Developmental determinants in non-communicable chronic diseases and ageing.

Prenatal and peri-natal events play a fundamental role in health, development of diseases and ageing (Developmental Origins of Health and Disease (DOHaD)). Research on the determinants of active and healthy ageing is a priority to: (i) inform strategies for reducing societal and individual costs of an ageing population and (ii) develop effective novel prevention strategies. It is important to compare the trajectories of respiratory diseases with those of other chronic diseases.

Circulating TSLP associates with decreased wheezing in non-atopic preschool children: data from the URECA birth cohort.

BACKGROUND: 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 < 0.01). CONCLUSIONS AND CLINICAL RELEVANCE: Contrary to our expectations, circulating TSLP was not significantly associated with eczema, allergen sensitization, or recurrent wheezing during the first three years of life. Early presence of circulating TSLP was significantly associated with reduced incidence of recurrent wheeze in those children not sensitized to aeroallergen. These findings suggest a possible underlying distinction between pathogenesis of developing atopic vs. non-atopic recurrent wheeze.

Age-dependent interaction between atopy and eosinophils in asthma cases: results from NHANES 2005-2006.

BACKGROUND: Atopy is an established risk factor for asthma, and an elevated eosinophil level is a hallmark of atopic and non-atopic asthma. Whether atopy and eosinophils act independently or interact to influence asthma has clinical and public health implications. OBJECTIVE: To investigate the relationship between atopy and eosinophils in asthma. METHODS: Data on current asthma, atopy (IgE positive to ≥ 1 allergen), and blood eosinophil percent (dichotomized at the median) were obtained for persons aged ≥ 6 years from the National Health and Nutrition Examination Survey 2005-2006. Interaction on an additive scale was evaluated by estimating the prevalences of asthma for combinations of atopy (yes or no) and eosinophil percent (high or low) and calculating the excess prevalence due to interaction. RESULTS: For all ages combined, the adjusted prevalences of asthma were 4.6%, 7.6%, 6.9% and 17.2% for persons with neither factor, atopy alone, a high eosinophil percent alone and both factors respectively. The excess prevalence of asthma due to interaction was 7.2%, indicating synergism. The excess prevalence was greatest in children aged 6-17 years (15.3%), and it decreased with each older age category until it was absent in adults aged ≥ 55 years (-0.2%). In children, 94% of asthma cases attributable to the 2 factors were attributable to the interaction, whereas in the oldest adults, no cases were attributable to the interaction. CONCLUSIONS AND CLINICAL RELEVANCE: Interaction between atopy and an elevated eosinophil level in asthma cases was very strong in children but absent in the oldest adults, which suggests different mechanistic pathways for these factors by age and supports the notion that asthma is a heterogeneous disease. In addition, the age-dependent interaction between the factors has potential implications for the selection of asthma patients for treatments that would target either IgE or a high eosinophil level.

Umbilical cord plasma 25-hydroxyvitamin D concentration and immune function at birth: the Urban Environment and Childhood Asthma study.

BACKGROUND: Recent studies have reported conflicting data on the association between maternal intake of vitamin D during pregnancy and asthma. OBJECTIVE: To assess the influence of prenatal vitamin D status on immune function at birth. METHODS: In an inner-city birth cohort of 568 newborns, 520 of whom had at least one atopic parent, we measured the umbilical cord (UC) plasma concentration of 25-hydroxyvitamin D (25(OH)D) and the cytokine responses of UC blood mononuclear cells (UCMCs) to stimuli including phytohaemagglutinin (PHA), lipopolysaccharide (LPS), and peptidoglycan. In a subset, the UCMC expression of regulatory T cell markers and the suppressive activity of CD4(+) CD25(+) UCMCs were measured. Results The 25th, 50th, and 75th percentiles of UC plasma 25(OH)D level were 15.0, 20.2, and 25.6 ng/mL, respectively. Most cytokine responses of UCMC were not correlated with UC 25(OH)D concentration; however, IFN-γ release after LPS stimulation was weakly positively correlated with UC 25(OH)D concentration (r=0.11, P=0.01). PHA responses were not significantly correlated with 25(OH)D concentration. The UC plasma 25(OH)D concentration was inversely related to the number of CD25(+) (r=-0.20, P=0.06), CD25(Bright) (r=-0.21, P=0.05), and CD25(+) FoxP3 (r=-0.29, P=0.06) cells as a proportion of CD4(+) T cells in UC blood (r=-0.26, P=0.04) but not to the suppressive activity of CD4(+) CD25(+) cells (r=0.17, P=0.22). CONCLUSION AND CLINICAL RELEVANCE: UC 25(OH)D concentration was not correlated with most UCMC cytokine responses to multiple stimuli. There was a suggestion of a weakly positive correlation with IFN-γ release after LPS stimulation. The proportions of CD25(+) , CD25(Bright) , and CD25(+) FoxP3 cells to total CD4(+) T cells were inversely correlated with UC 25(OH)D concentration. Our findings suggest that higher vitamin D levels at birth may be associated with a lower number of T-regulatory cells. Vitamin D status in utero may influence immune regulation in early life.

