Search

Genetic factors and early-life exposures1 are both important determinants of childhood asthma. Among the more than 150 loci identified in genome-wide association studies (GWAS), 17q12-q21 is the most replicated childhood-onset asthma locus.2 Fine-mapping at this locus has been difficult in populations of European ancestry because of extensive linkage disequilibrium (LD) in this region. Taking advantage of the reduced LD in African ancestry populations, we3 and others4,5 have shown that single nucleotide polymorphisms (SNPs) in GSDMB are likely causal for childhood-onset asthma at this locus. However, it remains unclear whether the same variants underlie the many genotype-exposure interaction (GEI) effects.

Background: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12–21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12–21 locus. Methods: We first did a genetic association study and meta-analysis using 17q12–21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12–21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12–21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA). Findings: 17q12–21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p

Background Few studies have examined longitudinal asthma incidence rates (IRs) from a public health surveillance perspective. Objective Our aim was to calculate descriptive asthma IRs in children over time with consideration for demographics and parental asthma history. Methods Data from 9 US birth cohorts were pooled into 1 population covering the period from 1980 to 2017. The outcome was earliest parental report of a doctor diagnosis of asthma. IRs per 1,000 person-years were calculated. Results The racial/ethnic backgrounds of the 6,283 children studied were as follows: 55% European American (EA), 25.5% African American (AA), 9.5% Mexican-Hispanic American (MA) and 8.5% Caribbean-Hispanic American (CA). The average follow-up was 10.4 years (SD = 8.5 years; median = 8.4 years), totaling 65,291 person-years, with 1789 asthma diagnoses yielding a crude IR of 27.5 per 1,000 person-years (95% CI = 26.3-28.8). Age-specific rates were highest among children aged 0 to 4 years, notably from 1995 to 1999, with a decline in EA and MA children in 2000 to 2004 followed by a decline in AA and CA children in 2010 to 2014. Parental asthma history was associated with statistically significantly increased rates. IRs were similar and higher in AA and CA children versus lower but similar in EA and MA children. The differential rates by sex from birth through adolescence principally resulted from a decline in rates among males but relatively stable rates among females. Conclusions US childhood asthma IRs varied dramatically by age, sex, parental asthma history, race/ethnicity, and calendar year. Higher rates in the 0- to 4-year-olds group, particularly among AA/CA males with a parental history of asthma, as well as changes in rates over time and by demographic factors, suggest that asthma is driven by complex interactions between genetic susceptibility and variation in time-dependent environmental and social factors.

BACKGROUND: Prenatal and early life exposure to maternal stress and depression is linked to development of recurrent wheezing in young children. OBJECTIVE: To determine whether maternal stress and depression in early life is associated with non-atopic wheezing phenotype in urban children. METHODS: The Urban Environment and Childhood Asthma Study examined a birth cohort of children at high risk for asthma in low-income neighborhoods. Prenatal and postnatal (through age three years) maternal stress and depression scores were compared to respiratory phenotypes through age ten years (multinomial regression), self-reported colds (linear regression) and detection of respiratory viruses (Poisson regression). RESULTS: Scores for maternal depression, and, to a lesser extent, maternal perceived stress, were positively related to multiple wheezing phenotypes. In particular, cumulative measures of maternal depression in the first three years were related to the moderate wheeze-low atopy (MW-LA) phenotype (OR=1.13; [1.05, 1.21]; p

BACKGROUND: Black and Hispanic children growing up in disadvantaged urban neighborhoods have the highest rates of asthma and related morbidity in the United States. OBJECTIVE: To identify specific respiratory phenotypes of health and disease in this population, associations with early-life exposures, and molecular patterns of gene expression in nasal epithelial cells that underlie clinical disease. METHODS: The study population consisted of 442 high-risk urban children who had repeated assessments of wheezing, allergen-specific IgE, and lung function through age 10 years. Phenotypes were identified by developing temporal trajectories for these data, and then compared to early life exposures and patterns of nasal epithelial gene expression at age 11. RESULTS: Of the 6 identified respiratory phenotypes, a high-wheeze high-atopy low-lung-function (HW-HA-LF) group had the greatest respiratory morbidity. In early life, this group had low exposure to common allergens and high exposure to ergosterol in house dust. While all high atopy groups were associated with increased expression of a type-2 inflammation gene module in nasal epithelial samples, an epithelium IL-13 response module tracked closely with impaired lung function, and a MUC5AC hypersecretion module was uniquely upregulated in HW-HA-LF. In contrast, a medium-wheeze low-atopy (MW-LA) group showed altered expression of modules of epithelial integrity, epithelial injury, and antioxidant pathways. CONCLUSION: In the first decade of life, high-risk urban children develop distinct phenotypes of respiratory health versus disease that link early-life environmental exposures to childhood allergic sensitization and asthma. Moreover, unique patterns of airway gene expression demonstrate how specific molecular pathways underlie distinct respiratory phenotypes, including allergic and non-allergic asthma. CAPSULE SUMMARY: We have demonstrated both distinct respiratory phenotypes – which develop by age 10 and link to asthma development – and related functional gene expression networks in respiratory epithelium.

Environmental exposures in early life appear to play an important role in the pathogenesis of childhood asthma, but the potentially modifiable exposures that lead to asthma remain uncertain.We sought to identify early-life environmental risk factors for childhood asthma in a birth cohort of high-risk inner-city children.We examined the relationship of prenatal and early-life environmental factors to the occurrence of asthma at 7 years of age among 442 children.Higher house dust concentrations of cockroach, mouse, and cat allergens in the first 3 years of life were associated with lower risk of asthma (for cockroach allergen: odds ratio per interquartile range increase in concentration, 0.55; 95% CI, 0.36-0.86; P .01). House dust microbiome analysis using 16S ribosomal RNA sequencing identified 202 and 171 bacterial taxa that were significantly (false discovery rate 0.05) more or less abundant, respectively, in the homes of children with asthma. A majority of these bacteria were significantly correlated with 1 of more allergen concentrations. Other factors associated significantly positively with asthma included umbilical cord plasma cotinine concentration (odds ratio per geometric SD increase in concentration, 1.76; 95% CI, 1.00-3.09; P = .048) and maternal stress and depression scores.Among high-risk inner-city children, higher indoor levels of pet or pest allergens in infancy were associated with lower risk of asthma. The abundance of a number of bacterial taxa in house dust was associated with increased or decreased asthma risk. Prenatal tobacco smoke exposure and higher maternal stress and depression scores in early life were associated with increased asthma risk.

