C.J. Tisler

Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children.

RATIONALE Virus-induced wheezing episodes in infancy often precede the development of asthma. Whether infections with specific viral pathogens confer differential future asthma risk is incompletely understood. OBJECTIVES To define the relationship between specific viral illnesses and early childhood asthma development. METHODS A total of 259 children were followed prospectively from birth to 6 years of age. The etiology and timing of specific viral wheezing respiratory illnesses during early childhood were assessed using nasal lavage, culture, and multiplex reverse transcriptase-polymerase chain reaction. The relationships of these virus-specific wheezing illnesses and other risk factors to the development of asthma were analyzed. MEASUREMENTS AND MAIN RESULTS Viral etiologies were identified in 90% of wheezing illnesses. From birth to age 3 years, wheezing with respiratory syncytial virus (RSV) (odds ratio [OR], 2.6), rhinovirus (RV) (OR, 9.8), or both RV and RSV (OR , 10) was associated with increased asthma risk at age 6 years. In Year 1, both RV wheezing (OR, 2.8) and aeroallergen sensitization (OR, 3.6) independently increased asthma risk at age 6 years. By age 3 years, wheezing with RV (OR, 25.6) was more strongly associated with asthma at age 6 years than aeroallergen sensitization (OR, 3.4). Nearly 90% (26 of 30) of children who wheezed with RV in Year 3 had asthma at 6 years of age. CONCLUSIONS Among outpatient viral wheezing illnesses in infancy and early childhood, those caused by RV infections are the most significant predictors of the subsequent development of asthma at age 6 years in a high-risk birth cohort.

Evidence for a Causal Relationship between Allergic Sensitization and Rhinovirus Wheezing in Early Life

RATIONALE Aeroallergen sensitization and virus-induced wheezing are risk factors for asthma development during early childhood, but the temporal developmental sequence between them is incompletely understood. OBJECTIVE To define the developmental relationship between aeroallergen sensitization and virus-induced wheezing. METHODS A total of 285 children at high risk for allergic disease and asthma were followed prospectively from birth. The timing and etiology of viral respiratory wheezing illnesses were determined, and aeroallergen sensitization was assessed annually for the first 6 years of life. The relationships between these events were assessed using a longitudinal multistate Markov model. MEASUREMENTS AND MAIN RESULTS Children who were sensitized to aeroallergens had greater risk of developing viral wheeze than nonsensitized children (hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.2-3.1). Allergic sensitization led to an increased risk of wheezing illnesses caused by human rhinovirus (HRV) but not respiratory syncytial virus. The absolute risk of sensitized children developing viral wheeze was greatest at 1 year of age; however, the relative risk was consistently increased at every age assessed. In contrast, viral wheeze did not lead to increased risk of subsequent allergic sensitization (HR, 0.76; 95% CI, 0.50-1.1). CONCLUSIONS Prospective, repeated characterization of a birth cohort demonstrated that allergic sensitization precedes HRV wheezing and that the converse is not true. This sequential relationship and the plausible mechanisms by which allergic sensitization can lead to more severe HRV-induced lower respiratory illnesses support a causal role for allergic sensitization in this developmental pathway. Therefore, therapeutics aimed at preventing allergic sensitization may modify virus-induced wheezing and the development of asthma.

Developmental cytokine response profiles and the clinical and immunologic expression of atopy during the first year of life

BACKGROUND Allergic diseases have been linked to abnormal patterns of immune development, and this has stimulated efforts to define the precise patterns of cytokine dysregulation that are associated with specific atopic phenotypes. OBJECTIVE Cytokine-response profiles were prospectively analyzed over the first year of life and compared with the clinical and immunologic expressions of atopy. METHODS Umbilical cord and 1-year PBMCs were obtained from 285 subjects from allergic families. PHA-stimulated cytokine-response profiles (IL-5, IL-10, IL-13, and IFN-gamma) were compared with blood eosinophil counts and total and specific IgE levels (dust mites, cat, egg, Alternaria species, peanut, milk, and dog) at age 1 year and at the development of atopic dermatitis and food allergy. RESULTS For the cohort as a whole, cytokine responses did not evolve according to a strict TH1 or TH2 polarization pattern. PHA-stimulated cord blood cells secreted low levels of IL-5 (2.1 pg/mL), moderate levels of IFN-gamma (57.4 pg/mL), and greater amounts of IL-13 (281.8 pg/mL). From birth to 1 year, IL-5 responses dramatically increased, whereas IL-13 and IFN-gamma responses significantly decreased. Reduced cord blood secretion of IL-10 and IFN-gamma was associated with subsequent sensitization to egg. In addition, there was evidence of TH2 polarization (increased IL-5 and IL-13 levels) associated with blood eosinophilia and increased total IgE levels by age 1 year. CONCLUSION These findings demonstrate that cytokine responses change markedly during the first year of life and provide further evidence of a close relationship between TH2 skewing of immune responses and the incidence of atopic manifestations in children.

