Steroid variability in pediatric inpatient asthmatics: survey on provider preferences of dexamethasone versus prednisone.

Objective: Our hospital's pediatric Emergency Department (ED) began using dexamethasone for treating asthma exacerbations after ED studies showed non-inferiority of dexamethasone compared to prednisone. However, providers have not reached consensus on optimal inpatient steroid regimen. This study evaluates provider preference for inpatient steroid treatment.Methods: A survey was distributed to providers who care for inpatient pediatric asthmatics. Respondents answered questions about steroid choice and timing. Data were summarized as percentages; bivariate comparisons were analyzed with Pearson's chi-squared test.Results: Ninety-two providers completed the survey (60% response rate). When patients received dexamethasone in the ED, subsequent inpatient management was variable: 44% continued dexamethasone, 14% switched to prednisone, 2% said no additional steroids, and 40% said it depended on the scenario. Hospitalists were more likely to continue dexamethasone than pulmonologists (61% and 15%, respectively; p < .001). Factors that influenced providers to switch to prednisone in the inpatient setting included severity of exacerbation (73%) and asthma history (47%). Fifty-one percent felt uncomfortable using dexamethasone because of "minimal data to support [its] use inpatient." In case-based questions, 28% selected dexamethasone dosing intervals outside the recommended range. Thirteen percent reported experiencing errors in clinical practice.Conclusions: Use of dexamethasone in the ED for asthma exacerbations has led to uncertainty in inpatient steroid prescribing practices. Providers often revert to prednisone, especially in severe asthma exacerbations, possibly due to experience with prednisone and limited research on dexamethasone in the inpatient setting. Further research comparing the effectiveness of dexamethasone to prednisone in inpatient asthmatic children with various severities of illness is needed.

Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial.

RATIONALE: New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach that complements traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation and inflammation may ultimately prolong the time to Pa recurrence. OBJECTIVES: To test the hypothesis that the addition of azithromycin to TIS in children with cystic fibrosis and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence. METHODS: The OPTIMIZE (Optimizing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis) trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF, 6 months to 18 years of age, with early Pa. Azithromycin or placebo was given 3× weekly with standardized TIS. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the time to pulmonary exacerbation requiring antibiotics and the secondary endpoint was the time to Pa recurrence, in addition to other clinical and safety outcomes. A total of 221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrollment was stopped early by the NHLBI because the trial had reached the prespecified interim boundary for efficacy. The risk of pulmonary exacerbation was reduced by 44% in the azithromycin group as compared with the placebo group (hazard ratio, 0.56; 95% confidence interval, 0.37-0.83; P = 0.004). Weight increased by 1.27 kg in the azithromycin group compared with the placebo group (95% confidence interval, 0.01-2.52; P = 0.046). No significant differences were seen in microbiological or other clinical or safety endpoints. CONCLUSIONS: Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and a sustained improvement in weight, but had no impact on microbiological outcomes in children with early Pa. Clinical trial registered with clinicaltrials.gov (NCT02054156).

Lung function from infancy to preschool in a cohort of children with cystic fibrosis.

This study aimed to describe lung function in a cohort of children with cystic fibrosis (CF) who underwent infant pulmonary function tests (IPFTs) and preschool spirometry. Children performed up to four IPFTs (raised volume rapid thoracic compression technique) over 1 yr and five preschool spirometry tests over up to 2 yrs during participation in prospective, multicentre studies of infant and preschool lung function. All lung function data were reviewed centrally for measurement acceptability. 45 children had 252 acceptable measurements (137 IPFTs and 115 preschool spirometries) at ages 0.3-6.5 yrs. The median number of measurements per participant was 6 (range 3-9). Recent Pseudomonas aeruginosa infection was associated with 5.1% (95% CI 0.01-9.9%) lower forced expiratory volume in 0.5 s (FEV(0.5)) and 16.4% (95% CI 7.0-24.9%) lower forced expiratory flow at 25-25% of forced vital capacity (FEF(25-75%)), after adjustment for length, test type and centre. Recent cough was associated with 5.7% (95% CI 1.1-10.1%) lower FEV(0.5) and 10.1% (95% CI 0.6-18.7%) lower FEF(25-75%). Even after accounting for infection status, cough, sex, length, test type and centre, there was significant inter-individual variability in lung function (p<0.01 for each of FEV(0.5), FEF(25-75%) and forced vital capacity). Recent P. aeruginosa infection and cough are associated with lower lung function in children with CF. Significant inter-individual variability in lung function remains to be explained.

