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1.  Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations 
Short-term targeted treatment can potentially prevent fall asthma exacerbations while limiting therapy exposure.
We sought to compare (1) omalizumab with placebo and (2) omalizumab with an inhaled corticosteroid (ICS) boost with regard to fall exacerbation rates when initiated 4 to 6 weeks before return to school.
A 3-arm, randomized, double-blind, double placebo-controlled, multicenter clinical trial was conducted among inner-city asthmatic children aged 6 to 17 years with 1 or more recent exacerbations ( #NCT01430403).
Guidelines-based therapy was continued over a 4- to 9-month run-in phase and a 4-month intervention phase. In a subset the effects of omalizumab on IFN-α responses to rhinovirus in PBMCs were examined.
Before the falls of 2012 and 2013, 727 children were enrolled, 513 were randomized, and 478 were analyzed. The fall exacerbation rate was significantly lower in the omalizumab versus placebo arms (11.3% vs 21.0%; odds ratio [OR], 0.48; % CI, 0.25–.92), but there was no significant difference between omalizumab and ICS boost (8.4% vs 11.1%; OR, 0.73; 95% CI, 0.33–1.64). In a prespecified subgroup analysis, among participants with an exacerbation during the run-in phase, omalizumab was significantly more efficacious than both placebo (6.4% vs 36.3%; OR, 0.12; 95% CI, 0.02–0.64) and ICS boost (2.0% vs 27.8%; OR, 0.05; 95% CI, 0.002–0.98). Omalizumab improved IFN-α responses to rhinovirus, and within the omalizumab group, greater IFN-α increases were associated with fewer exacerbations (OR, 0.14; 95% CI, 0.01–0.88). Adverse events were rare and similar among arms.
Adding omalizumab before return to school to ongoing guidelines-based care among inner-city youth reduces fall asthma exacerbations, particularly among those with a recent exacerbation.
PMCID: PMC4679705  PMID: 26518090
Asthma; fall season; omalizumab; inhaled corticosteroid; asthma exacerbations; rhinovirus; IFN-α
2.  Hygiene factors associated with childhood food allergy and asthma 
Allergy and Asthma Proceedings  2016;37(6):e140-e146.
Childhood food allergy and asthma rates are increasing. The hygiene hypothesis has been proposed as an explanation for the increased incidence of allergic disease.
To describe the association of childhood food allergy and asthma with hygiene factors, such as the number of siblings, antibiotic use, infection history, pet exposure, child care exposure, and maternal–child factors.
Children ages 0–21 years old (N = 1359) were recruited for a cross-sectional family-based study, including children with food allergy and children without food allergy, and their siblings. We assessed the associations between childhood food allergy and asthma with hygiene factors.
Of the 1359 children, 832 (61.2%) had food allergy, and 406 (30%) had asthma. In the adjusted analysis, the prevalence of food allergy was increased if there was a history of skin infection (prevalence ratio [RRR] 1.12 [95% confidence interval {CI}, 1.01–1.24]) or eczema (RRR 1.89 [95% CI, 1.70–2.10]). The prevalence of asthma was increased with a history of respiratory syncytial virus infection (RRR 1.60 [95% CI, 1.34–1.90]) or eczema (RRR 1.54 [95% CI, 1.27–1.86]). A greater number of siblings were associated with a decreased prevalence of food allergy (RRR 0.79 [95% CI, 0.75–0.84]) and asthma (RRR 0.82 [95% CI, 0.74–0.91]).
Our findings supported the accumulating evidence of an association between skin infections and eczema with food allergy. Because these results could be subject to recall bias, additional prospective studies are needed to substantiate these findings.
PMCID: PMC5080537
Hygiene factors; pediatric; food allergy; asthma; cohort; hygiene hypothesis; eczema; skin infections; siblings; respiratory syncytial virus.
3.  Safety, clinical and immunologic efficacy of a Chinese herbal medicine (FAHF-2) for food allergy 
FAHF-2 is a 9-herb formula based on Traditional Chinese Medicine that blocks peanut anaphylaxis in a murine model. In Phase I studies, FAHF-2 was found to be safe, and well tolerated.
To evaluate the safety and effectiveness of FAHF-2 as a treatment for food allergy.
In this double-blind, randomized, placebo-controlled study, 68 subjects, 12-45 years of age, with allergies to peanut, tree nut, sesame, fish, and/or shellfish, confirmed by baseline double-blind, placebo controlled food challenge (DBPCFC), received FAHF-2 (n=46) or placebo (n=22). After 6 months of therapy, subjects underwent DBPCFC. For those who demonstrated increases in eliciting dose, a repeat DBPCFC was performed 3 months after stopping therapy.
Treatment was well-tolerated with no serious adverse events. By intent-to-treat analysis, the placebo group had a higher eliciting dose and cumulative dose (p=0.05) at the end of treatment DBPCFC. There was no difference in the requirement for epinephrine to treat reactions (p=0.55). There were no significant differences in allergen-specific IgE and IgG4, cytokine production by PBMCs or basophil activation between active and placebo groups. In vitro immunological studies performed on subject baseline PBMCs incubated with FAHF-2 and food allergen produced significantly less IL-5, greater IL-10 and increased numbers of Tregs than untreated cells. Notably, 44% of subjects had poor drug adherence for at least one-third of the study period.
