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1.  Wheezing in Children with Sickle Cell Disease 
Current opinion in pediatrics  2014;26(1):9-18.
Purpose of review
The purpose of this article is to provide a comprehensive review of wheezing in sickle cell disease (SCD) including epidemiology, pathophysiology, associations between wheezing and SCD morbidity and finally the clinical approach to evaluation and management of individuals with SCD who wheeze.
Recent findings
Wheezing is common in SCD and in some individuals represents an intrinsic component of SCD related lung disease rather than asthma. Emerging data suggest that regardless of the etiology, individuals with SCD and with recurrent wheezing are at increased risk for subsequent morbidity and premature mortality. We believe Individuals that acutely wheeze and have respiratory symptoms should be managed with a beta agonist and short term treatment of oral steroids, typically less than 3 days to attenuate rebound vaso-occlusive disease. For those that wheeze and have a history or examination associated with atopy, we consider asthma treatment and monitoring per NHLBI asthma guidelines.
Wheezing in SCD should be treated aggressively in both the acute setting and with controller medications. Prospective SCD-specific clinical trials will be necessary to address whether anti-inflammatory asthma therapies (leukotriene antagonists, inhaled corticosteroids) can safely mitigate the sequelae of wheezing in SCD.
PMCID: PMC4167421  PMID: 24370489
Sickle cell; wheezing; asthma
The Journal of pediatrics  2013;163(5):10.1016/j.jpeds.2013.05.008.
To describe pediatric primary care providers’ attitudes toward retail clinics and their experiences of retail clinics use by their patients.
Study design
A 51-item, self-administered survey from four pediatric practice-based research networks from the Midwestern United States, which gauged providers’ attitudes toward and perceptions of their patients’ interactions with retail clinics, and changes to office practice to better compete.
A total of 226 providers participated (50% response). Providers believed that retail clinics were a business threat (80%) and disrupted continuity of chronic disease management (54%). Few (20%) agreed that retail clinics provided care within recommended clinical guidelines. Most (91%) reported that they provided additional care after a retail clinic visit (median 1–2 times per week) and 37% felt this resulted from suboptimal care at retail clinics “most or all of the time.” Few (15%) reported being notified by the retail clinic within 24 hours of a patient visit. Those reporting prompt communication were less likely to report suboptimal retail clinic care (OR 0.20, 95%CI 0.10 to 0.42) or disruption in continuity of care (OR 0.32, 95%CI 0.15 to 0.71). Thirty-six percent reported changes to office practice to compete with retail clinics (most commonly adjusting or extending office hours) and change was more likely if retail clinics were perceived as a threat (OR 3.70, 95%CI 1.56 to 8.76); 30% planned to make changes in the near future.
Based on the perceived business threat, pediatric providers are making changes to their practice to compete with retail clinics. Improved communication between the clinic and providers may improve collaboration.
PMCID: PMC3812257  PMID: 23810720
Retail clinic; practice-based research network
JAMA pediatrics  2013;167(9):845-850.
To describe the rationale and experiences of families with a pediatrician who also use retail clinics (RCs) for pediatric care.
Cross-sectional study
19 pediatric practices in a Midwestern practice-based research network
Self-administered paper survey
Parents attending the pediatrician’s office
Outcome Measures
Parents’ experience with RC care for their children
1484 parents (92% response) completed the survey. Parents (23%) who used RC for pediatric care were more likely to report RC care for themselves (OR 7.79, 95% CI, 5.13 to 11.84), have > 1 child (OR 2.16, 95%CI 1.55 to 3.02), and be older (OR 1.05, 95%CI 1.03 to 1.08). Seventy-four percent first considered going to the pediatrician but reported they chose the RC because the RC had more convenient hours (37%), no office appointment was available (25%), they did not want to bother the pediatrician after hours (15%), or because the problem was not serious enough (13%). Forty-six percent of RC visits occurred between 8am and 4pm on weekdays or 8am and noon on the weekend. Most commonly, visits were reportedly for acute upper respiratory illnesses (34% sore throat, 26% ear infection, 19% colds or flu) and for physicals (13%). While 7% recalled the RC indicating they would inform the pediatrician of the visit, only 42% informed the pediatrician themselves.
Parents with established relationships with a pediatrician most commonly took their children to RCs for care because access was convenient. Almost half the visits occurred when the pediatricians’ offices were likely open.
PMCID: PMC4019395  PMID: 23877236
Retail clinic; practice-based research network
4.  Recurrent, severe wheezing is associated with morbidity and mortality in adults with sickle cell disease 
American journal of hematology  2011;86(9):756-761.
