Prenatal antibiotic exposure increases the risk of infant atopic dermatitis: data from a Greek cohort.

Summary: Background. The human microbiome is important due to the impact it has on host immunologic development and allergy-associated diseases. This study aimed to investigate the impact of prenatal exposure to antibiotics on the incidence of atopic dermatitis (AD) in children at 18 months of age. Methods. Mothers were interviewed at baseline, in the maternity ward and by phone questionnaire after 18 months. Demographic data, mode of delivery, yoghurt consumption, antibiotic and other drug use during pregnancy, atopic history, diagnosis of AD and history of infections in the offspring were noted. Results. 385 mothers were interviewed at baseline. 231 (60%) mothers with 236 children responded at follow up. Cesarean section was reported in 116 (50.2%) deliveries while antibiotic use during pregnancy in 55/231 (23.8%) women. 43/236 (18.22%) infants were diagnosed with AD. Intravenous antibiotic use was associated with a 7.7 increased risk of AD diagnosis in the offspring (95%CI 1.23-48.27, p = 0.029). An increased odd for AD was recorded for mothers 30-40 years of age (OR 4.50, 95%CI 1.08-18.7, p = 0.039). No significant association between cesarean section and AD (p = 0.70) was recorded. In multivariate analysis, reported food allergy (OR 8.03, 95%CI 2.30-27.97, p = 0.001) and otitis media episodes in children (OR 3.76, 95%CI 1.60-8.83, p = 0.002) were significantly associated with AD diagnosis. Conclusions. An increased risk of AD was recorded only when antibiotics were given prenatally by intravenous route and in women between 30-40 years of age. Children with food allergy had an increased risk for AD. The relatively high percentage of cesarean sections was not a risk factor for AD.

Incidence and natural history of hen's egg allergy in the first 2 years of life-the EuroPrevall birth cohort study.

BACKGROUND: Parents and health staff perceive hen's egg allergy (HEA) as a common food allergy in early childhood, but the true incidence is unclear because population-based studies with gold-standard diagnostic criteria are lacking. OBJECTIVE: To establish the incidence and course of challenge-confirmed HEA in children, from birth until the age of 24 months, in different European regions. METHODS: In the EuroPrevall birth cohort study, children with a suspected HEA and their age-matched controls were evaluated in 9 countries, using a standardized protocol including measurement of HE-specific immunoglobulin E-antibodies in serum, skin prick tests, and double-blind, placebo-controlled food challenges (DBPCFC). RESULTS: Across Europe, 12 049 newborns were enrolled, and 9336 (77.5%) were followed up to 2 years of age. In 298 children, HEA was suspected and DBPCFC was offered. HEA by age two was confirmed in 86 of 172 challenged children (mean raw incidence 0.84%, 95% confidence interval (95% CI) 0.67-1.03). Adjusted mean incidence of HEA was 1.23% (95% CI 0.98-1.51) considering possible cases among eligible children who were not challenged. Centre-specific incidence ranged from United Kingdom (2.18%, 95% CI 1.27-3.47) to Greece (0.07%). Half of the HE-allergic children became tolerant to HE within 1 year after the initial diagnosis. CONCLUSIONS: The largest multinational European birth cohort study on food allergy with gold-standard diagnostic methods showed that the mean adjusted incidence of HEA was considerably lower than previously documented, although differences in incidence rates among countries were noted. Half of the children with documented HEA gained tolerance within 1 year postdiagnosis.

The obesity-asthma link in different ages and the role of body mass index in its investigation: findings from the Genesis and Healthy Growth Studies.

