Characterization of Transient Receptor Potential Vanilloid-1 (TRPV1) Variant Activation by Coal Fly Ash Particles and Associations with Altered Transient Receptor Potential Ankyrin-1 (TRPA1) Expression and Asthma.

Transient receptor potential (TRP) channels are activated by environmental particulate materials. We hypothesized that polymorphic variants of transient receptor potential vanilloid-1 (TRPV1) would be uniquely responsive to insoluble coal fly ash compared with the prototypical soluble agonist capsaicin. Furthermore, these changes would manifest as differences in lung cell responses to these agonists and perhaps correlate with changes in asthma symptom control. The TRPV1-I315M and -T469I variants were more responsive to capsaicin and coal fly ash. The I585V variant was less responsive to coal fly ash particles due to reduced translation of protein and an apparent role for Ile-585 in activation by particles. In HEK-293 cells, I585V had an inhibitory effect on wild-type TRPV1 expression, activation, and internalization/agonist-induced desensitization. In normal human bronchial epithelial cells, IL-8 secretion in response to coal fly ash treatment was reduced for cells heterozygous for TRPV1-I585V. Finally, both the I315M and I585V variants were associated with worse asthma symptom control with the effects of I315M manifesting in mild asthma and those of the I585V variant manifesting in severe, steroid-insensitive individuals. This effect may be due in part to increased transient receptor potential ankyrin-1 (TRPA1) expression by lung epithelial cells expressing the TRPV1-I585V variant. These findings suggest that specific molecular interactions control TRPV1 activation by particles, differential activation, and desensitization of TRPV1 by particles and/or other agonists, and cellular changes in the expression of TRPA1 as a result of I585V expression could contribute to variations in asthma symptom control.

Activation of Transient Receptor Potential Ankyrin-1 by Insoluble Particulate Material and Association with Asthma.

Inhaled irritants activate transient receptor potential ankyrin-1 (TRPA1), resulting in cough, bronchoconstriction, and inflammation/edema. TRPA1 is also implicated in the pathogenesis of asthma. Our hypothesis was that particulate materials activate TRPA1 via a mechanism distinct from chemical agonists and that, in a cohort of children with asthma living in a location prone to high levels of air pollution, expression of uniquely sensitive forms of TRPA1 may correlate with reduced asthma control. Variant forms of TRPA1 were constructed by mutating residues in known functional elements and corresponding to single-nucleotide polymorphisms in functional domains. TRPA1 activity was studied in transfected HEK-293 cells using allyl-isothiocynate, a model soluble electrophilic agonist; 3,5-ditert butylphenol, a soluble nonelectrophilic agonist and a component of diesel exhaust particles; and insoluble coal fly ash (CFA) particles. The N-terminal variants R3C and R58T exhibited greater, but not additive, activity with all three agonists. The ankyrin repeat domain-4 single nucleotide polymorphisms E179K and K186N exhibited decreased response to CFA. The predicted N-linked glycosylation site residues N747A and N753A exhibited decreased responses to CFA, which were not attributable to differences in cellular localization. The pore-loop residue R919Q was comparable to wild-type, whereas N954T was inactive to soluble agonists but not CFA. These data identify roles for ankyrin domain-4, cell surface N-linked glycans, and selected pore-loop domain residues in the activation of TRPA1 by insoluble particles. Furthermore, the R3C and R58T polymorphisms correlated with reduced asthma control for some children, which suggest that TRPA1 activity may modulate asthma, particularly among individuals living in locations prone to high levels of air pollution.

Fluticasone propionate pharmacogenetics: CYP3A4*22 polymorphism and pediatric asthma control.