Specific patterns of allergic sensitization in early childhood and asthma & rhinitis risk

Specific patterns of allergic sensitization as well as quantification of the in vitro IgE response in early life may provide relevant clinical insight into future rhinitis and asthma risk.

Fractional exhaled nitric oxide measurements are most closely associated with allergic sensitization in school-age children

BACKGROUND Factors affecting fractional exhaled nitric oxide (FeNO) in early childhood are incompletely understood. OBJECTIVE To examine the relationships between FeNO and allergic sensitization, total IgE, atopic dermatitis, rhinitis, asthma, and lung function (spirometry) in children. METHODS Children at high risk of asthma and other allergic diseases because of parental history were enrolled at birth and followed prospectively. FeNO was measured by an online technique at ages 6 and 8 years. Relationships among FeNO, various atopic characteristics, and asthma were evaluated. RESULTS Reproducible FeNO measurements were obtained in 64% (135/210) of 6-year-old and 93% (180/194) of 8-year-old children. There was seasonal variability in FeNO. Children with aeroallergen sensitization at ages 6 and 8 years had increased levels of FeNO compared with those not sensitized (geometric mean; 6 years, 10.9 vs 6.7 parts per billion [ppb], P < .0001; 8 years, 14.6 vs 7.1 ppb, P < .0001). FeNO was higher in children with asthma than in those without asthma at 8 years but not 6 years of age (6 years, 9.2 vs 8.3 ppb, P = .48; 8 years, 11.5 vs 9.2 ppb, P = .03). At 8 years of age, this difference was no longer significant in a multivariate model that included aeroallergen sensitization (P = .33). There were no correlations between FeNO and spirometric indices at 6 or 8 years of age. CONCLUSION These findings underscore the importance of evaluating allergen sensitization status when FeNO is used as a potential biomarker in the diagnosis and/or monitoring of atopic diseases, particularly asthma.

Viral infections, cytokine dysregulation and the origins of childhood asthma and allergic diseases.

Background: The origins of asthma and allergic disease begin in early life for many individuals. It is vital to understand the factors and/or events leading to their development. Methods: The Childhood Origins of Asthma project evaluated children at high risk for asthma to study the relationships among viral infections, environmental factors, immune dysregulation, genetic factors, and the development of atopic diseases. Consequently wheezing illnesses, viral respiratory pathogen identification, and in vitro cytokine response profiles were comprehensively evaluated from birth to 3 years of age, and associations of the observed phenotypes with genetic polymorphisms were investigated. Results: For the entire cohort, cytokine responses did not develop according to a strict T helper cell 1 or T helper cell 2 polarization pattern during infancy. Increased cord blood mononuclear cell phytohemagglutin-induced interferon-γ responses of mononuclear cells were associated with decreased numbers of moderate to severe viral infections during infancy, especially among subjects with the greatest exposure to other children. In support of the hygiene hypothesis, an increased frequency of viral infections in infancy resulted in increased mitogen-induced interferon-γ responses at 1 year of age. First year wheezing illnesses caused by respiratory viral infection were the strongest predictor of subsequent third year wheezing. Also, genotypic variation interacting with environmental factors, including day care, was associated with clinical and immunologic phenotypes that may precede the development of asthma. Conclusions: Associations between clinical wheezing, viral identification, specific cytokine responses and genetic variation provide insight into the immunopathogenesis of childhood asthma and allergic diseases.