Background Given the strong environmental influence on both epigenetic marks and allergic asthma in children, the epigenetic alterations in respiratory epithelia might provide insight into allergic asthma. Objective We sought to identify DNA methylation and gene expression changes associated with childhood allergic persistent asthma. Methods We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma (n = 36) versus healthy control subjects (n = 36). Results were validated in an independent population of asthmatic children (n = 30) by using a shared healthy control population (n = 36) and in an independent population of white adult atopic asthmatic patients (n = 12) and control subjects (n = 12). Results We identified 186 genes with significant methylation changes, differentially methylated regions or differentially methylated probes, after adjustment for age, sex, race/ethnicity, batch effects, inflation, and multiple comparisons. Genes differentially methylated included those with established roles in asthma and atopy and genes related to extracellular matrix, immunity, cell adhesion, epigenetic regulation, and airflow obstruction. The methylation changes were substantial (median, 9.5%; range, 2.6% to 29.5%). Hypomethylated and hypermethylated genes were associated with increased and decreased gene expression, respectively ( P −6 for differentially methylated regions and P −10 for differentially methylated probes). Quantitative analysis in 53 differentially expressed genes demonstrated that 32 (60%) have significant methylation-expression relationships within 5 kb of the gene. Ten loci selected based on the relevance to asthma, magnitude of methylation change, and methylation-expression relationships were validated in an independent cohort of children with atopic asthma. Sixty-seven of 186 genes also have significant asthma-associated methylation changes in nasal epithelia of adult white asthmatic patients. Conclusions Epigenetic marks in respiratory epithelia are associated with allergic asthma and gene expression changes in inner-city children.

Maternal depression and prenatal and early life stress may influence childhood wheezing illnesses, potentially through effects on immune development.To test the hypothesis that maternal stress and/or depression during pregnancy and early life are associated with recurrent wheezing and aeroallergen sensitivity and altered cytokine responses (enhanced type 2 or reduced virus-induced cytokine responses) from stimulated peripheral blood mononuclear cells at age 3 years.URECA (Urban Environment and Childhood Asthma) is a birth cohort at high risk for asthma (n = 560) in four inner cities. Maternal stress, depression, and childhood wheezing episodes were assessed by quarterly questionnaires beginning at birth. Logistic and linear regression techniques were used to examine the relation of maternal stress/depression to recurrent wheezing and peripheral blood mononuclear cell cytokine responses at age 3 years.Overall, 166 (36%) children had recurrent wheeze at age 3 years. Measures of maternal perceived stress at Years 2 and 3 were positively associated with recurrent wheeze (P 0.05). Maternal depression (any year) was significantly associated with recurrent wheezing (P ≤ 0.01). These associations were also significant when considered in a longitudinal analysis of cumulative stress and depression (P ≤ 0.02). Neither stress nor depression was significantly related to aeroallergen sensitization or antiviral responses. Contrary to our original hypothesis, prenatal and Year 1 stress and depression had significant inverse associations with several type 2 cytokine responses.In urban children at high risk for asthma, maternal perceived stress and depression were significantly associated with recurrent wheezing but not increased atopy or reduced antiviral responses.

Background Allergy to German cockroach (CR) is common in urban environments and is an important allergen in children with asthma. Objective We hypothesize that the evolution of allergic sensitization and clinical disease is associated with distinct patterns of allergen-specific T cell reactivity. To test this hypothesis, a subset of high-risk inner-city children participating in the URECA (Urban Environment and Childhood Asthma) birth cohort were selected to evaluate CR-specific T cell reactivity from three distinct groups based on acquisition of aeroallergen sensitivity from ages 2 to 10: low atopy with minimal to no sensitivity (n = 26), early-onset allergic sensitization (n = 25) and late-onset allergic sensitization (n = 25). Methods Using pools of previously identified CR-derived T cell epitopes, we characterized the allergen-specific T cell response in these 76 subjects from blood samples obtained at age 10. CR-specific production of IL-5, IFNγ and IL-10 was measured by ELISPOT following two-week in vitro culture with CR extract. Results T cell responses were significantly higher in the early-onset atopy group compared to low atopy (P = 0.01), and a trend for higher cytokine production in the late onset compared to the low atopy cohort was also observed (P = 0.06). T cell responses were similar between early- and late-onset cohorts. Furthermore, a comparison of T cell reactivity between asthmatic and non-asthmatic individuals revealed significantly higher cytokine production in asthmatics compared to non-asthmatics (P = 0.02) within both the CR-allergic and non-allergic cohorts. Conclusions and clinical relevance In conclusion, the present study reports that higher T cell reactivity is associated with allergen sensitization and asthma. Interestingly, no significant difference in T cell reactivity was observed in allergic children with early-onset versus late-onset atopy.

Background Single birth cohort studies have been the basis for many discoveries about early life risk factors for childhood asthma but are limited in scope by sample size and characteristics of the local environment and population. The Children’s Respiratory and Environmental Workgroup (CREW) was established to integrate multiple established asthma birth cohorts and to investigate asthma phenotypes and associated causal pathways (endotypes), focusing on how they are influenced by interactions between genetics, lifestyle, and environmental exposures during the prenatal period and early childhood. Methods and results CREW is funded by the NIH Environmental influences on Child Health Outcomes (ECHO) program, and consists of 12 individual cohorts and three additional scientific centers. The CREW study population is diverse in terms of race, ethnicity, geographical distribution, and year of recruitment. We hypothesize that there are phenotypes in childhood asthma that differ based on clinical characteristics and underlying molecular mechanisms. Furthermore, we propose that asthma endotypes and their defining biomarkers can be identified based on personal and early life environmental risk factors. CREW has three phases: 1) to pool and harmonize existing data from each cohort, 2) to collect new data using standardized procedures, and 3) to enroll new families during the prenatal period to supplement and enrich extant data and enable unified systems approaches for identifying asthma phenotypes and endotypes. Conclusions The overall goal of CREW program is to develop a better understanding of how early life environmental exposures and host factors interact to promote the development of specific asthma endotypes.

Background Children with asthma in low-income urban areas have high morbidity. Phenotypic analysis in these children is lacking, but may identify characteristics to inform successful tailored management approaches. Objective We sought to identify distinct asthma phenotypes among inner-city children receiving guidelines-based management. Methods Nine inner-city asthma consortium centers enrolled 717 children aged 6 to 17 years. Data were collected at baseline and prospectively every 2 months for 1 year. Participants' asthma and rhinitis were optimally managed by study physicians on the basis of guidelines. Cluster analysis using 50 baseline and 12 longitudinal variables was performed in 616 participants completing 4 or more follow-up visits. Results Five clusters (designated A through E) were distinguished by indicators of asthma and rhinitis severity, pulmonary physiology, allergy (sensitization and total serum IgE), and allergic inflammation. In comparison to other clusters, cluster A was distinguished by lower allergy/inflammation, minimally symptomatic asthma and rhinitis, and normal pulmonary physiology. Cluster B had highly symptomatic asthma despite high step-level treatment, lower allergy and inflammation, and mildly altered pulmonary physiology. Cluster C had minimally symptomatic asthma and rhinitis, intermediate allergy and inflammation, and mildly impaired pulmonary physiology. Clusters D and E exhibited progressively higher asthma and rhinitis symptoms and allergy/inflammation. Cluster E had the most symptomatic asthma while receiving high step-level treatment and had the highest total serum IgE level (median, 733 kU/L), blood eosinophil count (median, 400 cells/mm 3 ), and allergen sensitizations (15 of 22 tested). Conclusions Allergy distinguishes asthma phenotypes in urban children. Severe asthma often coclusters with highly allergic children. However, a symptomatic phenotype with little allergy or allergic inflammation was identified.

