Fernando D. Martinez

SIBLINGS, DAY-CARE ATTENDANCE, AND THE RISK OF ASTHMA AND WHEEZING DURING CHILDHOOD

BACKGROUNDnYoung children with older siblings and those who attend day care are at increased risk for infections, which in turn may protect against the development of allergic diseases, including asthma. However, the results of studies examining the relation between exposure to other children and the subsequent development of asthma have been conflicting.nnnMETHODSnIn a study involving 1035 children followed since birth as part of the Tucson Childrens Respiratory Study, we determined the incidence of asthma (defined as at least one episode of asthma diagnosed by a physician when the child was 6 to 13 years old) and the prevalence of frequent wheezing (more than three wheezing episodes during the preceding year) in relation to the number of siblings at home and in relation to attendance at day care during infancy.nnnRESULTSnThe presence of one or more older siblings at home protected against the development of asthma (adjusted relative risk for each additional older sibling, 0.8; 95 percent confidence interval, 0.7 to 1.0; P=0.04), as did attendance at day care during the first six months of life (adjusted relative risk, 0.4; 95 percent confidence interval, 0.2 to 1.0; P=0.04). Children with more exposure to other children at home or at day care were more likely to have frequent wheezing at the age of 2 years than children with little or no exposure (adjusted relative risk, 1.4; 95 percent confidence interval, 1.1 to 1.8; P=0.01) but were less likely to have frequent wheezing from the age of 6 (adjusted relative risk, 0.8; 95 percent confidence interval, 0.6 to 1.0; P=0.03) through the age of 13 (adjusted relative risk, 0.3; 95 percent confidence interval, 0.2 to 0.5; P<0.001).nnnCONCLUSIONSnExposure of young children to older children at home or to other children at day care protects against the development of asthma and frequent wheezing later in childhood.

Skin test reactivity and number of siblings

Abstract Objective: To investigate the relation between skin test reactivity in children and number of siblings. Design: Cross sectional survey among school-children aged 9-11 years. Skin prick tests in the children and self completion of written questionnaire by their parents. Subjects: 5030 children in Munich and 2623 children in Leipzig and Halle, Germany. Main outcome measures: Atopic status assessed by skin prick tests. Results: After possible confounders were controlled for, the prevalence of atopic sensitisation decreased linearly with increasing number of siblings (odds ratio=0.96 for one sibling, 0.67 for five or more siblings; P=0.005). In atopic children the severity of the skin test reaction as assessed by the weal size was not associated with the number of siblings. Conclusions: Factors directly or indirectly related to the number of siblings may decrease the susceptibility of children to become atopic. Thus, declining family size may in part contribute to the increased prevalence of atopic diseases reported in Western countries over the past few decades.

Single nucleotide polymorphisms in innate immunity genes: abundant variation and potential role in complex human disease.

Summary: Under selective pressure from infectious microorganisms, multicellular organisms have evolved immunological defense mechanisms, broadly categorized as innate or adaptive. Recent insights into the complex mechanisms of human innate immunity suggest that genetic variability in genes encoding its components may play a role in the development of asthma and related diseases. As part of a systematic assessment of genetic variability in innate immunity genes, we have thus far have examined 16 genes by resequencing 93 unrelated subjects from three ethnic samples (European American, African American and Hispanic American) and a sample of European American asthmatics. Approaches to discovering and understanding variation and the subsequent implementation of disease association studies are described and illustrated. Although highly conserved across a wide range of species, the innate immune genes we have sequenced demonstrate substantial interindividual variability predominantly in the form of single nucleotide polymorphisms (SNPs). Genetic variation in these genes may play a role in determining susceptibility to a range of common, chronic human diseases which have an inflammatory component. Differences in population history have produced distinctive patterns of SNP allele frequencies, linkage disequilibrium and haplotypes when ethnic groups are compared. These and other factors must be taken into account in the design and analysis of disease association studies.

Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. ethnic groups and exploratory case-control disease association studies.

TLR9 is a mammalian Toll-like receptor homologue that appears to function as an innate immune pattern recognition protein for motifs that are far more common in bacterial than in mammalian DNA. The gene was sequenced in 71 subjects from three self-identified U.S. ethnic groups to identify single-nucleotide polymorphisms (SNPs). A total of 20 SNPs were found of which only 20% were in the public dbSNP database. Four SNPs were relatively common in all three ethnic samples. Using these four SNPs, seven distinct haplotypes were statistically inferred, of which four accounted for 75% or more chromosomes. These four haplotypes could be distinguished from each other by the alleles of two SNPs (-1237 and 2848). Five exploratory nested case-control disease-association studies (asthma, DVT, MI, and COPD in European Americans and asthma in African Americans) were performed by genotyping DNA collected from four ongoing cohort studies. There was evidence suggesting increased risk for asthma with a C allele at -1237 (odds ratio 1.85, 95%CI 1.05 to 3.25) among European Americans (genotypes available from 67 cases and 152 controls). No other significant disease associations were detected. Replication of this finding in other, larger samples is needed. This study suggests that there is substantial diversity in human TLR9, possibly associated with asthma in Europeans but not African Americans. No association was detected with three other diseases potentially related to innate immunity.

The origins of asthma and chronic obstructive pulmonary disease in early life.

