An examination of geographic access to outpatient stroke rehabilitation services in Tennessee, a stroke belt state.

BACKGROUND: While over half of US stroke patients were discharged to home, estimates of geographic access to outpatient stroke rehab facilities are unavailable. The objective of our study was to assess distance and travel time to the nearest outpatient stroke rehab facility in Tennessee, a high stroke prevalence state. METHODS: We systematically scraped Google Maps with the terms "stroke", "rehabilitation", and "outpatient" to identify Tennessee stroke rehab facilities. We then averaged/aggregated Census block-level travel distance and travel time to determine the mean travel distance/time to a facility for each of the 95 Tennessee counties and the overall state. Comparisons of mean travel time/distance were made between rural and urban counties and between low, medium, and high stroke prevalence counties. RESULTS: We found that 79% of facilities were in urban areas. Significantly higher median of mean travel times and distances (p values both <0.001) were observed in rural (22.0 miles, 31.6 min) versus urban counties (10.5 miles, 18.4 min). High (21.5 miles, 32.5 min) and medium (18.7 miles, 28.3 minutes) stroke prevalence counties, which often overlap with rural counties, had significantly higher median of mean travel times and distance than low stroke prevalence counties (7.3 miles, 14.5 min). CONCLUSIONS: Rural Tennessee counties were faced with high stroke prevalence, inadequate facilities, and significantly greater travel distance and time to access care. Additional efforts to address transportation barriers and accelerate telerehabilitation implementation are crucial for improving equal access to stroke aftercare in these areas.

Non-invasive forced oscillometry to quantify respiratory mechanics in term neonates.

BACKGROUND: To determine normative data by forced oscillation technique (FOT) in non-sedated normal term neonates and test the hypothesis that infants with transient tachypnea of the newborn (TTN) have higher resistance (R) and lower reactance (X) on day 1. METHODS: Healthy term infants (n = 138) and infants with TTN (n = 17) were evaluated on postnatal days 1 through 3 (NCT03346343). FOT was measured with a mask using a TremoFlo C-100 Airwave System™. R, X, and area under the reactance curve (AX) were measured at prime frequencies 7-41 Hz for 8 s. RESULTS: In all, 86% of control infants had adequate measurements (coherence >0.8, CV < 0.25) on day 1. Infants with TTN had higher resistance at 13 Hz (TTN 32.5 cm H2O·s/L [95% CI 25.5-39.4]; controls 23.8 cm H2O·s/L [95% CI 22.2 to 25.3], P = 0.007) and lower reactance from 17 to 37 Hz (TTN -35.1 to -10.5; controls -26.3 to -6.1, P < 0.05). In healthy controls, lung mechanics were unchanged from days 1 to 3. In TTN, lung mechanics normalized on days 2 and 3. CONCLUSIONS: FOT is feasible in neonates and distinguishes normal control infants from those with TTN on postnatal day 1. Oscillometry offers a non-invasive, longitudinal technique to assess lung mechanics in newborns.

MicroRNA-145 Antagonism Reverses TGF-ß Inhibition of F508del CFTR Correction in Airway Epithelia.

RATIONALE: MicroRNAs (miRNAs) destabilize mRNA transcripts and inhibit protein translation. miR-145 is of particular interest in cystic fibrosis (CF) as it has a direct binding site in the 3'-untranslated region of CFTR (cystic fibrosis transmembrane conductance regulator) and is upregulated by the CF genetic modifier TGF (transforming growth factor)-ß. OBJECTIVES: To demonstrate that miR-145 mediates TGF-ß inhibition of CFTR synthesis and function in airway epithelia. METHODS: Primary human CF (F508del homozygous) and non-CF airway epithelial cells were grown to terminal differentiation at the air-liquid interface on permeable supports. TGF-ß (5 ng/ml), a miR-145 mimic (20 nM), and a miR-145 antagonist (20 nM) were used to manipulate CFTR function. In CF cells, lumacaftor (3 µM) and ivacaftor (10 µM) corrected mutant F508del CFTR. Quantification of CFTR mRNA, protein, and function was done by standard techniques. MEASUREMENTS AND MAIN RESULTS: miR-145 is increased fourfold in CF BAL fluid compared with non-CF (P < 0.01) and increased 10-fold in CF primary airway epithelial cells (P < 0.01). Exogenous TGF-ß doubles miR-145 expression (P < 0.05), halves wild-type CFTR mRNA and protein levels (P < 0.01), and nullifies lumacaftor/ivacaftor F508del CFTR correction. miR-145 overexpression similarly decreases wild-type CFTR protein synthesis (P < 0.01) and function (P < 0.05), and eliminates F508del corrector benefit. miR-145 antagonism blocks TGF-ß suppression of CFTR and enhances lumacaftor correction of F508del CFTR. CONCLUSIONS: miR-145 mediates TGF-ß inhibition of CFTR synthesis and function in airway epithelia. Specific antagonists to miR-145 interrupt TGF-ß signaling to restore F508del CFTR modulation. miR-145 antagonism may offer a novel therapeutic opportunity to enhance therapeutic benefit of F508del CFTR correction in CF epithelia.

