL. HTG had a 9.5-fold increased incidence (95% confidence interval [CI]:3.4, 26.7, p<0.0001, 32.7% vs 3.4%) of NOD versus NL. HTG had a sensitivity of 82% and specificity of 75% for subsequent NOD. Negative predictive value of a NL US for subsequent NOD was 96%. Multivariate logistic prediction model that included baseline US, age, and log(GPR) improved the C-index to 0.90 compared to only baseline US (C-index 0.78). Based on survival analysis, 50% of HTG develop NOD after 8 years. CONCLUSIONS: Research US finding of HTG identifies children with CF with a 30-50% risk for aCFLD. A score based on US pattern, age and GPR may refine the identification of individuals at high risk for aCFLD. CLINICAL TRIAL REGISTRATION: Prospective Study of Ultrasound to Predict Hepatic Cirrhosis in CF: NCT 01,144,507 (observational study, no consort checklist).

Gravity Amplitudes from Double Bonus Relations.

In this Letter, we derive new expressions for tree-level graviton amplitudes in N=8 supergravity from Britto-Cachazo-Feng-Witten (BCFW) recursion relations combined with new types of bonus relations. These bonus relations go beyond the famous 1/z^{2} behavior under a large BCFW shift and use knowledge about certain zeros of graviton amplitudes in collinear kinematics. This extra knowledge can be used in the context of global residue theorems by writing the amplitude in a special form using canonical building blocks. In the next-to-maximally-helicity-violating case, these building blocks are dressed one-loop leading singularities, the same objects that appear in the expansion of Yang-Mills amplitudes, where each term corresponds to an R invariant. Unlike other approaches, our formula is not an expansion in terms of cyclic objects and does not manifest color-kinematics duality but rather preserves the permutational symmetry of its building blocks. We also comment on the possible connection to Grassmannian geometry and give some nontrivial evidence of such structure for graviton amplitudes.

Health-related Quality of Life in a Prospective Study of Ultrasound to Detect Cystic Fibrosis-related Liver Disease in Children.

OBJECTIVES: Cystic fibrosis liver disease (CFLD) begins early in life. Symptoms may be vague, mild, or nonexistent. Progressive liver injury may be associated with decrements in patient health before liver disease is clinically apparent. We examined Health-Related Quality of Life (HRQOL) in children enrolled in a multi-center study of CFLD to determine the impact of early CFLD on general and disease-specific QOL. METHODS: Ultrasound (US) patterns of normal (NL), heterogeneous (HTG), homogeneous (HMG), or nodular (NOD) were assigned in a prospective manner to predict those at risk for advanced CFLD. Parents were informed of results. We assessed parent/child-reported (age ≥5 years) HRQOL by PedsQL 4.0 Generic Core and CF Questionnaire-revised (CFQ-R) prior to US and annually. HRQOL scores were compared by US pattern at baseline (prior to US), between baseline and 1 year and at 5 years. Multivariate analysis of variance (MANOVA) with Hotelling-Lawley trace tested for differences among US groups. RESULTS: Prior to US, among 515 participants and their parents there was no evidence that HTG or NOD US was associated with reduced PedsQL/CFQ-R at baseline. Parents of NOD reported no change in PedsQL/CFQ-R over the next year. Child-report PedsQL/CFQ-R (95 NL, 20 NOD) showed improvement between baseline and year 5 for many scales, including Physical Function. Parents of HMG children reported improved CFQ-R scores related to weight. CONCLUSIONS: Early undiagnosed or pre-symptomatic liver disease had no impact on generic or disease-specific HRQoL, and HRQoL was remarkably stable in children with CF regardless of liver involvement.

Real World Experience of Pseudomonas aeruginosa Eradication at an Urban Pediatric Cystic Fibrosis Center.