Results from birth cohort and cross-sectional studies of young children with wheezing have uncovered strong associations between both lung function and immune responses in early life and the subsequent development of persistent wheezing and chronic airway obstruction up to mid-adulthood. It is now apparent that the pattern of bronchial hyperresponsiveness, deficits in lung function, and structural airway remodeling that are characteristic of asthma may be already established during the preschool years in most patients. Interactions between acute viral infections, especially those due to rhinovirus and respiratory syncytial virus, and exposure to perennial aeroallergens may induce persistent alterations in immune responses and airway function in susceptible subjects. Similarly, deficits in airway function present shortly after birth predict airflow limitation in early adult life, which in turn is a strong predisposing factor for chronic obstructive pulmonary disease. The fact that these alterations are more likely to occur during early life and even in utero than later during childhood suggests that there a developmental window of susceptibility during which exposures can disrupt normal growth trajectories. Novel strategies for primary prevention of chronic respiratory diseases will be based on the identification of the genetic and environmental factors that interactively cause these disruptions.

Genes, environments, development and asthma: a reappraisal

Significant advances have been made in our understanding of the role of genetic variation in determining complex human phenotypes such as asthma. It is now well established that there is no single “gene for asthma”, in the way that the cystic fibrosis transmembrane receptor is the “gene for cystic fibrosis”. It is also clear that among all genetic variants eventually found to be associated with asthma, only a few will be replicated, and in the same direction, in the majority of well-performed studies. Current evidence suggests that most asthma-related polymorphisms determine risk for the disease in a context-dependent manner, i.e. they interact with environmental factors, with polymorphisms in other genes and with the specific developmental phase of the disease in which the association is tested. Elucidating these complex interactions will allow us to understand better the heterogeneity of the disease and thus to develop therapeutic tools tailored to the specific form of the disease in each patient.

The coming-of-age of the hygiene hypothesis

The hygiene hypothesis, as originally proposed, postulated an inverse relation between the incidence of infectious diseases in early life and the subsequent development of allergies and asthma. New evidence from epidemiological, biological and genetic studies has significantly enlarged the scope of the hypothesis. It now appears probable that environmental danger signals regulate the pattern of immune responses in early life. Microbial burden in general, and not any single acute infectious illness, is the main source of these signals. The latter interact with a sensitive and complex receptor system, and genetic variations in this receptor system may be an important determinant of inherited susceptibility to asthma and allergies.

Prematurity as a risk factor for asthma in preadolescent children

Information on long-term respiratory symptoms in prematurely born children is scanty. We studied an unselected population of 9- to 11-year-old schoolchildren. A self-administered questionnaire was distributed to the parents. Children underwent lung function testing, cold air challenge, and skin prick tests. A gestational age < 37 weeks in children with a birth weight < or = 2500 gm was reported by 5% of the parents. Premature girls had significantly more current asthma (odds ratio (OR) 2.6; 95% confidence interval (CI) 1.4, 4.7; p < 0.05), recurrent wheezing (OR 1.7; 95% CI 1.1, 2.7; p < 0.001), recurrent shortness of breath (OR 2.4; 95% CI 1.5, 3.9; p < 0.001), and frequent cough with exercise (OR 1.8; 95% CI 1.1, 2.9; p < 0.05) than term girls, especially if they required mechanical ventilation after birth. No such differences could be shown in boys. More prematurely born children who required mechanical ventilation (OR 3.7; 95% CI 2.2, 6.4; p < 0.0001) had a family history of asthma than children born at term. Significant decrements could be demonstrated for different measurements of lung function in premature girls. These results remained significant after control for confounders in a multivariate regression analysis. No difference was found between groups for bronchial hyperresponsiveness to cold, dry air or for atopic sensitization. We conclude that a family history of asthma may predispose premature children to more severe respiratory disease. Respiratory symptoms and decrements in lung function seen in girls may reflect abnormalities of lung function in survivors of severe neonatal respiratory disease.

Maturation of immune responses at the beginning of asthma

The prevalence of childhood asthma appears to be increasing worldwide. A critical element in the development of childhood asthma is maturation of the childs immune system. Most asthmatic children have a history of recurrent lower respiratory tract illnesses associated with airway obstruction during the first year of life. Most infants and young children who will go on to have persistent wheezing and asthma show high IgE production and eosinophilic immune responses at the time of their first viral lower respiratory tract illness. Understanding the genetic and environmental factors that regulate the maturation of the immune response during early life will greatly enhance the development of strategies for the primary and secondary prevention of asthma.

Risk factors for developing wheezing and asthma in childhood

Wheezing lower respiratory tract illness in infancy and asthma share the clinical findings of wheezing and respiratory distress. Although the link between wheezing lower respiratory tract illness in infancy and the subsequent development of asthma is a limited one, both conditions do share some common risk factors, including exposure to environmental tobacco smoke, difficult living conditions (low socioeconomic class, crowding, allergen exposure), and increased risk in males. The impact of baseline lung function on wheezing lower respiratory tract illness risk is substantial and may be independent of airway reactivity. In contrast, the development of chronic airway inflammation mediated by allergic sensitization plays a central role in the development of persistent asthma. Although the endogenous risks for these two outcomes may be fixed, it is clear that caregivers may help to reduce or eliminate the exogenous risks listed earlier by parental education and improvement of the living conditions of young children.