Early life rhinovirus wheezing, allergic sensitization, and asthma risk at adolescence

Background: Early life rhinovirus (RV) wheezing illnesses and aeroallergen sensitization increase the risk of asthma at school age. Whether these remain risk factors for the persistence of asthma out to adolescence is not established. Objective: We sought to define the relationships among specific viral illnesses and the type and timing of aeroallergen sensitization with the persistence of asthma into adolescence. Methods: A total of 217 children were followed prospectively from birth to age 13 years. The etiology and timing of viral wheezing illnesses during the first 3 years of life were assessed along with patterns of allergen sensitization. The associations between viral wheezing illnesses, presence and pattern of aeroallergen sensitization, and asthma diagnosis at age 13 years were evaluated. Results: When adjusted for all viral etiologies, wheezing with RV (odds ratio = 3.3; 95% CI, 1.5‐7.1), but not respiratory syncytial virus (odds ratio = 1.0; 95% CI, 0.4‐2.3), was associated with asthma at age 13 years. Age of aeroallergen sensitization also influenced asthma risk; 65% of children sensitized by age 1 year had asthma at age 13 years, compared with 40% of children not sensitized at age 1 year but sensitized by age 5 years, and 17% of children not sensitized at age 5 years. Early life aeroallergen sensitization and RV wheezing had additive effects on asthma risk at adolescence. Conclusions: In a high‐risk birth cohort, the persistence of asthma at age 13 years was most strongly associated with outpatient wheezing illnesses with RV and aeroallergen sensitization in early life.

IFNG genotype and sex interact to influence the risk of childhood asthma

BACKGROUND Asthma is a complex disease characterized by sex-specific differences in incidence, prevalence, and severity, but little is known about the molecular basis of these sex-based differences. OBJECTIVE To investigate the genetic architecture of sex differences in asthma risk, we evaluated (1) associations between polymorphisms in the IFNG gene and childhood-onset asthma in combined and sex-specific samples and (2) interactions between polymorphisms and sex on asthma risk. METHODS Main and sex-interaction effects of IFNG genetic diversity on asthma risk and IFN-γ levels were examined in a birth cohort of children at high risk for asthma and allergic diseases. Replication of the genetic association was assessed in an independent sample of asthma cases. RESULTS Significant genotype-sex interactions on asthma were observed for 2 IFNG single nucleotide polymorphisms, rs2069727 and rs2430561, which were in strong linkage disequilibrium with each other. In contrast, none of the 10 IFNG single nucleotide polymorphisms showed significant main effects on asthma. The observed genotype-sex interaction on asthma was characterized by nonadditivity; that is, heterozygous boys had the highest risk for asthma, and heterozygous girls had the lowest risk. The interaction effect was robust to other asthma risk factors but was limited to children who experienced wheezing illnesses with viral infections during the first 3 years of life. Genotype-sex interactions were also observed in the IFN-γ response to LPS in the first year of life. Finally, the sex-interaction effect was replicated in an independent population of childhood asthma cases. CONCLUSIONS These results provide insight into the genetic basis of sex differences in asthma and highlight the potential importance of interactions among sex, genotype, and environmental factors in asthma pathogenesis.

The influence of processing factors and non‐atopy‐related maternal and neonate characteristics on yield and cytokine responses of cord blood mononuclear cells

Rationale Several studies have evaluated the associations between cord blood cellular responses and atopic diseases in children, but the results of these studies are inconsistent. Variations in blood processing factors and maternal and infant characteristics are typically not accounted for and may contribute to these inconsistencies.

Protection from asthma in a high-risk birth cohort by attenuated P2X7 function

BACKGROUND Viral illnesses are important factors in both asthma inception and exacerbations, and allergic sensitization in early life further enhances asthma risk through unclear mechanisms. Cellular damage caused by infection or allergen inhalation increases ATP levels in the airways with subsequent purinergic receptor activation. The purinergic receptor P2X(7) can enhance airway leukocyte recruitment to the airways, and P2X(7) knockout mice display a reduced asthma-like phenotype. OBJECTIVE Based on the P2X(7) knockout mouse, we hypothesized that children with low P2X(7) function would have decreased rates of asthma. METHODS We used a functional assay to determine P2X(7) pore-producing capacity in whole-blood samples in a birth cohort at high risk for asthma development. The P2X(7) assay was validated with known loss-of-function alleles in human subjects. P2X(7) pore status categorization was used to assess asthma and allergy status in the cohort. RESULTS Attenuated P2X(7) function was associated with lower asthma rates at ages 6 and 8 years, and the greatest effects were observed in boys. Children with asthma at age 11 years who had low P2X(7) capacity had less severe disease in the previous year. Attenuated P2X(7) function was also associated with sensitization to fewer aeroallergens. CONCLUSION P2X(7) functional capacity is associated with asthma risk or disease severity, and these relationships appear to be age related.