Diagnostic value of exhaled nitric oxide in childhood asthma and allergy.

Fractional exhaled nitric oxide (FE(NO) ) has been proposed as a diagnostic test of asthma. We aimed to investigate in a population based birth cohort of children the usefulness of FE(NO) as a diagnostic tool. The 10-yr follow up of the Environment and Childhood Asthma Study in Oslo included 616 children representative of the prospective birth cohort. Both FE(NO) (single breath technique) and skin prick test (SPT) were measured in 331, limited at the time by equipment availability. Structural parental interview, spirometry, methacholine challenge and exercise test were performed. FE(NO) was significantly elevated in children with current asthma (geometric mean 9.6 (95% confidence interval (CI) (6.9, 13.4) p.p.b.) compared with healthy children (5.8 (5.4, 6.3) p.p.b.; p < 0.001). FE(NO) was highest among children with current allergic asthma (asthma and positive SPT) (14.0 (8.9, 22.1) p.p.b.), whereas children with non-allergic asthma (6.1 (4.0, 9.2) p.p.b.) had comparable FE(NO) levels to healthy children (p = 0.99). Allergic sensitization was most closely associated with FE(NO) . A FE(NO) cut-off value of 20.4 p.p.b. had a high specificity (0.97), but a low sensitivity (0.41) and a Positive Likelihood Ratio of 16.1 for current allergic asthma. In the present childhood population-based study, high FE(NO) levels were closely associated with current allergic asthma and not with current asthma without allergic sensitization. Estimating the individual predictive probability of having asthma by use of FE(NO,) improves the diagnostic utility of the test.

Asthma prediction in school children; the value of combined IgE-antibodies and obstructive airways disease severity score.

BACKGROUND: Allergic sensitisation increases the risk for asthma development. In this prospective birth cohort (Environment and Childhood Asthma) study, we hypothesized that combining quantitative measures of IgE antibodies (Sigma-IgE) and Severity score of obstructive airways disease (OAD) at 2 years of age (Severity score) is superior to predict current asthma (CA) at 10 years than either measure alone. Secondarily, we assessed if gender modified the prediction of CA. METHODS: A follow-up study at 10 years of age was performed in 371 2-year-old children with recurrent (n = 219) or no (n = 152) bronchial obstruction with available serum analysed for Sigma-IgE to common food and inhalant allergens through a panel test, Phadiatop Infant) (Phadia, Uppsala, Sweden). Clinical variables included allergic sensitisation and exercise testing to characterise children with CA vs not CA at 10 years and the Severity score (0-12, 0 indicating no OAD) was used to assess risk modification. RESULTS: Severity score alone explained 24% (Nagelkerke R(2) = 0.24) of the variation in CA, whereas Sigma-IgE explained only 6% (R(2) = 0.06). Combining the two increased the explanatory capacity to R(2) = 0.30. Gender interacted significantly with Sigma-IgE; whereas Severity score predicted CA in both genders, the predictive capacity of Sigma-IgE for CA at 10 years was significant in boys only. CONCLUSION: Combining Sigma-IgE to inhalant allergens and Severity score at 2 years was superior to predict asthma at 10 years than either alone. Severity score predicted CA in both genders, whereas Sigma-IgE significantly predicted CA in boys only.

Do allergic families avoid keeping furry pets?

UNLABELLED: Studies addressing the relationship between pet keeping and development of asthma and allergies may be influenced by pet avoidance in families with a history of allergic disease. Following a cohort of 1019 children in Oslo till 10 years of age, we studied the association of pet keeping with socio-economic factors and allergic disease in the family. A family history of asthma and rhinoconjunctivitis was not significantly associated with pet ownership at birth or with pet removal by 10 years. Acquiring cats and dogs was less likely if the child had allergic rhinoconjunctivitis, whereas no association was seen with asthma (in any family member). Single parenthood increased the likelihood of acquiring a cat, smoking parents more often had cats or dogs, and having older siblings was associated with keeping dogs and other furry pets. Among 319 families reporting pet avoidance, 70% never had pets, 8% had given up pets, and 22% avoided a particular type of pet only. Twenty-four per cent of the parents failed to retrospectively report pet keeping during the child's first year of life. Overall, allergic rhinitis, but not asthma was associated with actual pet avoidance, whereas the strongest predictors for keeping pets were found to be socio-economic factors. PRACTICAL IMPLICATIONS: Allergic disease in a child most often does not lead to the removal of the family's furry pet. Pet avoidance is associated with allergic symptoms, but not asthma. Socio-economic factors like parental education, single parenthood and smoking affects the families' decisions on pet keeping, including the type of pets the families will avoid or acquire. The large recall error demonstrated points to the need for prospective data regarding pet keeping.

A TLR2 polymorphism is associated with type 1 diabetes and allergic asthma.

Type 1 diabetes (T1D) and allergic asthma are immune-mediated diseases. Pattern recognition receptors are proteins expressed by cells in the immune system to identify microbial pathogens and endogenous ligands. Toll-like receptors (TLRs) and CD14 are members of this family and could represent a molecular link between microbial infections and immune-mediated diseases. Diverging hypotheses regarding whether there exists a common or inverse genetic etiology behind these immune-mediated diseases have been presented. We aimed to test whether there exist common or inverse associations between polymorphisms in the pattern recognition receptors TLR2, TLR4 and CD14 and T1D and allergic asthma. Eighteen single nucleotide polymorphisms (SNPs) were genotyped in TLR2 (2), TLR4 (12) and CD14 (4) in 700 T1D children, 357 nuclear families with T1D children and 796 children from the 'Environment and Childhood Asthma' study. Allele and haplotype frequencies were analyzed in relation to diseases and in addition transmission disequilibrium test analyses were performed in the family material. Both T1D and allergic asthma were significantly associated with the TLR2 rs3804100 T allele and further associated with the haplotype including this SNP, possibly representing a susceptibility locus common for the two diseases. Neither TLR4 nor CD14 were associated with T1D or allergic asthma.