FAHF-2 is a safe herbal medication for food allergic individuals and shows favorable in vitro immunomodulatory effects; however, efficacy for improving tolerance to food allergens is not demonstrated at the dose and duration used.
PMCID: PMC4600418  PMID: 26044855
food allergy; FAHF-2; Chinese herbal therapy; peanut allergy
5.  Early Administration of Azithromycin and Prevention of Severe Lower Respiratory Tract Illnesses in Preschool Children With a History of Such Illnesses 
JAMA  2015;314(19):2034-2044.
Many preschool children develop recurrent, severe episodes of lower respiratory tract illness (LRTI). Although viral infections are often present, bacteria may also contribute to illness pathogenesis. Strategies that effectively attenuate such episodes are needed.
To evaluate if early administration of azithromycin, started prior to the onset of severe LRTI symptoms, in preschool children with recurrent severe LRTIs can prevent the progression of these episodes.
A randomized, double-blind, placebo-controlled, parallel-group trial conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute’s AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by December 2014. Participants were 607 children aged 12 through 71 months with histories of recurrent, severe LRTIs and minimal day-to-day impairment.
Participants were randomly assigned to receive azithromycin (12 mg/kg/d for 5 days; n = 307) or matching placebo (n = 300), started early during each predefined RTI (child’s signs or symptoms prior to development of LRTI), based on individualized action plans, over a 12-through 18-month period.
The primary outcome measure was the number of RTIs not progressing to a severe LRTI, measured at the level of the RTI, that would in clinical practice trigger the prescription of oral corticosteroids. Presence of azithromycin-resistant organisms in oropharyngeal samples, along with adverse events, were among the secondary outcome measures.
A total of 937 treated RTIs (azithromycin group, 473; placebo group, 464) were experienced by 443 children (azithromycin group, 223; placebo group, 220), including 92 severe LRTIs (azithromycin group, 35; placebo group, 57). Azithromycin significantly reduced the risk of progressing to severe LRTI relative to placebo (hazard ratio, 0.64 [95% CI, 0.41-0.98], P = .04; absolute risk for first RTI: 0.05 for azithromycin, 0.08 for placebo; risk difference, 0.03 [95% CI, 0.00-0.06]). Induction of azithromycin-resistant organisms and adverse events were infrequently observed.
Among young children with histories of recurrent severe LRTIs, the use of azithromycin early during an apparent RTI compared with placebo reduced the likelihood of severe LRTI. More information is needed on the development of antibiotic-resistant pathogens with this strategy.
PMCID: PMC4757487  PMID: 26575060
6.  Cardiovascular Risk Factors in Parents of Food-Allergic Children 
Medicine  2016;95(15):e3156.
Previous studies suggest that chronic stress may induce immune system malfunction and a broad range of adverse health outcomes; however, the underlying pathways for this relationship are unclear.
Our study aimed to elucidate this question by examining the relationship between parental cardiovascular risk factors including systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), and waist-to-hip ratio (WHR) and maternal psychological stress score (MPSS) relative to the severity of the child's food allergy (FA) and number of affected children.
SBP, DBP, BMI, and WHR were measured and calculated at the time of recruitment by trained nurses. MPSS was obtained based on self-report questionnaires covering lifestyle adjustments, perceived chronic stress, and quality of life. General linear models examined whether caregiver chronic stress was associated with FA.
For mothers with children under age 5 years, SBP, DBP and number of affected children had strong and graded relationships with severity of the child's FA. MPSS was also significantly and positively associated with child FA severity (P < 0.001). However, no relationships were found between FA severity, BMI, or WHR for either parent. This was also the case for paternal SBP, DBP, and number of affected children of any age.
There is a strong and graded link between cardiovascular risk and perceived stress in mothers of food-allergic children under age 5. Findings may have important implications for family-centered care of FA, may generalize to caregivers of children with chronic conditions, and extend the literature on allostatic load.
PMCID: PMC4839798  PMID: 27082554
7.  Differential effects of outdoor vs indoor fungal spores on asthma morbidity in inner-city children 
While sensitization to fungal allergens is prevalent in inner-city children with asthma, the relationship between fungal exposure and morbidity is poorly understood.
We examined relationships between fungal sensitization, exposure and asthma morbidity in inner-city children.
Participants were 5–11 years old and enrolled in the Inner-City Asthma Study. This report includes the subset of children with at least 1 positive skin test to a fungal allergen extract; for these children, indoor and outdoor airborne culturable fungi were measured at baseline and throughout the 2 year study. Asthma morbidity measures were collected prospectively. The primary outcome was symptom days per 2 weeks.