OBJECTIVE: To determine the relationship between allelic variations in genes involved in fluticasone propionate (FP) metabolism and asthma control among children with asthma managed with inhaled FP. STUDY DESIGN: The relationship between variability in asthma control scores and genetic variation in drug metabolism was assessed by genotyping 9 single nucleotide polymorphisms in the CYP3A4, CYP3A5, and CYP3A7 genes. Genotype information was compared with asthma control scores (0=well controlled to 15=poorly controlled), determined using a questionnaire modified from the National Heart Lung and Blood Institute's Expert Panel 3 guidelines. RESULTS: Our study cohort comprised 734 children with asthma (mean age, 8.8±4.3 years) and was predominantly male (61%) and non-Hispanic white (53%). More than one-half of the children (56%; n=413) were receiving an inhaled glucocorticoid daily, with FP the most frequently prescribed agent (65%). Among the children receiving daily FP, single nucleotide polymorphisms in CYP3A5 and CYP3A7 were not associated with asthma control scores. In contrast, asthma control scores were significantly improved in the 20 children (7%) with the CYP3A4*22 allele (median, 3; range, 0-6) compared with the 201 children without the CYP3A4*22 allele (median, 4; range, 0-15; P=.02). The presence of CYP3A4*22 was associated with improved asthma control scores by 2.1 points (95% CI, 0.5-3.8). CONCLUSION: The presence of CYP3A4*22, which is associated with decreased hepatic CYP3A4 expression and activity, was accompanied by improved asthma control in the FP-treated children. Decreased CYP3A4 activity may improve asthma control with inhaled FP.

Late presentation of double aortic arch in school-age children presumed to have asthma: the benefits of spirometry and examination of the flow-volume curve.

Children with double aortic arch most often present in infancy. This report presents 3 patients in whom the diagnosis of double aortic arch was not revealed until later in childhood. They were all given a misdiagnosis of asthma, but abnormalities detected on the flow-volume curve led to the true diagnosis.

Contextual Factors Influencing Implementation of Evidence-Based Care for Children Hospitalized With Asthma.

BACKGROUND AND OBJECTIVES: The translation of research findings into routine care remains slow and challenging. We previously reported successful implementation of an asthma evidence-based care process model (EB-CPM) at 8 (1 tertiary care and 7 community) hospitals, leading to a high health care provider (HCP) adherence with the EB-CPM and improved outcomes. In this study, we explore contextual factors perceived by HCPs to facilitate successful EB-CPM implementation. METHODS: Structured and open-ended questions were used to survey HCPs (n = 260) including physicians, nurses, and respiratory therapists, about contextual factors perceived to facilitate EB-CPM implementation. Quantitative analysis was used to identify significant factors (correlation coefficient ≥0.5; P ≤ .05) and qualitative analysis to assess additional facilitators. RESULTS: Factors perceived by HCPs to facilitate EB-CPM implementation were related to (1) inner setting (leadership support, adequate resources, communication and/or collaboration, culture, and previous experience with guideline implementation), (2) intervention characteristics (relevant and applicable to the HCP's practice), (3) individuals (HCPs) targeted (agreement with the EB-CPM and knowledge of supporting evidence), and (4) implementation process (participation of HCPs in implementation activities, teamwork, implementation team with a mix of expertise and professional's input, and data feedback). Additional facilitators included (1) having appropriate preparation and (2) providing education and training. CONCLUSIONS: Multiple factors were associated with successful EB-CPM implementation and may be used by others as a guide to facilitate implementation and dissemination of evidence-based interventions for pediatric asthma and other chronic diseases in the hospital setting.

Ambulatory Management of Childhood Asthma Using a Novel Self-management Application.

BACKGROUND AND OBJECTIVES: Pediatric ambulatory asthma control is suboptimal, reducing quality of life (QoL) and causing emergency department (ED) and hospital admissions. We assessed the impact of the electronic-AsthmaTracker (e-AT), a self-monitoring application for children with asthma. METHODS: Prospective cohort study with matched controls. Participants were enrolled January 2014 to December 2015 in 11 pediatric clinics for weekly e-AT use for 1 year. Analyses included: (1) longitudinal changes for the child (QoL, asthma control, and interrupted and missed school days) and parents (interrupted and missed work days and satisfaction), (2) comparing ED and hospital admissions and oral corticosteroid (OCS) use pre- and postintervention, and (3) comparing ED and hospital admissions and OCS use between e-AT users and matched controls. RESULTS: A total of 327 children and parents enrolled; e-AT adherence at 12 months was 65%. Compared with baseline, participants had significantly (P < .001) increased QoL, asthma control, and reduced interrupted and missed school and work days at all assessment times. Compared with 1 year preintervention, they had reduced ED and hospital admissions (rate ratio [RR]: 0.68; 95% confidence interval [CI]: 0.49-0.95) and OCS use (RR: 0.74; 95% CI: 0.61-0.91). Parent satisfaction remained high. Compared with matched controls, participants had reduced ED and hospital admissions (RR: 0.41; 95% CI: 0.22-0.75) and OCS use (RR: 0.65; 95% CI: 0.46-0.93). CONCLUSIONS: e-AT use led to high and sustained participation in self-monitoring and improved asthma outcomes. Dissemination of this care model has potential to broadly improve pediatric ambulatory asthma care.