Prior studies of asthma in children with sickle cell disease (SCD) were based on reports of a doctor-diagnosis of asthma with limited description of asthma features. Doctor-diagnoses of asthma may represent asthma or wheezing unrelated to asthma. Objectives of this study were to determine if asthma characteristics are present in adults with a doctor-diagnosis of asthma and/or wheezing, and to examine the relationship between doctor-diagnosis of asthma, wheezing and SCD morbidity. This was an observational cohort study of 114 adults with SCD who completed respiratory symptom questionnaires and had serum IgE measurements. A subset of 79 participants completed pulmonary function testing. Survival analysis was based on a mean prospective follow-up of 28 months and data were censored at the time of death or loss to follow-up. Adults reporting a doctor-diagnosis of asthma (N = 34) were more likely to have features of asthma including wheeze, eczema, family history of asthma, and an elevated IgE level (all P < 0.05). However, there was no difference in pain or ACS rate, lung function, or risk of death between adults with and without a doctor-diagnosis of asthma. In contrast, adults who reported recurrent, severe episodes of wheezing (N = 34), regardless of asthma, had twice the rates of pain and ACS, decreased lung function and increased risk of death compared with adults without recurrent, severe wheezing. Asthma features were not associated with recurrent, severe wheezing. Our data suggest that wheezing in SCD may occur independently of asthma and is a marker of disease severity.
PMCID: PMC4103016  PMID: 21809369
5.  Prenatal Tobacco Smoke Exposure Is Associated with Childhood DNA CpG Methylation 
PLoS ONE  2014;9(6):e99716.
Smoking while pregnant is associated with a myriad of negative health outcomes in the child. Some of the detrimental effects may be due to epigenetic modifications, although few studies have investigated this hypothesis in detail.
To characterize site-specific epigenetic modifications conferred by prenatal smoking exposure within asthmatic children.
Using Illumina HumanMethylation27 microarrays, we estimated the degree of methylation at 27,578 distinct DNA sequences located primarily in gene promoters using whole blood DNA samples from the Childhood Asthma Management Program (CAMP) subset of Asthma BRIDGE childhood asthmatics (n = 527) ages 5–12 with prenatal smoking exposure data available. Using beta-regression, we screened loci for differential methylation related to prenatal smoke exposure, adjusting for gender, age and clinical site, and accounting for multiple comparisons by FDR.
Of 27,578 loci evaluated, 22,131 (80%) passed quality control assessment and were analyzed. Sixty-five children (12%) had a history of prenatal smoke exposure. At an FDR of 0.05, we identified 19 CpG loci significantly associated with prenatal smoke, of which two replicated in two independent populations. Exposure was associated with a 2% increase in mean CpG methylation in FRMD4A (p = 0.01) and Cllorf52 (p = 0.001) compared to no exposure. Four additional genes, XPNPEP1, PPEF2, SMPD3 and CRYGN, were nominally associated in at least one replication group.
These data suggest that prenatal exposure to tobacco smoke is associated with reproducible epigenetic changes that persist well into childhood. However, the biological significance of these altered loci remains unknown.
PMCID: PMC4070909  PMID: 24964093
6.  Classification of childhood asthma phenotypes and long-term clinical responses to inhaled anti-inflammatory medications 
Although recent studies have identified the presence of phenotypic clusters in asthmatic patients, the clinical significance and temporal stability of these clusters have not been explored.
Our aim was to examine the clinical relevance and temporal stability of phenotypic clusters in children with asthma.
We applied spectral clustering to clinical data from 1041 children with asthma participating in the Childhood Asthma Management Program. Posttreatment randomization follow-up data collected over 48 months were used to determine the effect of these clusters on pulmonary function and treatment response to inhaled anti-inflammatory medication.
We found 5 reproducible patient clusters that could be differentiated on the basis of 3 groups of features: atopic burden, degree of airway obstruction, and history of exacerbation. Cluster grouping predicted long-term asthma control, as measured by the need for oral prednisone (P < .0001) or additional controller medications (P = .001), as well as longitudinal differences in pulmonary function (P < .0001). We also found that the 2 clusters with the highest rates of exacerbation had different responses to inhaled corticosteroids when compared with the other clusters. One cluster demonstrated a positive response to both budesonide (P = .02) and nedocromil (P = .01) compared with placebo, whereas the other cluster demonstrated minimal responses to both budesonide (P = .12) and nedocromil (P = .56) compared with placebo.