Background Treatment levels required to control asthma vary greatly across a population with asthma. The factors that contribute to variability in treatment requirements of inner-city children have not been fully elucidated. Objective We sought to identify the clinical characteristics that distinguish difficult-to-control asthma from easy-to-control asthma. Methods Asthmatic children aged 6 to 17 years underwent baseline assessment and bimonthly guideline-based management visits over 1 year. Difficult-to-control and easy-to-control asthma were defined as daily therapy with 500 μg of fluticasone or greater with or without a long-acting β-agonist versus 100 μg or less assigned on at least 4 visits. Forty-four baseline variables were used to compare the 2 groups by using univariate analyses and to identify the most relevant features of difficult-to-control asthma by using a variable selection algorithm. Nonlinear seasonal variation in longitudinal measures (symptoms, pulmonary physiology, and exacerbations) was examined by using generalized additive mixed-effects models. Results Among 619 recruited participants, 40.9% had difficult-to-control asthma, 37.5% had easy-to-control asthma, and 21.6% fell into neither group. At baseline, FEV 1 bronchodilator responsiveness was the most important characteristic distinguishing difficult-to-control asthma from easy-to-control asthma. Markers of rhinitis severity and atopy were among the other major discriminating features. Over time, difficult-to-control asthma was characterized by high exacerbation rates, particularly in spring and fall; greater daytime and nighttime symptoms, especially in fall and winter; and compromised pulmonary physiology despite ongoing high-dose controller therapy. Conclusions Despite good adherence, difficult-to-control asthma showed little improvement in symptoms, exacerbations, or pulmonary physiology over the year. In addition to pulmonary physiology measures, rhinitis severity and atopy were associated with high-dose asthma controller therapy requirement.

Background Pathway analyses can be used to determine how host and environmental factors contribute to asthma severity. Objective To investigate pathways explaining asthma severity in inner-city children. Methods On the basis of medical evidence in the published literature, we developed a conceptual model to describe how 8 risk-factor domains (allergen sensitization, allergic inflammation, pulmonary physiology, stress, obesity, vitamin D, environmental tobacco smoke [ETS] exposure, and rhinitis severity) are linked to asthma severity. To estimate the relative magnitude and significance of hypothesized relationships among these domains and asthma severity, we applied a causal network analysis to test our model in an Inner-City Asthma Consortium study. Participants comprised 6- to 17-year-old children (n = 561) with asthma and rhinitis from 9 US inner cities who were evaluated every 2 months for 1 year. Asthma severity was measured by a longitudinal composite assessment of day and night symptoms, exacerbations, and controller usage. Results Our conceptual model explained 53.4% of the variance in asthma severity. An allergy pathway (linking allergen sensitization, allergic inflammation, pulmonary physiology, and rhinitis severity domains to asthma severity) and the ETS exposure pathway (linking ETS exposure and pulmonary physiology domains to asthma severity) exerted significant effects on asthma severity. Among the domains, pulmonary physiology and rhinitis severity had the largest significant standardized total effects on asthma severity (−0.51 and 0.48, respectively), followed by ETS exposure (0.30) and allergic inflammation (0.22). Although vitamin D had modest but significant indirect effects on asthma severity, its total effect was insignificant (0.01). Conclusions The standardized effect sizes generated by a causal network analysis quantify the relative contributions of different domains and can be used to prioritize interventions to address asthma severity.

Asthma in the inner‐city population is usually atopic in nature, and is associated with significant morbidity and mortality. However, the underlying immune abnormalities that underlie asthma in urban adults have not been well defined. We investigated the influence of atopy and asthma on cytokine responses of inner‐city adult women to define immune abnormalities associated with asthma and atopy. Blood samples were collected from 509 of 606 inner‐city women enrolled in the Urban Environment and Childhood Asthma (URECA) study. We tested for associations between atopy and asthma status and cytokine responses in peripheral blood mononuclear cells incubated ex vivo with a panel of innate and adaptive immune stimulants. Atopic subjects had heightened Th2 cytokine responses (IL‐4, IL‐5, IL‐13) to cockroach and dust mite antigens, tetanus toxoid, and phytohemagglutinin (P

Characterization of patterns of wheezing and allergic sensitization in early life may allow for identification of specific environmental exposures impacting asthma development.To define respiratory phenotypes in inner-city children and their associations with early-life environmental exposures.Data were collected prospectively from 442 children in the URECA (Urban Environment and Childhood Asthma) birth cohort through age 7 years, reflecting symptoms (wheezing), aeroallergen sensitization, pulmonary function, and body mass index. Latent class mixed models identified trajectories of wheezing, allergic sensitization, and pulmonary function. Cluster analysis defined nonoverlapping groups (termed phenotypes). Potential associations between phenotypes and early-life environmental exposures were examined.Five phenotypes were identified and mainly differentiated by patterns of wheezing and allergic sensitization (low wheeze/low atopy; low wheeze/high atopy; transient wheeze/low atopy; high wheeze/low atopy; high wheeze/high atopy). Asthma was most often present in the high-wheeze phenotypes, with greatest respiratory morbidity among children with frequent wheezing and allergic sensitization. These phenotypes differentially related to early-life exposures, including maternal stress and depression, antenatal environmental tobacco smoke, house dust microbiome, and allergen content (all P 0.05). Prenatal smoke exposure, maternal stress, and depression were highest in the high-wheeze/low-atopy phenotype. The high-wheeze/high-atopy phenotype was associated with low household microbial richness and diversity. Early-life aeroallergen exposure was low in high-wheeze phenotypes.Patterns of wheezing, allergic sensitization, and lung function identified five respiratory phenotypes among inner-city children. Early-life environmental exposure to stress, depression, tobacco smoke, and indoor allergens and microbes differentially associate with specific phenotypes.

