Early-life antibiotic use is associated with wheezing among children with high atopic risk: a prospective European study.

BACKGROUND: Little is known about the relationship between antibiotic use and asthma in the children with a higher risk of allergic sensitization. We examine the association between the use of specific therapeutic antibiotics in the first year of life and development of wheezing by 36 months among children with a higher risk of allergic sensitization. METHODS: A multi-center prospective cohort study was conducted among children at high risk for allergic sensitization. A validated questionnaire was used to prospectively collect information on antibiotic use and potential risk factors for wheezing from parents or guardians of 606 children from three European countries at 6, 12, 24 and 36 months of age. Multivariate linear and logistic regression models were used to adjust for potential confounders and effect modifiers and to estimate the association of antibiotic use with the development of early childhood wheezing. RESULTS: Of the antibiotics assessed, only macrolide use in the first year of life was associated with increasing risk for wheezing by 36 months, after adjusting for gender, socioeconomic status, breast feeding >6 months, tobacco smoke exposure, family history of asthma, and respiratory infection (RR = 1.09; 95% CI 1.05-1.13). To avoid a bias by indication, we analyzed children with and without respiratory infection separately. Similar associations were observed for macrolides use in children who had no respiratory infection. CONCLUSIONS: In European children with a familial risk for allergic sensitization, we found a positive association between macrolide use in the first year of life and wheezing until 36 months old which was independent of the effect of respiratory infection.

Omalizumab (Xolair) in children with seasonal allergic rhinitis: leukotriene release as a potential in vitro parameter to monitor therapeutic effects.

To investigate the effect of omalizumab, a humanized monoclonal antibody, in addition to specific immunotherapy (SIT) on in vitro sulfidoleukotriene release (SLT) (A) before, (B) directly after, and (C) 1 yr after treatment with omalizumab. Children and adolescents (6.3-17.6 yr) with sensitization to birch and grass pollens and suffering from seasonal allergic rhinitis were included in a Phase III, placebo-controlled, multicenter clinical study. Within the four-arm study, patients were randomly chosen to receive SIT for either birch or grass pollen and either subcutaneous omalizumab or placebo for 24 wk during the pollen season. Thereafter, omalizumab or placebo treatment ended, but SIT therapy continued. Blood samples were collected from 92 (A, B) and 78 children (C), respectively. Leukocytes were isolated and stimulated with grass and birch pollen allergens. In the supernatants, SLT (LTC4, LTD4, LTE4) were measured using ELISA [cellular allergen stimulation test, DPC-Biermann, Germany]. At the end of treatment the combination of omalizumab + SIT-grass [median SLT-release: 2125 (before) and 416 ng/ml (after omalizumab treatment); p < 0.001] as well as omalizumab + SIT-birch [1404 and 207 ng/ml; p < 0.001] resulted in significantly lower SLT release after stimulation with the corresponding allergen compared to placebo + SIT-grass [2231 and 2490 ng/ml] or placebo + SIT-birch [1324 and 2489 ng/ml]. One year after omalizumab or placebo treatment, there was no significant difference in SLT release between the 4 groups (omalizumab + SIT-grass: 2855; SIT-grass + placebo: 2543; omalizumab + SIT-birch: 2417; SIT-birch + placebo: 2573 ng/ml). These results strongly suggest that the observed effects of decreased SLT release after omalizumab treatment were attributable to the treatment with omalizumab, rather than to SIT therapy.

CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis.