Phenotypic clustering can be used to identify longitudinally consistent and clinically relevant patient subgroups, with implications for targeted therapeutic strategies and clinical trials design.
PMCID: PMC4047642  PMID: 24892144
Childhood asthma; asthma phenotypes; inhaled corticosteroids; cluster analysis; asthma classification; longitudinal study
7.  Do oral corticosteroids reduce the severity of acute lower respiratory tract illnesses in preschool children with recurrent wheezing? 
The Journal of allergy and clinical immunology  2013;131(6):10.1016/j.jaci.2013.01.034.
Oral corticosteroids (OCSs) are recommended for severe wheezing episodes in children. However, limited evidence supports this intervention in preschool children with outpatient wheezing illnesses.
We sought to investigate whether OCSs reduce symptom scores during acute lower respiratory tract illnesses (LRTIs) in preschool children with recurrent wheeze
We performed post hoc and replication analyses in 2 outpatient cohorts of children aged 1 to 5 years with episodic wheezing participating in clinical trials. We compared symptom scores during LRTIs that were or were not treated with OCSs, adjusting for differences in disease and episode severity covariates.We stratified episodes by severity by using a propensity model. The primary outcome was the area under the curve (AUC) of total symptom scores among the more severe episodes.
Two hundred fifteen participants from the Acute Intervention Management Strategies trial experienced 798 acute LRTIs, 112 of which were defined as severe based on propensity scores. The AUCs of total symptom scores did not differ between the episodes that were (n = 70) and were not (n = 42) treated with OCSs (P = .46) nor was there an OCS treatment effect on individual symptom scores. Similar analyses of the Maintenance Versus Intermittent Inhaled Corticosteroids in Wheezing Toddlers trial, involving 278 participants with 133 severe LRTIs, confirmed the above findings (P =.46 for AUC of total symptoms score comparison).
In 2 separate cohorts of preschool children with episodic wheezing, OCS treatment during clinically significant LRTIs did not reduce symptom severity during acute LRTIs, despite asthma controller medication use during most episodes. These findings need to be confirmed in a prospective randomized controlled trial.
PMCID: PMC3810170  PMID: 23498594
Oral corticosteroids; episodic wheezing; preschool children
To reduce symptoms and emergency department (ED) visits, the National Asthma Education and Prevention Program (NAEPP) guidelines recommend early treatment of acute asthma symptoms with albuterol and oral corticosteroids. Yet, ED visits for asthma are frequent and often occur several days after onset of increased symptoms, particularly for children from low-income urban neighborhoods.
To describe home use of albuterol and identify factors associated with appropriate albuterol use.
114 caregivers in the intervention group of a randomized trial to reduce emergent care for low-income, urban children completed a structured telephone interview with an asthma nurse to assess home management of their child’s acute asthma symptoms. Albuterol use as reported by caregivers was categorized as appropriate or inappropriate based on NAEPP recommendations.
Albuterol use for worsening asthma symptoms was categorized as appropriate for only 68% of caregivers and was more likely if the children had an ED visit or hospitalization for asthma in the prior year. The remaining 32% of caregivers used albuterol inappropriately (over or under treatment). Appropriate albuterol use was not associated with caregiver report of having an Asthma Action Plan (AAP) or a recent primary care provider visit to discuss asthma maintenance care.
Caregivers reported they would use albuterol to treat their child’s worsening asthma symptoms, but many described inappropriate use. Detailed assessment of proper albuterol use at home may provide insight into how healthcare providers can better educate and support parents in their management of acute exacerbations and more effective use of AAPs.
PMCID: PMC3809955  PMID: 19558010
Childhood asthma; asthma action plan
9.  Detection and Home Management of Worsening Asthma Symptoms 
Asthma guidelines recommend early home treatment of exacerbations. However, home treatment is often suboptimal and delayed.
To describe antecedent symptoms and signs of asthma exacerbations noticed by parents, and learn when and how parents intensify asthma treatment.
Parents of children 2-12 years old with asthma exacerbations requiring urgent care in the past 12 months completed telephone questionnaires. For some questions, multiple responses were possible and percentages for the frequency of responses may sum to more than 100%.
