Deepa Rastogi

Obesity-Associated Asthma in Children: A Distinct Entity

BACKGROUND Obesity-associated asthma has been proposed to be a distinct entity, differing in immune pathogenesis from atopic asthma. Both obesity-mediated inflammation and increase in adiposity are potential mechanistic factors that are poorly defined among children. We hypothesized that pediatric obesity-associated asthma would be characterized by T helper (Th) 1, rather than the Th2 polarization associated with atopic asthma. Moreover, we speculated that Th1 biomarkers and anthropometric measures would correlate with pulmonary function tests (PFTs) in obese asthmatic children. METHODS We recruited 120 children, with 30 in each of the four study groups: obese asthmatic children, nonobese asthmatic children, obese nonasthmatic children, and nonobese nonasthmatic children. All children underwent pulmonary function testing. Blood was collected for measurement of serum cytokines. T-cell responses to mitogen, phorbol 12-myristate 13-acetate (PMA), or antigens tetanus toxoid or Dermatophagoides farinae were obtained by flow cytometric analysis of intracellular cytokine staining for interferon-γ (IFN-γ) (Th1) or IL-4 (Th2) within the CD4 population. RESULTS Obese asthmatic children had significantly higher Th1 responses to PMA (P < .01) and tetanus toxoid (P < .05) and lower Th2 responses to PMA (P < .05) and D farinae (P < .01) compared with nonobese asthmatic children. Th-cell patterns did not differ between obese asthmatic children and obese nonasthmatic children. Obese asthmatic children had lower FEV(1)/FVC (P < .01) and residual volume/total lung capacity ratios (P < .005) compared with the other study groups, which negatively correlated with serum interferon-inducible protein 10 and IFN-γ levels, respectively. PFTs, however, did not correlate with BMI z score or waist to hip ratio. CONCLUSIONS We found that pediatric obesity-associated asthma differed from atopic asthma and was characterized by Th1 polarization. The altered immune environment inversely correlated with PFTs in obese asthmatic children.

Inflammation, Metabolic Dysregulation, and Pulmonary Function among Obese Urban Adolescents with Asthma

RATIONALE Insulin resistance and low high-density lipoprotein (HDL) are associated with pulmonary morbidity, including asthma, but the underlying mechanisms are not well elucidated. OBJECTIVES To investigate whether systemic inflammation underlies the association of metabolic abnormalities with pulmonary function among urban adolescents. METHODS Th-cell responses and monocyte subsets, and their association with serum homeostatic model assessment of insulin resistance (HOMA-IR) and HDL, and pulmonary function were quantified in 168 adolescents, including 42 obese subjects with asthma, 42 normal-weight subjects with asthma, 40 obese subjects without asthma, and 44 healthy control subjects. Th-cell responses (Th1 [CD4(+)IFNγ(+)] and Th2 [CD4(+)IL4(+)] cells) to stimulation with phytohemagglutinin, leptin, and dust mite, and classical (CD14(+)CD16(-)), resident (CD14(+)CD16(+)), and patrolling (CD14dimCD16(+)) monocytes, and their C-C chemokine receptor type-2 (CCR2) expression were quantified by flow cytometry. MEASUREMENTS AND MAIN RESULTS Th1/Th2 ratio to all three stimuli was higher in obese subjects with asthma than normal-weight subjects with asthma and directly correlated with HOMA-IR. Classical monocytes inversely associated with Th1/Th2 ratio to phytohemagglutinin (r = -0.43; P = 0.01) and directly with Asthma Control Test score (β = 1.09; P = 0.04), while patrolling monocytes correlated with Composite Asthma Severity Index score (β = 1.11; P = 0.04) only among obese subjects with asthma. HDL was inversely associated with patrolling monocytes and directly associated with CCR2 expression on resident monocytes. CCR2 expression on patrolling monocytes predicted residual volume (RV), RV/TLC ratio, and FRC, after adjusting for HDL, but not after adjusting for body mass index. Association of Th1/Th2 ratio with RV, FRC, and inspiratory capacity was attenuated after adjusting for HOMA-IR. CONCLUSIONS Th1 polarization and monocyte activation among obese subjects with asthma correlates with metabolic abnormalities. Association of monocyte activation with pulmonary function is mediated by body mass index, whereas that of Th1 polarization is mediated by insulin resistance.