Allergen-specific IgE as a biomarker of exposure plus sensitization in inner-city adolescents with asthma.

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 (FE(NO)) 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 < 0.0001 for cockroach and dust mite and P = 0.03 for mouse), but not cat (r = -0.02, P = 0.71). Higher cockroach-, mite-, mouse-, and cat-specific IgE levels were associated with higher FE(NO) concentrations, poorer lung function, and higher blood eosinophils. Higher cat, dust mite, and mouse allergen-specific IgE levels were also associated with an increasing risk of exacerbations or hospitalization. CONCLUSIONS: Allergen-specific IgE levels were correlated with allergen exposure among sensitized participants, except for cat. Allergen-specific IgE levels were also associated with more severe asthma across a range of clinical and biologic markers. Adjusting for exposure did not provide additional predictive value, suggesting that higher allergen-specific IgE levels may be indicative of both higher exposure and a greater degree of sensitization, which in turn may result in greater asthma severity.

Effect of environmental allergen sensitization on asthma morbidity in inner-city asthmatic children.

BACKGROUND: Asthma causes significant morbidity in children, and studies have demonstrated that environmental allergies contribute to increased asthma morbidity. OBJECTIVE: We investigated the differences between allergen skin tests and specific IgE (SIgE) and the role of IgG in regards to allergen exposure levels, and asthma morbidity in inner-city children. METHODS: Five hundred and six serum samples from the National Cooperative Inner City Asthma Study (NCICAS) were evaluated for SIgE to cockroach (Blattella germanica), dust mite (Dermatophagoides farinae), and Alternaria as well as specific IgG (SIgG) and IgG(4) to cockroach (B. germanica) and total IgE levels. Associations between sensitization to these allergens, exposures, and asthma morbidity were determined. RESULTS: Sensitization to environmental allergens and total IgE correlated with increased health care and medication use, but not with symptoms of wheeze. Sensitization with exposure to cockroach was associated with increased asthma morbidity, whereas dust mite sensitization was correlated with asthma morbidity independent of exposure. There was also a strong correlation between SIgE levels and skin test results, but the tests did not always agree. The relationship between SIgE and asthma morbidity is linear with no obvious cutoff value. Increased Bla g 1 in the home was a good predictor for sensitization; however, this relationship was not demonstrated for Der f 1. Cockroach SIgG correlated with increased health care use, however, there was no modifying effect of SIgG or SIgG(4) on the association between cockroach SIgE and asthma morbidity. CONCLUSIONS: SIgE levels and skin prick test results to environmental allergens can serve as markers of severe asthma for inner-city children. Asthma morbidity increased in a linear manner with SIgE levels. IgG was not an important predictor or modifier of asthma morbidity.

Biological potency of German cockroach allergen extracts determined in an inner city population.

BACKGROUND: Cockroach allergy is an important cause of inner city asthma. To perform valid studies on the diagnosis and treatment of cockroach allergy, biological potencies of test extracts need to be established, and a surrogate in vitro test for biological potency should be chosen. METHODS: Sixty-two cockroach-allergic adult subjects were recruited for quantitative skin testing with three commercial German cockroach extracts. The intradermal D50 values were determined using linear interpolation, and the biologic potencies were determined from D50 data. The extracts were also analysed for relative potency, using a competition ELISA, and for specific allergen content, using a two-site ELISA. RESULTS: Estimates of each extract's D50 were analysable in 48-55 subjects, with D50s between 10.3 and 11.8. All three extracts were bioequivalent using pre-set criteria. The biological potencies of the extracts were 1738-8570 bioequivalent allergy units (BAU)/mL (geometric mean=3300), and these relative potencies were similar to those estimated by competition ELISA and specific allergen content. IgE against cockroach allergens were detected in sera from 34 subjects with analysable D50s, and 17 subjects had IgE directed against specific cockroach allergens. Although the presence of anti-Bla g 5 correlated with the subjects' skin test responses for 2/3 extracts, no single allergen was immunodominant. Antibody responses among the subjects were heterogeneous. CONCLUSIONS: Although commercial cockroach extracts are relatively low in potency, immunotherapeutic doses should be achievable. Biological potency may be estimated using D50 testing, a combination of specific allergen determinations, or by an overall potency assay such as the competition ELISA. CAPSULE SUMMARY: The biological potency of three German cockroach allergen extracts, determined in an inner city population, was 1738-8570 BAU/mL. No one allergen was immunodominant, and surrogate in vitro testing methods were examined.