One hundred and one parents were enrolled and interviewed; 94% were the children's mothers. 70% of the children were African American and 64% had Medicaid insurance. Parents reported multiple antecedent symptoms and signs (median number per child = 3, range 1-6). These included respiratory symptoms (79%), allergy/cold symptoms (43%), behavioral changes (24%), and other non-specific symptoms (29%). Twenty-three parents reported late respiratory symptoms such as gasping for breath, and using accessory muscles to breath as the earliest antecedent signs. Treatment was most often intensified when the parent noticed cough (55%), shortness of breath (54%), and wheeze (25%), and included adding albuterol (92%), oral corticosteroid (17%), inhaled corticosteroid (8%) or other non-asthma medications (16%).
Although parents described antecedent symptoms and signs of impending asthma exacerbations they consistently noticed in their children, many waited for lower respiratory signs to be present before intensifying treatment. Oral corticosteroids were used infrequently. Interventions to improve the ability of parents and children to accurately recognize worsening symptoms and initiate timely, effective treatment are needed.
PMCID: PMC3799865  PMID: 20084839
Childhood asthma; asthma exacerbation
10.  Factors associated with attaining coaching goals during an intervention to improve child asthma care 
Contemporary clinical trials  2012;33(5):912-919.
To examine parent and child characteristics associated with engagement in a coaching intervention to improve pediatric asthma care and factors associated with readiness to adopt and maintain targeted asthma management behaviors.
Using methods based on the Transtheoretical Model, trained lay coaches worked with 120 parents of children with asthma promoting adoption and maintenance of asthma management strategies (behaviors). Coaches assigned stage-of-change (on continuum: pre-contemplation, contemplation, preparation, action, maintenance) for each behavior every time it was discussed. Improvement in stage-of-change was analyzed for association with characteristics of the participants (parents and children) and coaching processes.
Having more coach contacts was associated with earlier first contact (p<0.001), fewer attempts per successful contact (p<0.001), prior asthma hospitalization (p=0.021), more intruding events (p<0.001), and less social support (p=0.048). In univariable models, three factors were associated with forward movement at least one stage for all three behaviors: more coach contacts overall, fewer attempts per successful contact, and more discussion/staging episodes for the particular behavior. In multivariable models adjusting for characteristics of participants and coaching process, the strongest predictor of any forward stage movement for each behavior was having more contacts (p<0.05).
Improvement in readiness to adopt and maintain asthma management behaviors was mostly associated with factors reflecting more engagement of participants in the program. Similar coaching interventions should focus on early and frequent contacts to achieve intervention goals, recognizing that parents of children with less severe disease and who have more social support may be more difficult to engage.
PMCID: PMC3408563  PMID: 22664649
asthma; child; parent; coach; stage-of-change; engagement
Clinical pediatrics  2012;51(9):840-847.
Patient-centered care requires pediatricians to address parents’ health concerns, but their willingness to solicit parental concerns may be limited by uncertainty about which topics will be raised. We conducted surveys of parents to identify current health-related issues of concern.
Participants rated 30 items as health problems for children in their community (large, medium, small, or no problem) and volunteered concerns for their own children.
1,119 parents completed the survey. Allergies (69%), lack of exercise (68%), asthma (65%), attention deficit hyperactivity disorder (65%), Internet safety (63%), obesity (59%), smoking (58%), and bullying (57%) were identified as important problems (large or medium), with variation among demographic subgroups. Concerns for their own children included healthy nutrition, obesity, and lack of exercise, healthy growth and development, safety and injury prevention, and mental health issues.
Parents’ health concerns for children are varied and may differ from those routinely addressed during well-child care.
PMCID: PMC3608110  PMID: 22843294
Health needs assessment; practice-based research network; well-child care
12.  ITGB5 and AGFG1 variants are associated with severity of airway responsiveness 
BMC Medical Genetics  2013;14:86.
Airway hyperresponsiveness (AHR), a primary characteristic of asthma, involves increased airway smooth muscle contractility in response to certain exposures. We sought to determine whether common genetic variants were associated with AHR severity.
A genome-wide association study (GWAS) of AHR, quantified as the natural log of the dosage of methacholine causing a 20% drop in FEV1, was performed with 994 non-Hispanic white asthmatic subjects from three drug clinical trials: CAMP, CARE, and ACRN. Genotyping was performed on Affymetrix 6.0 arrays, and imputed data based on HapMap Phase 2, was used to measure the association of SNPs with AHR using a linear regression model. Replication of primary findings was attempted in 650 white subjects from DAG, and 3,354 white subjects from LHS. Evidence that the top SNPs were eQTL of their respective genes was sought using expression data available for 419 white CAMP subjects.
