Association of lung function, chest radiographs and clinical features in infants with cystic fibrosis.

The optimal strategy for monitoring cystic fibrosis lung disease in infancy remains unclear. Our objective was to describe longitudinal associations between infant pulmonary function tests, chest radiograph scores and other characteristics. Cystic fibrosis patients aged ≤24 months were enrolled in a 10-centre study evaluating infant pulmonary function tests four times over a year. Chest radiographs ∼1 year apart were scored using the Wisconsin and Brasfield systems. Associations of infant pulmonary function tests with clinical characteristics were evaluated with mixed effects models. The 100 participants contributed 246 acceptable flow/volume (forced expiratory volume in 0.5 s (FEV0.5) and forced expiratory flow at 75% of the forced vital capacity (FEF75%)), 303 functional residual capacity measurements and 171 chest radiographs. Both Brasfield and Wisconsin chest radiograph scores worsened significantly over the 1-year interval. Worse Wisconsin chest radiograph scores and Staphylococcus aureus were both associated with hyperinflation (significantly increased functional residual capacity), but not with diminished FEV0.5 or FEF75%. Parent-reported cough was associated with significantly diminished forced expiratory flow at 75% but not with hyperinflation. In this infant cohort in whom we previously reported worsening in average lung function, chest radiograph scores also worsened over a year. The significant associations detected between both Wisconsin chest radiograph score and S. aureus and hyperinflation, as well as between cough and diminished flows, reinforce the ability of infant pulmonary function tests and chest radiographs to detect early cystic fibrosis lung disease.

Multicenter evaluation of infant lung function tests as cystic fibrosis clinical trial endpoints.

RATIONALE: The conducting of clinical trials in infants with cystic fibrosis (CF) has been hindered by lack of sensitive outcome measures. OBJECTIVES: To evaluate safety, feasibility, and ability to detect abnormalities in lung function of serial pulmonary function tests (PFTs) in infants with CF. METHODS: Multicenter observational study using a commercial device, rigorous training, ongoing quality control, and over-reading of data by an independent panel. Raised volume rapid thoracoabdominal compression technique and plethysmography were performed at enrollment and at 6 and 12 months, with an additional 1-month reproducibility visit. MEASUREMENTS AND MAIN RESULTS: A total of 342 procedures were performed in 100 infants with CF at 10 centers. FRC measurements were acceptable at a higher proportion of study visits (89%) than raised volume (72%) or fractional lung volume (68%) measurements. Average Z scores for many parameters differed significantly from historical control values. Mean (95% confidence interval) Z scores were: -0.52 (-0.78 to -0.25) for forced expiratory flow at 75% (FEF75) for FVC; 1.92 (1.39-2.45) for FRC; 1.22 (0.68-1.76) for residual volume; 0.87 (0.60-1.13) for FRC/total lung capacity; and 0.66 (0.27-1.06) for residual volume/total lung capacity. For future multicenter clinical trials using infant PFTs as primary endpoints, minimum detectable treatment effects are presented for several sample sizes. CONCLUSIONS: In this 10-center study, key PFT measures were significantly different in infants with CF than in historical control subjects. However, infant PFTs do not yet appear ready as primary efficacy endpoints for multicenter clinical trials, particularly at inexperienced sites, based on acceptability rates, variability, and potentially large sample sizes required to detect reasonable treatment effects.

Improvements in lung function outcomes in children with cystic fibrosis are associated with better nutrition, fewer chronic pseudomonas aeruginosa infections, and dornase alfa use.