At baseline, children with a positive skin test to a fungal allergen extract had significantly more symptom days compared to those without positive skin test to any fungal allergen extract (6.3 vs 5.7 days per 2 weeks, p=0.04). During the study, elevations in total fungal exposure and indoor Penicillium exposure were associated with increases in symptom days and asthma unscheduled visits. Indoor exposures to total fungi and to Penicillium were associated with significant increases in unscheduled visits, even after controlling for outdoor fungal levels. Adverse effects associated with exposure to a specific fungus were stronger among children with positive skin test to that fungal allergen extract compared to skin test negative children.
Outdoor fungal exposure is primarily associated with increased asthma symptoms and increased risk of exacerbations in this population.
PMCID: PMC4754109  PMID: 20132971
asthma; inner city; airborne fungi; indoor fungi; outdoor fungi; fungal allergens; children
8.  Genome-wide Association Study Identifies Peanut Allergy-Specific Loci and Evidence of Epigenetic Mediation in U.S. Children 
Nature communications  2015;6:6304.
Food allergy (FA) affects 2–10% of U.S. children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk, and egg) in 2,759 U.S. participants (1,315 children; 1,444 parents) from the Chicago Food Allergy Study; and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (p=5.5×10−8) and rs9275596 (p=6.8×10−10), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites (p<5×10−8); and differential DNA methylation of the HLA-DQB1 and HLA-DRB1 genes partially mediate the identified SNP-PA associations. This study suggests that the HLA-DR and -DQ gene region likely poses significant genetic risk for PA.
PMCID: PMC4340086  PMID: 25710614
9.  Development of cockroach immunotherapy by the Inner-City Asthma Consortium 
Cockroach allergy is a key contributor to asthma morbidity in children living in urban environments.
We sought to document immune responses to cockroach allergen and provide direction for the development of immunotherapy for cockroach allergy.
Four pilot studies were conducted: (1) an open-label study to assess the safety of cockroach sublingual immunotherapy (SLIT) in adults and children; (2) a randomized, double-blind biomarker study of cockroach SLIT versus placebo in adults; (3) a randomized, double-blind biomarker study of 2 doses of cockroach SLIT versus placebo in children; and (4) an open-label safety and biomarker study of cockroach subcutaneous immunotherapy (SCIT) in adults.
The adult SLIT trial (n = 54; age, 18–54 years) found a significantly greater increase in cockroach-specific IgE levels between the active and placebo groups (geometric mean ratio, 1.92; P < .0001) and a trend toward increased cockroach-specific IgG4 levels in actively treated subjects (P = .09) but no evidence of functional blocking antibody response. The pediatric SLIT trial (n = 99; age, 5–17 years) found significant differences in IgE, IgG, and IgG4 responses between both active groups and the placebo group but no consistent differences between the high- and low-dose groups. In the SCIT study the treatment resulted in significant changes from baseline in cockroach IgE, IgG4, and blocking antibody levels. The safety profile of cockroach immunotherapy was reassuring in all studies.
The administration of cockroach allergen by means of SCIT is immunologically more active than SLIT, especially with regard to IgG4 levels and blocking antibody responses. No safety concerns were raised in any age group. These pilot studies suggest that immunotherapy with cockroach allergen is more likely to be effective with SCIT.
PMCID: PMC3943647  PMID: 24184147
Cockroach; immunotherapy; sublingual immunotherapy; subcutaneous immunotherapy; inner city asthma
10.  Reassessment of Omalizumab-Dosing Strategies and Pharmacodynamics in Inner-City Children and Adolescents 
Treatment regimens for omalizumab are guided by a dosing table that is based on total serum IgE and body weight. Limited data exist about onset and offset of omalizumab efficacy in children and adolescents or subgroups that most benefit from treatment.
Post hoc analyses were conducted to (1) examine patient characteristics of those eligible and ineligible for omalizumab, (2) describe onset of effect after initiation of omalizumab and offset of treatment effect after stopping therapy, and (3) determine whether the efficacy differs by age, asthma severity, dosing regimen, and prespecified biomarkers.
Inner-city children and adolescents with persistent allergic asthma were enrolled in the Inner-City Anti-IgE Therapy for Asthma trial that compared omalizumab with placebo added to guidelines-based therapy for 60 weeks.
Two hundred ninety-three of 889 participants (33%) clinically suitable for omalizumab were ineligible for dosing according to a modified dosing table specifying IgE level and body weight criteria. Baseline symptoms were comparable among those eligible and ineligible to receive omalizumab, but other characteristics (rate of health care utilization and skin test results) differed. The time of onset of omalizumab effect was <30 days and time of offset was between 30 and 120 days. No difference in efficacy was noted by age or asthma severity, but high exhaled nitric oxide, blood eosinophils, and body mass index predicted efficacy.
A significant portion of children and adolescents particularly suited for omalizumab because of asthma severity status may be ineligible due to IgE >1300 IU/mL. Omalizumab reduced asthma symptoms and exacerbations rapidly; features associated with efficacy can be identified to guide patient selection.
PMCID: PMC4254887  PMID: 24565455
Asthma exacerbations; Biomarkers; Dosing regimens; Inhaled corticosteroids; Omalizumab; Pharmacodynamics; Response predictors
11.  The Longitudinal Trajectory of Vitamin D Status from Birth to Early Childhood on the Development of Food Sensitization 
Pediatric research  2013;74(3):321-326.