The top primary GWAS associations were in rs848788 (P-value 7.2E-07) and rs6731443 (P-value 2.5E-06), located within the ITGB5 and AGFG1 genes, respectively. The AGFG1 result replicated at a nominally significant level in one independent population (LHS P-value 0.012), and the SNP had a nominally significant unadjusted P-value (0.0067) for being an eQTL of AGFG1.
Based on current knowledge of ITGB5 and AGFG1, our results suggest that variants within these genes may be involved in modulating AHR. Future functional studies are required to confirm that our associations represent true biologically significant findings.
PMCID: PMC3765944  PMID: 23984888
Asthma; Airway hyperresponsiveness; Genome-wide association study; ITGB5; AGFG1
13.  A randomized controlled trial of parental asthma coaching to improve outcomes in urban minority children 
Investigate if asthma coaching reduces emergency department (ED) visits and hospitalizations and increases outpatient asthma monitoring (AM) visits.
Randomized controlled trial
Urban tertiary-care children’s hospital
Primary caregivers (“parents”) of children age 2–10 years with asthma, Medicaid-insurance, and urban residence who were attending the ED for acute asthma care.
18 months of coaching focused on asthma home management, completing periodic outpatient AM visits, and developing collaborative relationship with primary care provider (PCP); or usual care (control group).
Outcome Measures
Primary = ED visits. Secondary = hospitalizations and AM visits (non-acute visits focused on asthma care). Outcomes were measured during year before and 2 years after enrollment.
We included 120 intervention and 121 control parents. More children of coached parents had ≥ 1 AM visit after enrollment (relative risk [RR], 1.21; 95% confidence interval [CI], 1.04–1.41), but proportions with ≥ 4 AM visits over 2 years were low (intervention=20%; control=10%). Similar proportions of children per study group had ≥ 1 ED visit (71/120 versus 76/121; RR, 0.94; 95% CI, 0.77–1.15) and ≥ 1 hospitalization (29/120 versus 32/121; RR, 0.91; 95% CI 0.59–1.41) after enrollment. An ED visit after enrollment was more likely if one occurred before enrollment (RR, 1.46; 95% CI 1.16–1.86; adjusted for study group), but risk was similar per study group when adjusted for previous ED visits (RR, 1.02; 95% CI, 0.82–1.27).
This parental asthma coaching intervention increased outpatient asthma monitoring visits, although these visits were infrequent, but did not reduce ED visits.
PMCID: PMC3733385  PMID: 21646584
14.  Elevated urinary leukotriene E4 levels are associated with hospitalization for pain in children with sickle cell disease 
American journal of hematology  2008;83(8):640-643.
Cysteinyl leukotrienes (CsyLTs) are inflammatory mediators produced by white blood cells. Leukotriene LTE4 is the stable metabolite of CsyLTs, which can be measured in urine. We tested two hypotheses among children with sickle cell disease (SCD): (1) baseline urinary LTE4 levels are elevated in children with SCD when compared with controls; and (2) baseline LTE4 levels are associated with an increased incidence rate of hospitalization for SCD-related pain. Baseline LTE4 levels were measured in children with SCD (cases) and children without SCD matched for age and ethnicity (controls). Medical records of cases were reviewed to assess the frequency of hospitalization for pain within 3 years of study entry. LTE4 levels were obtained in 71 cases and 22 controls. LTE4 levels were higher in cases compared with controls (median LTE4: 100 vs. 57 pg/mg creatinine, P < 0.001). After adjustment for age and asthma diagnosis, a greater incidence rate of hospitalization for pain was observed among children with SCD in the highest LTE4 tertile when compared with the lowest (114 vs. 52 episodes per 100 patient-years, P = 0.038). LTE4 levels are elevated in children with SCD when compared with controls. LTE4 levels are associated with an increased rate of hospitalizations for pain.
PMCID: PMC3729258  PMID: 18506703
15.  Hospital Admission for Acute Painful Episode Following Methacholine Challenge in an Adolescent With Sickle Cell Disease 
Pediatric pulmonology  2009;44(7):728-730.
Asthma is associated with increases in sickle cell disease (SCD)-related morbidity and mortality. A thorough evaluation for asthma in children with SCD is important and may involve methacholine challenge (MCh). In this report, we present a 14-year-old male with SCD who was admitted for an acute painful episode following MCh. Pain events after MCh have not been previously reported in children with SCD. The risk–benefit ratio should be strongly considered prior to performance of MCh in this patient population, and all possible complications, including an acute painful episode, should be openly discussed with the parents and pediatric patient.