Asthma and body weight change: a 20-year prospective community study of young adults.

OBJECTIVE: There is increasing evidence for an association between asthma and body weight change. The objectives of these analyses were to examine the temporal relationships of this association and to explore the role of childhood depression as an explanatory factor. METHODS: Data were derived from six subsequent semistructured interviews on health habits and health conditions from a single-age community study of 591 young adults followed up between ages 20 and 40 years. RESULTS: Cross-sectionally (over the whole study period), asthma was significantly associated with obesity (odds ratio=3.9 [95% confidence interval 1.2, 12.2]). Multivariate longitudinal analyses revealed that asthma was associated with increased later weight gain and later obesity among women after controlling for potentially confounding variables, whereas weight gain and obesity were not associated with later asthma. A secondary analysis showed that depressive symptoms during childhood were associated with adult obesity and asthma, partially explaining the asthma-obesity comorbidity. CONCLUSION: This study encourages further research on mechanisms underlying the asthma-obesity comorbidity, particularly on shared psychosocial factors operating during critical periods in childhood and adolescence that may influence the development and persistence of both obesity and asthma during adulthood.

Sociodemographic correlates of indoor allergen sensitivity among United States children.

BACKGROUND: Exposure to indoor allergens is associated with asthma morbidity. Nationally, asthma morbidity disproportionately affects socially disadvantaged populations, but it is unclear whether exposure to indoor allergens follows a similar pattern. OBJECTIVE: We sought to examine the national prevalences and demographic correlates of sensitivity to indoor allergens related to asthma. METHODS: Analysis of a cross-sectional survey of a representative sample of 4164 United States children aged 6 to 16 years who participated in allergen testing in the Third National Health and Nutrition Examination Survey from 1988 to 1994 was performed. The main outcome measures were sensitivity reactions to cockroach, dust mite, cat, and Alternaria alternata, as measured via skin prick testing. RESULTS: Multivariate models, including sex, age, race-ethnicity, education, poverty, family history, region of country, housing age, crowding, and urban residence, revealed significant racial-ethnic disparities in sensitivity. Compared with white children, African American children had higher odds ratios (ORs) of cockroach or dust mite sensitivity (cockroach OR, 2.5 [95% CI, 1.9-3.2]; dust mite OR, 1.3 [95% CI, 1.0-1.7]), as did Mexican American children (cockroach OR, 1.9 [95% CI, 1.3-2.8]; dust mite OR, 1.6 [95% CI, 1.2-2.2]). African American children also had significantly higher odds of sensitivity to A alternata (OR, 2.1 [95% CI, 1.5-2.8]). CONCLUSIONS: African American and Mexican American children are substantially more likely than white children to be sensitized to allergens important in asthma. Differences in indoor allergen sensitivity are consistent with racial differences in asthma morbidity. Along with other data, these findings suggest that racial disparities in housing, community, or both environmental factors play a role in determining national patterns of asthma morbidity.

Differences in asthma prevalence between samples of American Indian and Alaska Native children.

OBJECTIVES: To better understand the prevalence of asthma among American Indian and Alaska Native (AI/AN) children and to explore the contribution of locale to asthma symptoms and diagnostic assignment, the authors surveyed AI/AN middle school students, comparing responses from metropolitan Tacoma, Washington (metro WA) and a non-metropolitan area of Alaska (non-metro AK). METHODS: Students in grades 6-9 completed an asthma screening survey. The authors compared self-reported rates of asthma symptoms, asthma diagnoses, and health care utilization for 147 children ages 11-16 self-reporting as AI/AN in metro WA and 365 in non-metro AK. RESULTS: The prevalences of self-reported asthma symptoms were similar for the metro WA and non-metro AK populations, but a significantly higher percentage of metro WA than of non-metro AK respondents reported having received a physician diagnosis of asthma (OR 2.33; 95% CI 1.23, 4.39). The percentages of respondents who reported having visited a medical provider for asthma-like symptoms in the previous year did not differ. CONCLUSIONS: The difference in rates of asthma diagnosis despite similar rates of asthma symptoms and respiratory-related medical visits may reflect differences in respiratory disease patterns, diagnostic labeling practices, or environmental factors. Future attempts to describe asthma prevalence should consider the potential contribution of non-biologic factors such as diagnostic practices.