OBJECTIVE: To compare lung function and nutritional outcomes in cystic fibrosis (CF) for 2 birth cohorts in our CF center. STUDY DESIGN: Patients with CF born between 1985 and 2000 treated in our CF center before age 5 years were included. The patients were divided into 2 equal birth cohorts for comparison: birth cohort 1 (born between 1985 and 1992) and birth cohort 2 (born between 1993 and 2000). To compare lung function, we used forced expiratory volume in the first second (FEV(1))% predicted and FEV(1)% predicted slope from age 6 to 12 years. We hypothesized that we would find significant improvements in lung function and nutritional outcomes in our patients with CF. RESULTS: The patients born between 1993 and 2000 (birth cohort 2) had better lung function, a slower rate of decline in lung function, and better nutritional outcomes compared with those born between 1985 and 1992 (birth cohort 1). Factors associated with a slower rate of decline in lung function in both groups were a higher baseline body mass index (BMI)%, a slower BMI% rate of decline, absence of chronic Pseudomonas aeruginosa respiratory infection, and initiation of dornase alfa (Pulmozyme) therapy before age 9 years. CONCLUSION: Our results demonstrate dramatically improved lung function and nutritional outcomes in the children with CF in our center. The improvements in lung function outcomes are associated with better nutrition, fewer chronic P aeruginosa infections, and dornase alfa therapy.

Obliterative bronchiolitis in a 13-year-old pre-transplant cystic fibrosis patient.

Cystic fibrosis (CF)-related lung disease is characterized by a broad spectrum of pathologic changes. Most of these changes relate to progressive bronchiectasis and airway destruction due to recurrent infections. Other airway pathologies include but are not limited to nasal polyposis, bronchial hyperactivity, pneumothorax and allergic bronchopulmonary aspergillosis (ABPA). Constrictive obliterative bronchiolitis (COB) in CF is usually seen in post-transplant settings including lung and heart-lung transplants. We report a 13-year-old boy with CF and intractable deterioration in lung function that was ultimately diagnosed as COB.

Is an FEV1 of 80% predicted a normal spirometry in cystic fibrosis children and adults?

INTRODUCTION: FEV1 is considered the gold standard spirometric measure for the assessment and management of cystic fibrosis lung disease. Recent evidence suggests that tests at lower lung volumes may be more sensitive. OBJECTIVES: To assess how many other spirometric tests are abnormal in the presence of a normal FEV1 (≥80%) and which spirometric tests are most sensitive in detecting airway obstruction. METHODS: This was a retrospective analysis of 3169 spirometry tests on 184 patients with cystic fibrosis aged 6-57 years. Tests were acceptable if they met ATS criteria. RESULTS: Tests with normal FEV1 , FEF75 showed obstruction in 58% of tests, FEF25-75 in 31% and FEV1 /FVC ratio in 72%. Overall 75% of tests had an abnormality. FEF75 , FEF25-75 , FEF50 and FEV1 /FVC ratio were all significantly more sensitive in identifying obstruction than FEV1 . The FEV1 /FVC ratio was the most sensitive of all tests in identifying obstruction except in adults (> 20 years), in whom FEF75 at 90%, was more sensitive than the ratio at 85%. FEF25-75 was also at 85% sensitive. Even though the FEV1 /FVC ratio was the most sensitive of all tests, in the presence of a normal ratio, 35% other tests were abnormal. CONCLUSIONS: Normal FEV1 , is not indicative of normal spirometry. FEV1 /FVC is the most sensitive measure of early or mild airway obstruction in children with cystic fibrosis. If only the FEV1 /FVC ratio was considered, many cases of obstruction would be missed, therefore all spirometric measures should be considered in the clinical evaluation of airway obstruction.

Case study: providing evidence-based behavioral and nutrition treatment to a toddler with cystic fibrosis and multiple food allergies via telehealth.

Barriers to successful outcome for cystic fibrosis (CF) therapies can include distance from a CF care center, co-morbid conditions that require individualized alterations to the prescribed treatment, and patient-provider interactions, among others. We present the case of a 21-month-old female with CF for whom modifications of an efficacious behavioral and nutrition treatment were made due to food allergies and distance from the CF care center. She was classified as at-risk nutritionally. Following treatment a significant increase in energy intake (calories) was observed in addition to her meeting weight and height growth rates for a child of this age and gender who is growing normally at the 50th percentile.