BACKGROUND & AIMS: Cystic fibrosis (CF) is caused by over 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and presents with a widely variable phenotype. Genotype-phenotype studies identified CFTR mutations that were associated with pancreatic sufficiency (PS). Residual Cl- channel function was shown for selected PS mutations in heterologous cells. However, the functional consequences of most CFTR mutations in native epithelia are not well established. METHODS: To elucidate the relationships between epithelial CFTR function, CFTR genotype, and patient phenotype, we measured cyclic adenosine monophosphate (cAMP)-mediated Cl- secretion in rectal biopsy specimens from 45 CF patients who had at least 1 non-DeltaF508 mutation carrying a wide spectrum of CFTR mutations. We compared CFTR genotypes and clinical manifestations of CF patients who expressed residual CFTR-mediated Cl- secretion with patients in whom Cl- secretion was absent. RESULTS: Residual anion secretion was detected in 40% of CF patients, and was associated with later disease onset (P < 0.0001), higher frequency of PS (P < 0.0001), and less severe lung disease (P < 0.05). Clinical outcomes correlated with the magnitude of residual CFTR activity, which was in the range of approximately 12%-54% of controls. CONCLUSIONS: Specific CFTR mutations confer residual CFTR function to rectal epithelia, which is related closely to a mild disease phenotype. Quantification of rectal CFTR-mediated Cl- secretion may be a sensitive test to predict the prognosis of CF disease and identify CF patients who would benefit from therapeutic strategies that would increase residual CFTR activity.

Urinary leukotriene E4 levels in children with allergic rhinitis treated with specific immunotherapy and anti-IgE (Omalizumab).

Recently, we were able to demonstrate that Omalizumab, a humanized monoclonal anti-IgE antibody, reduces in vitro leukotriene (LT) release of peripheral leukocytes stimulated with allergen in children with allergic rhinitis undergoing allergen immunotherapy. The aim of this study was to investigate the effect of anti-IgE in combination with specific immunotherapy (SIT) on urinary leukotriene E4 (LTE4) levels. Children and adolescents with sensitization to birch and grass pollens and suffering from seasonal allergic rhinitis were included in a phase III, placebo-controlled, multicenter clinical study. Within the four-arm study, patients were randomized to receive SIT for either birch or grass pollen and to receive either subcutaneous anti-IgE or placebo for 24 weeks during the pollen season. From a total population of 225 children, we collected three urine samples in a subgroup of 19 children [n = 12 boys (63%); mean age 11.8 years; range 7.2-17.5 years; Group A (n = 10): SIT (grass or birch) + anti-IgE; Group B (n = 9): SIT (grass or birch) + placebo]. Urine samples were collected before, during and at the end of treatment. Endogenous urinary LTE4 was separated by high-performance liquid chromatography (HPLC) and determined by enzyme immunoassay with a specific antibody. No differences in urinary LTE4 concentrations were observed between the anti-IgE and the placebo groups before (A: 35.2; B: 36.5 nmol/mol creatinine), during (A: 27.0; B: 29.3) and after treatment (A: 28.9; B: 26.5 nmol/mol creatinine). We conclude that urinary LTE4 levels are not helpful in monitoring patients treated with anti-IgE and SIT.

A randomized controlled trial on the effect of montelukast on sputum eosinophil cationic protein in children with corticosteroid-dependent asthma.

Previous adult studies demonstrated the clinical efficacy of an additional treatment with leukotriene receptor antagonists on steroid-dependent asthma, but there is little knowledge about anti-inflammatory add-on effects within the lung. In this study, we hypothesized that steroid-treated children exhibit a decrease in bronchial inflammation in induced sputum under additional treatment with montelukast. Twenty-five asthmatic children aged 6 to 14 y, who had been taking inhaled corticosteroids (400-800 microg/d budesonide) regularly for at least 12 wk, were randomized to receive additional treatment with either montelukast (5 mg orally, once daily) or placebo over a 4-wk period. As primary efficacy variable, eosinophil cationic protein (ECP) in induced sputum as direct measurement of bronchial inflammation was assessed before and after treatment. To assure a baseline level of inflammation, an ECP concentration above 100 microg/L was required. Sputum eosinophil count, concentration of exhaled nitric oxide, urinary excretion of eosinophil protein X, and quality-of-life items were considered as secondary outcome variables. After treatment with montelukast, ECP in sputum was significantly reduced (montelukast: median -975 microg/L [5 to 95% confidence interval: -4295 to 583 microg/L]; placebo: 561 microg/L [-1335 to 3320 microg/L]; p < 0.01) and the quality-of-life score had significantly improved (p < 0.05) compared with placebo. Partly explained by low baseline levels, no statistically significant change in concentration of exhaled nitric oxide (p > 0.05), urinary excretion of eosinophil protein X (p > 0.05), or eosinophil count (p > 0.05) was found. In conclusion, add-on treatment with montelukast can suppress sputum ECP in children with steroid-dependent asthma, while at the same time an improvement in quality of life items occurs.