Effect of Prenatal versus Postnatal Vitamin D Deficiency on Pulmonary Structure and Function in Mice.

Epidemiologic studies have linked gestational vitamin D deficiency to respiratory diseases, although mechanisms have not been defined. We hypothesized that antenatal vitamin D deficiency would impair airway development and alveolarization in a mouse model. We studied the effect of antenatal vitamin D deficiency by inducing it in pregnant mice and then compared lung development and function in their offspring to littermate controls. Postnatal vitamin D deficiency and sufficiency models from each group were also studied. We developed a novel tracheal ultrasound imaging technique to measure tracheal diameter in vivo. Histological analysis estimated tracheal cartilage total area and thickness. We found that vitamin D-deficient pups had reduced tracheal diameter with decreased tracheal cartilage minimal width. Vitamin D deficiency increased airway resistance and reduced lung compliance, and led to alveolar simplification. Postnatal vitamin D supplementation improved lung function and radial alveolar count, a parameter of alveolar development, but did not correct tracheal narrowing. We conclude that antenatal vitamin D deficiency impairs airway and alveolar development and limits lung function. Reduced tracheal diameter, cartilage irregularity, and alveolar simplification in vitamin D-deficient mice may contribute to increased airways resistance and diminished lung compliance. Vitamin D supplementation after birth improved lung function and, potentially, alveolar simplification, but did not improve defective tracheal structure. This mouse model offers insight into the mechanisms of vitamin D deficiency-associated lung disease and provides an in vivo model for investigating preclinical preventive and therapeutic strategies.

Airway microbiota across age and disease spectrum in cystic fibrosis.

Our objectives were to characterise the microbiota in cystic fibrosis (CF) bronchoalveolar lavage fluid (BALF), and determine its relationship to inflammation and disease status.BALF from paediatric and adult CF patients and paediatric disease controls undergoing clinically indicated bronchoscopy was analysed for total bacterial load and for microbiota by 16S rDNA sequencing.We examined 191 BALF samples (146 CF and 45 disease controls) from 13 CF centres. In CF patients aged <2 years, nontraditional taxa (e.gStreptococcus, Prevotella and Veillonella) constituted ∼50% of the microbiota, whereas in CF patients aged ≥6 years, traditional CF taxa (e.gPseudomonas, Staphylococcus and Stenotrophomonas) predominated. Sequencing detected a dominant taxon not traditionally associated with CF (e.gStreptococcus or Prevotella) in 20% of CF BALF and identified bacteria in 24% of culture-negative BALF. Microbial diversity and relative abundance of Streptococcus, Prevotella and Veillonella were inversely associated with airway inflammation. Microbiota communities were distinct in CF compared with disease controls, but did not differ based on pulmonary exacerbation status in CF.The CF microbiota detected in BALF differs with age. In CF patients aged <2 years, Streptococcus predominates, whereas classic CF pathogens predominate in most older children and adults.

Risk factors for acute kidney injury during aminoglycoside therapy in patients with cystic fibrosis.