OBJECTIVES: Clinical practice guidelines for eradication of Pseudomonas aeruginosa (PA) in patients with cystic fibrosis (CF) have been established, but current studies have not assessed how these guidelines translate into clinical practice. This study aimed to characterize the real-world eradication strategies, eradication rates, and microbiologic outcomes of patients with first acquisition of PA at an urban pediatric CF center. METHODS: The Cystic Fibrosis Foundation Patient Registry was used to identify patients with CF who received care between January 2014 and September 2018 and had PA isolated from an airway culture. Patients were included if they had a first positive PA culture or the first positive culture in 2 years. Data regarding patient demographics, timing and results of airway cultures, and treatment regimens were collected. RESULTS: Over a 3.75-year period, 75 patients had an initial positive culture for PA. Of those patients, 74 (98.7%) received eradication treatment. Tobramycin inhalation solution (TIS) monotherapy was the most common regimen prescribed (52.7%) followed by TIS plus an oral fluoroquinolone (28.4%) (TIS + FQ). Of those treated, 62 (83.8%) patients had eradication of PA at first follow-up culture (median, 58 days; IQR, 49-77 days). Eradication rates (84.6% vs 76.2%, p = 0.421) and times to recurrence (6.37 months vs 5.1 months, p = 0.726) were comparable between TIS and TIS + FQ cohorts. CONCLUSIONS: The eradication rate for PA in clinical practice is similar to that published in the literature. Consistent with published guidelines, these microbiologic outcomes do not support the addition of an oral FQ to TIS for initial PA eradication.

Heterogeneous Liver on Research Ultrasound Identifies Children with Cystic Fibrosis at High Risk of Advanced Liver Disease: Interim Results of a Prospective Observational Case-Controlled Study.

OBJECTIVE: To assess if a heterogeneous pattern on research liver ultrasound examination can identify children at risk for advanced cystic fibrosis (CF) liver disease. STUDY DESIGN: Planned 4-year interim analysis of a 9-year multicenter, case-controlled cohort study (Prospective Study of Ultrasound to Predict Hepatic Cirrhosis in CF). Children with pancreatic insufficient CF aged 3-12 years without known cirrhosis, Burkholderia species infection, or short bowel syndrome underwent a screening research ultrasound examination. Participants with a heterogeneous liver ultrasound pattern were matched (by age, Pseudomonas infection status, and center) 1:2 with participants with a normal pattern. Clinical status and laboratory data were obtained annually and research ultrasound examinations biannually. The primary end point was the development of a nodular research ultrasound pattern, a surrogate for advanced CF liver disease. RESULTS: There were 722 participants who underwent screening research ultrasound examination, of which 65 were heterogeneous liver ultrasound pattern and 592 normal liver ultrasound pattern. The final cohort included 55 participants with a heterogeneous liver ultrasound pattern and 116 participants with a normal liver ultrasound pattern. All participants with at least 1 follow-up research ultrasound were included. There were no differences in age or sex between groups at entry. Alanine aminotransferase (42 ± 22 U/L vs 32 ± 19 U/L; P = .0033), gamma glutamyl transpeptidase (36 ± 34 U/L vs 15 ± 8 U/L; P < .001), and aspartate aminotransferase to platelet ratio index (0.7 ± 0.5 vs 0.4 ± 0.2; P < .0001) were higher in participants with a heterogeneous liver ultrasound pattern compared with participants with a normal liver ultrasound pattern. Participants with a heterogeneous liver ultrasound pattern had a 9.1-fold increased incidence (95% CI, 2.7-30.8; P = .0004) of nodular pattern vs a normal liver ultrasound pattern (23% in heterogeneous liver ultrasound pattern vs 2.6% in normal liver ultrasound pattern). CONCLUSIONS: Research liver ultrasound examinations can identify children with CF at increased risk for developing advanced CF liver disease.

Cystic fibrosis in the era of precision medicine.