Background Childhood asthma in inner-city populations is a major public health burden, and understanding early-life immune mechanisms that promote asthma onset is key to disease prevention. Children with asthma demonstrate a high prevalence of aeroallergen sensitization and T H 2-type inflammation; however, the early-life immune events that lead to T H 2 skewing and disease development are unknown. Objective We sought to use RNA sequencing of PBMCs collected at age 2 years to determine networks of immune responses that occur in children with allergy and asthma. Methods In an inner-city birth cohort with high asthma risk, we compared gene expression using RNA sequencing in PBMCs collected at age 2 years between children with 2 or more aeroallergen sensitizations, including dust mite, cockroach, or both, by age 3 years and asthma by age 7 years (cases) and matched control subjects who did not have any aeroallergen sensitization or asthma by age 7 years. Results PBMCs from the cases showed higher levels of expression of natural killer (NK) cell–related genes. After cockroach or dust mite allergen but not tetanus antigen stimulation, PBMCs from the cases compared with the control subjects showed differential expression of 244 genes. This gene set included upregulation of a densely interconnected NK cell–like gene network reflecting a pattern of cell activation and induction of inflammatory signaling molecules, including the key T H 2-type cytokines IL9 , IL13 , and CCL17 , as well as a dendritic cell–like gene network, including upregulation of CD1 lipid antigen presentation molecules. The NK cell–like response was reproducible in an independent group of children with later-onset allergic sensitization and asthma and was found to be specific to only those children with both aeroallergen sensitization and asthma. Conclusion These findings provide important mechanistic insight into an early-life immune pathway involved in T H 2 polarization, leading to the development of allergic asthma.

BACKGROUND: Comparisons of the technical acceptability of spirometry and impulse oscillometry (IOS) and clinical correlations of the measurements have not been well studied in young children. There are no large studies focused on African American and Hispanic children. OBJECTIVES: We sought to (1) compare the acceptability of spirometry and IOS in 3–5 year old children and (2) examine the relationship of maternal smoking during pregnancy to later lung function. METHODS: Spirometry and IOS were attempted at 4 sites from the URECA birth cohort at ages 3, 4 and 5 years (472, 471 and 479 children respectively). We measured forced expiratory flow in 0.5 sec (FEV(0.5)) with spirometry and area of reactance (A(X)), resistance and reactance at 5 Hz (R5 and X5 respectively) using IOS. RESULTS: Children were more likely to achieve acceptable maneuvers with spirometry than with IOS at age 3 (60% vs 46%, p< 0.001) and 5 years (89% vs 84%, p=0.02). Performance was consistent among the 4 study sites. In children without recurrent wheeze, there were strong trends for higher FEV(0.5) and lower R5 and A(X) over time. Maternal smoking during pregnancy was associated with higher A(X)at ages 4 and 5 years (p

BACKGROUND: Small airways instability, resulting in premature airway closure, has been recognized as a risk for asthma severity and poor control. Although spirometry has limited sensitivity for detecting small airway dysfunction, a focus on the air-trapping component of obstruction may identify a risk factor for asthma instability. OBJECTIVE: To use spirometric measurements to identify patterns of airway obstruction in children, and define obstruction phenotypes that relate to asthma instability. METHODS: Pre- and post-bronchodilation spirometry data were obtained from 560 children in the Asthma Phenotypes in the Inner City study. An air-trapping obstruction phenotype (A Trpg) was defined as forced vital capacity (FVC) Z-score < −1.64, or an increase of FVC ≥ 10% predicted with bronchodilation. The airflow limitation phenotype (A Limit) had forced expiratory volume in 1 s (FEV(1))/FVC Z-score < −1.64, but not A Trpg. The None phenotype had neither A Trpg nor A Limit. The 3 obstruction phenotypes were assessed as predictors of number of exacerbations, asthma severity, and airway lability. RESULTS: The A Trpg phenotype (14% of the cohort) had more exacerbations during the 12-month study, compared with the A Limit (P

African Americans have higher rates of asthma prevalence, morbidity, and mortality in comparison with other racial groups. We sought to characterize endotypes of childhood asthma severity in African American patients in an inner-city pediatric asthma population. Baseline blood neutrophils, blood eosinophils, and 38 serum cytokine levels were measured in a sample of 235 asthmatic children (6-17 years) enrolled in the NIAID (National Institute of Allergy and Infectious Diseases)-sponsored Asthma Phenotypes in the Inner City (APIC) study (ICAC (Inner City Asthma Consortium)-19). Cytokines were quantified using a MILLIPLEX panel and analyzed on a Luminex analyzer. Patients were classified as Easy-to-Control or Difficult-to-Control based on the required dose of controller medications over one year of prospective management. A multivariate variable selection procedure was used to select cytokines associated with Difficult-to-Control versus Easy-to-Control asthma, adjusting for age, sex, blood eosinophils, and blood neutrophils. In inner-city African American children, 12 cytokines were significant predictors of Difficult-to-Control asthma (n = 235). CXCL-1, IL-5, IL-8, and IL-17A were positively associated with Difficult-to-Control asthma, while IL-4 and IL-13 were positively associated with Easy-to-Control asthma. Using likelihood ratio testing, it was observed that in addition to blood eosinophils and neutrophils, serum cytokines improved the fit of the model. In an inner-city pediatric population, serum cytokines significantly contributed to the definition of Difficult-to-Control asthma endotypes in African American children. Mixed responses characterized by TH2 (IL-5) and TH17-associated cytokines were associated with Difficult-to-Control asthma. Collectively, these data may contribute to risk stratification of Difficult-to-Control asthma in the African American population.

SummaryBackground Mouse models of atopic march suggest that systemic, skin-derived thymic stromal lymphopoietin (TSLP) mediates progression from eczema to asthma. Objective We investigated whether circulating TSLP is associated with eczema, allergic sensitization, or recurrent wheezing in young children. Methods A prospective analysis of the relationship between plasma levels of TSLP to allergic sensitization and recurrent wheezing was conducted in the birth cohort from the Urban Environment and Childhood Asthma (URECA) study. Plasma TSLP levels were measured at 1, 2, and 3 years of age and analysed for correlation with clinical parameters in each of the three years. Only those children with consecutive samples for all three years were included in this analysis. Results We detected TSLP in 33% of 236 children for whom plasma samples were available for all three years. Overall, a consistently significant association was not found between TSLP and eczema or allergic sensitization. With regard to recurrent wheezing, children with detectable TSLP at one year of age were significantly less likely to experience recurrent wheezing by 3 years compared with those children without detectable TSLP, but this was only seen in children without aeroallergen sensitization at 3 years (P

Asthma definitions vary widely across research studies and feature a trade-off between inclusivity and precision. Harmonizing definitions across multiple asthma birth cohort studies highlights these challenges.

Background Variability in response to inhaled corticosteroids (ICSs) can result in less than optimal asthma control. Development of biomarkers assessing the therapeutic efficacy of corticosteroids is important. Objective We sought to examine whether in vitro PBMC responses to corticosteroids relate to the clinical ICS response. Methods PBMCs were collected from 125 children with asthma (6-17 years) at enrollment (visit 0 [V0]) and after 1 year of bimonthly guidelines-based management visits (visit 6 [V6]). Difficult-to-control and easy-to-control asthma were defined as requiring daily therapy with 500 μg or more of fluticasone propionate (FLU) with or without a long-acting β-agonist versus 100 μg or less of FLU in at least 4 visits. mRNA levels of glucocorticoid receptor α and corticosteroid transactivation (FK506-binding protein 5) and transrepression markers (IL-8 and TNF-α) were measured by using RT-PCR in freshly isolated cells and in response to 10−8 mol/L FLU. Results Compared with PBMCs from patients with easy-to-control asthma, PBMCs from those with difficult-to-control asthma had significantly lower glucocorticoid receptor α levels at V0 (P = .05). A 30% increase in IL-8 suppression by FLU (P = .04) and a trend for increased TNF-α suppression by FLU between V0 and V6 (P = .07) were observed in patients with easy-to-control asthma. In contrast, no changes between V0 and V6 in IL-8 and TNF-α suppression by FLU were observed in patients with difficult-to-control asthma. Corticosteroid-mediated transactivation (FK506-binding protein 5 induction by FLU) increased in the PBMCs of patients with difficult-to-control and easy-to-control asthma between V0 and V6 (P = .05 and P = .03, respectively). Conclusions PBMCs of children with difficult-to-control asthma treated with guidelines-based therapy and requiring high-dose ICSs had reduced in vitro responsiveness to corticosteroids.