Differential epigenome-wide DNA methylation patterns in childhood obesity-associated asthma

While DNA methylation plays a role in T-helper (Th) cell maturation, its potential dysregulation in the non-atopic Th1-polarized systemic inflammation observed in obesity-associated asthma is unknown. We studied DNA methylation epigenome-wide in peripheral blood mononuclear cells (PBMCs) from 8 obese asthmatic pre-adolescent children and compared it to methylation in PBMCs from 8 children with asthma alone, obesity alone and healthy controls. Differentially methylated loci implicated certain biologically relevant molecules and pathways. PBMCs from obese asthmatic children had distinctive DNA methylation patterns, with decreased promoter methylation of CCL5, IL2RA and TBX21, genes encoding proteins linked with Th1 polarization, and increased promoter methylation of FCER2, a low-affinity receptor for IgE, and of TGFB1, inhibitor of Th cell activation. T-cell signaling and macrophage activation were the two primary pathways that were selectively hypomethylated in obese asthmatics. These findings suggest that dysregulated DNA methylation is associated with non-atopic inflammation observed in pediatric obesity-associated asthma.

Humoral and Cell-Mediated Immune Responses to Monovalent 2009 Influenza A/H1N1 and Seasonal Trivalent Influenza Vaccines in High-Risk Children

OBJECTIVE Humoral and cell-mediated immune responses to monovalent 2009 pandemic influenza A (H1N1/2009) and seasonal trivalent influenza (TIV) vaccines were evaluated in healthy children and children with asthma, sickle cell disease (SCD), systemic lupus erythematosus (SLE), and solid organ transplantation (SOT). STUDY DESIGN Blood was collected from 112 subjects at the time of H1N1/2009 vaccination and 46 ± 15 days later for hemagglutination inhibition titers and γ-interferon ELISPOT responses to H1N1/2009 vaccine and TIV; unvaccinated children also received TIV at enrollment. RESULTS A significant increase in the percentage of subjects with seroprotective hemagglutination inhibition titers to both vaccines was observed in all high-risk groups. Children with asthma and SCD were most likely to achieve seroprotective titers to H1N1/2009, whereas <50% of subjects with SOT and SLE had a seroprotective response. Subjects with SOT and SLE also had lower rates of seroprotection after TIV, and subjects with SLE had the lowest ELISPOT responses to both vaccines. Overall, 73% of healthy children exhibited protective responses to TIV; only 35% achieved seroprotection for H1N1/2009. CONCLUSIONS This evaluation of immune responses to H1N1/2009 in high-risk children suggests suboptimal responses for SOT and SLE subjects, but not for subjects with SCD or asthma. Higher antigen dose, additional dose regimens, or both for immunocompromised children warrant further investigation.

Comparison of patterns of allergen sensitization among inner-city Hispanic and African American children with asthma

BACKGROUND Among Hispanics, the largest minority ethnic group in the United States, asthma prevalence is increasing, particularly in inner-city neighborhoods. Although allergen sensitization among asthmatic African Americans has been extensively studied, similar details are not available for Hispanic children. OBJECTIVES To examine patterns of allergen sensitization, including the association with illness severity, in asthmatic children overall and in Hispanic and African American children living in a socioeconomically disadvantaged area of New York City. METHODS A retrospective medical record review of asthmatic children attending a community hospital in the South Bronx area of New York City was performed. Information abstracted included demographics, asthma severity classification, reported exposures to indoor allergens, and results of allergy testing. RESULTS Among 384 children in the analysis, 270 (70.3%) were Hispanic and 114 (29.7%) were African American. Sensitization to indoor and outdoor allergens, respectively, did not differ between Hispanic (58.5% and 27.0%) and African American (58.8% and 32.6%) children. Allergen sensitization exhibited a direct, significant association with asthma severity for indoor allergens for the 2 ethnic groups combined and for Hispanics separately but not between asthma severity and outdoor allergens (P < .01). No correlation was found between self-reported allergen exposure and sensitization. CONCLUSIONS Patterns of allergen sensitization among inner-city Hispanic asthmatic children resemble those among African American children, a finding that is likely explained by the similarity in levels of environmental exposures. With the increasing prevalence of asthma among inner-city Hispanic children, skin testing should be used frequently for objective evaluation of asthma in this ethnic group.