The treatment of people with cystic fibrosis (CF) has been transformed by the availability of drugs that target the basic chloride defect in the disease. The use of drugs that target specific molecular defects embodies the goals of precision medicine, which incorporate preventive and therapeutic strategies and takes into account differences among individuals. However, the entirety of CF care, from diagnosis to understanding the clinical phenotype and developing a therapeutic strategy, depends on taking into account individual characteristics to achieve optimal outcomes. Future therapies are likely to be even more individualized ushering in a new era of precision medicine.

An Observational Study of Outcomes and Tolerances in Patients with Cystic Fibrosis Initiated on Lumacaftor/Ivacaftor.

RATIONALE: In July 2015, the U.S. Food and Drug Administration approved lumacaftor/ivacaftor for use in patients with cystic fibrosis (CF). This drug targets the primary defect in the CFTR protein that is conferred by the F508del CFTR mutation. OBJECTIVE: As there is limited experience with this therapy outside of clinical trials, this study aims to examine the clinical experience of this new drug in a population with CF. RESULTS: Retrospective cohort study of individuals followed at the Johns Hopkins CF Center who initiated treatment with lumacaftor/ivacaftor. Patients were followed from 1 year before drug initiation to up to 11 months postinitiation. Key exclusion criteria include previous exposure to lumacaftor/ivacaftor through participation in a clinical trial. Of 116 individuals identified who started lumacaftor/ivacaftor treatment, 46 (39.7%) reported adverse effects related to lumacaftor/ivacaftor, with the vast majority (82.2%) being pulmonary adverse effects, and 20 (17.2%) discontinued lumacaftor/ivacaftor because of adverse effects. The mean change in FEV1% predicted was 0.11% (range: -39% to +20%; P = 0.9). Nineteen individuals had an FEV1% predicted of 40% or less before treatment, and there was a higher percentage of patients in this subgroup who reported adverse effects (57.9%) and a higher percentage of patients who discontinued lumacaftor/ivacaftor (31.6%). Female sex was associated with a higher odds of drug discontinuation (adjusted odds ratio, 3.12, 95% confidence interval, 1.04-9.38). CONCLUSIONS: This study highlights the prevalence of adverse effects in a CF population newly exposed to lumacaftor/ivacaftor and demonstrates a relatively high rate of drug intolerance.

Polysomnographic Markers in Children With Cystic Fibrosis Lung Disease.

BACKGROUND AND OBJECTIVES: Children with cystic fibrosis (CF) often report poor sleep, increased daytime sleepiness, and fatigue. The purpose of this study was to identify respiratory patterns over the spectrum of disease severity in children with CF. The overall hypothesis for the current study is that children with CF compared with snoring control subjects demonstrate gas exchange abnormalities and increased respiratory loads during sleep that are not reported or recognized by conventional polysomnography (PSG). METHODS: Analysis of breathing patterns and gas exchange on PSG was performed in children with CF and healthy controls matched by age and BMI. For all CF and control subjects, the indication for PSG was evaluation for obstructive sleep apnea based on a history of snoring. RESULTS: Children with CF, compared with age- and BMI-matched snoring controls, demonstrated lower oxyhemoglobin saturation (95% ± 1.6% vs 98% ± 0.6%, P = .005), higher respiratory rate (19.5 ± 4.9 vs 16.5 ± 1.2 breaths per minute, P = .03), and a higher proportion of inspiratory flow limitation (44.1% ± 24.7% vs 12.1% ± 13.5%, P = .007) during non-rapid eye movement sleep. The respiratory disturbance index did not differ between CF and snoring control groups (1.5 ± 2.7 vs 0.6 ± 0.6 events per hour, P = .11). CONCLUSIONS: Children with CF exhibited abnormalities in gas exchange and increased respiratory load during sleep compared with normal age- and BMI-matched snoring controls. Because these abnormalities were independent of weight and lung function, sleep state may serve as an opportunity for early detection of breathing abnormalities and possibly CF lung disease progression.

Baseline Ultrasound and Clinical Correlates in Children with Cystic Fibrosis.