Background. The risk of developing childhood asthma has been linked to the severity and etiology of viral respiratory illnesses in early childhood. Since inner-city infants have unique environmental exposures, we hypothesized that patterns of respiratory viral infections would also be distinct. Methods. We compared the viral etiology of respiratory illnesses in 2 groups: a cohort of 515 infants from 4 inner-city areas and a cohort of 285 infants from mainly suburban Madison, Wisconsin. Nasal secretions were sampled during periods of respiratory illness and at 1 year of age and were analyzed for viral pathogens by multiplex polymerase chain reaction. Results. Overall, inner-city infants had lower rates of viral detection. Considering specific viruses, sick urban infants had lower rates of detectable rhinovirus or respiratory syncytial virus infection and higher rates of adenovirus infection. Every urban site had a higher proportion of adenovirus-positive samples associated with illnesses (10%–21%), compared with Madison (6%). Conclusions. These findings provide evidence that inner-city babies have different patterns of viral respiratory illnesses than babies who grow up in a more suburban location. These findings raise important questions about the etiology of virus-negative illnesses in urban infants and the possibility of long-term consequences of early life infections with adenovirus in this population. Children who grow up in large, low-income urban areas are especially prone to develop asthma, and this has prompted efforts to identify urban environmental or lifestyle factors that promote this disease. Factors under investigation include exposure to allergens, such as those of cockroaches and mice; stress; diet; lack of exercise; genetics; and exposure to indoor and outdoor pollutants [1, 2]. Another factor that is strongly related to asthma is the development of virus-induced wheezing illnesses in infancy. Recently, it has been reported that wheezing illnesses caused by human rhinoviruses (HRVs) are associated with a particularly high risk of recurrent wheezing and asthma [3, 4], as is airway colonization in the first few months with specific

SummaryBackground Immunomodulatory T cells are thought to influence development of allergy and asthma, but early life longitudinal data on their phenotype and function are lacking. Objectives As part of the Urban Environment and Childhood Asthma (URECA) study, we investigated the development of immunomodulatory T cell phenotype and function, and characterized their relation to allergic disease progression from birth through to 2 years of age. Methods Immunomodulatory T cell phenotype and function in cord blood mononuclear cells (CBMC) and peripheral blood mononuclear cells (PBMC) at 1 and 2 years of age were characterized by analysing CD25bright and FoxP3+ expression, proliferative responses and cytokine production. The relation of immunomodulatory T cell characteristics to allergic sensitization and disease at 1- and 2-years of age was investigated. Results The proportion of CD4+CD25bright and CD4+CD25+FoxP3+ T cells (n = 114, 83, 82 at birth, 1- and 2-years respectively) increased significantly, whereas there were no significant changes in the suppressive function of CD25+ T cells (n = 78, 71, 81 at birth, 1- and 2-years respectively). Birth immunomodulatory T cell characteristics were not related to subsequent allergic sensitization or disease. However, increases in the numbers of CD4+CD25bright cells and their ability to suppress lymphoproliferative responses at 1 year of age were associated with reduced allergic sensitization at 1 (P = 0.03) and 2 (P = 0.02) years of age. Production of the anti-inflammatory cytokine IL-10 by CD25+ T cells appeared to mediate this protective suppressive function. In contrast, by 2 years of age, we observed the emergence of a positive association of CD4+CD25+FoxP3+ T cell numbers with allergic sensitization (P = 0.05) and eczema (P = 0.02). Conclusions and clinical relevance These findings suggest that the relationship between immunomodulatory T cell subsets, allergic sensitization and eczema is developmentally regulated. In the first year of life, CD4+CD25+IL-10 producing T cells are associated with a reduced incidence of allergic sensitization. Once allergic sensitization or eczema is established, CD4+CD25+FoxP3+ T-reg cells expand to potentially counteract the allergic inflammatory response. Understanding the relationship between development of immunoregulatory T cells and early onset atopy could lead to new preventive strategies for allergic diseases.

Background Studies have demonstrated that IgE-binding cross-reactive epitopes between shrimp, cockroach, and house dust mite tropomyosins can account for the presence of detectable IgE to shrimp in patients with cockroach and dust mite allergies. Objective We investigated the correlation between IgE-mediated sensitization to shrimp, cockroach, and dust mite in relation to allergen exposure in inner-city children. Methods Five hundred four serum samples from the National Cooperative Inner-City Asthma Study were evaluated for specific IgE to shrimp, and the results were compared with specific IgE to cockroach (Blattella germanica) and dust mite (Dermatophagoides farinae). Associations between IgE sensitization to these allergens and environmental exposures were determined. Results There was a strong positive correlation between shrimp, cockroach, and dust mite IgE levels. High exposure to cockroach (B germanica) in the home, particularly in the bedroom and television room, was significantly correlated with higher shrimp and cockroach IgE levels. In contrast, high exposure to dust mite in the home was highly correlated with IgE levels to D farinae but not with shrimp IgE levels. There is a synergistic relationship between cockroach IgE levels and exposure in predicting shrimp IgE levels. Conclusions For children with evidence of IgE-mediated sensitization to cockroach and shrimp, having high exposure to cockroach in the home can contribute to higher shrimp IgE levels, which might not correlate with clinical reactivity. Further patient evaluations with clinical histories of shrimp exposure and reactions, as well as oral food challenges, would have to be performed to confirm these findings.

Background Recent studies have reported conflicting data on the association between maternal intake of vitamin D during pregnancy and asthma.