Behavioral and nutritional treatment for preschool-aged children with cystic fibrosis: a randomized clinical trial.

IMPORTANCE: Evidence-based treatments that achieve optimal energy intake and improve growth in preschool-aged children with cystic fibrosis (CF) are a critical need. OBJECTIVE: To test whether behavioral and nutritional treatment (intervention) was superior to an education and attention control treatment in increasing energy intake, weight z (WAZ) score, and height z (HAZ) score. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial included 78 children aged 2 to 6 years (mean age, 3.8 years) with CF and pancreatic insufficiency (intervention, n = 36 and control, n = 42). The study was conducted at 7 CF centers between January 2006 and November 2012; all 78 participants who met intent-to-treat criteria completed through follow-up. INTERVENTIONS: Behavioral intervention combined individualized nutritional counseling targeting increased energy intake and training in behavioral child management skills. The control arm provided education and served as a behavioral placebo controlling for attention and contact frequency. Both treatments were delivered in person or telehealth (via telephone). Sessions occurred weekly for 8 weeks then monthly for 4 months (6 months). Participants then returned to standard care for 1 year, with 12-month follow-up thereafter. MAIN OUTCOMES AND MEASURES: Changes in energy intake and WAZ score were examined from pretreatment to posttreatment (6 months) and change in HAZ score was assessed pretreatment to follow-up (18 months). Covariates included sex, Pseudomonas aeruginosa status at baseline, and treatment modality (in person vs telehealth). RESULTS: At baseline, mean (SD) energy intake was 1462 (329) kcals/d, WAZ score was -0.44 (0.81), and HAZ score was -0.55 (0.84). From pretreatment to posttreatment, the intervention increased daily energy intake by 485 calories vs 58 calories for the control group (adjusted difference, 431 calories; 95% CI, 282 to 581; P < .001) and increased the WAZ score by 0.12 units vs 0.06 for the control (adjusted difference, 0.09; 95% CI, -0.06 to 0.24; P = .25). From pretreatment to follow-up, the intervention increased the HAZ score by 0.09 units vs -0.02 for the control (adjusted difference, 0.14 units; 95% CI, 0.001 to 0.27; P = .049). Measured treatment integrity and credibility were high for both groups. CONCLUSIONS AND RELEVANCE: Behavioral and nutritional intervention improved energy intake and HAZ score outcomes but not WAZ score outcomes. Our results provide evidence that behavioral and nutritional treatment may be efficacious as a nutritional intervention for preschoolers aged 2 to 6 years with CF and pancreatic insufficiency. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT00241969.

The impact of transforming healthcare delivery on cystic fibrosis outcomes: a decade of quality improvement at Cincinnati Children's Hospital.

BACKGROUND: In 2001, Cincinnati Children's Hospital embarked on a journey to improve healthcare delivery to patients with cystic fibrosis (CF). Data from the Cystic Fibrosis Foundation National Patient Registry revealed our below-average clinical outcomes, prompting us to initiate improvement interventions. OBJECTIVE: To improve clinical outcomes for patients with CF through a comprehensive quality-improvement approach directed at increasing patient centredness and improving healthcare delivery. INTERVENTIONS: In 2001, we shared our below-average outcomes with patients, families and care providers. We instituted a quality-improvement steering committee with parental and hospital leadership, and our data-management support was restructured to provide real-time clinical data to monitor our progress. In 2002, our weekly chart conference changed to a prospective planning session and individualised daily schedules were created for inpatients. In 2003, an influenza vaccination campaign was initiated and our infection-control practices were redesigned. In 2005, best-practice guidelines were developed for airway-clearance therapy. In 2007, evidence-based clinical algorithms were designed and implemented and key care-team members were added. MEASUREMENTS: Primary outcome measures were median forced expiratory volume in 1 s per cent predicted (age range 6-17 years) and median body mass index percentile (age range 2-20 years). RESULTS: From 2000 to 2010, median forced expiratory volume in 1 s increased from 81.7% to 100.1% predicted and median body mass index increased from the 35th to the 55th centile. DISCUSSION: By focusing on specific outcomes, empowering families and patients, effectively using data, and standardising care processes, we transformed the culture and delivery of care for our patients with CF and learned valuable lessons potentially translatable to other chronic-care providers.