Increasing evidence supports the immunomodulatory effect of vitamin D on allergic diseases. The combined role of prenatal and postnatal vitamin D status in the development of food sensitization (FS) and food allergy remains under-studied.
460 children in the Boston Birth Cohort had plasma 25(OH)D measured at birth and early childhood, and were genotyped for rs2243250 (C-590T) in the IL4 gene. We defined FS as specific IgE ≥0.35kUA/L to any of eight common food allergens; and persistently low vitamin D status as cord blood 25(OH)D <11ng/ml and postnatal 25(OH)D <30ng/ml.
We observed a moderate correlation between cord blood 25(OH)D at birth and venous blood 25(OH)D measured at 2–3 years (r=0.63), but a weak correlation at <1 year (r=0.28). There was no association between low vitamin D status and FS at any single time point alone. However, in combination, persistence of low vitamin D status at birth and early childhood increased the risk of FS (OR=2.03, 95%CI:1.02–4.04), particularly among children carrying the C allele of rs2243250 (OR=3.23, 95%CI:1.37–7.60).
Prenatal and early postnatal vitamin D levels, along with individual genetic susceptibility, should be considered in assessing the role of vitamin D in the development of FS and food allergy.
PMCID: PMC3773018  PMID: 23797532
12.  IgE but not IgG4 Antibodies to Ara h 2 Distinguish Peanut Allergy from Asymptomatic Peanut Sensitization 
Allergy  2012;67(12):1538-1546.
There are no available clinical tests that can accurately predict peanut allergy (PA) and/or anaphylaxis. This study is aimed at evaluating whether the component-resolved diagnostic (CRD) IgE and IgG4 tests can 1) distinguish PA from asymptomatic peanut sensitization; and 2) differentiate anaphylactic vs. non-anaphylactic PA.
This study included 20 non-atopic controls, 58 asymptomatically peanut-sensitized children, 55 non-anaphylactic and 53 anaphylactic PA cases from the Chicago Food Allergy Study. IgE and IgG4 to 103 allergens were measured using the ImmunoCAP ISAC technology, and were compared among each group of children. The random forest test was applied to estimate each allergen’s ability to predict PA and/or peanut anaphylaxis.
PA cases (with or without anaphylaxis) had significantly higher IgE reactivity to Ara h 1–3 (peanut allergens) and Gly m 5–6 (soy allergens) than asymptomatically-sensitized children (p<0.00001). Similar but more modest relationships were found for IgG4 to Ara h 2 (p<0.01). IgE to Ara h 2 was the major contributor to accurate discrimination between PA and asymptomatic sensitization. With an optimal cutoff point of 0.65 ISU-E, it conferred 99.1% sensitivity, 98.3% specificity, and a 1.2% misclassification rate in the prediction of PA, which represented a higher discriminative accuracy than IgE to whole peanut extract (p=0.008). However, none of the IgE and/or IgG4 tests could significantly differentiate peanut anaphylaxis from non-anaphylactic PA.
IgE to Ara h 2 can efficiently differentiate clinical PA from asymptomatic peanut sensitization, which may represent a major step forward in the diagnosis of PA.
PMCID: PMC3499645  PMID: 23094689
Ara h 2; Component-resolved diagnostics; Diagnostic performance; Peanut allergy; Peanut anaphylaxis
13.  Maternal Smoking during Pregnancy, Prematurity and Recurrent Wheezing in Early Childhood 
Pediatric pulmonology  2012;47(7):666-673.
Prenatal maternal smoking and prematurity independently affect wheezing and asthma in childhood.
We sought to evaluate the interactive effects of maternal smoking and prematurity upon the development of early childhood wheezing.
We evaluated 1448 children with smoke exposure data from a prospective urban birth cohort in Boston. Maternal antenatal and postnatal exposure was determined from standardized questionnaires. Gestational age was assessed by the first day of the last menstrual period and early prenatal ultrasound (preterm<37 weeks gestation). Wheezing episodes were determined from medical record extraction of well and ill/unscheduled visits. The primary outcome was recurrent wheezing, defined as ≥ 4 episodes of physician documented wheezing. Logistic regression models and zero inflated negative binomial regression (for number of episodes of wheeze) assessed the independent and joint association of prematurity and maternal antenatal smoking on recurrent wheeze, controlling for relevant covariates.
In the cohort, 90 (6%) children had recurrent wheezing, 147 (10%) were exposed to in utero maternal smoke and 419 (29%) were premature. Prematurity (odds ratio [OR] 2.0; 95% CI, 1.3-3.1) was associated with an increased risk of recurrent wheezing, but in utero maternal smoking was not (OR 1.1, 95% CI 0.5-2.4). Jointly, maternal smoke exposure and prematurity caused an increased risk of recurrent wheezing (OR 3.8, 95% CI 1.8-8.0). There was an interaction between prematurity and maternal smoking upon episodes of wheezing (p=0.049).
We demonstrated an interaction between maternal smoking during pregnancy and prematurity on childhood wheezing in this urban, multiethnic birth cohort.