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.

Barriers and Motivators for Smoking Cessation Among Caregivers of Inpatient Pediatric Patients.

OBJECTIVE: To examine perceived barriers and motivators for smoking cessation among caregivers of inpatient pediatric patients. METHODS: From December 2014 to June 2018, trained tobacco counselors conducted motivational interviews (MI) with caregivers of inpatient pediatric patients ages 0 to 17, who participated in the intervention arm of a smoking cessation randomized controlled trial. By using NVivo 12 software, the first MI session with each caregiver was evaluated by 3 individuals to identify and categorize motivators and barriers; agreement among reviewers was reached. Barriers and motivators were examined in bivariable analysis with χ2 or Fisher's exact tests for categorical factors and with t-tests for continuous factors by using SAS 9.4 software. RESULTS: Of the 124 caregivers randomized to intervention, 99 subjects (80%) completed ≥1 MI sessions. The most prevalent barriers to cessation were stress (57%) and social influence (37%).The most prevalent motivators were desire to lead a healthy life (54%) and desire to improve the child and family's well-being (47%). Older parent age was associated with wanting to lead a healthy life, and younger child age was associated with wanting to improve the child and family's well-being. CONCLUSIONS: Understanding barriers and motivators to cessation among caregivers is crucial in reducing pediatric secondhand smoke (SHS). When developing caregiver cessation programs in an inpatient clinic encounter, caregiver barriers and motivators may help in targeting education and strategies to help counselors and clinicians better identify and support caregivers who wish to quit smoking.

Intervening With Smoking Parents of Inpatients to Reduce Exposure: The INSPIRE Randomized Controlled Trial.

BACKGROUND: Hospitalized children have high rates of tobacco smoke exposure; parents who smoke may be receptive to interventions during their child's hospitalization. OBJECTIVE: We tested the efficacy of a smoking cessation intervention for parents of hospitalized children. METHODS: We conducted a randomized, single-blind clinical trial from 12/14-5/18 at the Children's Hospital Colorado. Hospitalized children who had a parent who smoked tobacco were eligible. INTERVENTION: Intervention participants received motivational interviewing sessions, 2 weeks of nicotine replacement therapy; both groups received referral to the Quitline Consenting parents completed a questionnaire; urine was collected from the child for measurement of cotinine. Our primary outcome was: 1) increase in reporting "no one is allowed to smoke anywhere" in the home (smoke-free home rule). Additional outcomes included: 2) change in child's cotinine from baseline to 1 year, and 3) parental quitting at 1 year. Data were analyzed using Chi-square and t tests for bivariable data, and multivariable logistic and linear regression. RESULTS: Of 1641 eligible families approached, 252 were randomized (15%); 149 families had follow-up data at 12 months (59%). In the adjusted analysis, there was no difference between the groups in smoke free home rules, or child cotinine level; in an intention-to-treat analysis, 15% in the intervention group versus 8% of controls reported quit (p=0.07). CONCLUSIONS: A smoking cessation intervention can be delivered to parents of hospitalized children. While hospitalization provides an opportunity to help parents quit smoking, more efficient and effective engagement strategies are needed to optimize tobacco control success.

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.

Tobacco Smoke Exposure Reduction Strategies-Do They Work?

