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1.  Diagnostic accuracy of the bronchodilator response in children 
Background
The bronchodilator response (BDR) reflects the reversibility of airflow obstruction and is recommended as an adjunctive test to diagnose asthma. The validity of the commonly used definition of BDR, a 12% or greater change in FEV1 from baseline, has been questioned in childhood.
Objectives
We sought to examine the diagnostic accuracy of the BDR test by using 3 large pediatric cohorts.
Methods
Cases include 1041 children with mild-to-moderate asthma from the Childhood Asthma Management Program.
Control subjects (nonasthmatic and nonwheezing) were chosen from Project Viva and Home Allergens, 2 population-based pediatric cohorts. Receiver operating characteristic curves were constructed, and areas under the curve were calculated for different BDR cutoffs.
Results
A total of 1041 cases (59.7% male; mean age, 8.9 ± 2.1 years) and 250 control subjects (46.8% male; mean age, 8.7 ± 1.7 years) were analyzed, with mean BDRs of 10.7% ± 10.2% and 2.7% ± 8.4%, respectively. The BDR test differentiated asthmatic patients from nonasthmatic patients with a moderate accuracy (area under the curve, 73.3%).
Despite good specificity, a cutoff of 12% was associated with poor sensitivity (35.6%). A cutoff of less than 8% performed significantly better than a cutoff of 12% (P = .03, 8% vs 12%).
Conclusions
Our findings highlight the poor sensitivity associated with the commonly used 12% cutoff for BDR. Although our data show that a threshold of less than 8% performs better than 12%, given the variability of this test in children, we conclude that it might be not be appropriate to choose a specific BDR cutoff as a criterion for the diagnosis of asthma.
doi:10.1016/j.jaci.2013.03.031
PMCID: PMC3759549  PMID: 23683464
Asthma; bronchodilator response; diagnosis
2.  Higher adiposity in infancy associated with recurrent wheeze in a prospective cohort of children 
Background
Few prospective data link early childhood adiposity with asthma-related symptoms.
Objective
We sought to examine the associations of weight-for-length (WFL) at age 6 months with incidence of wheezing by age 3 years.
Methods
We studied 932 children in a prospective cohort of children. The main outcome was recurrent wheezing, which was defined as parents’ report of wheezing between 2 and 3 years of age plus wheezing in either year 1 or 2 of life. Secondary outcomes included any wheezing from 6 months to 3 years and current asthma. We used multiple logistic regression to examine associations of 6-month WFL z scores with these outcomes.
Results
At 6 months, the infants’ mean WFL z score was 0.68 (SD, 0.94; range −2.96 to 3.24). By age 3 years, 14% of children had recurrent wheezing. After adjustment for a variety of potential confounders, we found that each 1-unit increment in 6-month WFL z score was associated with greater odds of recurrent wheezing (odds ratio [OR], 1.46; 95% CI, 1.11–1.91) and any wheezing (OR, 1.23; 95% CI, 1.03–1.48). We observed a weaker association between 6-month WFL z score and current asthma (OR, 1.22; 95% CI, 0.94–1.59).
Conclusion
Infants with higher WFL z scores at 6 months of age had a greater risk of recurrent wheezing by age 3 years. It is unclear whether the relationship of infant adiposity and early-life wheeze extends to allergic asthma or wheeze that can persist into later childhood. Our findings suggest that early interventions to prevent excess infant adiposity might help reduce children’s risk of asthma-related symptoms.
doi:10.1016/j.jaci.2008.03.021
PMCID: PMC3253368  PMID: 18466784
Asthma; wheeze; adiposity; children; prospective study
3.  Prenatal, perinatal, and heritable influences on cord blood immune responses 
Background
Maternal and perinatal environmental exposures, as well as inherited factors, may influence neonatal immune responses.
Objective
To determine relations of maternal and perinatal exposures to antigen-specific cord blood lymphoproliferative responses.
Methods
In 427 newborns from a Boston pregnancy/birth cohort, lymphoproliferative responses in cord blood mononuclear cells to stimulation with cockroach (Bla g 2), house dust mite (Der f 1), ovalbumin, and mitogen phytohemagglutinin were measured as stimulation index (SI). We used the Wilcoxon rank sum and χ2 tests to evaluate predictors of ovalbumin SI as a continuous ranked or dichotomous outcome. We used t test and Spearman correlation for univariate testing and linear regression to evaluate predictors of natural log-transformed Bla g 2, Der f 1, and phytohemagglutinin SI. Logistic multivariate regression was applied to evaluate predictors of Bla g 2, Der f 1, and phytohemagglutinin SI dichotomized at 2 or at the median for phytohemagglutinin.