BACKGROUND: Aminoglycoside (AG) therapy is a common cause of acute kidney injury (AKI) in cystic fibrosis (CF) patients. The aim of this study was to identify factors associated with AKI during intravenous AG courses in this population. METHODS: This was a matched case-control study utilizing two independent cohorts of hospitalized CF patients receiving ≥ 3 days of intravenous AG at Cincinnati Children's Hospital Medical Center and Children's of Alabama. All admissions with AKI (cases, N = 82) were matched to two randomly selected admissions without AKI (controls, N = 164) by center, gender, and age ±3 years of the case. AKI was defined as a 1.5-fold increase in the baseline serum creatinine (SCr) level or by an increase in SCr level of 0.3 mg/dL within 48 h. Admissions with AKI before day 4 or without at least weekly SCr monitoring were excluded from the analysis. Factors were compared between cases and controls using simple and multiple conditional logistic regression. RESULTS: Multivariable analysis identified receipt of an AG within 90 days prior to admission, longer duration of AG therapy, low serum albumin, and receipt of trimethoprim/sulfamethoxazole as independent risk factors for developing AKI. Infection with Staphylococcus aureus diminished the odds of developing AKI. CONCLUSIONS: This study identifies risk factors contributing to AG-associated AKI in CF patients. These findings can be used to anticipate high-risk scenarios and limit AKI in CF patients under clinical care.

Population based surveillance in sickle cell disease: methods, findings and implications from the California registry and surveillance system in hemoglobinopathies project (RuSH).

BACKGROUND: There are no population-based surveillance systems to determine prevalence, impact or outcomes in sickle cell disease (SCD). Estimates of the SCD population in California range broadly from 4,500 to 7,000, and little is known about their health status, health care utilization or health outcomes. A surveillance strategy was implemented using diverse data sources to develop a multi-dimensional, state-based surveillance system for SCD that includes adults and children and describes utilization, treatment and outcomes. PROCEDURE: Data from California newborn screening, inpatient and emergency room records, Medi-Cal/Medicaid claims and two SCD special care centers were collected for 2004-2008. A multi-step, iterative linkage process was used to link and de-duplicate these data sources, and case definitions were used to categorize cases. RESULTS: After linking and de-duplicating, there were 1,975 confirmed cases of SCD, 3,159 probable cases as well as 8,024 possible cases. Among individual data sources, newborn screening and data from clinics contributed the greatest number of unique cases to the total. Select analyses of utilization and treatments for the population are described. CONCLUSIONS: Using linked existing data sources, an estimate of the statewide count of the SCD population is possible. The approach can be used to create an in-depth health status profile of the affected population by aggregating utilization, treatment, and outcomes data including mortality and morbidity information. This effort sets the stage for development of an on-going, state-based surveillance system.

Flexible bronchoscopy findings and management impact in children with oropharyngeal dysphagia.

INTRODUCTION: Flexible bronchoscopy (FB) and bronchoalveolar lavage (BAL) are frequently performed in children with known or suspected aspiration, however, the additive value of FB in conjunction with direct laryngoscopy and rigid bronchoscopy (DLB) has not been previously quantified. This study details the common endoscopic/cytological findings and associated management impact of FB and BAL in pediatric Aerodigestive patients undergoing combined airway evaluation (FB and DLB) for oropharyngeal dysphagia. MATERIALS AND METHODS: A retrospective chart review was performed in children <3 years of age followed through a large Aerodigestive center undergoing outpatient, combined airway endoscopy for dysphagia. Patient and procedural characteristics, endoscopic and BAL findings, and management metrics were collected and analyzed. A secondary analysis evaluated the association between endoscopic findings and medication changes. RESULTS: Ninety-one procedures (median patient age, 15 months) were identified. All procedures included both FB and DLB, and just over half (52.7%) included esophagogastroduodenoscopy. Common endoscopic findings included bronchitis (73.6%), adenoidal hypertrophy (31.9%), and tracheomalacia (10.8%). BAL cytology frequently identified neutrophilic inflammation (mean 39.6% neutrophils [interquartile range 6.5%-71%)]. Cultured pathogens commonly included Streptococcus viridans (46.6%), Hemophilus influenzae (36.3%), Moraxella catarrhalis (30.1%), and Streptococcus pneumoniae (25.0%). FB and BAL results contributed to clinical decisions in 65 of 91 (71.4%) patients. Endoscopically-diagnosed bronchitis (odds ratio [OR] 7.27, 95% confidence interval [CI] 2.4-21.99) and tracheomalacia (OR 5.79, 95% CI 1.20-27.85) were significantly associated with increased odds of medication adjustments following FB. CONCLUSION: In pediatric Aerodigestive patients undergoing combined airway evaluation for oropharyngeal dysphagia, FB and BAL are high-yield and clinically impactful procedures.

Association between biomarkers of tobacco smoke exposure and clinical efficacy of ivacaftor in the G551D observational trial (GOAL).