PMCID: PMC3729266  PMID: 19504562
methacholine challenge; sickle cell disease; pain; asthma
16.  Longitudinal analysis of pulmonary function in adults with sickle cell disease 
American journal of hematology  2008;83(7):574-576.
Among adults with sickle cell disease (SCD), pulmonary complications are a leading cause of death. Yet, the natural history of lung function in adults with SCD is not well established. We conducted a retrospective cohort study of adults with SCD who had repeated pulmonary function tests performed over 20 years of age. Ninety-two adults were included in this cohort. Rate of decline in FEV1 for men and women with SCD was 49 cc/year (compared with 20–26 cc/year in the general population). Further studies are needed to identify factors which impact the rate of lung function decline in adults with SCD.
PMCID: PMC3729267  PMID: 18383325
17.  Methacholine Challenge in Children With Sickle Cell Disease: A Case Series 
Pediatric pulmonology  2008;43(9):924-929.
Lung disease is a major cause of morbidity in children with sickle cell disease (SCD). Asthma in children with SCD is associated with a twice greater rate of pain and acute chest syndrome (ACS) episodes when compared to children with SCD but without asthma. Provocation challenges with methacholine are used to diagnose asthma when spirometry is normal, bronchodilator reactivity is absent, or the clinical picture is ambiguous. There have been only limited descriptions of use of methacholine challenge in individuals with SCD. We conducted a retrospective cohort study of 21 children with SCD and recurrent respiratory tract symptoms who were challenged with methacholine to determine if airway hyper responsiveness (AHR) was present. Fourteen (67%) of the children had a positive challenge. Of the 14 patients, four were given a new diagnosis of asthma based on the presence of chronic chest symptoms and the newly determined AHR and started on inhaled corticosteroids (ICS). In each positive challenge, forced expiratory volume in one second (FEV1) was reversed to at least 90% of baseline 15 min after bronchodilator treatment. Oxygen saturation decreased in 93% of those with a positive challenge, but returned to baseline values 15 min after bronchodilator treatment. No patient developed a pain or ACS episode within at least 1 month after the challenge. Evaluation of AHR with methacholine challenge in patients with SCD appears to be well tolerated and may elucidate a cause of SCD morbidity.
PMCID: PMC3722869  PMID: 18671275
methacholine challenge; sickle cell disease; children; airway hyper responsiveness
18.  Enuresis Associated with Sleep Disordered Breathing in Children with Sickle Cell Anemia 
The Journal of urology  2012;188(4 0):1572-1576.
Enuresis and sleep disordered breathing are common among children with sickle cell anemia. We evaluated whether enuresis is associated with sleep disordered breathing in children with sickle cell anemia.
Materials and Methods
Baseline data were used from a multicenter prospective cohort study of 221 unselected children with sickle cell anemia. A questionnaire was used to evaluate, by parental report during the previous month, the presence of enuresis and its severity. Overnight polysomnography was used to determine the presence of sleep disordered breathing by the number of obstructive apneas and/or hypopneas per hour of sleep. Logistic and ordinal regression models were used to evaluate the association of sleep disordered breathing and enuresis.
The mean age of participants was 10.1 years (median 10.0, range 4 to 19). Enuresis occurred in 38.9% of participants and was significantly associated with an obstructive apnea-hypopnea index of 2 or more per hour after adjusting for age and gender (OR 2.19; 95% CI 1.09, 4.40; p = 0.03). Enuresis severity was associated with obstructive apneas and hypopneas with 3% or more desaturation 2 or more times per hour with and without habitual snoring (OR 3.23; 95% CI 1.53, 6.81; p = 0.001 and OR 2.07; 95% CI 1.09, 3.92; p = 0.03, respectively).
In this unselected group of children with sickle cell anemia, sleep disordered breathing was associated with enuresis. Results of this study support that children with sickle cell anemia who present with enuresis should be evaluated by a pulmonologist for sleep disordered breathing.
PMCID: PMC3722896  PMID: 22910247
enuresis; sleep; anemia; sickle cell
19.  The Impact of Self-Identified Race on Epidemiologic Studies of Gene Expression 
Genetic epidemiology  2011;35(2):93-101.