Screening for symptoms of depression and anxiety in adolescents and young adults with cystic fibrosis.

BACKGROUND: Although studies have assessed symptoms of depression and anxiety in individuals with cystic fibrosis (CF), few have been conducted since the advent of new medical treatments (e.g., nebulized antibiotics, ThAIRpy Vest). Study objectives were to: (1) document symptoms of depression and anxiety for adolescents and young adults with CF and compare with normative values, (2) examine the associations among depressive/anxiety symptoms and gender, age, lung function, and body mass index, and (3) determine the relations between adolescent and caregiver symptoms of depression and anxiety. METHODS: Patients and caregivers completed the Hospital Anxiety and Depression Scale (HADS) anytime (e.g., beginning or end) during routine CF clinic appointments. RESULTS: Participants included 59 adolescents/young adults with CF (M(age) = 15.8 years, 54% female, 98% Caucasian, M(FEV1% predicted) = 84.6) and caregivers of 40 adolescents. Although symptom scores were in the normative range for patients with CF (M(Depression) = 2.27 and M(Anxiety) = 5.59), 3% and 32% exhibited clinically elevated symptoms of depression and anxiety, respectively. Symptoms of depression and anxiety were significantly associated with age (r = 0.28, 0.36). Symptoms of depression and anxiety were also positively correlated (r = 0.48). Females endorsed higher anxiety symptoms than males. While adolescent and caregiver anxiety scores were not related, higher caregiver depressive symptoms were associated with older patient age and worse lung function. CONCLUSIONS: Data from the current study suggest low levels of depressive symptoms and substantial levels of anxiety symptoms in adolescents and young adults with CF. Consistent with prior literature, depressive symptoms appear higher in older patients and are significantly associated with anxiety symptoms. Caregiver symptomology appears to be more affected by an adolescent's health status, suggesting a need to screen caregivers when health begins to decline.

Neuroendocrine cell distribution and frequency distinguish neuroendocrine cell hyperplasia of infancy from other pulmonary disorders.

BACKGROUND: The diagnostic gold standard for neuroendocrine cell hyperplasia of infancy (NEHI) is demonstration of increased numbers of neuroendocrine cells (NECs) amid otherwise near-normal lung histology. Typical clinical and radiographic features often are present. However, NECs are also increased after lung injury and in other disorders, which can complicate biopsy specimen interpretation and diagnosis of suspected NEHI. Our objective was to determine whether NEC prominence is specific for the diagnosis of NEHI. METHODS: Bombesin immunoreactivity was quantified in lung biopsy specimens from 13 children with characteristic clinical presentation and imaging appearance of NEHI. The primary comparison group was 13 age-matched patients selected from children with lung disorders that are known to be associated with NEC prominence. RESULTS: Bombesin-immunopositive epithelial area was significantly increased in NEHI compared with other diseases. Patchy bronchiolar inflammation or fibrosis was frequently observed in NEHI, with no direct association between airway histopathology and bombesin-immunopositive area. NEC prominence correlated with severity of small airway obstruction demonstrated on infant pulmonary function testing. Immunohistochemical colocalization of bombesin with Ki67 did not reveal active NEC proliferation. There was wide intra- and intersubject variability in NEC number, which did not relate to radiographic appearance of the region biopsied. CONCLUSIONS: Our findings demonstrate that NEC prominence is a distinguishing feature of NEHI independent of airway injury. The extent of intrasubject variability and potential for overlap with control subjects suggest that clinical-radiologic-pathologic correlation is required for diagnosis and that the abundance of NECs may not fully explain the disease pathogenesis.