Atopic manifestations, breast-feeding protection and the adverse effect of DDE.

Despite the numerous studies on the possible protective effect of breast feeding against the onset of atopic manifestations during childhood, this issue remains controversial. As part of an environmental epidemiological study, we investigated whether different blood concentrations of dichlorodiphenyl-dichloroethylene (DDE) modified the protective effect of breast feeding against atopic manifestations in 338 children. DDE concentration, duration of breast feeding and manifestation of atopic disorders were measured in 1994-95 at age 7-8 years. Information gathered on asthma, atopic eczema and hay fever was based on questionnaire data. We measured the total serum concentration of immunoglobulin E (IgE) and specific IgE levels against inhalant allergens. In 1997, we also determined bronchial hyper-reactivity with a hypertonic saline challenge test. To estimate odds ratios from our cross-sectional analysis, we applied logistic regressions, controlling for confounders. Breast feeding had a protective effect on the two asthma variables (e.g.> 12 weeks breast feeding for doctor-diagnosed asthma, OR = 0.32 [95% CI 0.11, 0.87]; for 'ever' asthma, OR = 0.13 [95% CI 0.02, 0.68]), but not on bronchial hyper-reactivity, hay fever, atopic eczema or the two IgE variables. The protective effect became stronger in children with DDE blood levels below the median of 0.29 micro g/L (e.g. doctor-diagnosed asthma,> 12 weeks breast feeding, OR = 0.24 [95% CI 0.06, 0.95]). Also, for specific IgE against inhalant allergens, the association gained statistical significance. For children with a DDE concentration of 0.29 micro g/L and higher, breast feeding did not show a significant protective effect. Our results suggest that contaminants such as DDE may modify the protective effect and may have contributed to inconsistent findings on the protective effect of breast feeding in previous studies. We recommend determining levels of breast milk contaminants in children when assessing the impact of breast feeding on atopic manifestations.

Modulation of Ca2+-activated Cl- secretion by basolateral K+ channels in human normal and cystic fibrosis airway epithelia.

Human airway epithelia express Ca2+-activated Cl- channels (CaCC) that are activated by extracellular nucleotides (ATP and UTP). CaCC is preserved and seems to be up-regulated in the airways of cystic fibrosis (CF) patients. In the present study, we examined the role of basolateral K+ channels in CaCC-mediated Cl- secretion in native nasal tissues from normal individuals and CF patients by measuring ion transport in perfused micro Ussing chambers. In the presence of amiloride, UTP-mediated peak secretory responses were increased in CF compared with normal nasal tissues. Activation of the cAMP pathway further increased CaCC-mediated secretion in CF but not in normal nasal mucosa. CaCC-dependent ion transport was inhibited by the chromanol 293B, an inhibitor of cAMP-activated hKvLQT1 K+ channels, and by clotrimazole, an inhibitor of Ca2+-activated hSK4 K+ channels. The K+ channel opener 1-ethyl-2-benzimidazolinone further increased CaCC-mediated Cl- secretion in normal and CF tissues. Expression of hSK4 as well as hCACC-2 and hCACC-3 but not hCACC-1 was demonstrated by reverse transcriptase PCR on native nasal tissues. We conclude that Ca2+-activated Cl- secretion in native human airway epithelia requires activation of Ca2+-dependent basolateral K+ channels (hSK4). Co-activation of hKvLQT1 improves CaCC-mediated Cl- secretion in native CF airway epithelia, and may have a therapeutic effect in the treatment of CF lung disease.