Improving Pediatric Asthma Care and Outcomes Across Multiple Hospitals.

BACKGROUND AND OBJECTIVES: Gaps exist in inpatient asthma care. Our aims were to assess the impact of an evidence-based care process model (EB-CPM) 5 years after implementation at Primary Children's Hospital (PCH), a tertiary care facility, and after its dissemination to 7 community hospitals. METHODS: Participants included asthmatics 2 to 17 years admitted at 8 hospitals between 2003 and 2013. The EB-CPM was implemented at PCH between January 2008 and March 2009, then disseminated to 7 community hospitals between January and June 2011. We measured compliance using a composite score (CS) for 8 quality measures. Outcomes were compared between preimplementation and postimplementation periods. Confounding was addressed through multivariable regression analyses. RESULTS: At PCH, the CS increased and remained at >90% for 5 years after implementation. We observed sustained reductions in asthma readmissions (P = .026) and length of stay (P < .001), a trend toward reduced costs (P = .094), and no change in hospital resource use, ICU transfers, or deaths. The CS also increased at the 7 community hospitals, reaching 80% to 90% and persisting >2 years after dissemination, with a slight but not significant readmission reduction (P = .119), a significant reduction in length of stay (P < .001) and cost (P = .053), a slight increase in hospital resource use (P = .032), and no change in ICU transfers or deaths. CONCLUSIONS: Our intervention resulted in sustained, long-term improvement in asthma care and outcomes at the tertiary care hospital and successful dissemination to community hospitals.

Longitudinal validation of a tool for asthma self-monitoring.

OBJECTIVES: To establish longitudinal validation of a new tool, the Asthma Symptom Tracker (AST). AST combines weekly use of the Asthma Control Test with a color-coded graph for visual trending. METHODS: Prospective cohort study of children age 2 to 18 years admitted for asthma. Parents or children (n = 210) completed baseline AST assessments during hospitalization, then over 6 months after discharge. Concurrent with the first 5 AST assessments, the Asthma Control Questionnaire (ACQ) was administered for comparison. RESULTS: Test-retest reliability (intraclass correlation) was moderate, with a small longitudinal variation of AST measurements within subjects during follow-ups. Internal consistency was strong at baseline (Cronbach's α 0.70) and during follow-ups (Cronbach's α 0.82-0.90). Criterion validity demonstrated a significant correlation between AST and ACQ scores at baseline (r = -0.80, P < .01) and during follow-ups (r = -0.64, -0.72, -0.63, and -0.69). The AST was responsive to change over time; an increased ACQ score by 1 point was associated with a decreased AST score by 2.65 points (P < .01) at baseline and 3.11 points (P < .01) during follow-ups. Discriminant validity demonstrated a strong association between decreased AST scores and increased oral corticosteroid use (odds ratio 1.13, 95% confidence interval, 1.10-1.16, P < .01) and increased unscheduled acute asthma visits (odds ratio 1.23, 95% confidence interval, 1.18-1.28, P < .01). CONCLUSIONS: The AST is reliable, valid, and responsive to change over time, and can facilitate ongoing monitoring of asthma control and proactive medical decision-making in children.

Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1.