Improving evidence-based care in cystic fibrosis through quality improvement.

OBJECTIVE: To increase clinician adherence to prescribing guidelines for pulmonary medications in children with cystic fibrosis (CF). DESIGN: Quality improvement project with multiple time series design. SETTING: The CF center at a tertiary care pediatric hospital in the United States. PATIENTS: Children with CF who were eligible to receive oral azithromycin, nebulized dornase alfa, or inhaled tobramycin sulfate based on prescribing guidelines for CF lung disease. INTERVENTION: Evidence-based prescribing guidelines were designed by a local committee to reflect consensus recommendations from the CF Foundation. Clinicians and families were educated about guidelines. Adherence to prescribing guidelines was tracked using a local CF database and record reviews. Weekly meetings were used to highlight adherence failures and promote clinician accountability. MAIN OUTCOME MEASURE: The rate of clinician adherence to prescribing guidelines. RESULTS: One hundred seventy patients with CF were included. At the start of the project, the rate of clinician adherence to prescribing guidelines was 62%. After 3 months of the project, the rate of clinician adherence to prescribing guidelines was 87% (odds ratio = 4.6; 95% confidence interval, 3.0-7.0). The improvements in adherence to prescribing guidelines were sustained for 21 months of follow-up. CONCLUSIONS: Educating clinicians about prescribing guidelines, sharing guidelines with families, and monitoring clinician adherence improve prescribing adherence to evidence-based recommendations.

Relations between depressive and anxious symptoms and quality of life in caregivers of children with cystic fibrosis.

UNLABELLED: Little is known about depressive and anxious symptoms and quality of life (QOL) in caregivers of children with cystic fibrosis (CF). The aims of this study were to: (1) assess rates of female and male caregiver depressive and anxious symptoms, and (2) evaluate relations between depressive and anxious symptoms, caregiver QOL, and health outcomes. PATIENTS AND METHODS: Eligible participants were caregivers of children with CF who completed three questionnaires assessing depressive and anxious symptoms and caregiver QOL during routine CF Clinic appointments. RESULTS: Rates of depressive and anxious symptoms were elevated in female and male caregivers of children with CF. Rates were higher for anxious (51% for females, 43% for males) than depressive symptoms (20-28% for females; 14-31% for males). Female caregiver depressive symptoms increased as child lung functioning decreased. As depressive and anxious symptoms increased, caregiver QOL decreased. In addition, female caregiver depressive and anxious symptoms were positively correlated with male caregiver anxious and depressive symptoms in a small subsample of couples. CF disease severity and caregiver depressive symptoms predicted caregiver QOL. CONCLUSION: Rates of depressive and anxious symptoms are high among caregivers of children with CF. The results of this study highlight the need to screen for female and male caregiver depressive and anxious symptoms in the CF Clinic as CF Team members are well positioned to provided assistance around solving CF-related challenges. In addition, alleviation of depressive and anxious symptoms could potentially lead to improvements in the psychological functioning and well-being of caregivers of children with CF.

Outcomes of fundoplication in children with cystic fibrosis.

PURPOSE: Children with cystic fibrosis (CF) have a high prevalence of gastroesophageal reflux disease (GERD). As GERD is associated with chronic respiratory symptoms and feeding problems, fundoplication is often performed in children with CF. Although the outcomes of fundoplication have been described across diverse pediatric groups, there is no published experience with CF. METHODS: The records of 25 children with CF who underwent fundoplication in our center were reviewed. Data on symptoms and diagnostic testing results as well as on complications related to fundoplication were collected. Nutritional parameters and pulmonary function were compared before and after fundoplication. RESULTS: There was no mortality associated with fundoplication, but 12% had complications that required a subsequent surgical procedure. Whereas 28% were able to discontinue their antireflux medications, 48% developed symptoms of recurrent GERD. Overall, there was no change in body mass index, body mass index percentile, or the slope of forced expiratory volume in 1 second (FEV1) after fundoplication. Children who had an FEV1 of less than 60% predicted at the time of fundoplication exhibited an improvement in FEV1 slope compared to those with FEV1 of 60% or more (+5.3% vs -8.6% per year, P = .004). CONCLUSION: The complication rate of fundoplication is similar to what has been reported in large series in children without CF. There is a high rate of recurrent GERD and little apparent benefit for either nutritional or pulmonary outcomes. The observed difference on FEV1 slope, in those with moderate-severe vs mild lung disease, highlights the need to thoroughly evaluate the role of fundoplication in children with CF.