Study on the Prevention of Allergy in Children in Europe (SPACE): allergic sensitization at 1 year of age in a controlled trial of allergen avoidance from birth.

Several studies have demonstrated that early intervention may modulate the natural course of atopic disease. The objective of this study was to prevent sensitization to house dust mite and food allergens, as well as development of atopic symptoms, during infancy. To achieve this we employed the combination of an educational package with the use of mite allergen-impermeable mattress encasings. A multi-center European, population-based, randomized controlled study of children at increased atopic risk [study on the prevention of Allergy in Children in Europe (SPACE)] was performed in five countries (Austria, Germany, Greece, Great Britain, Lithuania) and included three cohorts of schoolchildren, toddlers and newborns. We report on the newborn cohort. A total of 696 newborns were included in Austria, Great Britain and Germany. Inclusion criteria were a positive history of parental allergy and a positive skin-prick test or specific immunoglobulin E (IgE) of >or= 1.43 kU/l against at least one out of a panel of common aeroallergens in one or both parents. At 1 year of age the overall sensitization rate against the tested allergens [dust mite allergens: Dermatophagoides pteronyssinus and D. farinae (Der p and Der f, respectively)] and food allergens (egg, milk) in the prophylactic group was 6.21% vs. 10.67% in the control group. The prevalence of sensitization against Der p was 1.86% in the prophylactic group vs. 5% in the control group. In conclusion, we demonstrated, in a group of newborns at risk for atopic diseases, that the sensitization rate to a panel of aero- and food allergens could be effectively decreased through the use of impermeable mattress encasings and the implementation of preventive measures that were easy to perform.

Polymorphisms in the IL 18 gene are associated with specific sensitization to common allergens and allergic rhinitis.

BACKGROUND: Atopy has been linked to chromosome 11q22, a region that harbors the IL18 gene. IL-18 enhances IL-4/IL-13 production and induces IgE production that is directly associated with the pathogenesis of atopic disorders. OBJECTIVE: We sought to investigate whether genetic abnormalities in the regulatory regions of the IL18 gene predispose, in part, to susceptibility to atopy. METHODS: Among a white population of 105 families, the oldest child was examined with regard to atopic phenotypes and single-nucleotide polymorphisms (SNPs) within the IL18 gene. RESULTS: We have identified 5 novel SNPs in the IL18 gene (-920[t/c], -133[c/g], and -132[a/g] in promoter 2 [upstream of exon 2]; +179[c/a; Ser35Ser] in exon 4; and +486[c/t; Phe137Phe] in exon 6). Three SNPs are located in promoter 2, and one (-133[c/g]; nuclear factor 1 site) was significantly associated with high serum IgE levels (P =.001; odds ratio, 3.96) and specific sensitization to common allergens (P =.005; OR, 4.12). In addition, previously identified SNPs in exon 1 (+113[t/g] and +127[c/t]) and in promoter 1 (-137[g/c], GATA3 site) of the IL18 gene were significantly associated with high IgE levels (P < or =.005; OR, 3.27-3.90) and specific sensitization (P =.02 to.008; OR, 3.27-3.83). The SNP +127(g/t) in exon 1 was also a susceptibility locus for seasonal allergic rhinitis (P =.008; OR, 3.22). CONCLUSION: IL18 might be responsible for the linkage effects seen in the chromosomal region 11q22, which has been found previously with the phenotype "sensitization to mite allergen." Thus a suspected direct role of IL18 in the pathogenesis of atopy has been strengthened by the presence of 8 common SNPs in the promoter regions of IL18.

The effect of anti-IgE treatment on in vitro leukotriene release in children with seasonal allergic rhinitis.