BACKGROUND: Acrolein, an aldehyde in smoke from tobacco products, inhibits CFTR function in vitro. Ivacaftor is an FDA-approved potentiator that improves mutant CFTR function. This human clinical study investigated the relationship between two urinary markers of tobacco smoke exposure - the acrolein metabolite 3-HPMA and the nicotine metabolite NNAL - and sweat chloride response to ivacaftor in the G551D Observational Trial (GOAL). METHODS: 3-HPMA (low: <50th centile; moderate: 50-75th centile; high: >75th centile) and NNAL (detectable/undetectable) in GOAL samples was quantified with LC-MS/MS. Self-report of tobacco smoke exposure (Y/N) served as a subjective measure. Change in sweat chloride from pre- to 6 months post-ivacaftor treatment (ΔSC) was the primary CFTR-dependent readout. RESULTS: The sample included 151 individuals, mean age 20.7 (SD 11.4) years, range 6-59 years. Smoke exposure prevalence was 15 % per self-reports but 27 % based on detectable NNAL. 3-HPMA was increased in those reporting tobacco smoke exposure (607 vs 354 ng/ml, p = 0.008), with a higher proportion of smoke-exposed in the high- vs low-acrolein group (31 % vs 9 %, p=0.040). Compared to low-acrolein counterparts, high-acrolein participants experienced less decrease in sweat chloride (-35.2 vs -48.2 mmol/L; p = 0.020) and had higher sweat chloride values (50.6 vs 37.6 mmol/L; p = 0.020) 6 months post-ivacaftor. The odds of ivacaftor-mediated potentiation to near normative CFTR function (defined as SC6mo <40 mmol/L) was more than twice as high in the low-acrolein cohort (OR: 2.51, p = 0.026). CONCLUSIONS: Increased urinary 3-HPMA, an acrolein metabolite of tobacco smoke, is associated with a diminished sweat chloride response to ivacaftor potentiation of CFTR function.

Tobacco smoke exposure limits the therapeutic benefit of tezacaftor/ivacaftor in pediatric patients with cystic fibrosis.

OBJECTIVES: Tobacco smoke exposure reduces CFTR functional expression in vitro and contributes to acquired CFTR dysfunction. We investigated whether it also inhibits the clinical benefit of CFTR modulators, focusing on tezacaftor/ivacaftor, approved in February 2018 for individuals with CF age ≥12 years. METHODS: A retrospective longitudinal analysis of encounter-based data from the CF Foundation Patient Registry (2016-2018) compared the slope of change in lung function (GLI FEV1% predicted) before and after tezacaftor/ivacaftor initiation in smoke-exposed vs unexposed age-eligible pediatric patients. Tobacco smoke exposure (Ever/Never) was determined from caregiver self-report. Statistical analyses used hierarchical linear mixed modeling and fixed effects regression modeling. RESULTS: The sample included 6,653 individuals with a total of 105,539 person-period observations. Tezacaftor/ivacaftor was prescribed to 19% (1,251) of individuals, mean age 17 years, mean baseline ppFEV1 83%, 28% smoke-exposed. Tezacaftor/ivacaftor users who were smoke-exposed had a lower baseline ppFEV1 and experienced a greater lung function decline. Over two years, the difference in ppFEV1 by smoke exposure among tezacaftor/ivacaftor users increased by 1.2% (7.6% to 8.8%, p<0.001). In both mixed effects and fixed effects regression models, tezacaftor/ivacaftor use was associated with improved ppFEV1 among unexposed individuals (1.2% and 1.7%, respectively; p<0.001 for both) but provided no benefit among smoke-exposed counterparts (0.3%, p = 0.5 and 0.6%, p = 0.07, respectively). CONCLUSION: Tobacco smoke exposure nullifies the therapeutic benefit of tezacaftor/ivacaftor among individuals with CF aged 12-20 years old. To maximize the therapeutic opportunity of CFTR modulators, every effort must be taken to eliminate smoke exposure in CF.

Cessation of smoke exposure improves pediatric CF outcomes: Longitudinal analysis of CF Foundation Patient Registry data.