OBJECTIVE: Many children experience tobacco smoke exposure (TSE) and parents may take preventive measures to reduce TSE. The study goal is to assess if these strategies are associated with lower cotinine values, an objective biological measure of TSE. METHODS: Families admitted to Children's Hospital Colorado from 2014 to 2018 who screened positive for TSE were invited to participate in a tobacco smoking cessation/reduction program. Caregivers were consented and asked about demographics, beliefs around smoking, and strategies to reduce TSE. Child urine samples were collected, tested for cotinine levels, and analyzed using geometric means. Bivariable comparisons and multivariable linear regression were completed using SAS v9.4 (SAS Institute, Cary, NC). RESULTS: Two hundred thirteen children (81.4%) are included in this analysis. The median ages of children and parents were 4 and 32 years respectively. Fifty-seven percent of children were male, 36% were Hispanic, and 55% were white. Fifty-six percent of parents had at least some college education and 69% had an annual income less than $50K. The median daily cigarettes smoked per day were 10. Eighty-eight percent reported using at least 1 type of protective measure to prevent TSE and 90% believed they protect other household members from TSE. None of the strategies had a significant relationship with lower cotinine levels on bivariable or multivariable analyses. CONCLUSIONS: Parental strategies to decrease TSE did not result in lower cotinine levels. Many measures are not evidence-based and do not protect children. Parent's clothing and homes may create a reservoir for nicotine. Education should focus on exposure elimination and cessation rather than protective measures.

Smoking Behaviors Among Tobacco-Using Parents of Hospitalized Children and Association With Child Cotinine Level.

OBJECTIVES: Understanding patterns of parental tobacco use and their association with child exposure can help us target interventions more appropriately. We aimed to examine the association between parental smoking practices and cotinine levels of hospitalized children. METHODS: This is a secondary analysis of data collected from parents of hospitalized children, recruited for a cessation intervention randomized controlled trial. Smoking parents were identified by using a medical record screening question. Parent-reported demographics and smoking habits were compared to child urine cotinine by using geometric means and log-transformed cotinine levels in multivariable linear regression analyses. RESULTS: A total of 213 patients had complete baseline parent-interview and urine cotinine data. The median age was 4 (interquartile range: 1-9); 57% were boys; 56% were white, 12% were Black, and 23% were multiracial; 36% identified as Hispanic. Most families (54%) had 1 smoker in the home; 36% had 2, and 9% had ≥3. Many (77%) reported having a ban on smoking in the home, and 86% reported smoking only outside. The geometric mean cotinine level of the cohort was 0.98 ng/mL. Higher cotinine levels were associated with more smokers in the home (ratio of 2.99) and smoking inside the house (ratio of 4.11). CONCLUSIONS: Having more smokers in the home and parents who smoke inside are associated with increased smoke exposure; however, even children whose families who smoke only outside the home have significant levels of cotinine, a marker for toxin exposure.

Electronic Health Records and Pulmonary Function Data: Developing an Interoperability Roadmap. An Official American Thoracic Society Workshop Report.

A workshop "Electronic Health Records and Pulmonary Function Data: Developing an Interoperability Roadmap" was held at the American Thoracic Society 2019 International Conference. "Interoperability" is defined as is the ability of different information-technology systems and software applications to directly communicate, exchange data, and use the information that has been exchanged. At present, pulmonary function test (PFT) equipment is not required to be interoperable with other clinical data systems, including electronic health records (EHRs). For this workshop, we assembled a diverse group of experts and stakeholders, including representatives from patient-advocacy groups, adult and pediatric general and pulmonary medicine, informatics, government and healthcare organizations, pulmonary function laboratories, and EHR and PFT equipment and software companies. The participants were tasked with two overarching Aobjectives: 1) identifying the key obstacles to achieving interoperability of PFT systems and the EHR and 2) recommending solutions to the identified obstacles. Successful interoperability of PFT data with the EHR impacts the full scope of individual patient health and clinical care, population health, and research. The existing EHR-PFT device platforms lack sufficient data standardization to promote interoperability. Cost is a major obstacle to PFT-EHR interoperability, and incentives are insufficient to justify the needed investment. The current vendor-EHR system lacks sufficient flexibility, thereby impeding interoperability. To advance the goal of achieving interoperability, next steps include identifying and standardizing priority PFT data elements. To increase the motivation of stakeholders to invest in this effort, it is necessary to demonstrate the benefits of PFT interoperability across patient care and population health.