BACKGROUND: Binding of allergens with IgE to the IgE receptors on mast cells and basophils results in the release of inflammatory mediators as sulfidoleukotrienes (SLTs), triggering allergic cascades that result in allergic symptoms, such as asthma and rhinitis. OBJECTIVE: We sought to investigate whether anti-IgE (Oma-lizumab), a humanized monoclonal anti-IgE antibody, in addition to specific immunotherapy (SIT) affects the leukotriene pathway. METHODS: Ninety-two children (age range, 6-17 years) with sensitization to birch and grass pollens and with seasonal allergic rhinitis were included in a phase III, placebo- controlled, multicenter clinical study. All subjects were randomized to one of 4 treatment groups. Two groups subcutaneously received birch SIT and 2 groups received grass SIT for at least 14 weeks before the start of the birch pollen season. After 12 weeks of SIT titration, placebo or anti-IgE was added for 24 weeks. The primary clinical efficacy variable was symptom load (ie, the sum of daily symptom severity score and rescue medication score during pollen season). Blood samples taken at baseline and at the end of study treatment after the grass pollen season were used for separation of leukocytes in this substudy. After in vitro stimulation of the blood cells with grass and birch pollen allergens, SLT release (LTC4, LTD4, and LTE4) was quantified by using the ELISA technique. RESULTS: Before the study treatment, SLT release to birch and grass pollen exposure did not differ significantly among the 4 groups. Under treatment with anti-IgE + SIT-grass (n = 23), a lower symptom load occurred during the pollen season compared to placebo + SIT-grass (n = 24, P =.012). The same applied to both groups receiving birch SIT (n = 23 and n = 22, respectively; P =.03). At the end of treatment, the combination of anti-IgE plus grass SIT, as well as anti-IgE plus birch SIT, resulted in significantly lower SLT release after stimulation with the corresponding allergen (416 ng/L [5th-95th percentile, 1-1168] and 207 ng/L [1-860 ng/L], respectively) compared with placebo plus SIT (2490 ng/L [384-6587 ng/L], P =.001; 2489 ng/L [1-5670 ng/L], P =.001). In addition, treatment with anti-IgE was also followed by significantly lower SLT releases to the allergens unrelated to SIT (grass SIT: 300 ng/L [1-2432 ng/L] in response to birch allergen; birch SIT: 1478 ng/L [1-4593 ng/L] in response to grass pollen) in comparison with placebo (grass SIT: 1850 ng/L [1-5499 ng/L], P =.001; birch SIT: 2792 ng/L [154-5839 ng/L], P =.04]. CONCLUSION: Anti-IgE therapy reduces leukotriene release of peripheral leukocytes stimulated with allergen in children with allergic rhinitis undergoing allergen immunotherapy independent of the type of SIT allergen used.

Randomized trial to prevent sensitization to mite allergens in toddlers and preschoolers by allergen reduction and education: one-year results.

OBJECTIVE: To evaluate the effectiveness of prevention measures against dust mite sensitization. DESIGN: European (England, Germany, Greece, Lithuania) multicenter prospective single-blind randomized control trial with a follow-up of 12 months. PARTICIPANTS: Toddlers and preschoolers, with at least 1 parent with atopic symptoms and sensitization, who initially were not sensitized to mite allergens. INTERVENTIONS: A combination of education and a simple preventive measure (mattress encasement) to reduce mite allergen exposure. SETTING: Community-based study. MAIN OUTCOME MEASURES: Sensitization to mite allergens (skin-prick test or specific immunoglobulin E). RESULTS: Of 636 children (mean age, 3.1 years) included in the study, 566 (89%) participated in the first-year follow-up. The incidence of sensitization to mite allergens was 10 (3%) of 330 in the intervention vs 20 (6.5%) of 306 in the control arm, including loss of follow-up (intention-to-treat principle). Allergic symptoms were more common in sensitized than in nonsensitized children and so was the prevalence of physician-diagnosed asthma, eczema, and food allergy. CONCLUSIONS: This simple, harmless, and inexpensive measure can be used in toddlers and preschoolers of parents with atopic disorders to reduce sensitization to mite allergens. With regard to clinical manifestations of atopy, follow-up studies are needed to determine the effectiveness of the intervention.

Intrinsic defect in T cell production of interleukin (IL)-13 in the absence of both IL-5 and eotaxin precludes the development of eosinophilia and airways hyperreactivity in experimental asthma.