PMCID: PMC3756665  PMID: 22290763
Smoking; Prematurity; Wheeze
14.  Gestational Diabetes, Atopic Dermatitis and Allergen Sensitization in Early Childhood 
The relationship between the prenatal environment, maternal-fetal interaction, and allergic disease in the offspring remains understudied.
We sought to determine whether gestational diabetes modifies the risk of early childhood atopic manifestations including atopic dermatitis and allergen sensitization.
This study includes 680 children from the Boston Birth Cohort. Mother-child dyads were recruited at birth and followed prospectively to a mean age of 3.2±2.3 years with study visits aligned with the pediatric primary care schedule. The primary outcomes were physician diagnosed atopic dermatitis on standardized medical record abstraction and allergen sensitization based on Immunocap to 7 common foods and 5 common aeroallergens (sIgE≥0.10 kUA/L, Phadia). Gestational diabetes was determined by standardized medical record review. Logistic regression analysis, stratified by term/preterm status, evaluated the association of gestational diabetes with atopic dermatitis and allergen sensitization respectively, controlling for maternal pre-pregnancy BMI, fetal growth, and pertinent covariates.
Of the 680 children, 488 were term and 192 were preterm (<37 weeks gestation). Overall, 4.9% of the mothers developed gestational diabetes. Among the 680 children, 34.4% developed atopic dermatitis and 51% developed allergen sensitization. In term births, gestational diabetes was significantly associated with atopic dermatitis (OR, 95%CI=7.2, 1.5-34.5) and allergen sensitization (OR, 95%CI=5.7, 1.2-28.0). Adjusting for fetal growth had little effect. The association with sensitization was driven primarily by food sensitization (OR, 95%CI=8.3, 1.6-43.3). The above associations were not observed in preterm births.
In term births, gestational diabetes increased the risk of atopic dermatitis and early childhood allergen sensitization, independent of maternal pre-pregnancy BMI and fetal growth.
PMCID: PMC3756674  PMID: 19733904
atopic dermatitis; eczema; food allergen sensitization; gestational diabetes
15.  Development and Validation of the Composite Asthma Severity Index – An Outcome Measure for use in Children and Adolescents 
Asthma severity is reflected in many aspects of the disease, including impairment and future risks, particularly for exacerbations. According to the EPR-3, however, to assess more comprehensively the severity of asthma the level of current treatment needed to maintain a level of control should be included.
Development and validation of a new instrument, the Composite Asthma Severity Index (CASI), which can quantify disease severity by taking into account impairment, risk and the amount of medication needed to maintain control. At present, there is no instrument available to measure and assess the multidimensional nature of asthma.
Twenty-six established asthma investigators, who are part of the NIH-supported Inner City Asthma Consortium (ICAC), participated in a modified Delphi consensus process to identify and weight the dimensions of asthma. Factor analysis was performed to identify independent domains of asthma using the Asthma Control Evaluation (ACE) trial. CASI was validated using the Inner City Anti-IgE Therapy for Asthma (ICATA) trial.
CASI scores include five domains: day symptoms and albuterol use, night symptoms and albuterol use, controller treatment, lung function measures, and exacerbations. At ACE enrollment, CASI ranged from 0 to 17 with a mean of 6.2. CASI was stable, with minimal change in variance after 1 year of treatment. In external validation, CASI detected a 32% larger improvement than symptoms alone.
CASI retained its discriminatory ability even with low levels of symptoms reported after months of guidelines-directed care. Thus, CASI has the ability to determine the level of asthma severity, and provide a composite clinical characterization of asthma.
PMCID: PMC3294274  PMID: 22244599
Asthma; composite score; morbidity; treatment; exacerbations; symptoms; severity
16.  Gene-Vitamin D Interactions on Food Sensitization: A prospective birth cohort study 
Allergy  2011;66(11):1442-1448.
It has been hypothesized that vitamin D deficiency (VDD) contributes to the development of food sensitization (FS) and then food allergy. However, the epidemiological evidence is conflicting. We aim to examine if cord blood VDD is associated with FS and if such association can be modified by genetic variants in a prospective birth cohort.
This study included 649 children who were enrolled at birth and followed from birth onward at the Boston Medical Center. We defined VDD as cord blood 25(OH)D < 11ng/ml, and FS as specific IgE ≥ 0.35kUA/L to any of eight common food allergens in early childhood. We genotyped potentially functional single nucleotide polymorphisms (SNPs) in 11 genes known to be involved in regulating IgE and 25(OH)D concentrations. Logistic regressions were used to test the effects of VDD on FS individually and jointly with SNPs.
Among the 649 children, 44% had VDD and 37% had FS. When examined alone, VDD was not associated with FS. When examined jointly with SNPs, a significant interaction between IL4 gene polymorphism (rs2243250) and VDD (pinteraction=0.003, pFDR=0.10) was found: VDD increased the risk of FS among children carrying CC/CT genotypes (OR=1.79, 95%CI: 1.15–2.77). Similar but weaker interactions were observed for SNPs in MS4A2 (rs512555), FCER1G (rs2070901), and CYP24A1 (rs2762934). When all four SNPs were simultaneously considered, a strong gene-VDD interaction was evident (pinteraction=9×10−6).