Examining clinical trial results with single-subject analysis: an example involving behavioral and nutrition treatment for young children with cystic fibrosis.

OBJECTIVE: To examine the process of change in a clinical trial of behavioral and nutrition treatment for children age 18-48 months with cystic fibrosis (CF) using single-subject analysis. METHODS: The 5-week treatment included nutrition counseling and child behavioral management training for parents and was designed to increase energy intake measured by diet diaries 600-800 calories per day. RESULTS: Energy intake changed at each meal, only when treatment was introduced (week 1: snacks, 420 to 691; week 2: breakfast, 325 to 443; week 4: lunch, 350 to 443; and week 5: dinner, 373 to 460 calories per day). Total daily intake increased in a systematic fashion that exceeded the criterion set each week during treatment. CONCLUSIONS: Toddlers and preschoolers with CF meet energy intake recommendations as a result of behavioral intervention. Single-subject research designs are important methodologies for advancing clinical investigation in pediatric psychology.

Randomized clinical trial of behavioral and nutrition treatment to improve energy intake and growth in toddlers and preschoolers with cystic fibrosis.

OBJECTIVE: To conduct a randomized clinical trial comparing a behavioral and nutrition intervention (BEH) with a usual care control condition (CTL) for children (ages 18 months to 4 years) with cystic fibrosis (CF) and pancreatic insufficiency. This trial was designed to (1) evaluate a randomized comparison of BEH with CTL over 8 weeks, (2) provide a replication of the impact of BEH by inviting the CTL group to receive BEH after 8 weeks, and (3) examine the maintenance of BEH at 3- and 12-month follow-up. METHODS: Of 14 eligible children, 10 were randomly assigned and initiated treatment (71% recruitment rate). Four participants were randomly assigned to BEH, and 6 were assigned to CTL (5 of whom chose to crossover to BEH). BEH included nutrition counseling to increase energy intake (via types of foods and addables/spreadables) and child behavioral management training to teach parents differential attention and contingency management skills. CTL was consistent with the 2002 CF Foundation Consensus Conference Guidelines for nutritional care. RESULTS: BEH led to greater increases in energy intake pre- to posttreatment than CTL as measured by calories per day (842 kcal/day vs -131 kcal/day change). On receiving BEH, the change in energy intake was replicated with the CTL group (892 kcal/day change). At 3- and 12-month follow-up, energy intake was maintained (672 kcal/day increase from baseline and 750 kcal/day increase from baseline, respectively). Children in this study met or exceeded normal weight and height velocities from pretreatment to the 3-month follow-up (mean weight: 1.4 kg/6 months; mean height: 5.1 cm/6 months) and from posttreatment to the 12-month follow-up (mean weight: 2.5 kg/12 months; mean height: 8.3 cm/12 months). CONCLUSIONS: Toddlers and preschoolers who have CF and received BEH were able to meet the energy intake recommendations for this disease and maintain these gains up to 12 months after treatment. In addition, these children demonstrated weight and height velocities from pretreatment to 12-month follow-up, consistent with the goal of normal growth. BEH is a promising, evidence-based, early nutritional intervention for children with CF. An upcoming multisite clinical trial will test BEH versus an attention control condition using a larger sample (N = 100), providing additional evidence about the efficacy of this treatment for energy intake and growth in young children with CF.