Interleukin (IL)-5 and IL-13 are thought to play key roles in the pathogenesis of asthma. Although both cytokines use eotaxin to regulate eosinophilia, IL-13 is thought to operate a separate pathway to IL-5 to induce airways hyperreactivity (AHR) in the allergic lung. However, identification of the key pathway(s) used by IL-5 and IL-13 in the disease process is confounded by the failure of anti-IL-5 or anti-IL-13 treatments to completely inhibit the accumulation of eosinophils in lung tissue. By using mice deficient in both IL-5 and eotaxin (IL-5/eotaxin(-/-)) we have abolished tissue eosinophilia and the induction of AHR in the allergic lung. Notably, in mice deficient in IL-5/eotaxin the ability of CD4(+) T helper cell (Th)2 lymphocytes to produce IL-13, a critical regulator of airways smooth muscle constriction and obstruction, was significantly impaired. Moreover, the transfer of eosinophils to IL-5/eotaxin(-/-) mice overcame the intrinsic defect in T cell IL-13 production. Thus, factors produced by eosinophils may either directly or indirectly modulate the production of IL-13 during Th2 cell development. Our data show that IL-5 and eotaxin intrinsically modulate IL-13 production from Th2 cells and that these signaling systems are not necessarily independent effector pathways and may also be integrated to regulate aspects of allergic disease.

Bee-venom allergy in children: long-term predictive value of standardized challenge tests.

Venom immunotherapy (VIT) is able to protect insect venom-allergic patients against life-threatening sting reactions. Standardized sting challenges can be used as a diagnostic tool to check whether VIT is required. No data are available on the long-term predictive value of sting challenge tests. The purpose of this study was to investigate the long-term predictive value of sequential bee-sting challenges with respect to the ability to predict future sting reactions in bee-venom (BV) allergic children. Between 1988 and 1992, 92 BV-allergic children had been challenged with sequential bee stings at intervals of 2-6 weeks to determine the necessity of VIT. In 1996, all 92 families were followed-up using standardized telephone interviews. Until the follow-up, 61 children (66.3%) had experienced at least one natural bee sting. Based on the results of the initial challenge tests, 13 of the 61 patients had been started on VIT. Two of these 13 (15.4%) developed systemic reactions 1 year after VIT of 5 years, of which one was mild and one was severe. Among the 48 re-stung patients who were not treated with VIT, three children (6.3%) experienced mild systemic reactions, whereas 45 children reported no more than a local reaction. The long-term predictive value of sequential bee-sting challenge tests for systemic reactions in children not treated with VIT remained at a level of 93.8% (95% confidence interval: 82.8-98.7%) even over a period of more than 6 years. Based on this data, we conclude that sequential bee-sting challenges are a powerful tool to determine the necessity for VIT in BV-allergic children.

Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children and adolescents with seasonal allergic rhinitis.

BACKGROUND: Specific immunotherapy (SIT) and treatment with monoclonal anti-IgE antibody have complementary modes of action. OBJECTIVE: The purpose of this study was to determine whether combined therapy could provide better efficacy than either treatment alone. METHODS: We conducted a randomized, double-blinded trial to assess the efficacy and safety of subcutaneously administered anti-IgE (omalizumab) or placebo in children and adolescents with seasonal allergic rhinitis in both a birch pollen season and a grass pollen season (sequential seasons together lasting an average of 84 days). There were 4 treatment arms. Each subject was started on SIT-birch or SIT-grass, and anti-IgE or placebo was started before and maintained during the anticipated pollen seasons (a total of 24 weeks). The primary efficacy variable was symptom load, the sum of daily symptom severity score plus rescue medication use. RESULTS: A total of 221 subjects (intent-to-treat population) aged 6 to 17 years were analyzed for efficacy. Combination therapy reduced symptom load over the 2 pollen seasons by 48% (P <.001) over SIT alone. When analyzed separately by season, the 2 groups receiving unrelated SIT were considered placebo controls. In the grass season, symptom loads were as follows: unrelated (birch) SIT + placebo, 0.89 (reference value); unrelated (birch) SIT + anti-IgE, 0.49 (-45%); SIT-grass + placebo, 0.61 (-32%); SIT-grass + anti-IgE, 0.26 (-71%). CONCLUSION: Anti-IgE therapy conferred a protective effect independent of the type of allergen. Additional clinical benefit was demonstrated in both pollen seasons, whether there was coverage by SIT or not. This combination might prove useful for the treatment of allergic rhinitis, particularly for polysensitized patients.