Our data demonstrate that VDD may increase the risk of FS among individuals with certain genotypes, providing evidence of gene-vitamin D interaction on FS.
PMCID: PMC3189275  PMID: 21819409
cord blood plasma 25(OH)D; food sensitization; gene-vitamin D deficiency interaction; SNP
17.  Race, Ancestry, and Development of Food-Allergen Sensitization in Early Childhood 
Pediatrics  2011;128(4):e821-e829.
We examined whether the risk of food-allergen sensitization varied according to self-identified race or genetic ancestry.
We studied 1104 children (mean age: 2.7 years) from an urban multiethnic birth cohort. Food sensitization was defined as specific immunoglobulin E (sIgE) levels of ≥0.35 kilo–units of allergen (kUA)/L for any of 8 common food allergens. Multivariate logistic regression analyses were used to evaluate the associations of self-identified race and genetic ancestry with food sensitization. Analyses also examined associations with numbers of food sensitizations (0, 1 or 2, and ≥3 foods) and with logarithmically transformed allergen sIgE levels.
In this predominantly minority cohort (60.9% black and 22.5% Hispanic), 35.5% of subjects exhibited food sensitizations. In multivariate models, both self-reported black race (odds ratio [OR]: 2.34 [95% confidence interval [CI]: 1.24–4.44]) and African ancestry (in 10% increments; OR: 1.07 [95% CI: 1.02–1.14]) were associated with food sensitization. Self-reported black race (OR: 3.76 [95% CI: 1.09–12.97]) and African ancestry (OR: 1.19 [95% CI: 1.07–1.32]) were associated with a high number (≥3) of food sensitizations. African ancestry was associated with increased odds of peanut sIgE levels of ≥5 kUA/L (OR: 1.25 [95% CI: 1.01–1.52]). Similar ancestry associations were seen for egg sIgE levels of ≥2 kUA/L (OR: 1.13 [95% CI: 1.01–1.27]) and milk sIgE levels of ≥5 kUA/L (OR: 1.24 [95% CI: 0.94–1.63]), although findings were not significant for milk.
Black children were more likely to be sensitized to food allergens and were sensitized to more foods. African ancestry was associated with peanut sensitization.
PMCID: PMC3182844  PMID: 21890831
food allergy; sensitization; racial disparities; genetic ancestry
18.  Gene Polymorphisms, Breastfeeding and Development of Food Sensitization in Early Childhood 
The impact of breastfeeding on the development of allergic disease is uncertain. There are no data that show whether this relationship varies by individual genotypes.
To evaluate the effect of breastfeeding and gene-breastfeeding interactions on food sensitization (FS) in a prospective U.S. birth cohort.
This study included 970 children who were prospectively followed since birth. Breastfeeding history was obtained from a standardized questionnaire interview. FS was defined as specific IgE ≥0.35 kUA/L to any of eight common food allergens. Eighty-eight potentially functional SNPs were genotyped from 18 genes involved in innate immunity or TH1/TH2 balance. Logistic regression models were used to test the effects of breastfeeding and gene-breastfeeding interactions on FS, with adjustment for pertinent covariates.
Children who were ever breastfed (n=739), including exclusively breastfed children, were at a 1.5 (95%CI=1.1-2.1, p=0.019) times higher risk of FS than never breastfed children (n=231). This association was significantly modified by rs425648 in the IL12RB1gene (pinteraction=0.0007): breastfeeding increased the risk of FS (OR=2.0, 95%CI=1.4-3.1, p= 0.0005) in children carrying the GG genotype but decreased the risk (OR=0.6, 95%CI=0.3-1.4, p=0.252) in children carrying the GT/TT genotype. Similar interactions were observed for SNPs in the TLR9 (rs352140) and TSLP (rs3806933) genes. The interaction between the combined genotypes of the three SNPs and breastfeeding on FS was even stronger (pinteraction<10-5).
Our data suggest that the effect of breastfeeding on FS was modified by SNPs in the IL12RB1, TLR9, and TSLP genes both individually and jointly. Our findings underscore the importance of considering individual genetic variations in assessing this relationship.
PMCID: PMC3149737  PMID: 21689850
Breastfeeding; food sensitization; gene-environment interaction
19.  Pediatric Allergy 
Journal of Allergy  2012;2012:414762.
PMCID: PMC3363991  PMID: 22685480
20.  Association between Short Sleep Duration and the Risk of Sensitization to Food and Aero Allergens in Rural Chinese Adolescents 
Both long and short sleep duration have been associated with obesity, cardiovascular disease, and diabetes. However, there have been no previous studies investigating the potential relationship between altered sleep duration and allergen sensitization.
To explore the association between sleep duration and sensitization to food and aeroallergens.
This study includes 1534 rural Chinese adolescent twins aged 12 to 21 years who completed standard sleep questionnaires and skin prick tests (SPTs) to 9 food and 5 aeroallergens. Total sleep time was defined as the interval from bedtime to wake-up time minus sleep latency. Sensitization was defined as having at least one positive SPT.