Rationale: Stress-elicited disruption of immunity begins in utero. Objectives: Associations among prenatal maternal stress and cord blood mononuclear cell (CBMC) cytokine responses were prospectively examined in the Urban Environment and Childhood Asthma Study (n = 557 families). Methods: Prenatal maternal stress included financial hardship, difficult life circumstances, community violence, and neighborhood/block and housing conditions. Factor analysis produced latent variables representing three contexts: individual stressors and ecological-level strains (housing problems and neighborhood problems), which were combined to create a composite cumulative stress indicator. CBMCs were incubated with innate (lipopolysaccharide, polyinosinic-polycytidylic acid, cytosine-phosphate-guanine dinucleotides, peptidoglycan) and adaptive (tetanus, dust mite, cockroach) stimuli, respiratory syncytial virus, phytohemagglutinin, or medium alone. Cytokines were measured using multiplex ELISAs. Using linear regression, associations among increasing cumulative stress and cytokine responses were examined, adjusting for sociodemographic factors, parity, season of birth, maternal asthma and steroid use, and potential pathway variables (prenatal smoking, birth weight for gestational age). Measurements and Main Results: Mothers were primarily minorities (Black [71%], Latino [19%]) with an income less than $15,000 (69%). Mothers with the highest cumulative stress were older and more likely to have asthma and deliver lower birth weight infants. Higher prenatal stress was related to increased IL-8 production after microbial (CpG, PIC, peptidoglycan) stimuli and increased tumor necrosis factor-α to microbial stimuli (CpG, PIC). In the adaptive panel, higher stress was associated with increased IL-13 after dust mite stimulation and reduced phytohemagglutinin-induced IFN-γ. Conclusions: Prenatal stress was associated with altered innate and adaptive immune responses in CBMCs. Stress-induced perinatal immunomodulation may impact the expression of allergic disease in these children.

To cite this article: Matsui EC, Sampson HA, Bahnson HT, Gruchalla RS, Pongracic JA, Teach SJ, Gergen PJ, Bloomberg GR, Chmiel JF, Liu AH, Kattan M, Sorkness CA, Steinbach SF, Story RE, Visness CM, on behalf of the Inner-city Asthma Consortium. Allergen-specific IgE as a biomarker of exposure plus sensitization in inner-city adolescents with asthma. Allergy 2010; 65: 1414–1422. Abstract Background: Relationships among allergen-specific IgE levels, allergen exposure and asthma severity are poorly understood since sensitization has previously been evaluated as a dichotomous, rather than continuous characteristic. Methods: Five hundred and forty-six inner-city adolescents enrolled in the Asthma Control Evaluation study underwent exhaled nitric oxide (FENO) measurement, lung function testing, and completion of a questionnaire. Allergen-specific IgE levels and blood eosinophils were quantified. Dust samples were collected from the participants’ bedrooms for quantification of allergen concentrations. Participants were followed for 12 months and clinical outcomes were tracked. Results: Among sensitized participants, allergen-specific IgE levels were correlated with the corresponding settled dust allergen levels for cockroach, dust mite, and mouse (r = 0.38, 0.34, 0.19, respectively; P

Background Immunologic responses at birth likely relate to subsequent risks for allergic diseases and wheezing in infancy; however, the influences of parental characteristics and prenatal factors on neonatal immune responses are incompletely understood. Objective This study investigates potential correlations between urban parental, prenatal, and perinatal factors on innate and adaptive stimuli-induced cytokine responses. Methods Five hundred sixty and 49 children of parents with and without allergic disease or asthma, respectively, were enrolled into a prospective birth cohort study (Urban Environment and Childhood Asthma). Cord blood mononuclear cells were incubated with innate and adaptive immune stimuli, and cytokine responses (ELISA) were compared with season of birth, parental characteristics, in utero stressors, and fetal growth. Results Many cytokine responses varied by season of birth, including 2-fold to 3-fold fluctuations with specific IFN-α and IFN-γ responses. Birth weight was inversely associated with IFN-γ responses to respiratory syncytial virus ( R = −0.16), but positively associated with IL-8 responses to a variety of innate stimuli ( R = 0.08-0.12). Respiratory syncytial virus–induced cytokine responses were 21% to 54% lower in children of mothers with asthma. Cytokine responses were generally lower in babies born to parents with allergy/asthma. Conclusions Innate cytokine responses are associated with parental allergic or airway disease, somatic fetal growth, ethnicity, and season of birth. Collectively, these findings suggest that urban prenatal exposures and familial factors affect the development of the fetal immune system.

Dillon, M. B. C. et al., [Background and objective] The allergenicity of several German cockroach (Bla-g) antigens at the level of IgE responses is well established. However, less is known about the specificity of CD4+ TH responses, and whether differences exist in associated magnitude or cytokine profiles as a function of disease severity., [Methods] Proteomic and transcriptomic techniques were used to identify novel antigens recognized by allergen-specific T cells. To characterize different TH functionalities of allergen-specific T cells, ELISPOT assays with sets of overlapping peptides covering the sequences of known allergens and novel antigens were employed to measure release of IL-5, IFNγ, IL-10, IL-17 and IL-21., [Results] Using these techniques, we characterized TH responses in a cohort of adult Bla-g-sensitized subjects, either with (n = 55) or without (n = 17) asthma, and nonsensitized controls (n = 20). T cell responses were detected for ten known Bla-g allergens and an additional ten novel Bla-g antigens, representing in total a 5-fold increase in the number of antigens demonstrated to be targeted by allergen-specific T cells. Responses of sensitized individuals regardless of asthma status were predominantly TH2, but higher in patients with diagnosed asthma. In asthmatic subjects, Bla-g 5, 9 and 11 were immunodominant, while, in contrast, nonasthmatic-sensitized subjects responded mostly to Bla-g 5 and 4 and the novel antigen NBGA5., [Conclusions] Asthmatic and nonasthmatic cockroach-sensitized individuals exhibit similar TH2-polarized responses. Compared with nonasthmatics, however, asthmatic individuals have responses of higher magnitude and different allergen specificity., This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract numbers HHSN272200900052C and HHSN272201000052I and grant numbers 1UM1AI114271-01 and U19AI100275.

Background Women in poor urban neighborhoods have high rates of stress and allergic diseases, but whether stress or stress correlates such as depression promote inflammatory and type 2 cytokine responses is unknown. Objective To examine associations among external stressors, perceived stress, depression, and peripheral blood mononuclear cell cytokine responses of mothers enrolled in the Urban Environment and Childhood Asthma Study and test the hypothesis that stress would be positively associated with type 2 and selected proinflammatory (tumor necrosis factor-α and interleukin-8) responses. Methods Questionnaire data from mothers living in 4 inner cities included information about external stress, stress perception, and depression. The external stress domains (interpersonal problems, housing, and neighborhood stress) were combined into a Composite Stressor score. Peripheral blood mononuclear cells were stimulated ex vivo and cytokine responses to innate, adaptive, and polyclonal immune stimuli were compared with stress and depression scores for 469 of the 606 study participants. Results There were no significant positive associations between Composite Stressor scores, perceived stress, or depression scores and proinflammatory or type 2 cytokine responses, and these findings were not modified by allergy or asthma status. There were some modest associations with individual stressors and cytokine responses, but no consistent relations were noted. Depression was associated with decreased responses to some stimuli, particularly dust mite. Conclusion Composite measurements of stressors, perceived stress, or depression were not positively related to proinflammatory or type 2 cytokine responses in these young urban women. These data do not support the hypothesis that these factors promote cytokine responses associated with allergy. Trial Registration ClinicalTrials.gov, identifier NCT00114881.