Although population differences in gene expression have been established, the impact on differential gene expression studies in large populations is not well understood. We describe the effect of self-reported race on a gene expression study of lung function in asthma. We generated gene expression profiles for 254 young adults (205 non-Hispanic whites and 49 African Americans) with asthma on whom concurrent total RNA derived from peripheral blood CD4+ lymphocytes and lung function measurements were obtained. We identified four principal components that explained 62% of the variance in gene expression. The dominant principal component, which explained 29% of the total variance in gene expression, was strongly associated with self-identified race (P<10−16). The impact of these racial differences was observed when we performed differential gene expression analysis of lung function. Using multivariate linear models, we tested whether gene expression was associated with a quantitative measure of lung function: pre-bronchodilator forced expiratory volume in one second (FEV1). Though unadjusted linear models of FEV1 identified several genes strongly correlated with lung function, these correlations were due to racial differences in the distribution of both FEV1 and gene expression, and were no longer statistically significant following adjustment for self-identified race. These results suggest that self-identified race is a critical confounding covariate in epidemiologic studies of gene expression and that, similar to genetic studies, careful consideration of self-identified race in gene expression profiling studies is needed to avoid spurious association.
PMCID: PMC3718033  PMID: 21254216
ancestry; gene expression; population stratification; self-identified race
20.  Determinants of asthma after severe respiratory syncytial virus bronchiolitis 
The development of asthma after respiratory syncytial virus (RSV) bronchiolitis has been demonstrated in case-control studies, although the determinants of post-RSV asthma remain undefined.
We sought to evaluate the potential determinants of physician-diagnosed asthma after severe RSV bronchiolitis during infancy.
We enrolled 206 children during an initial episode of severe RSV bronchiolitis at 12 months of age or less in a prospective cohort study and followed these children for up to 6 years. In a subset of 81 children, we analyzed CCL5 (RANTES) mRNA expression in upper airway epithelial cells.
Forty-eight percent of children had physician-diagnosed asthma before the seventh birthday. Independent determinants significantly associated with increased risk for physician-diagnosed asthma by the seventh birthday included maternal asthma (odds ratio [OR], 5.2; 95% CI, 1.7-15.9; P = .004), exposure to high levels of dog allergen (OR, 3.2; 95% CI, 1.3-7.7; P = .012), aeroallergen sensitivity at age 3 years (OR, 10.7; 95% CI, 2.1-55.0; P = .005), recurrent wheezing during the first 3 years of life (OR, 7.3; 95% CI, 1.2-43.3; P = .028), and CCL5 expression in nasal epithelia during acute RSV infection (OR, 3.8; 95% CI, 1.2-2.4; P < .001). White children (OR, 0.19; 95% CI, 0.04-0.93; P = .041) and children attending day care (OR, 0.18; 95% CI, 0.04-0.84; P = .029) had a decreased risk of physician-diagnosed asthma.
Approximately 50% of children who experience severe RSV bronchiolitis have a subsequent asthma diagnosis. The presence of increased CCL5 levels in nasal epithelia at the time of bronchiolitis or the development of allergic sensitization by age 3 years are associated with increased likelihood of subsequent asthma.
PMCID: PMC3612548  PMID: 22444510
Bronchiolitis; respiratory syncytial virus; asthma; prospective cohort; CCL5
21.  Prevalence of Daily Medication Adherence Among Children with Sickle Cell Disease: A One-Year Retrospective Cohort Analysis 
Pediatric blood & cancer  2010;55(3):554-556.
The objective of this study is to determine the prevalence of adherence to daily medications among children with sickle cell disease (SCD). Prescription records for 12 months were obtained from participants who had insurance in a Medicaid-based single health maintenance organization. Adherence was measured as a ratio between the number of expected days and the observed days between two refill periods for daily medications. A total of 93 children were studied. The average refill prescription rate was 58.4%. More formal strategies are required to identify barriers to prescription refills among children with SCD.
PMCID: PMC3665080  PMID: 20658630
Sickle cell disease; medications; adherence; children
22.  Elevated Exhaled Nitric Oxide Levels Increases Risk of Respiratory Tract Illness in Preschool Children with Moderate to Severe Intermittent Wheezing 
The fractional concentration of exhaled nitric oxide (FeNO) is a noninvasive marker for airway inflammation but requires further study in pre-school children to determine its clinical relevance.
To determine whether the risk of respiratory tract illnesses (RTI), disease burden and atopic features are related to FeNO in preschool children with moderate-to-severe intermittent wheezing.
We determined FeNO using the off-line tidal breathing technique in 89 children, 12–59 months old, with moderate-severe intermittent wheezing. Risk of RTI was determined by comparing participants with baseline FeNO >75th percentile (24.4ppb) to those with FeNO ≤75th percentile using Cox regression analysis.