Environmental tobacco smoke as a risk factor for respiratory disease in children.

Respiratory diseases are a frequent reason for using health care. In 1995-1996, diseases of the respiratory tract (ICD 460-519) contributed seven of the top 15 reasons for visits to physician offices among children under 15 years of age in the United States. Environmental tobacco smoke (ETS) is a wide-spread environmental pollutant that has been long linked with respiratory problems. This paper will review the available literature on the role ETS plays in respiratory diseases, including asthma. This review focuses not only on the respiratory problems caused by ETS, but also examines the influence of age at exposure on the consequences of ETS and the importance of the differing sources of ETS exposure. As ETS is a completely preventable form of environmental pollution, the success or failure of various types of interventions will also be reviewed.

Understanding the economic burden of asthma.

The economic impact of asthma is large and growing, and the use of economic outcomes is increasing. Such outcomes serve as the basis for studies of the efficiency of care and are being reported increasingly as outcomes of clinical trials. This article presents the basic components of a cost-of-illness study, the in-fluences that have an impact on these components, the relation of economic indicators to clinical outcomes, and the relative importance of the economic factors for differing groups in society.

Health status of the Pakistani population: a health profile and comparison with the United States.

OBJECTIVES: The health status of the Pakistani population was compared with that of the US population to provide a better understanding of the health problems in a developing nation and shed light on the dynamics of selected diseases. METHODS: Results from the National Health Survey of Pakistan (n = 18,315) and the US National Health and Nutrition Examination Survey (n = 31,311) were compared. Standardized and comparable methods were used in both surveys. RESULTS: Indicators of undernutrition among children were high throughout Pakistan. Among adults, there were urban-rural differences and economic gradients in indicators of undernutrition and risk factors for heart disease and cancer. In comparison with the US population, the Pakistani population has a higher rate of undernutrition, a lower rate of high cholesterol, and an approximately equal rate of high blood pressure. CONCLUSIONS: There are major inequalities in health within Pakistan and between Pakistan and the United States. Standardized national health examination survey methodology can be used to monitor health status and plan health transition policy in developing countries.

Is allergen skin test reactivity a predictor of mortality? Findings from a national cohort.

BACKGROUND: The importance of atopy on subsequent mortality is controversial. A clearer understanding is important as atopy is increasing worldwide. OBJECTIVE: To determine the influence of allergen skin test reactivity on observed mortality of a national cohort. METHODS: Baseline health status and atopic status (allergen skin testing) was measured as part of the second National Health and Nutrition Examination Survey (NHANES II), a representative sample of the US population, during the years 1976-80. Vital status and cause of death were assessed through December 31, 1992 for all examinees 30 years of age or older at baseline (n = 9252) as part of the NHANES II Mortality Study (NH2MS). The analytic sample contained 8179 men and women after excluding missing data. Allergen skin test reactivity was defined as weal >/= 3 mm to one of eight 1 : 20 (w/v), 50% glycerinated ('No US Standard of Potency') allergens licensed by the FDA: house dust, cat, dog, Alternaria, mixed giant/short ragweed, oak, perennial rye grass, and Bermuda grass. Survival analyses were conducted using multivariate adjusted Cox regression models to evaluate the association between atopy and all-cause, cardiovascular, and cancer mortality. RESULTS: There was no association between allergen skin test reactivity and all cause mortality: 30-44 years RR = 1.07 (95% CI 0.63-1.84); 45-59 years RR = 1.10 (0.78-1.55); 60-75 years RR = 1.07 (0.91-1.25). Results were unchanged when cancer or heart disease mortality were examined separately. The presence or absence of allergic symptoms, using the flare to define skin test reactivity, eliminating deaths in the first 5 years of follow-up, or eliminating individuals with pre-existing conditions did not alter the findings. CONCLUSIONS: Atopy, defined by allergen skin test reactivity, with or without symptoms, is not a predictor of subsequent mortality.

An English and Spanish Pediatric Asthma Symptom Scale.