Perceptions of Parental Tobacco Dependence Treatment Among a Children's Hospital Staff.

OBJECTIVES: To assess employee support for and knowledge of smoking cessation programs for patients' parents and staff and employees' level of comfort discussing smoking with patients and their families before and during a hospital-wide study of a tobacco cessation and/or exposure reduction program for inpatients' parents who smoke. METHODS: Clinical staff were invited to complete online surveys at the beginning of and 19 months into a randomized controlled trial to test the efficacy of an inpatient tobacco cessation and exposure reduction program for parents of hospitalized children. The program included educating pediatric inpatient clinical staff about available resources, such as the Colorado QuitLine, and smoking cessation interventions for the parents of hospitalized children. Clinical staff were recruited via e-mail listservs, a weekly e-mail newsletter, and posted flyers. Baseline and midstudy results were compared, and χ2 tests were performed. RESULTS: At the baseline, 192 clinical staff responded; 235 responded midstudy. At the baseline and midstudy, at least 90% of the respondents believed that the hospital should support parents in quitting smoking, although the support for free nicotine replacement therapy was low (27% at the baseline to 35% at midstudy). One-fifth of the respondents were uncomfortable discussing smoking; this proportion decreased after educational interventions. Knowledge about hospital cessation resources had also increased at midstudy. CONCLUSIONS: There was strong support for helping parents and staff quit smoking. Comfort among clinical staff in addressing tobacco dependence in patients and families and awareness of cessation resources increased over the course of the study.

Measuring Pediatric Bronchoscopy Outcomes Using an Electronic Medical Record.

RATIONALE: Bronchoscopy procedures should be tracked for safety, quality improvement, and federal regulations. OBJECTIVE: The aim of this study was to develop and test a method for evaluating flexible bronchoscopy use and outcomes using the electronic medical record (EMR) system in current clinical use at a large children's hospital. METHODS: We created a custom bronchoscopy procedure note for our EMR system (Epic Systems Corporation) to track demographics, bronchoscopist, coordinated procedures, and outcome. Unplanned outcomes in children were defined as a disposition (admission to the hospital or elevation of care) after flexible bronchoscopy that differed from the preoperative plan. Readmissions to the hospital and emergency visits within our hospital system were also tracked electronically. Unplanned outcomes and readmissions were evaluated by a bronchoscopy quality team. MEASUREMENTS AND MAIN RESULTS: Over 2.5 years, we tracked 1,297 bronchoscopic procedures performed on 1,161 patients (60% male, 78% American Society of Anesthesiologists class 2 or 3, mean age 5.5 yr [range, 0.02-40 yr]). Overall, 27 unplanned outcomes occurred (2.1%). The risk of unplanned outcomes did not appear to be different between procedures performed by a trainee with faculty oversight and those performed by a faculty member alone. Patients with multiple same-day procedures were more likely to have unplanned outcomes (21 of 27 [78%], P = 0.004) than were patients who had flexible bronchoscopy alone. The relative risk (RR) of having an unplanned outcome was not different from flexible bronchoscopy alone in the subset of patients with multiple procedures coordinated through our multidisciplinary aerodigestive clinic (RR 0.7; 95% CI, 0.1-3.4). The risk of unplanned events was significantly elevated in children with coordinated procedures scheduled outside the aerodigestive group (RR, 5.8; 95% CI, 2.4-14.5). Ten patients (<1%) were readmitted or seen urgently within 1 week; three of these unplanned outcomes were attributed to complications of the bronchoscopy. CONCLUSIONS: An EMR system may be used to track procedural outcomes. Unplanned outcomes after flexible bronchoscopy were infrequent at our institution. Children who underwent multiple procedures had unplanned outcomes more often; however, the subset of children who underwent coordinated procedures through our multidisciplinary aerodigestive clinic did not demonstrate this increased risk.

Infant lung function tests as endpoints in the ISIS multicenter clinical trial in cystic fibrosis.