Association of pulmonary function with adiposity and metabolic abnormalities in urban minority adolescents.

RATIONALE Childhood obesity is a known risk factor for pulmonary diseases, likely due to obesity-mediated alteration of pulmonary function. Inflammation and mechanical fat load are two proposed causative mechanisms for altered pulmonary function among obese children; however, the association of metabolic abnormalities with pulmonary function among children is poorly understood. OBJECTIVES We investigated the independent association of truncal and general adiposity and metabolic abnormalities with pulmonary function in a sample of urban minority adolescents. METHODS Spirometry and lung volume indices were compared between adolescents with general (body mass index [BMI] > 95th percentile) or truncal adiposity (waist circumference > 90th percentile) and normal-weight (BMI < 85th percentile or waist circumference ≤ 90th percentile) and between those with metabolic abnormalities (homeostatic model assessment of insulin resistance [HOMA-IR] in the top quartile or high-density lipoprotein [HDL] < 40 mg/dl) and those with a normal metabolic profile. MEASUREMENTS AND MAIN RESULTS Obese adolescents had lower lung volumes, including residual volume (RV), RV/TLC ratio, expiratory reserve volume (ERV), and FRC, and higher inspiratory capacity (IC) than normal-weight adolescents, but did not differ in measures of lower airway obstruction, FEV1/FVC ratio, and mid-expiratory flow rate. Adolescents with high HOMA-IR had lower FEV1/FVC ratio, RV, RV/TLC ratio, ERV, and FRC and higher IC, whereas those with low HDL had lower FEV1/FVC and RV/TLC ratios. After adjusting for adiposity, HOMA-IR remained a predictor of ERV (β = -1.4; P = 0.02) and FEV1/FVC ratio (β = -0.5; P = 0.03), and HDL remained a predictor of FEV1/FVC ratio (β = 0.1; P = 0.01). General adiposity was a predictor of FRC (β = -0.5; P < 0.001), IC (β = 0.3; P < 0.001), RV (β = -0.8; P < 0.0001), and RV/TLC ratio (β = -0.2; P < 0.0001), and truncal adiposity was a predictor of RV (β = -20.3; P = 0.03) and FRC (β = -13.8; P = 0.004). Thus, adiposity and metabolic abnormalities were independent predictors of ERV, but only metabolic abnormalities independently predicted FEV1/FVC ratio. Although general adiposity predicted RV and RV/TLC ratio, truncal adiposity was predictive of RV and FRC, conferring additional risk above general adiposity. CONCLUSIONS These results suggest that metabolic abnormalities and adiposity are independently associated with pulmonary function deficits among urban adolescents. Metabolic assessment of obese adolescents may identify those at risk of developing obesity-associated pulmonary morbidity.

The Association of Overweight and Obesity with Spirometric Values in Minority Children Referred for Asthma Evaluation

Background. Overweight, obesity, and asthma are more prevalent in minority children; yet, the association of overweight and obesity with spirometric values in asthmatic minorities is not well characterized. Objective. To study the relationship between weight, ethnicity, and spirometric values in children referred for asthma evaluation to a large inner-city hospital in Bronx, NY. Methods. Retrospective review of spirometry done at the first pulmonary clinic visit of 980 asthmatic children, aged 7–20 years, was conducted. Linear regression analysis was performed to elucidate the association of overweight and obesity with pulmonary function among Whites, African Americans, and Hispanics compared with their normal weight counterparts. Results. More African Americans (58%) and Hispanics (65.4%) were overweight and obese than Whites (51.2%) (p < .05). Compared with their normal weight counterparts, percent forced expiratory volume in the 1st second (FEV1)/forced vital capacity (FVC) ratio was lower in both overweight and obese African Americans (2.99%, p < .05 and 3.56%, p < .01, respectively) and Hispanics (2.64%, p < .05 and 2.36%, p < .05, respectively); these differences were found in obese (3.73%, p < .05) but not in overweight (0.68%, p = .7) Whites. Conclusions. FEV1/FVC ratio was lower in both overweight and obese African American and Hispanic children, while this association was present only among obese Whites compared with their normal weight counterparts. These results suggest that spirometric measures of lower airway obstruction decrease with smaller weight increments in minority children when compared with White children. In the context of the higher prevalence of overweight and obesity among African Americans and Hispanics, our findings offer one potential explanation for increased asthma among minority children.