BACKGROUND: Tobacco smoke exposure is a major risk factor for the health of children and adolescents with CF. In this study, we assess whether cessation of smoke exposure is associated with improved outcomes in this population. METHODS: We used annualized and encounter-based data from the U.S. CF Foundation Patient Registry (2006-2018) on all individuals born 1998-2010. The analytical sample included those who ever reported second-hand smoke exposure (daily or weekly), ever lived with a smoker, or ever reported smoking themselves. We used non-linear mixed models for pulmonary exacerbations and linear mixed models for ppFEV1 and BMI as a function of ceased exposure. RESULTS: The sample included 3,633 individuals contributing 19,629 person-years. Cessation of smoke exposure reduced the odds of a pulmonary exacerbation in 12 months by 17% (OR 0.83, p < 0.001) in the first year of cessation, with an additional 6% decrease (OR 0.94, p = 0.003) for each additional year of cessation. Cessation was associated with improvements in ppFEV1 and BMI: 0.7% ppFEV1 increase (p < 0.001) in the first year of cessation and 0.4% increase (p = 0.001) for each additional year of cessation; 1% increase in BMI percentile (p < 0.001) in the first year of cessation plus 0.4% increase (p = 0.009) for each additional year. Three years of cessation reduce the predicted probability of a pulmonary exacerbation in 12 months by 8% and improve ppFEV1 and BMI by 2%. CONCLUSION: Eliminating smoke exposure may reduce pulmonary exacerbations and improve respiratory and nutritional outcomes in children and adolescents with CF. Both smoking cessation and exposure prevention should be prioritized in pediatric CF care.

Tobacco smoke exposure and socioeconomic factors are independent predictors of pulmonary decline in pediatric cystic fibrosis.

BACKGROUND: Pulmonary decline in CF is heterogeneous, with socio-environmental factors contributing to this variability. Few studies have attempted to disentangle the effects of tobacco smoke exposure and socioeconomic factors on lung function deterioration in pediatric CF. The current study evaluates their contributions longitudinally across the entire U.S. CF care network population. METHODS: Data from the CF Foundation Patient Registry were obtained on all individuals who at the end of 2016 were 6-18 years old. Lung function measures (ppFEV1) for each person were calculated at each attained age. Multivariable analyses used mixed modeling to assess the impact of smoke exposure and socioeconomic factors on initial lung function and change over time. RESULTS: The sample included 10,895 individuals contributing 65,581 person years. At age 6, ppFEV1 of smoke-exposed children was 4.7% lower than among unexposed. The deficit persisted through age 18. In adjusted mixed models, smoke exposure and socioeconomic factors had independent, additive associations with lung function. Median ppFEV1 declined 2.4% with smoke exposure, 4.9% with lower paternal education, 0.3% with public insurance, and increased 0.2% with each $10,000 annual household income. The effect of smoke exposure on ppFEV1 was larger in disadvantaged children compared to privileged counterparts (3.2% vs 1.2%). CONCLUSIONS: Smoke exposure and socioeconomic factors are independent risk factors for decreased ppFEV1 in pediatric CF. Smoking cessation strategies should be emphasized at the time of CF diagnosis and reiterated during infancy and early childhood. Interventions may be prioritized in disadvantaged families, where the exposure has a disproportionately large effect.

Tobacco smoke exposure in pediatric cystic fibrosis: A qualitative study of clinician and caregiver perspectives on smoking cessation.

OBJECTIVE: Tobacco smoke exposure has negative impacts on the lung health of children with cystic fibrosis (CF), yet evidence-based strategies for smoking cessation have not been tested with or tailored to CF caregivers. This qualitative study identified barriers and facilitators of smoking cessation in this population and outlined potential interventional approaches. METHODS: We conducted semi-structured interviews with CF familial caregivers who were current or former smokers, and with members of the CF care team. We asked about experiences, practices, and prerequisites for a successful program. Interviews were recorded, transcribed verbatim, and coded by two investigators. Analysis used a thematic approach guided by the PRECEDE model, which identifies predisposing (intrapersonal), reinforcing (interpersonal), and enabling (structural) factors relevant to health behaviors and programs. RESULTS: Seventeen interviews were conducted-eight with familial caregivers and nine with CF team members. Whereas caregivers provided greater insight into internal difficulties and motivators to quit smoking, clinicians offered more extensive input on barriers and solutions related to the clinical environment. Based on study recommendations, a successful tobacco cessation program should include (a) family education about the harms of smoke exposure for children with CF; (b) screening for exposure, ideally with biochemical verification; (c) access to trained tobacco counselors; (d) affordable pharmacotherapy; and (e) outpatient follow-up of those undergoing tobacco treatment. CONCLUSION: This qualitative study revealed intrapersonal, interpersonal, and structural barriers to eliminating tobacco smoke exposure in children with CF, outlined opportunities to address these barriers, and made recommendations for a comprehensive tobacco cessation strategy.