OBJECTIVE: To investigate the relationship between abdominal ultrasound findings and demographic, historical, and clinical features in children with cystic fibrosis (CF). STUDY DESIGN: Children age 3-12 years with CF without known cirrhosis, were enrolled in a prospective, multicenter study of ultrasound to predict hepatic fibrosis. Consensus ultrasound patterns were assigned by 3 radiologists as normal, heterogeneous, homogeneous, or cirrhosis. Data were derived from direct collection and US or Toronto CF registries. χ(2) or ANOVA were used to compare variables among ultrasound groups and between normal and abnormal. Logistic regression was used to study risk factors for having abnormal ultrasound. RESULTS: Findings in 719 subjects were normal (n = 590, 82.1%), heterogeneous (64, 8.9%), homogeneous (41, 5.7%), and cirrhosis (24, 3.3%). Cirrhosis (P = .0004), homogeneous (P < .0001), and heterogeneous (P = .03) were older than normal. More males were heterogeneous (P = .001). More heterogeneous (15.0%, P = .009) and cirrhosis (25.0%, P = .005) had CF-related diabetes or impaired glucose tolerance vs normal (5.4%). Early infection with Pseudomonas aeruginosa (<2 years old) was associated with a lower risk (OR 0.42, P = .0007) of abnormal. Ursodeoxycholic acid use (OR 3.69, P < .0001) and CF-related diabetes (OR 2.21, P = .019) were associated with increased risk of abnormal. CONCLUSIONS: Unsuspected cirrhosis is seen in 3.3% of young patients with CF, heterogeneous in 8.9%. Abnormal ultrasound is associated with CF-related diabetes, and early P aeruginosa is associated with normal ultrasound. Prospective assessment of these risk factors may identify potential interventional targets. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01144507.

Self-reported exercise and longitudinal outcomes in cystic fibrosis: a retrospective cohort study.

BACKGROUND: Cystic fibrosis (CF) is characterized by recurrent respiratory infections and progressive lung disease. Whereas exercise may contribute to preserving lung function, its benefit is difficult to ascertain given the selection bias of healthier patients being more predisposed to exercise. Our objective was to examine the role of self-reported exercise with longitudinal lung function and body mass index (BMI) measures in CF. METHODS: A total of 1038 subjects with CF were recruited through the U.S. CF Twin-Sibling Study. Questionnaires were used to determine exercise habits. Questionnaires, chart review, and U.S. CF Foundation Patient Registry data were used to track outcomes. RESULTS: Within the study sample 75% of subjects self-reported regular exercise. Exercise was associated with an older age of diagnosis (p = 0.002), older age at the time of ascertainment (p < 0.001), and higher baseline FEV1 (p = 0.001), but not CFTR genotype (p = 0.64) or exocrine pancreatic function (p = 0.19). In adjusted mixed models, exercise was associated with both a reduced decline in FEV1 (p < 0.001) and BMI Z-score (p = 0.001) for adults, but not children aged 10-17 years old. CONCLUSIONS: In our retrospective study, self-reported exercise was associated with improved longitudinal nutritional and pulmonary outcomes in cystic fibrosis for adults. Although prospective studies are needed to confirm these associations, programs to promote regular exercise among individuals with cystic fibrosis would be beneficial.

Cystic fibrosis in a Hispanic adolescent.

We describe the presentation of a Hispanic adolescent with chronic respiratory symptoms and poor growth that led to a diagnosis of cystic fibrosis (CF) based on an indeterminate sweat chloride result and DNA sequence analysis that revealed a single new frameshift mutation, Nt3878insATCAG, which results in a premature stop codon in exon 20 of the CFTR gene. This case, highlighted by the identification of a deleterious, disease-causing mutation, illustrates the importance of maintaining both a high clinical suspicion for CF and low threshold for obtaining genetic testing in a non-Caucasian Hispanic adolescent with a characteristic clinical presentation.

Using electrospun poly(ethylene-oxide) nanofibers for improved retention and efficacy of bacteriolytic antibiotics.