Background Exposure to indoor allergens contributes to increased asthma morbidity. The Inner-City Asthma Study, a randomized trial involving home environmental allergen and irritant remediation among children aged 6 through 11 years with moderate-to-severe asthma, successfully reduced asthma symptoms. A cost-effectiveness analysis can help stakeholders to evaluate the potential costs and benefits of adopting such a program. Objective We sought to assess the cost-effectiveness of the environmental intervention of the Inner-City Asthma Study. Methods Incremental cost-effectiveness ratios for a 2-year study period were calculated. Health outcome was measured as symptom-free days. Resource use measures included ambulatory visits, hospitalizations, and pharmaceutical use. CIs were obtained by using bootstrapping. Results The intervention, which cost $1469 per family, led to statistically significant reductions in symptom days, unscheduled clinic visits, and use of β-agonist inhalers. Over the year of the intervention and a year of follow-up, the intervention cost was $27.57 per additional symptom-free day (95% CI, $7.46-$67.42). Subgroup analysis showed that targeting the intervention to selected high-risk subgroups did not reduce the incremental cost-effectiveness ratio. Conclusions A targeted home-based environmental intervention improved health and reduced service use in inner-city children with moderate-to-severe asthma. The intervention is cost-effective when the aim is to reduce asthma symptom days and the associated costs.

Background Asthma continues to be an increasing cause of morbidity in the pediatric population, and studies have shown an association between food sensitivity and asthma. Objective We investigated the degree of food allergen sensitization in inner-city patients with asthma. Methods Five hundred four random serum samples from the National Cooperative Inner City Asthma Study were evaluated for specific IgE (UniCap) to 6 common food allergens (egg, milk, soy, peanut, wheat, and fish). Statistical analyses were performed to determine food sensitization prevalence and its association with asthma morbidity. Results Forty-five percent of patients had evidence of sensitization (food-specific IgE ≥0.35 kU/L) to at least 1 food. Nineteen percent had IgE levels at ≥50% positive predictive value for clinical reactivity to at least 1 food, with 4% of patients having levels >95% positive predictive value for food allergy. Children sensitized to foods had higher rates of asthma hospitalization ( P P =.025). Sensitization to foods also correlated with sensitization to more indoor and outdoor aeroallergens ( P Conclusion Food allergen sensitization is highly prevalent in the inner-city population with asthma, and it is associated with increased asthma healthcare and medication use. Therefore, food allergen sensitivity may be a marker for increased asthma severity.

Objectives. We examined the association between exposure to violence and asthma among urban children. Methods. We obtained reports from caretakers (n = 851) of violence, negative life events, unwanted memories (rumination), caretaker-perceived stress, and caretaker behaviors (keeping children indoors, smoking, and medication adherence). Outcomes included caretaker-reported wheezing, sleep disruption, interference with play because of asthma, and effects on the caretaker (nights caretaker lost sleep because of child’s asthma). Results. Increased exposure to violence predicted higher number of symptom days (P = .0008) and more nights that caretakers lost sleep (P = .02) in a graded fashion after control for socioeconomic status, housing deterioration, and negative life events. Control for stress and behaviors partially attenuated this gradient, although these variables had little effect on the association between the highest level of exposure to morbidity, which suggests there are other mechanisms. Conclusions. Mechanisms linking violence and asthma morbidity need to be further explored.

Objective Previous data suggest that food allergy (FA) might be more common in inner-city children; however, these studies have not collected data on both sensitization and clinical reactivity or early-life exposures. Methods Children in the Urban Environment and Childhood Asthma birth cohort were followed through age 5 years. Household exposures, diet, clinical history, and physical examinations were assessed yearly; levels of specific IgE to milk, egg, and peanut were measured at 1, 2, 3, and 5 years of age. On the basis of sensitization (IgE ≥0.35 kU/L) and clinical history over the 5-year period, children were classified as having FA or being possibly allergic, sensitized but tolerant, or not allergic/not sensitized. Results Five hundred sixteen children were included. Overall, 55.4% were sensitized (milk, 46.7%; egg, 31.0%; and peanut, 20.9%), whereas 9.9% were categorized as having FA (peanut, 6.0%; egg, 4.3%; and milk, 2.7%; 2.5% to >1 food). The remaining children were categorized as possibly allergic (17.0%), sensitized but tolerant (28.5%), and not sensitized (44.6%). Eighteen (3.5%) reported reactions to foods for which IgE levels were not measured. Food-specific IgE levels were similar in children with FA versus sensitized but tolerant children, except for egg, levels of which were higher in patients with FA at ages 1 and 2 years. FA was associated with recurrent wheeze, eczema, aeroallergen sensitization, male sex, breast-feeding, and lower endotoxin exposure in year 1 but not with race/ethnicity, income, tobacco exposure, maternal stress, or early introduction of solid foods. Conclusions Even given that this was designed to be a high-risk cohort, the cumulative incidence of FA is extremely high, especially considering the strict definition of FA that was applied and that only 3 common allergens were included.

Our purpose was to estimate the annual risk of death in the United States from cardiovascular disease attributable to low-dose combination oral contraceptives.Estimates of the risk of death from cardiovascular disease attributable to low-dose oral contraceptives were modeled on data from studies published through 1997 and from age-specific mortality rates in the United States for 1993 and 1994.Attributable risk of death from cardiovascular disease resulting from oral contraceptive use is 0.06 and 3.0 per 100,000 nonsmokers 15 to 34 years of age and 35 to 44 years of age, respectively. In smokers this risk increases, respectively, to 1.73 and 19.4 per 100,000 users in these 2 age groups; however, 97% and 85% of this risk is due to the combined effects of smoking and using oral contraceptives. The attributable risk of death from cardiovascular disease in nonsmoking oral contraceptive users is lower than the risk of death from pregnancy in nonusers of oral contraceptives at all ages; however, among smoking oral contraceptive users more than 35 years of age, the excess risk of death from oral contraceptives is higher than the risk of death from pregnancy.There is virtually no excess attributable risk of death from cardiovascular disease related to oral contraceptive use in young women. However, smokers more than 35 years of age should use a nonestrogen contraceptive.The annual risk of death in the US from cardiovascular disease attributable to low-dose combination oral contraceptives (OCs) was estimated through use of data from studies published in 1980-1997 and from age-specific mortality rates for 1993 and 1994. Four cardiovascular disease categories were included: myocardial infarction, venous thromboembolism and pulmonary embolism, ischemic stroke, and hemorrhagic stroke. The overall risk of death from cardiovascular disease among nonsmoking users of low-dose OCs is 0.06/100,000 women in the 15-34 year age group and 3.03/100,000 women in the 35-44 year age group. For young nonsmokers, the excess mortality risk associated with OC use is smaller than the risk of death from pregnancy, whether terminated by abortion or carried to term. Among OC users who smoke, the risk of cardiovascular mortality is 1.73/100,000 in 15-34 year olds and 19.4/100,000 in women 35-44 years old; however, 97% and 85% of this risk, respectively, is composed of the combined OC-smoking risk. Among smoking OC users over 35 years of age, the excess risk of death from OCs exceeds the risk of death from pregnancy. Young nonsmokers raise their risk of death from cardiovascular disease by less than 10% (0.60-0.65/100,000) by using OCs, while young women who do not use OCs increase their risk of death by 260% (0.60-1.57/100,000) by smoking cigarettes. For older women, the corresponding increases are 95% among nonsmoking OC users and 315% among smoking nonusers. These estimates indicate that women over 35 years of age who smoke should not be permitted to use either low- or high-dose OCs because of the excess attributable risk of death from cardiovascular disease.