Gradual Versus Sudden Weaning From Nasal CPAP in Preterm Infants: A Pilot Randomized Controlled Trial

BACKGROUND: There is paucity of information on the weaning of nasal CPAP (NCPAP) in preterm infants. As the weaning from NCPAP can be gradual or sudden, we wanted to determine which of the 2 methods was better. METHODS: A prospective randomized trial was conducted to compare the success of weaning from NCPAP when using the sudden and gradual weaning methods in infants born ≤ 32 weeks. We also compared the weight, post-menstrual age when these infants were successfully weaned from NCPAP, and their length of stay in the hospital. RESULTS: Of the 56 infants included in the study, 28 infants were randomized to each weaning method. The gestational age, birth weight, and other clinical factors were similar between the 2 groups. There was no difference in the rate of success of initial weaning between the 2 methods (P = .65). The infants were successfully weaned at 33.7 ± 2.8 weeks versus 33.8 ± 2.6 weeks (P = .93) post-menstrual age, and at 1,736 ± 487 g versus 1,736 ± 501 g (P = .99) weight in the sudden wean and gradual wean groups, respectively. Length of stay was 61.3 ± 19.6 days for the sudden wean group and 66.0 ± 27.1 days for the gradual wean group (P = .48). CONCLUSIONS: There was no difference in the success of weaning from NCPAP between the 2 weaning methods. The weight and post-menstrual age at the time of successful NCPAP wean also did not differ between the 2 groups. These findings suggest that factors other than the method of CPAP wean, such as pulmonary maturity, may determine the success of NCPAP wean in preterm infants.

Associations of obesity and asthma with functional exercise capacity in urban minority adolescents.

To examine the independent association of asthma and obesity and of their co‐existence with functional exercise capacity among urban adolescents.

Weaning of nasal CPAP in preterm infants: who, when and how? a systematic review of the literature

BackgroundThere is increased use of early nasal continuous positive airway pressure (NCPAP) to manage respiratory distress in preterm infants but optimal methods and factors associated with successful wean are not well defined. A systematic review was performed to define the corrected gestational age (CGA), weight to wean NCPAP and the methods associated with successful weaning of the NCPAP among preterm infants, along with factors affecting it.MethodsSearches were made of PubMed using the keywords-NCPAP, CPAP, weaning, withdrawal, preterm, and infants from its inception to January 1st, 2014, for studies in all languages but limited to humans. Previous reviews (including cross references) were also searched. We included all randomized and quasi-randomized controlled trials where preterm neonates were randomized to different NCPAP weaning strategies. Details of CGA, weight and methods used for weaning NCPAP were extracted along with factors which affect its withdrawal.ResultsSeven studies met the search criteria. The successful wean was at 32 to 33 weeks CGA and at 1600 g. Three different methods were used for weaning were sudden, gradual pressure wean and gradual graded time off wean. Criteria for readiness, success and failure to wean were defined. Factors affecting successful weaning were intubation, anemia, infection and gastro-esophageal reflux.ConclusionsThe successful wean was at 32 to 33 weeks CGA and 1600 g. Criteria for readiness, success and failure to wean are well defined. Sudden weaning may be associated with a shorter weaning time. Future trials are needed comparing weaning methods using defined criteria for readiness and success of NCPAP wean and stratify the results by gestational age and birth weight.