Results
Maternal smoking during pregnancy, inadequate or excessive maternal weight gain during pregnancy, neonate black race/ethnicity (compared with white), and Apgar score less than 8 were each independently associated with increased cord blood mononuclear cell proliferative responses to stimulation with Bla g 2 and/or Der f 1. Maternal history of asthma was associated only with increased lymphoproliferative response to ovalbumin stimulation.
Conclusions
Distinct fetal and perinatal exposures and black race/ethnicity may be associated with increased cord blood lymphoproliferative responses. The implications of these findings for future development of allergy or asthma are, as yet, unknown.
PMCID: PMC1562525  PMID: 16597079
4.  Associations of cord blood fatty acids with lymphocyte proliferation, IL-13, and IFN-γ 
Background. N-3 and n-6 polyunsaturated fatty acids (PUFAs) have been hypothesized to have opposing influences on neonatal immune responses that might influence the risk of allergy or asthma. However, both n-3 eicosapentaenoic acid (EPA) and n-6 arachidonic acid (AA) are required for normal fetal development.
Objective. We evaluated whether cord blood fatty acid levels were related to neonatal immune responses and whether n-3 and n-6 PUFA responses differed.
Methods. We examined the relation of cord blood plasma n-3 and n-6 PUFAs (n = 192) to antigen- and mitogen-stimulated cord blood lymphocyte proliferation (n = 191) and cytokine (IL-13 and IFN-γ; n = 167) secretion in a US birth cohort.
Results. Higher levels of n-6 linoleic acid were correlated with higher IL-13 levels in response to Bla g 2 (cockroach, P = .009) and Der f 1 (dust mite, P = .02). Higher n-3 EPA and n-6 AA levels were each correlated with reduced lymphocyte proliferation and IFN-γ levels in response to Bla g 2 and Der f 1 stimulation. Controlling for potential confounders, EPA and AA had similar independent effects on reduced allergen-stimulated IFN-γ levels. If neonates had either EPA or AA levels in the highest quartile, their Der f 1 IFN-γ levels were 90% lower (P = .0001) than those with both EPA and AA levels in the lowest 3 quartiles. Reduced AA/EPA ratio was associated with reduced allergen-stimulated IFN-γ level.
Conclusion. Increased levels of fetal n-3 EPA and n-6 AA might have similar effects on attenuation of cord blood lymphocyte proliferation and IFN-γ secretion.
Clinical implications. The implications of these findings for
doi:10.1016/j.jaci.2005.12.1322
PMCID: PMC1508138  PMID: 16630954
Asthma; child; cord blood; cytokine; fatty acids; lymphocyte proliferation; AA: Arachidonic acid; BMI: Body mass index; CBMC: Cord blood mononuclear cell; CI: Confidence interval; DHA: Docosohexaenoic acid; EPA: Eicosapentaenoic acid; FA: Fatty acid; LA: Linoleic acid; NICU: Neonatal intensive care unit; OVA: Ovalbumin; PG: Prostaglandin; PUFA: Polyunsaturated fatty acid; SI: Stimulation index
5.  Perinatal Predictors of Atopic Dermatitis Occurring in the First Six Months of Life 
Pediatrics  2004;113(3 Pt 1):468-474.
Objective
Previous studies of predictors of atopic dermatitis have had limited sample size, small numbers of variables, or retrospective data collection. The purpose of this prospective study was to investigate several perinatal predictors of atopic dermatitis occurring in the first 6 months of life.
Design
We report findings from 1005 mothers and their infants participating in Project Viva, a US cohort study of pregnant women and their offspring. The main outcome measure was maternal report of a provider’s diagnosis of eczema or atopic dermatitis in the first 6 months of life. We used multiple logistic regression models to assess the associations between several simultaneous predictors and incidence of atopic dermatitis.
Results
Cumulative incidence of atopic dermatitis in the first 6 months of life was 17.1%. Compared with infants born to white mothers, the adjusted odds ratio (OR) for risk of atopic dermatitis among infants born to black mothers was 2.41 (95% confidence interval [CI]: 1.47, 3.94) and was 2.58 among infants born to Asian mothers (95% CI: 1.27, 5.24). Male infants had an OR of 1.76 (95% CI: 1.24, 2.51). Increased gestational age at birth was a predictor (OR: 1.14; 95% CI: 1.02, 1.27, for each 1-week increment), but birth weight for gestational age was not. Infants born to mothers with a history of eczema had an OR of 2.67 (95% CI: 1.74, 4.10); paternal history of eczema also was predictive, although maternal atopic history was more predictive than paternal history. Several other perinatal, social, feeding, and environmental variables were not related to risk of atopic dermatitis.