BACKGROUND: The Infant Study of Inhaled Saline (ISIS) in CF was the first multicenter clinical trial to utilize infant pulmonary function tests (iPFTs) as an endpoint. METHODS: Secondary analysis of ISIS data was conducted in order to assess feasibility of iPFT measures and their associations with respiratory symptoms. Standard deviations were calculated to aid in power calculations for future clinical trials. RESULTS: Seventy-three participants enrolled, 70 returned for the final visit; 62 (89%) and 45 (64%) had acceptable paired functional residual capacity (FRC) and raised volume measurements, respectively. Mean baseline FEV0.5, FEF75 and FRC z-scores were 0.3 (SD: 1.2), -0.2 (SD: 2.0), and 1.8 (SD: 2.0). CONCLUSIONS: iPFTs are not appropriate primary endpoints for multicenter clinical trials due to challenges of obtaining acceptable data and near-normal average raised volume measurements. Raised volume measures have potential to serve as secondary endpoints in future clinical CF trials.

Abnormal infant pulmonary function in young children with neuroendocrine cell hyperplasia of infancy.

RATIONALE: Lung function in children with neuroendocrine cell hyperplasia of infancy (NEHI) and correlations with future clinical outcomes are needed to guide clinical management. OBJECTIVE: To compare results of infant pulmonary function tests (IPFTs) in children with NEHI to disease control (DC) subjects and to correlate NEHI IPFTs with future outcomes. METHODS: We performed a retrospective, single center study of IPFT in subjects diagnosed by lung biopsy (NEHI) or clinically (NEHI syndrome) and in DC subjects evaluated for cancer or pre-hematopoietic stem cell transplantation (HSCT). Raised volume rapid thoracoabdominal compression (RVRTC) and plethysmography were performed on all infants and evaluated for quality. Standard spirometry measures, room air oxygen saturations (RA O2 sat), and weight percentiles were collected during follow up. MEASUREMENTS AND MAIN RESULTS: Fifty-seven IPFTs were performed in 15 NEHI, 22 NEHI syndrome, and 20 DC subjects. RVRTC and FRC measurements were obtained in 85% or more of subjects in all groups. Significant airflow limitation (FEV0.5 P-value ≤ 0.01) and air trapping (FRC P-value ≤ 0.01) were seen in NEHI and NEHI syndrome subjects compared to DCs. No significant correlations were found between IPFT, oxygen use, RA O2 sat, and weight at the time of the IPFTs. Initial FEV0.5 and FRC z-scores correlated with RA O2 sat (r = 0.60 and -0.49) at short-term follow up (6-12 months). Most measurements of RVRTC correlated with FEV1 (n = 5) measured 4-5 years later (r > 0.50). CONCLUSIONS: IPFTs in NEHI subjects are feasible, demonstrate significant obstruction and air trapping, and correlate with future RA O2 sat and FEV1 . IPFTs may provide valuable clinical information when caring for NEHI patients. Pediatr Pulmonol. 2013; 48:1008-1015. © 2012 Wiley Periodicals, Inc.

Lung function distinguishes preschool children with CF from healthy controls in a multi-center setting.

RATIONALE: Conducting clinical trials in cystic fibrosis (CF) preschoolers has been limited by lack of sensitive lung function measures performed across sites. OBJECTIVES: (1) Assess feasibility and short-term reproducibility of spirometry, forced oscillometry (FO), and inductance plethysmography (IP) in a multi-center preschool population; (2) compare ability of each technique to differentiate lung function of CF preschoolers and controls; (3) evaluate longitudinal changes in lung function; (4) estimate sample sizes for future trials. METHODS: A longitudinal, multi-center study of CF preschoolers was conducted utilizing standardized equipment, rigorous site training, and centralized lung function data review. CF subjects participated in up to four study visits 6 months apart, plus a 2-week reproducibility visit. Controls had one study visit. RESULTS: Ninety-three CF subjects and 87 controls participated. Acceptability rates were lowest for spirometry (55%) and highest for IP (77%). Spirometry success increased with age and having a prior acceptable measurement. FEV(1) , FEV(0.5) , and FEF(25-75) were lower for CF subjects than for controls; spirometric z-scores declined with age. IP measures of thoracoabdominal asynchrony were greater for CF subjects than for controls. FO indices did not distinguish CF from controls. FEV(1) and FEV(0.5) are able to detect the smallest treatment effect for a given sample size. CONCLUSIONS: Spirometry appears more sensitive than IP or FO for detecting lung disease in CF preschoolers; spirometric indices decline with age. Future trials using spirometry should include a run-in period for training and require acceptable data prior to enrollment. However, near-normal spirometric measurements in CF preschoolers may lead to difficulty detecting a treatment effect.