Circadian variation of exhaled nitric oxide and urinary eosinophil protein X in asthmatic and healthy children.

Asthmatic symptoms and the frequency of admissions to hospital because of acute asthma tend to increase in the early morning hours, and it is therefore possible that airway inflammation increases during the night. To elucidate the hypothetical circadian variation of airway inflammation, we measured concentrations of exhaled nitric oxide (FeNo), urinary eosinophil protein X excretion (EPX), and forced expiratory volume in the first second (FEV1) in 20 asthmatic and 6 nonatopic nonasthmatic children every 3 h during a 21-h period. Compared with control subjects, asthmatic subjects had higher FeNo (median, 22.7 versus 10.3 ppb, p = 0.016) and lower FEV1 % predicted (median, 91.0 versus 101.9%, p = 0.045), but did not differ significantly in EPX (median, 153.8 versus 148.7 microg/mmol creatinine, p = 0.83) at 7 AM. However, differences in gender and age do not allow direct comparisons between asthmatic and control children. FeNo and EPX demonstrated a cosinelike circadian rhythm (log FeNo, p = 0.0001; log EPX, p = 0.0001) with lowest levels at 7 PM and highest at 7 AM. This was also the case for FEV1 % (p = 0.01). No difference in the amplitude of circadian rhythm was observed between asthmatic and healthy control children for log FeNo (p = 0.35), log EPX (p = 0.57), and FEV1 % (p = 0.17). A stratified analysis showed a significant circadian rhythm in the control group for log FeNo (p = 0.014) and log EPX (p = 0.0001). Our results therefore suggest a circadian rhythm of inflammatory markers, which peaks in the early morning. Rhythmicity of EPX excretion and FeNo in healthy children suggests a physiologic mechanism; however, pathologic effects during the night might occur under conditions of asthma-specific inflammation.

Study on the prevention of allergy in Children in Europe (SPACE): allergic sensitization in children at 1 year of age in a controlled trial of allergen avoidance from birth.

Several studies have demonstrated that early intervention may modulate the natural course of atopic disease. Our objective was to prevent sensitization to house-dust mite and food allergens, as well as the development of atopic symptoms during infancy, by the combination of an educational package and the use of mite allergen-impermeable mattress encasings. A multicentre European, population-based, randomized, controlled study of children at increased atopic risk [Study on the Prevention of Allergy in Children in Europe (SPACE)] was performed in five countries (Austria, Germany, Greece, the UK, and Lithuania), and included three cohorts - schoolchildren, toddlers, and newborns. We report on the newborn cohort. A total of 696 newborns were included from Austria, the UK, and Germany. Inclusion criteria were: a positive history of parental allergy; and a positive skin-prick test or specific immunoglobulin E (IgE) (IgE > or = 1.43 kU/L) against at least one out of a panel of common aeroallergens in one or both parents. At 1 year of age, the overall sensitization rate against the tested allergens [dust-mite allergens: Dermatophagoides pteronyssinus and Dermatophagoides farinae (Der p and Der f)] and food allergens (egg, milk) in the prophylactic group was 6.21% vs. 10.67% in the control group. The prevalence of sensitization against Der p was 1.86% in the prophylactic group vs. 5% in the control group. In conclusion, we were able to demonstrate, in a group of newborns at risk for atopic diseases, that the sensitization rate to a panel of aero- and food allergens could be effectively decreased through the use of impermeable mattress encasings and the implementation of easy-to-perform preventive measures.