Compared to individuals with the highest (3rd) tertile of sleep duration, those who slept less were more likely to be sensitized to any food allergen with odds ratios (ORs) of 1.9 (95% confidence interval(CI):1.3–2.7) and 1.4 (95%CI:1.0–1.9) for the 1st and 2nd tertiles (trend test Ptrend=3×10−4), respectively. The corresponding ORs for sensitization to any aeroallergen were 1.5 (95%CI: 1.1–2.0) and 1.3 (95%CI:1.0–1.7) (Ptrend=8×10−3). These associations were independent of percent body fat. In addition, we observed a significant dose-response association between the number of positive SPTs and percentage of shortest sleep duration (1st tertile) (Ptrend=1×10−3).
Conclusions and Clinical Relevance
In this sample of relatively lean rural Chinese adolescents, we found that short sleep duration was associated with increased risk of sensitization to food and aeroallergens, independent of percent body fat. Longitudinal studies are needed to further determine the temporal and causal relationships. If short sleep duration indeed is one of the risk factors for allergic sensitization, the global burden of allergic diseases could be dramatically reduced by providing appropriate guidance on sleep duration for youth.
PMCID: PMC3056931  PMID: 21255141
sleep duration; skin prick test; allergen; sensitization; adolescent
21.  Does Genetic Regulation of IgE Begin In-Utero? Evidence from TH1/TH2 Gene Polymorphisms and Cord Blood Total IgE 
Elucidation of early life factors is critical to understand the development of allergic diseases, especially those manifesting in early life such as food allergies and atopic dermatitis. Cord blood IgE (CBIgE) is a recognized risk factor for the subsequent development of allergic diseases. In contrast to numerous genetic studies of total serum IgE in children and adults, limited genetic studies on CBIgE have been conducted.
To test the associations between functional or tagging single nucleotide polymorphisms (SNPs) in genes involved in the TH1/TH2 pathway and CBIgE in a large U.S. inner-city birth cohort.
CBIgE, measured by Phadia ImmnunoCAP, was analyzed as a continuous and a binary variable. The association of each SNP with the two outcomes was tested using tobit and logistic regression models, respectively, with adjustment for pertinent covariates, ancestral proportion, and multiple testing. Ethnic heterogeneity and gene-gene interactions were also explored.
Three SNPs (rs1800925, rs2069743 and rs1295686) in the IL13 gene were significantly associated with CBIgE concentration (p≤6×10-4, pFDR<0.05). These SNPs jointly influenced CBIgE in a dose-response manner (ptrend=9×10-8). Significant associations also were observed for SNPs in the IL13RA1 (rs5956080) and STAT6 (rs11172106) genes. Ethnicity-specific genetic effects were observed for SNPs in the IL5 and GATA3 genes. Several gene-gene interactions (including IL13-IL4R and IL13-STAT6 interactions) were detected in relation to CBIgE.
Our data demonstrated that multiple SNPs were individually and jointly associated with CBIgE, with evidence of gene-gene interactions and ethnic heterogeneity. These findings suggest that genetic regulation of IgE may begin in-utero.
PMCID: PMC3020083  PMID: 21050946
Genetic association; candidate gene; cord blood IgE; gene-gene interaction
22.  Randomized Trial of Omalizumab (Anti-IgE) for Asthma in Inner-City Children 
The New England journal of medicine  2011;364(11):1005-1015.
Research has underscored the effects of exposure and sensitization to allergens on the severity of asthma in inner-city children. It has also revealed the limitations of environmental remediation and guidelines-based therapy in achieving greater disease control.
We enrolled inner-city children, adolescents, and young adults with persistent asthma in a randomized, double-blind, placebo-controlled, parallel-group trial at multiple centers to assess the effectiveness of omalizumab, as compared with placebo, when added to guidelines-based therapy. The trial was conducted for 60 weeks, and the primary outcome was symptoms of asthma.
Among 419 participants who underwent randomization (at which point 73% had moderate or severe disease), omalizumab as compared with placebo significantly reduced the number of days with asthma symptoms, from 1.96 to 1.48 days per 2-week interval, a 24.5% decrease (P<0.001). Similarly, omalizumab significantly reduced the proportion of participants who had one or more exacerbations from 48.8 to 30.3% (P<0.001). Improvements occurred with omalizumab despite reductions in the use of inhaled glucocorticoids and long-acting beta-agonists.
When added to a regimen of guidelines-based therapy for inner-city children, adolescents, and young adults, omalizumab further improved asthma control, nearly eliminated seasonal peaks in exacerbations, and reduced the need for other medications to control asthma. (Funded by the National Institute of Allergy and Infectious Diseases and Novartis; number, NCT00377572.)
PMCID: PMC3093964  PMID: 21410369
23.  Prematurity, Chorioamnionitis and the Development of Recurrent Wheezing: a Prospective Birth Cohort Study 
Prematurity (<37 weeks) has been inconsistently associated with asthma and wheezing. Chorioamnionitis may promote both prematurity and inflammatory pathways in infants’ airways.