Analysis of the associations between lung function and clinical features in preschool children with cystic fibrosis.

OBJECTIVE: To analyze cross-sectional and longitudinal associations between lung function measures and clinical features in a cohort of preschool children with cystic fibrosis (CF). METHODS: Longitudinal eight-center observational study of children with CF aged 36-60 months at enrollment, who underwent semiannual pulmonary function tests (PFTs) for up to 2 years consisting of spirometry (all 8 sites), forced oscillometry (FO, 5 sites), and measures of thoracoabdominal asynchrony using respiratory inductive plethysmography (IP, 5 sites). RESULTS: Ninety-three subjects were enrolled; 181 acceptable spirometry measurements from 71 subjects, 128 FO from 47 subjects, and 142 IP from 50 subjects were available for analysis. Cross sectional analyses did not detect an association between any PFT parameter at enrollment and Pseudomonas aeruginosa (Pa) status, CF gene mutation class, Wisconsin cough score, Shwachman score, environmental tobacco smoke exposure, family history of asthma, or nutritional indices. In longitudinal analyses, Pa infection within 6 months preceding enrollment was associated with a significantly greater rate of decline in z-scores for forced expiratory flow between 25 and 75% of forced vital capacity (FEF(25-75) ) (-1.3 vs. -0.4 Z scores/year, P = 0.024) and greater thoracoabdominal asynchrony measured by IP (mean phase angle difference 4.6°, P = 0.004). No other significant longitudinal associations were observed. CONCLUSIONS: Prior Pa infection is associated with a greater rate of decline in FEF(25-75) z-score and mild thoracoabdominal asynchrony in preschool children with CF. In this multicenter US study, significant associations between other lung function measures and clinical features were not detected.

Impairment of macrophage survival by NaCl: implications for early pulmonary inflammation in cystic fibrosis.

Inflammation, characterized by the presence of proinflammatory chemokines and neutrophils, is a hallmark of early airway disease in infants with cystic fibrosis (CF), although the underlying mechanisms remain poorly defined. In this study, we evaluated the role of NaCl and the ensuing hyperosmolar effect on tumor necrosis factor (TNF)-alpha signaling and apoptosis in macrophages. Incubation of mouse macrophages with NaCl activated p38(mapk) and the p46(jnk) and p54(jnk) c-jun NH(2)-terminal kinase isoforms, but not p42(mapk/erk2) or Akt. Similar results were obtained with sorbitol, suggesting a general response to hyperosmolarity. Strikingly, the activation of p42(mapk/erk2) and Akt by TNF-alpha was also inhibited in the presence of NaCl. Because the activation of p42(mapk/erk2) and Akt has been associated with survival responses, we investigated the effect of NaCl on macrophage apoptosis. The results indicated a synergistic increase in apoptosis when macrophages were exposed to TNF-alpha in the presence of NaCl compared with stimulation with TNF-alpha alone or NaCl alone. Furthermore, pharmacological inhibition of p42(mapk/erk2) and Akt mimicked the effect of NaCl. Collectively, these findings indicate that modest elevations in NaCl differentially regulate the activation of mitogen-activated protein kinases and Akt and potentiate macrophage apoptosis. We speculate that augmentation of macrophage apoptosis in CF airways may result in decreased clearance of neutrophils and in deficiencies in the elimination of common CF pathogens.