The aim of this study was to demonstrate targeted delivery of protein-based bactericidal antibiotics using electrospun polymer nanofibers. Previous studies have utilized electrospinning to create nanofibers for the localized delivery of therapeutic agents, including non-steroidal anti-inflammatory drugs (NSAIDs) and low molecular weight heparin. By employing established electrospinning techniques, nanofibers of varying diameters (100-500 nm) were generated from a 0.05 % solution of poly(ethylene-oxide) (PEO) and the antimicrobial peptide, LL-37 was incorporated into the nanofiber meshwork. Initial experiments determined that the strong electric fields caused by electrospinning do not disrupt the antimicrobial properties of LL-37, thus justifying the application of LL-37 as an electrospun component. Disk diffusion assays and especially bacterial filtration studies with E. coli were conducted to quantify the drug delivery potential of the nanofibers. Disk diffusion revealed a small zone of inhibition of about 1 mm around the LL-37-incorporated nanofiber disk. Filtration tests demonstrated that electrospun PEO fibers were capable of delivering LL-37 consistently while still maintaining their antimicrobial abilities.

Modulation of proinflammatory activity by the engineered cationic antimicrobial peptide WLBU-2.

BACKGROUND: Host-derived (LL-37) and synthetic (WLBU-2) cationic antimicrobial peptides (CAPs) are known for their membrane-active bactericidal properties. LL-37 is an important mediator for immunomodulation, while the mechanism of action of WLBU-2 remains unclear. OBJECTIVE: To determine if WLBU-2 induces an early proinflammatory response that facilitates bacterial clearance in cystic fibrosis (CF). METHODS: C57BL6 mice were given intranasal or intraperitoneal 1×10 (6) cfu/mL Pseudomonas aeruginosa (PA) and observed for 2h, followed by instillation of LL-37 or WLBU-2 (2-4mg/kg) with subsequent tissue collection at 24h for determination of bacterial colony counts and quantitative RT-PCR measurement of cytokine transcripts. CF airway epithelial cells (IB3-1, ΔF508/W1282X) were cultured in appropriate media with supplements. WLBU-2 (25µM) was added to the media with RT-PCR measurement of TNF-α and IL-1ß transcripts after 20, 30, and 60min. Flow cytometry was used to determine if WLBU-2 assists in cellular uptake of Alexa 488-labeled LPS. RESULTS: In murine lung exposed to intranasal or intraperitoneal WLBU-2, there was a reduction in the number of surviving PA colonies compared to controls. Murine lung exposed to intraperitoneal WLBU-2 showed fewer PA colonies compared to LL-37. After 24h WLBU-2 exposure, PA-induced IL-1ß transcripts from lungs showed a twofold decrease (p<0.05), while TNF-α levels were unchanged. LL-37 did not significantly change transcript levels. In IB3-1 cells, WLBU-2 exposure resulted in increased TNF-α and IL-1ß transcripts that decreased by 60min. WLBU-2 treatment of IB3-1 cells displayed increased LPS uptake, suggesting a potential role for CAPs in inducing protective proinflammatory responses. Taken together, the cytokine response, LPS uptake, and established antimicrobial activity of WLBU-2 demonstrate its ability to modulate proinflammatory signaling as a protective mechanism to clear infection. CONCLUSIONS: The immunomodulatory properties of WLBU-2 reveal a potential mechanism of its broad-spectrum antibacterial activity and warrant further preclinical evaluation to study bacterial clearance and rescue of chronic inflammation.

Exercise improves lung function and habitual activity in children with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) lung disease leads to progressive deterioration in exercise capacity. Because physical activity has been shown to improve lung function and quality of life (QoL), developing routine exercise programs can benefit this patient population. METHODS: Lung function, nutritional status, and exercise capacity and assessments of habitual activity and QoL were measured before and after a two-month, subject-designed exercise regimen based on self-reported activity assessment. Statistical analysis included Wilcoxon signed-rank, Wilcoxon rank sum, and Fisher's exact tests. RESULTS: Subjects completing the study demonstrated significant improvement in exercise capacity and body image perception, a CF-specific QoL measure (p<0.001). In secondary analyses, subjects improving exercise capacity showed significant increases in lung function and self-reported habitual activity. CONCLUSIONS: Increases in exercise capacity over a two-month period resulted in significantly improved lung function and self-reported habitual activity. Longer, controlled trials are needed to develop individualized exercise recommendations.