BACKGROUND: Pediatric asthma survey measures have not been adequately tested in non-English-speaking populations. OBJECTIVES: To test the reliability and validity of an English and Spanish symptom scale to measure asthma control in children. SUBJECTS: Parents (54% Spanish-speaking; 61% not high school graduates) of 234 children seen in the emergency department for an asthma exacerbation. MEASURES: Parent report of frequency and perceived severity of child asthma symptoms during the beginning and after resolution of the exacerbation. RESULTS: An 8-item scale composed of reports of cough, wheezing, shortness of breath, asthma attacks, chest pain, night symptoms, and overall perceived severity had very good psychometric properties in both English and Spanish. The reliability (Cronbach's alpha) of the scale ranged from 0.81 to 0.87 for both languages and time frames. In both languages, the validity of the scale was supported by responsiveness to changes in clinical status (lower symptom score after resolution of the exacerbation, P < 0.001) and by moderate to strong correlations (P < 0.001) with other asthma morbidity measures (parent report of child bother: r = 0.59-0.65; school days lost: r = 0.38-0.67; and activity days lost: r = 0.41-0.59). There were no statistically significant differences in the reliability or construct validity of the summary symptom scale by language, although Spanish speakers reported a lower frequency of some symptoms than did English speakers. CONCLUSIONS: A reliable and valid 8-item scale can be used to measure control of asthma symptoms in Spanish-speaking populations of low literacy. Additional research to evaluate language equivalency of asthma measures is necessary.

A randomized clinical trial to reduce asthma morbidity among inner-city children: results of the National Cooperative Inner-City Asthma Study.

OBJECTIVE: To evaluate a family-focused asthma intervention designed for inner-city children 5 to 11 years old with moderate to severe asthma. STUDY DESIGN: Randomized, multisite, controlled trial to minimize symptom days (wheeze, loss of sleep, reduction in play activity) measured by a 2-week recall assessed at 2-month intervals over a 2-year follow-up period. The intervention was tailored to each family's individual asthma risk profile assessed at baseline. RESULTS: Averaged over the first 12 months, participants in the intervention group (n = 515) reported 3.51 symptom days in the 2 weeks before each follow-up interview compared with 4.06 symptom days for the control group (n = 518), a difference of 0.55 (95% CI, 0.18 to 0.92, P =.004). The reduction among children with severe asthma was approximately 3 times greater (1.54 d/2 wk). More children in the control group (18.9%) were hospitalized during the intervention compared with children in the intervention group (14. 8%), a decrease of 4.19% (CI, -8.75 to 0.36, P =.071). These improvements were maintained in the intervention group during the second year of follow-up, during which they did not have access to the asthma counselor. CONCLUSIONS: We demonstrated that an individually tailored, multifaceted intervention carried out by Masters-level social workers trained in asthma management can reduce asthma symptoms among children in the inner city.

Structure and evolution of a pair-rule interaction element: runt regulatory sequences in D. melanogaster and D. virilis.

Pair-rule genes serve two important functions during Drosophila development: they first initiate periodic patterns, and subsequently interact with each other to refine these patterns to the precision required for definition of segmental compartments. Previously, we described a pair-rule input region of the runt gene. Here we further characterize this region through the use of reporter gene constructs and by comparison with corresponding sequences from Drosophila virilis. We find that many but not all regulatory properties of this '7-stripe region' are functionally conserved. Moreover, the similarity between these homologous sequences is surprisingly low. When compared to similar data for gap gene input element, our data suggest that pair-rule target sequences are less constrained during evolution, and that functional elements mediating pair-rule interactions can be dispersed over many kilobases.

Direct expenditures for the treatment of allergic rhinoconjunctivitis in 1996, including the contributions of related airway illnesses.

BACKGROUND: Previous estimates of the national economic burden of allergic rhinoconjunctivitis (AR/AC) have relied on data analyses in which AR/AC was the primary International Classification of Diseases-ninth revision-Clinical Modification (ICD-9-CM)-coded diagnosis. These studies ignore the costs when AR/AC was a secondary diagnosis to other disorders such as asthma and sinusitis. OBJECTIVE: We sought to determine the national direct cost of illness for AR/AC. METHODS: An expert panel used the Delphi technique to estimate the proportion of visits coded by other primary ICD-9-CM diagnoses in which AR/AC was a significant secondary comorbid condition. The costs of this proportion were deemed to be "attributable" to AR/AC and were added to the costs when allergic rhinitis and allergic conjunctivitis were the primary diagnoses. RESULTS: The cost when AR/AC was the primary diagnosis was $1.9 billion (in 1996 dollars). The cost when AR/AC was a secondary diagnosis was estimated at $4.0 billion, giving an estimate of $5.9 billion for the overall direct medical expenditures attributable to AR/AC. Outpatient services (63%, $3.7 billion), medications (25%, $1.5 billion), and inpatient services (12%, $0.7 billion) accounted for the expenditures. Children 12 years and younger accounted for $2.3 billion (38.0%). CONCLUSION: Upper airway allergy is an expensive disease process because of its readily apparent manifestations as AR/AC and its contribution to other airway disorders.