The risk of RTI was significantly higher in children with FeNO >24.4ppb relative to those with lower FeNO values (adjusted RR= 3.8, 95% CI: 1.74–8.22; p=0.0008). FeNO levels >24ppb were associated with a greater number of positive skin tests to aeroallergens (p=0.03), but not with other atopic characteristics or historic parameters of illness burden.
Elevated FeNO in preschool children with moderate-to-severe intermittent wheezing was associated with an increased risk of RTI during a one-year follow-up. In addition, higher FeNO was associated with aeroallergen sensitization.
PMCID: PMC3652587  PMID: 19739422
Preschool children; exhaled nitric oxide; respiratory tract illness; wheezing
23.  Effect of Inhaled Glucocorticoids in Childhood on Adult Height 
The New England journal of medicine  2012;367(10):904-912.
The use of inhaled glucocorticoids for persistent asthma causes a temporary reduction in growth velocity in prepubertal children. The resulting decrease in attained height 1 to 4 years after the initiation of inhaled glucocorticoids is thought not to decrease attained adult height.
We measured adult height in 943 of 1041 participants (90.6%) in the Childhood Asthma Management Program; adult height was determined at a mean (±SD) age of 24.9±2.7 years. Starting at the age of 5 to 13 years, the participants had been randomly assigned to receive 400 μg of budesonide, 16 mg of nedocromil, or placebo daily for 4 to 6 years. We calculated differences in adult height for each active treatment group, as compared with placebo, using multiple linear regression with adjustment for demographic characteristics, asthma features, and height at trial entry.
Mean adult height was 1.2 cm lower (95% confidence interval [CI], −1.9 to −0.5) in the budesonide group than in the placebo group (P = 0.001) and was 0.2 cm lower (95% CI, −0.9 to 0.5) in the nedocromil group than in the placebo group (P = 0.61). A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height (−0.1 cm for each microgram per kilogram of body weight) (P = 0.007). The reduction in adult height in the budesonide group as compared with the placebo group was similar to that seen after 2 years of treatment (−1.3 cm; 95% CI, −1.7 to −0.9). During the first 2 years, decreased growth velocity in the budesonide group occurred primarily in prepubertal participants.
The initial decrease in attained height associated with the use of inhaled glucocorticoids in prepubertal children persisted as a reduction in adult height, although the decrease was not progressive or cumulative.
PMCID: PMC3517799  PMID: 22938716
24.  Effects of Experimental Asthma on Inflammation and Lung Mechanics in Sickle Cell Mice 
Experimental asthma increases eosinophil and collagen deposition in the lungs of sickle cell disease (SCD) mice to a greater extent than in control mice. However, the effects of asthma on inflammation and airway physiology remain unclear. To determine effects of asthma on pulmonary inflammation and airway mechanics in SCD mice, hematopoietic stem cell transplantation was used to generate chimeric SCD and hemoglobin A mice. Experimental asthma was induced by sensitizing mice with ovalbumin (OVA). Airway mechanics were assessed using forced oscillation techniques. Mouse lungs were examined histologically and physiologically. Cytokine, chemokine, and growth factors in bronchoalveolar lavage fluid were determined by multiplex. IgE was quantified by ELISA. LDH was quantified using a colorimetric enzymatic assay. At baseline (nonsensitized), chimeric SCD mice developed hemolytic anemia with sickled red blood cells, mild leukocytosis, and increased vascular endothelial growth factor and IL-13 compared with chimeric hemoglobin A mice. Experimental asthma increased perialveolar eosinophils, plasma IgE, and bronchoalveolar lavage fluid IL-1β, IL-4, IL-6, and monocyte chemotactic protein 1 in chimeric hemoglobin A and SCD mice. IFN-γ levels were reduced in both groups. IL-5 was preferentially increased in chimeric SCD mice but not in hemoglobin A mice. Positive end-expiratory pressures and methacholine studies revealed that chimeric SCD mice had greater resistance in large and small airways compared with hemoglobin A mice at baseline and after OVA sensitization. SCD alone induces a baseline lung pathology that increases large and small airway resistance and primes the lungs to increased inflammation and airway hyperresponsiveness after OVA sensitization.
PMCID: PMC3326430  PMID: 22033263
sickle cell disease; OVA sensitization; IgE; IL-5; airway hyperresponsiveness
25.  Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene 
PLoS ONE  2013;8(2):e56179.
Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.
PMCID: PMC3572953  PMID: 23457522

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