Transient effectiveness of vitamin D2 therapy in pediatric cystic fibrosis patients.

BACKGROUND: The effectiveness of current treatment recommendations for vitamin D insufficiency in children with CF is unknown. Therefore, we assessed the effectiveness of vitamin D(2) 50,000 IU once daily for 28 days for vitamin D insufficiency. METHODS: Retrospective chart review of pediatric CF patients from 2006-2008. Vitamin D(2) 50,000 IU daily for 28 days was given to patients with 25-OHD <30 ng/mL and repeat 25-OHD levels were obtained after completion of therapy. RESULTS: One hundred forty-seven levels from 97 individuals were assessed. Success of treatment was 54% (n=80/147). Seventeen of 39 patients (43%) followed for an additional 6-18 months were able to maintain levels of >or=30 ng/mL. CONCLUSIONS: Vitamin D(2) 50,000 IU daily for 28 days was effective in correcting vitamin D insufficiency in approximately 50% of subjects. However, almost half of successfully treated patients were unable to maintain normal 25-OHD levels >6 months after completion of therapy, implying that this effect is transient.

Using behavioral interventions to assist with routine procedures in children with cystic fibrosis.

Routine cystic fibrosis (CF) medical care includes invasive procedures that may be difficult for young children and adolescents to tolerate because of anxiety, concern with health status, or unfamiliarity with the performed tasks. A growing body of pediatric psychology literature suggests that behavior therapy can effectively increase patient cooperation with stressful medical procedures such as tracheostomy care and needle sticks. Throat cultures are obtained at least quarterly in the outpatient setting or more frequently if a CF patient develops respiratory symptoms. Obtaining a throat culture from an anxious and uncooperative child poses a significant challenge for physicians, since the child may demonstrate emotional distress and avoidant behavior that disrupts efficient specimen collection during a routine clinic visit. The use of behavioral interventions, such as relaxation exercises, diaphragmatic breathing, differential reinforcement, gradual exposure, and systematic desensitization, is beneficial in addressing this commonly encountered problem in CF care. This case series describes the implementation of a behavioral therapy protocol utilizing two interventions, gradual exposure and systematic desensitization, in two young CF patients for the treatment of behavioral distress with routine throat cultures. The behavioral interventions were simple and transferred easily from mock procedures to actual specimen collection. Moreover, these cases highlight the important roles of the pediatric psychology staff on a comprehensive multidisciplinary CF care team to improve patient cooperation with routine clinic procedures and the medical treatment regimen overall.

Description of a standardized nutrition classification plan and its relation to nutritional outcomes in children with cystic fibrosis.

OBJECTIVE: Better nutrition enhances lung function and increases survival for children with cystic fibrosis (CF). Therefore, we developed a standardized strategy to evaluate nutritional status and create individualized treatment plans to ensure that all patients received the same high-quality care in a busy CF Center. METHODS: A quality improvement approach was undertaken to develop a novel nutrition classification strategy to identify and treat children with subtle manifestations of nutritional deficits in addition to those with obvious nutritional issues. RESULTS: During the 15-month study period, the median body mass index (BMI) percentile increased from 35.2 (0-95.9) to 42.0 (0-97.7), p < .005. Additionally, the number of children with a BMI >or=50th percentile increased by 11.8%. CONCLUSIONS: Adoption of a standardized approach to nutritional assessment and treatment led to significant improvement in nutritional outcomes of CF patients, demonstrating that systematic changes in clinical practice can improve clinical outcomes substantially over a short period of time.