Background: New mothers and clinicians would benefit from an understanding of typical sexual behavior during breastfeeding. Unfortunately, little information is available about both the typical length of time to resumption of coitus and the frequency of sexual relations during breastfeeding. This paper describes the commencement and frequency of coitus among breastfeeding women in a variety of settings. Methods: The analysis draws on data from two separate research studies. The first was undertaken in three sites (Birmingham, United Kingdom; Montreal, Canada; Sydney, Australia), the purpose of which was to correlate natural observations of fertility with the underlying hormonal profile among breastfeeding women using the sympto-thermal method of natural family planning. The second was a clinical trial of the lactational amenorrhea method of family planning conducted in Manila, the Philippines. Results: Coital frequency reported by these populations of breastfeeding women appears to be lower than that reported in other studies for married women in general. As other research demonstrated, we found coital frequency and postpartum resumption of coitus to be associated with age, but not with the number of children in the household. Conclusions: A better understanding of the level of sexual activity among breastfeeding women could inform and improve programs that offer postpartum support and counseling about family planning. (BIRTH 24:4, December 1997)

This study compares the 1988 National Maternal and Infant Health Survey (NMIHS) and the 1989 Ross Laboratories Mothers Survey with respect to sample characteristics and proportions of women who breastfed. Weighted proportions of women included in the two surveys were compared according to various characteristics to see how well they represented U.S. childbearing women. A z-statistic was produced to test for significant differences in the proportions who breastfed. In 1988-89, 52.2% of American women breastfed according to the Ross survey and 53.4% according to the NMIHS. Despite differences in sample size, sampling technique and the application of sample weights, the difference between the surveys was only 1 percentage point, and most levels of most variables examined were comparable. The Ross survey is a valuable source of data because it is ongoing, and it is generally corroborated by the NMIHS. The NMIHS is probably more representative of the U.S. population of childbearing women, and is a reliable source of data for setting U.S. objectives concerning infant feeding, and for the study of other issues vis-a-vis breastfeeding.

Objective: To determine the contraceptive efficacy of the lactational amenorrhoea method. Design: Non-comparative prospective trial. Setting: Urban Manila, the Philippines. Subjects: 485 lower income, educated women with extensive experience of breast feeding. Intervention: Women were offered all available contraceptives for use after birth. Those who chose the lactational amenorrhoea method were taught the method, screened for the study, and followed for 12 months to determine the risk of pregnancy when the method was used. Main outcome measures: Life table pregnancy rates during correct and incorrect use of the method, censored monthly in the event of sexual abstinence or the use of another contraceptive method. Results: The lactational amenorrhoea method was 99% effective when used correctly (that is, during lactational amenorrhoea and full or nearly full breast feeding for up to six months). At 12 months the effectiveness during amenorrhoea dropped to 97%. Conclusions: The lactational amenorrhoea method provided as much protection from pregnancy as non-breast feeding women experience with non-medicated intrauterine devices and barrier methods. The contraceptive effect of lactation cannot be attributed to lactational or postpartum abstinence. Key messages Henceforth, data from clinical trials on contra-ceptives must be subject to the rigours of multiple censoring such as applied here. By excluding periods of abstinence from the calculation of risk of pregnancy, the contraceptive protection of the method cannot be attributed to postpartum or lac- tational abstinence During the first year post partum, the rate of pregnancy before the return of menses in lactating women was less than 3%

To determine the efficacy of the lactational amenorrhea method of family planning (amenorrhea during full or nearly full breastfeeding for 6 months postpartum).Prospective noncomparative study.Normal breastfeeding women in Karachi and Multan, Pakistan, most delivered at home by a midwife.Three hundred ninety-nine newly delivered mothers who successfully had breastfed a previous child and chose the lactational amenorrhea method to prevent a subsequent pregnancy, 391 of whom were followed for a full year.Mothers were taught, before or shortly after delivery, to use the method and were interviewed in their homes each month by a Lady Health Visitor.Life-table pregnancy rates. Periods of postpartum or lactational abstinence were excluded in the calculation of the pregnancy rates.During full or nearly full breastfeeding, while the women were amenorrheic and not otherwise contracepting, the rate of pregnancy was 0.6%. The pregnancy rate during lactational amenorrhea alone was 1.1% at 1 year postpartum.The lactational amenorrhea method was found to be highly effective for 6 months. A high degree of contraceptive protection endures for a full year during lactational amenorrhea, but not after the return of menses during breastfeeding.399 mother-infant pairs were admitted into the study, 99 in the rural areas around Multan and 300 in Karachi. 378 remained in the follow-up for the full year. The mean age of the volunteers was 27.2. 25% were from the rural areas, and 37.6% were able to read and write. The women reported an average of 4.4 pregnancies and had 3.9 living children. Only 6% ever had used a family planning method in the past, and this included withdrawal as well as modern contraceptive methods. 26.4% of the women returned to menses during the first 6 months postpartum, and 40.7% of the infants were given regular supplements by this time. Considering both factors together, 47.9% of women were still protected by the lactational amenorrhea method (LAM) by the end of the 6th month postpartum. By the end of the 8th month, virtually all infants were receiving regular supplements, although only 7.4% had been weaned by the end of follow-up at 1 year postpartum. By the end of 12 months there were 29 pregnancies, including two miscarriages. Of the two pregnancies that occurred during amenorrhea, one occurred after 5 months postpartum (single LAM failure) and the other occurred at 9 months postpartum, 3.5 months after regular supplementation began. The single LAM failure, which occurred during the 6th postpartum month, resulted in a life-table pregnancy rate of 0.58% (95% confidence interval [CI], 0.00-1.58%). The rate of pregnancy during the first 6 months postpartum during breastfeeding in the absence of the use of another contraceptive constituted the failure rate of the LAM during correct plus incorrect use. During use of the LAM so defined, 0.96% were pregnant by the end of 5 months postpartum (95% CI, 0.00-2.15%) and 1.65% were pregnant by 6 months (95% CI, 0.12-3.18%). Two pregnancies occurred by the end of a year, for a 12-month life-table pregnancy rate of 1.12% (95% CI, 0.00-2.59%).