To investigate the relationship of prematurity and chorioamnionitis with the development of early childhood recurrent wheezing.
The Boston Birth Cohort (n=1096) were followed prospectively from birth to a mean age of 2.2±2 years. Perinatal and postnatal clinical data and placental pathology were collected. The primary outcome was recurrent wheezing (≥2 physician documented episodes). Secondary outcomes included physician diagnosed asthma, food allergy and eczema. Preterm children were grouped by gestational age into moderately (33-36.9 weeks) and very preterm (<33 weeks) with and without chorioamnionitis, and compared to term children without chorioamnionitis (reference group). Chorioamnionitis was diagnosed either by intrapartum fever or by placental histology findings. Logistic regression models were preformed to investigate the independent and joint associations of degree of prematurity and chorioamnionitis.
Prematurity was associated with recurrent wheezing (OR:1.7, 95%CI:1.2-2.6). However, when subjects were grouped by degree of prematurity with or without chorioamnionitis, the highest risk of wheezing (OR:4.0, 95%CI:2.0-8.0) and physician diagnosed asthma (OR:4.4 95%CI:2.2-8.7) was present in the very preterm children with chorioamnionitis. The effect on both wheezing (OR:5.4, 95%CI:2.4-12.0) and asthma (OR:5.2, 95%CI:2.3-11.9) was greater in African Americans. Neither prematurity nor chorioamnionitis were associated with food allergy or eczema.
We found a strong joint effect of prematurity and chorioamnionitis on early childhood wheezing. This effect was stronger in African Americans.
Clinical Implications
Chorioamnionitis may increase the risk of recurrent wheezing in very low birth weight infants.
PMCID: PMC2993062  PMID: 18313129
Chorioamnionitis; prematurity; recurrent wheezing
24.  Maternal Pre-Pregnancy Obesity and Recurrent Wheezing in Early Childhood 
A number of studies have linked obesity with asthma in adults and children. Few longitudinal studies have evaluated the effect of maternal pre-pregnancy obesity on either asthma or early childhood respiratory morbidity, and these have not been in urban, nonwhite populations. We sought to determine whether pre-pregnancy obesity was associated with recurrent wheezing in an urban, nonwhite population. This study includes 1,191 children from the Boston Birth Cohort (1998–present) followed prospectively to a mean age of 3.0 ± 2.4 years with study visits aligned with the pediatric primary care schedule. Multivariate logistic regression was used to evaluate the associations of maternal pre-pregnancy obesity (body mass index ≥30) with recurrent wheezing (≥4 lifetime episodes). Secondary outcomes included log-transformed cord-blood immunoglobulin E (Phadia), and physician diagnoses of eczema and food allergy. Pre-pregnancy obesity was present in 20.7% of mothers. Of the 1,191 children, 60 (5%) developed recurrent wheezing. Children of obese mothers had an increased risk of recurrent wheezing (adjusted odds ratio, 95% confidence interval: 3.51, 1.68–7.32). These associations persisted even after adjustment for fetal growth status. In contrast, maternal obesity was not associated with eczema or food allergy, and was inversely associated with log cord-blood immunoglobulin E (β, 95% confidence interval: −0.34, −0.66 to −0.02). In this predominantly urban, multiracial/ethnic birth cohort, maternal pre-pregnancy obesity was associated with an increased risk of recurrent wheezing. This association was not explained by fetal growth or increased atopy. Maternal pre-pregnancy obesity is a prevalent risk factor for respiratory morbidity in this urban, nonwhite population.
PMCID: PMC3281288  PMID: 22375278
25.  Early Life Eczema, Food Introduction, and Risk of Food Allergy in Children 
The effect of food introduction timing on the development of food allergy remains controversial. We sought to examine whether the presence of childhood eczema changes the relationship between timing of food introduction and food allergy. The analysis includes 960 children recruited as part of a family-based food allergy cohort. Food allergy was determined by objective symptoms developing within 2 hours of ingestion, corroborated by skin prick testing/specific IgE. Physician diagnosis of eczema and timing of formula and solid food introduction were obtained by standardized interview. Cox Regression analysis provided hazard ratios for the development of food allergy for the same subgroups. Logistic regression models estimated the association of eczema and formula/food introduction with the risk of food allergy, individually and jointly. Of the 960 children, 411 (42.8%) were allergic to 1 or more foods and 391 (40.7%) had eczema. Children with eczema had a 8.4-fold higher risk of food allergy (OR, 95% CI: 8.4, 5.9–12.1). Among all children, later (>6 months) formula and rice/wheat cereal introduction lowered the risk of food allergy. In joint analysis, children without eczema who had later formula (OR, 95% CI: 0.5, 0.3–0.9) and later (>1 year) solid food (OR, 95% CI: 0.5, 0.3–0.95) introduction had a lower risk of food allergy. Among children with eczema, timing of food or formula introduction did not modify the risk of developing food allergy. Later food introduction was protective for food allergy in children without eczema but did not alter the risk of developing food allergy in children with eczema.
PMCID: PMC3281290  PMID: 22375277

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