Objective Versus Self-Reported Adherence to Airway Clearance Therapy in Cystic Fibrosis.

BACKGROUND: Historically, studies of adherence to airway clearance therapy in cystic fibrosis (CF) have relied on self-reporting. We compared self-reported airway clearance therapy adherence to actual usage data from home high-frequency chest wall compressions (HFCWC) vests and identified factors associated with overestimation of adherence in self-reports. METHODS: Pediatric patients who perform airway clearance therapy with a HFCWC vest were eligible to participate. Objective adherence data were obtained from the HFCWC device, which records cumulative utilization time. Two readings at least 5 weeks apart were collected. Objective adherence was recorded as a ratio of mean-to-prescribed daily use (%). Self-reported adherence data were collected with a caregiver survey at enrollment. Adherence rates were categorized as low (< 35% of prescribed), moderate (36-79% of prescribed), and high (≥ 80% of prescribed). An overestimation was present when self-reported adherence was at least one category higher than objective adherence. RESULTS: In the final sample (N = 110), mean adherence by usage data was 61%. Only 35% of subjects (n = 38) were highly adherent, and 28% (n = 31) were low adherent. In contrast, 65% of subjects (n = 72) reported high adherence and only 8% (n = 9) reported low adherence (P < .001). Nearly half of self-reports (46%) overestimated adherence. In a multiple regression analysis, overestimation was associated with multiple airway clearance therapy locations (odds ratio 7.13, 95% CI 1.16-43.72, P = .034) and prescribed daily use ≥ 60 min (odds ratio 3.85, 95% CI 1.08-13.76, P < .038). Among subjects with prescribed daily airway clearance therapy ≥ 60 min, the odds of overestimating adherence increased 3-fold (odds ratio 3.04, 95% CI 1.17-7.87, P = .02) in a lower-income (< $50,000/y) environment. CONCLUSIONS: Self-reports overestimated actual adherence to airway clearance therapy, and the overestimation increased with treatment occurring in multiple households and prescribed therapy duration. Among participants with prescribed airway clearance therapy ≥ 60 min, overestimation increased with lower income. Objective measures of adherence are needed, particularly for lower-income children and those receiving treatments in multiple locations.

CFTR dysfunction increases endoglin and TGF-ß signaling in airway epithelia.

Endoglin (ENG) regulates signaling by transforming growth factor-ß (TGF-ß), a genetic modifier of cystic fibrosis (CF) lung disease severity. We hypothesized that ENG mediates TGF-ß pathobiology in CF airway epithelia. Comparing CF and non-CF human lungs, we measured ENG by qPCR, immunoblotting and ELISA. In human bronchial epithelial cell lines (16HBE), we used CFTR siRNA knockdown and functional inhibition (CFTRINH -172) to connect loss of CFTR to ENG synthesis. Plasmid overexpression of ENG assessed the direct effect of ENG on TGF-ß transcription and signal amplification in 16HBE cells. We found ENG protein to be increased more than fivefold both in human CF bronchoalveolar fluid (BALF) and human CF lung homogenates. ENG transcripts were increased threefold in CF, with a twofold increase in TGF-ß signaling. CFTR knockdown in 16HBE cells tripled ENG transcription and doubled protein levels with corresponding increases in TGF-ß signaling. Plasmid overexpression of ENG alone nearly doubled TGF-ß1 mRNA and increased TGF-ß signaling in 16HBE cells. These experiments identify that loss of CFTR function increases ENG expression in CF epithelia and amplifies TGF-ß signaling. Targeting ENG may offer a novel therapeutic opportunity to address TGF-ß associated pathobiology in CF.

An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5 years (KLIMB).