BACKGROUND: Mutations in the gene encoding thyroid transcription factor, NKX2-1, result in neurologic abnormalities, hypothyroidism, and neonatal respiratory distress syndrome (RDS) that together are known as the brain-thyroid-lung syndrome. To characterize the spectrum of associated pulmonary phenotypes, we identified individuals with mutations in NKX2-1 whose primary manifestation was respiratory disease. METHODS: Retrospective and prospective approaches identified infants and children with unexplained diffuse lung disease for NKX2-1 sequencing. Histopathologic results and electron micrographs were assessed, and immunohistochemical analysis for surfactant-associated proteins was performed in a subset of 10 children for whom lung tissue was available. RESULTS: We identified 16 individuals with heterozygous missense, nonsense, and frameshift mutations and five individuals with heterozygous, whole-gene deletions of NKX2-1. Neonatal RDS was the presenting pulmonary phenotype in 16 individuals (76%), interstitial lung disease in four (19%), and pulmonary fibrosis in one adult family member. Altogether, 12 individuals (57%) had the full triad of neurologic, thyroid, and respiratory manifestations, but five (24%) had only pulmonary symptoms at the time of presentation. Recurrent respiratory infections were a prominent feature in nine subjects. Lung histopathology demonstrated evidence of disrupted surfactant homeostasis in the majority of cases, and at least five cases had evidence of disrupted lung growth. CONCLUSIONS: Patients with mutations in NKX2-1 may present with pulmonary manifestations in the newborn period or during childhood when thyroid or neurologic abnormalities are not apparent. Surfactant dysfunction and, in more severe cases, disrupted lung development are likely mechanisms for the respiratory disease.

The Joint Commission Children's Asthma Care quality measures and asthma readmissions.

BACKGROUND AND OBJECTIVES: The Joint Commission introduced 3 Children's Asthma Care (CAC 1-3) measures to improve the quality of pediatric inpatient asthma care. Validity of the commission's measures has not yet been demonstrated. The objectives of this quality improvement study were to examine changes in provider compliance with CAC 1-3 and associated asthma hospitalization outcomes after full implementation of an asthma care process model (CPM). METHODS: The study included children aged 2 to 17 years who were admitted to a tertiary care children's hospital for acute asthma between January 1, 2005, and December 31, 2010. The study was divided into 3 periods: preimplementation (January 1, 2005-December 31, 2007), implementation (January 1, 2008-March 31, 2009), and postimplementation (April 1, 2009-December 31, 2010) periods. Changes in provider compliance with CAC 1-3 and associated changes in hospitalization outcomes (length of stay, costs, PICU transfer, deaths, and asthma readmissions within 6 months) were measured. Logistic regression was used to control for age, gender, race, insurance type, and time. RESULTS: A total of 1865 children were included. Compliance with quality measures before and after the CPM implementation was as follows: 99% versus 100%, CAC-1; 100% versus 100%, CAC-2; and 0% versus 87%, CAC-3 (P < .01). Increased compliance with CAC-3 was associated with a sustained decrease in readmissions from an average of 17% to 12% (P = .01) postimplementation. No change in other outcomes was observed. CONCLUSIONS: Implementation of the asthma CPM was associated with improved compliance with CAC-3 and with a delayed, yet significant and sustained decrease in hospital asthma readmission rates, validating CAC-3 as a quality measure. Due to high baseline compliance, CAC-1 and CAC-2 are of questionable value as quality measures.

Pulmonary nodules in a newborn with ATP-binding cassette transporter A3 (ABCA3) mutations.

Mutations in the gene for adenosine triphosphate-binding cassette transporter A3 (ABCA3) have been reported in infants and children with fatal surfactant deficiency and interstitial lung disease. Previously reported radiographic lung findings include ground-glass opacification, streaky infiltrates, and interstitial septal thickening. We report here the unusual case of a newborn who rapidly developed large rounded masses in the lung soon after birth that then resolved spontaneously by 3 months of age. She was found to be a compound heterozygote for both a known and a novel mutation in the ABCA3 gene. This report underscores the diverse clinical presentation of this condition.

Infarction of an extralobar pulmonary sequestration in a young child: diagnosis and excision by video-assisted thoracoscopy.

A 4-year-old male presented with abdominal pain. A computed tomography scan of the abdomen was negative, but a pleural effusion and mass was noted in the lower left thorax. Video-assisted thoracoscopic surgery revealed the mass to be a rare case of extralobar pulmonary sequestration that had undergone infarction.

Inflammatory myofibroblastic tumor in the airway of a child.

This report describes a 9-year-old boy who was found to have an inflammatory myofibroblastic tumor completely occluding the right mainstem bronchus. Initial subtotal resection at an outside facility resulted in prompt recurrence of the tumor. At our institution, total resection with bronchotomy and pericardial patch repair resulted in an excellent outcome with no evidence of recurrence at 1 year post-resection.