Conclusions
Black and Asian race/ethnicity, male gender, higher gestational age at birth, and family history of atopy, particularly maternal history of eczema, were associated with increased risk of atopic dermatitis in the first 6 months of life. These findings suggest that genetic and pre- and perinatal influences are important in the early presentation of this condition. Pediatrics
PMCID: PMC1488729  PMID: 14993536
atopic dermatitis; eczema; perinatal; infancy; gestational age; race/ethnicity; gender; BMI, body mass index; OR, odds ratio; CI, confidence interval; IgE, immunoglobulin E
6.  Association of Birth Weight With Asthma-Related Outcomes at Age 2 Years 
Pediatric pulmonology  2006;41(7):643-648.
Summary. Background: Although lower birth weight associated with prematurity raises the risk of asthma in childhood, few prospective studies have examined higher birth weight, and few have separated the two components of birth weight, fetal growth and length of gestation.
Objective. To examine the associations of fetal growth and length of gestation with asthma-related outcomes by age 2 years.
Methods. We studied 1,372 infants and toddlers born after 34 weeks’ gestation in Project Viva, a prospective cohort study of pregnant mothers and their children. The main outcome measures were parent report of (1) any wheezing (or whistling in the chest) from birth to age 2 years, (2) recurrent wheezing during the first 2 years of life, and (3) doctor’s diagnosis of asthma, wheeze or reactive airwaydisease (“asthma”) by age 2. We calculated gestational age from the last menstrual period or ultrasound examination, and determined birth weight for gestational age z-value (“fetal growth”) using US national reference data.
Results. Infants’ mean birth weight was 3,527 (SD, 517; range, 1,559–5,528) grams. By age 2 years, 34% of children had any wheezing, 14% had recurrent wheezing, and 16% had doctor-diagnosed asthma. After adjusting for several parent, child, and household characteristics in logistic regression models, we found that infants with birth weight ≥4,000 g were not more likely to have any wheezing (odds ratio (OR), 0.91; 95% confidence interval (CI): 0.62, 1.34) or doctor-diagnosed asthma (OR, 0.80; 95% CI: 0.49, 1.31) than infants with birth weight 3,500–3,999 g. In models examining length of gestation and fetal growth separately, neither the highest nor the lowest groups of either predictor were associated with the three outcomes. Boys had a higher incidence of asthma-related outcomes than girls, and exposure to passive smoking, parental history of asthma, and exposure to older siblings were all associated with greater risk of recurrent wheeze or asthma-related outcomes at age 2 years.
Conclusion. Although male sex, exposure to smoking, parental history of asthma, and exposure to older siblingswere associated with increased riskof wheezing and asthma-related outcomes in this prospective study of children born after 34 weeks gestation, fetal growth and length of gestation were not.
doi:10.1002/ppul.20427
PMCID: PMC1488724  PMID: 16703577
asthma; birth weight; fetal growth; length of gestation; wheezing
7.  Cord Blood Cytokines and Acute Lower Respiratory Illnesses in the First Year of Life 
Pediatrics  2006;119(1):e171-e178.
OBJECTIVES
Little is known about the relation between cytokine profile at birth and acute lower respiratory illnesses in the first year of life. The purpose of this work was to examine the relation between cytokine secretions by cord blood mononuclear cells and acute lower respiratory illness in a birth cohort of 297 children.
METHODS
Cord blood mononuclear cells were isolated, and secretion of interferon-γ, interleukin-13, interleukin-10, and tumor necrosis factor-α at baseline and in response to allergens (Blatella germanica 2 and Dermatophagoides farinae 1) and mitogen (phytohemagglutinin) were quantified using enzyme-linked immunosorbent assay. Acute lower respiratory illness was defined as a parental report of a diagnosis of bronchiolitis, pneumonia, bronchitis, and/or croup by a health care professional in the first year of life. Differences in the levels of cord blood cytokines between children with and without acute lower respiratory illness were examined using 2-sample Wilcoxon tests. Logistic regression models were used to examine the relation between various categories of cord blood cytokines and acute lower respiratory illness.
RESULTS
Median levels of interferon-γ secreted by cord blood mononuclear cells in response to Blatella germanica 2 and Dermatophagoides farinae 1 were higher among children without acute lower respiratory illness as compared with children with acute lower respiratory illness. After adjustment for other covariates, the odds of acute lower respiratory illness was reduced among children in the top category (at or more than the median of detectable values) of interferon-γ level, significantly so in response to Blatella germanica 2.
CONCLUSIONS
In a cohort of children from the general population, we found that upregulated interferon-γ secretion at birth is associated with reduced risk of acute lower respiratory illness in the first year of life.
doi:10.1542/peds.2006-0524
PMCID: PMC1994927  PMID: 17145902
lower respiratory illnesses; cytokines; neonates; IFN-γ

Results 1-7 (7)