BACKGROUND: KIWI (NCT01705145) was a 24-week, single-arm, pharmacokinetics, safety, and efficacy study of ivacaftor in children aged 2 to 5 years with cystic fibrosis (CF) and a CFTR gating mutation. Here, we report the results of KLIMB (NCT01946412), an 84-week, open-label extension of KIWI. METHODS: Children received age- and weight-based ivacaftor dosages for 84 weeks. The primary outcome was safety. Other outcomes included sweat chloride, growth parameters, and measures of pancreatic function. RESULTS: All 33 children who completed KIWI enrolled in KLIMB; 28 completed 84 weeks of treatment. Most adverse events were consistent with those reported during KIWI. Ten (30%) children had transaminase elevations >3 × upper limit of normal (ULN), leading to 1 discontinuation in a child with alanine aminotransferase >8 × ULN. Improvements in sweat chloride, weight, and body mass index z scores and fecal elastase-1 observed during KIWI were maintained during KLIMB; there was no further improvement in these parameters. CONCLUSIONS: Ivacaftor was generally well tolerated for up to 108 weeks in children aged 2 to 5 years with CF and a gating mutation, with safety consistent with the KIWI study. Improvements in sweat chloride and growth parameters during the initial 24 weeks of treatment were maintained for up to an additional 84 weeks of treatment. Prevalence of raised transaminases remained stable and did not increase with duration of exposure during the open-label extension.

Area Deprivation as a Risk Factor for Methicillin-resistant Staphylococcus aureus Infection in Pediatric Cystic Fibrosis.

BACKGROUND: In US cystic fibrosis (CF) patients, methicillin-resistant Staphylococcus aureus (MRSA) rates have tripled in the past 2 decades. Known clinical risk factors include exposure to a healthcare setting, Pseudomonas aeruginosa and CF-related diabetes. Area-level socio-environmental exposures have not been evaluated. We explored the association of area-level deprivation with MRSA prevalence in a pediatric CF Center in the Southeastern United States. METHODS: Patients' residential addresses were geocoded and linked to a composite Area Deprivation Index and Rural-Urban Commuting Area scores. The association of MRSA with Area Deprivation Index and Rural-Urban Commuting Area scores was evaluated using logistic regression with robust standard errors adjusted for sociodemographic covariates (age, sex, race, mother's and father's education and household income), clinical risk factors (P. aeruginosa, CF-related diabetes, hospitalizations and number of clinic visits) and clustering. RESULTS: The study included all pediatric patients (N = 231; mean age 12) at a single CF Center. MRSA was present in 44% of subjects. Higher area-level deprivation was correlated with rural residence, lack of parental college education and lower household income (P < 0.001 for each). In a multiple regression model fully adjusted for patient-level sociodemographic covariates, clinical risk factors and clustering, neighborhood deprivation was associated with more than 2-fold increase in the odds of having MRSA [OR 2.26 (1.14-4.45), P < 0.05]. CONCLUSIONS: Neighborhood deprivation is a risk factor for MRSA in pediatric CF, doubling the odds of infection. Community-level socioeconomic risk factors should be considered when developing prevention strategies and treatment plans for MRSA infection in pediatric patients with CF.

Physiologic, bronchoscopic, and bronchoalveolar lavage fluid findings in young children with recurrent wheeze and cough.

Assessing airway disease in young children with wheeze and/or cough is challenging. We conducted a prospective, descriptive study of lung function in children <3 years old with recurrent wheeze and/or cough, who had failed empiric antiasthma and/or antireflux therapy and subsequently underwent flexible bronchoscopy. Our goals were to describe radiographic, anatomical, microbiological, and physiological findings in these children, and generate hypotheses about their respiratory physiology. Plethysmography and raised-volume rapid thoracoabdominal compression (RVRTC) techniques were performed prior to bronchoscopy. Mean Z-scores (n = 19) were -1.34 for forced expiratory volume at 0.5 sec (FEV(0.5)), -2.28 for forced expiratory flows at 75% of forced vital capacity (FVC) (FEF(75)), -2.25 for forced expiratory flows between 25-75% of FVC (FEF(25-75)), 2.53 for functional residual capacity (FRC), and 2.23 for residual volume divided by total lung capacity (RV/TLC). Younger, shorter children had markedly depressed FEF(75) and FEF(25-75) Z-scores (P = 0.002 and P = <0.001, respectively). As expected, lower airway anatomical abnormalities, infection, and inflammation were common. Elevated FRC was associated with anatomical lower airway abnormalities (P = 0.03). FVC was higher in subjects with neutrophilic inflammation (P = 0.03). There was no association between other physiologic variables and bronchoscopic/bronchoalveolar lavage fluid findings. Half of those with elevated RV/TLC ratios (Z-score >2) had no evidence of chest radiograph hyperinflation. We conclude that in this population, plethysmography and RVRTC techniques are useful in identifying severity of hyperinflation and airflow obstruction, and we hypothesize that younger children may have relatively small airways caliber, significantly limiting airflow, and thus impairing secretion clearance and predisposing to lower airway infection.