Severity of obstructive airways disease by age 2 years predicts asthma at 10 years of age.

BACKGROUND: Predicting school-age asthma from obstructive airways disease (OAD) in early life is difficult, even when parental and children's atopic manifestations are taken into consideration. OBJECTIVE: To assess if the severity of OAD in the first 2 years of life predicts asthma at 10 years of age. METHODS: From a nested case control study within the Environment and Childhood Asthma study, 233 2-year-old subjects with recurrent (> or = 2 episodes) bronchial obstruction (rBO+) and 216 subjects without bronchial obstruction (rBO-) underwent clinical examination, parental interview, treadmill test and metacholine bronchial hyperresponsiveness (BHR) measurement at 10 years. A severity score at 2 years was calculated by frequency, persistence of bronchial obstruction and hospital admissions because of OAD. MAIN OUTCOMES: Current asthma at 10 years (asthma with symptoms and/or asthma medication during the past year and/or positive treadmill test). Secondary outcome was metacholine BHR at 10 years. RESULTS: Compared with rBO- subjects, adjusted odds ratio (95% CI) of current asthma among rBO+ was 7.9 (4.1, 15.3), and among rBO+ with a severity score of > 5, 20.2 (9.9, 41.3). In receiver operated characteristic analysis, positive and negative predictive values demonstrated the applicability and value of the score, with an optimal cut-off at severity score 5. Children with severity score > 5 had severe BHR more often (PD20 metacholine < 1 micromol) than children with a lower or 0 score (p = 0.0041). CONCLUSION: Using a simple scoring system, a high severity score of OAD by 2 years of age is a strong risk factor for, and may predict, current asthma at 10 years of age.

HLA Dr-Dq haplotypes and the TNFA-308 polymorphism: associations with asthma and allergy.

BACKGROUND: The HLA (human leukocyte antigen) class II genes DQB1 and DRB1 and the Tumor Necrosis Factor alpha gene (TNFA) within the HLA complex (chromosome 6p21) have been associated with asthma and allergy. Due to the strong linkage disequilibrium characterizing this complex and the multiple asthma/allergy expressions, we aimed to determine which of these genes were primarily involved in specific asthma/allergy traits. METHODS: The DRB1-DQB1 alleles and TNFA-308 polymorphism were genotyped in 959 children from the Environment and Childhood Asthma study and analyzed for possible associations with allergic and non-allergic asthma (with/without at least one positive skin prick test for allergens) and specific allergic sensitization, as well as bronchial hyperresponsiveness and total IgE, using both allele and extended haplotype analyses. RESULTS: Different genes within the HLA complex were associated with separate asthma and allergy traits. Nonallergic asthma was associated with both the TNFA-308A allele [Odds ratio (OR) 1.7 (1.3-2.3)] and DRB1 03 allele [OR 1.6(1-2.6)], but extended DRB1 03-TNFA-308 haplotype analysis suggested that the DRB1-DQB1 association was secondary to linkage disequilibrium with the TNFA-308 polymorphism. Allergies were associated with HLA class II alleles only; birch sensitization with DQB1 0603-DRB1 13 [OR 2.3 (1.4-4.0)] and mugwort sensitization with DQB1 0609-DRB1 13 [OR 7.1 (1.9-27.0)] and DQB1 0501-DRB1 01 [OR 2.0 (1.0-4.0)]. CONCLUSIONS: Our data suggests that asthma is not associated with DRB1 or DQB1 but rather TNFA or a gene(s) in linkage disequilibrium, while sensitization to specific allergens is associated with particular alleles at the DQ and/or DR loci. A novel association between DQB1 0603-DRB1 13 and birch allergy is identified.

Eosinophil cationic protein (ECP) polymorphisms and association with asthma, s-ECP levels and related phenotypes.

BACKGROUND: Eosinophil cationic protein (ECP) is a potent cytotoxic secretory protein with bactericidal and antiviral properties. ECP is released by activated eosinophils and regarded as a marker of eosinophilic inflammation. High levels of ECP have been reported in cases of active asthma and other allergic diseases. This study aimed to assess whether three single-nucleotide polymorphisms (SNPs) in the ECP gene (RNASE3) on chromosome 14 q24-q31 or their haplotypes are associated with asthma, allergy, or related phenotypes. METHODS: The three SNPs -38CA, +371CG and +499CG in RNASE3 and their haplotypes were analyzed for associations with asthma, serum-ECP (s-ECP) levels, allergic sensitization (positive skin-prick test to common allergens), bronchial hyperresponsiveness (BHR) assessed by methacholine inhalation, and serum-IgE (s-IgE) levels in 177 families from Norway and the Netherlands identified through siblings with asthma. RESULTS: Transmission disequilibrium test (TDT) demonstrated significant associations between the A-G-G haplotype and asthma as well as the specific phenotypes allergic asthma (but not non-allergic asthma), high s-ECP, high s-IgE and BHR, while the C-G-G haplotype was associated with reduced occurrence of these traits. In addition, the -38A allele was associated with high s-ECP levels and allergic asthma. CONCLUSION: The present study suggests that the A-G-G haplotype in the RNASE3 gene influences the development of asthma, in particular, an allergic form of asthma. Furthermore, as the -38CA SNP lies in close vicinity of known intron-regulatory sites, results of SNP analysis suggest that the detected association is possibly linked to a genetic transcriptional control of s-ECP levels.