BACKGROUND: To date, an obesity/asthma link is well defined in adults; however, the nature of such a link is obscure in children, partly due to Body Mass Index (BMI) limitations as a surrogate fat mass marker in childhood. We thus opted to investigate the association of adiposity with asthma in children of different ages, using several indices to assess fat mass. METHODS: Wheeze ever/in the last 12 months (current) and physician-diagnosed asthma were retrospectively reported via questionnaire by the parents of 3641 children, participating in two cross-sectional studies: 1626 children aged 2-5 (the Genesis Study) and 2015 children aged 9-13 (the Healthy Growth Study). Perinatal data were recorded from the children's medical records or reported by parents. Anthropometric measurements (i.e., BMI, waist/hip circumference, biceps/triceps/subscapular/suprailiac skinfold thickness) were conducted in both cohorts; bioelectric impedance analysis (BIA) was conducted only in preadolescent children. RESULTS: In children aged 2-5, asthma was positively correlated with conicity index, waist/hip circumference, waist-to-height ratio, skinfold thickness, and skinfold-derived percentage fat mass (P < 0.05) but not BMI or BMI-defined overweight/obesity, after adjusting for several confounders. In children aged 9-13, asthma was positively associated with conicity index, waist circumference, waist-to-height ratio, skinfold thickness, skinfold-derived percentage fat mass, BIA-derived percentage fat mass, BMI, and BMI-defined overweight/obesity, following adjustment (P < 0.05). Current/ever wheeze was not consistently associated with fat mass in either population. CONCLUSIONS: Fat mass is positively linked to asthma in both 2-5 and 9-13 age spans. However, the failure of BMI to correlate with preschool asthma suggests its potential inefficiency in asthma studies at this age range.

Conception via in vitro fertilization and delivery by Caesarean section are associated with paediatric asthma incidence.

BACKGROUND: The association between perinatal factors and asthma inception is under rigorous investigation. Nevertheless, evidence of a correlation between asthma, conception via in vitro fertilization (IVF) and delivery through Caesarean section (C-section) is inconclusive. OBJECTIVE: We aimed to assess the relation of asthma incidence with IVF and C-section, after controlling for several potential confounding factors. METHODS: Parent-reported wheeze in the last 12 months (current), wheeze ever, physician-diagnosed asthma, method of conception, and type of delivery were recorded from questionnaires filled in by the parents of 2016 Greek children aged 9-13, (the Healthy Growth Study population). Some perinatal data were recorded from children's medical records and others were reported by parents; anthropometric measurements were also conducted in children. RESULTS: IVF was correlated with physician-diagnosed asthma (OR = 2.25; 95% CI = 1.11-4.56), but not with current/ever wheeze after adjustment for potential confounding factors. After adjustment, C-section was also associated with asthma (OR = 1.39; 95% CI = 1.04-1.87), but not with current/ever wheeze. When the association of both IVF and C-section with asthma was examined in the same multivariate logistic regression model, it was weakened to borderline significance (OR = 2.04; 95% CI = 1-4.15 and OR = 1.34; 95% CI = 1-1.81 respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Conception via IVF and delivery by C-section may predispose children to future asthma development. Either variable could also exert a confounding effect on the link of the other to asthma; this may partially be accountable for inconsistencies in the findings of pertinent studies.

Viruses and bacteria in acute asthma exacerbations--a GA² LEN-DARE systematic review.

A major part of the burden of asthma is caused by acute exacerbations. Exacerbations have been strongly and consistently associated with respiratory infections. Respiratory viruses and bacteria are therefore possible treatment targets. To have a reasonable estimate of the burden of disease induced by such infectious agents on asthmatic patients, it is necessary to understand their nature and be able to identify them in clinical samples by employing accurate and sensitive methodologies. This systematic review summarizes current knowledge and developments in infection epidemiology of acute asthma in children and adults, describing the known impact for each individual agent and highlighting knowledge gaps. Among infectious agents, human rhinoviruses are the most prevalent in regard to asthma exacerbations. The newly identified type-C rhinoviruses may prove to be particularly relevant. Respiratory syncytial virus and metapneumovirus are important in infants, while influenza viruses seem to induce severe exacerbations mostly in adults. Other agents are relatively less or not clearly associated. Mycoplasma and Chlamydophila pneumoniae seem to be involved more with asthma persistence rather than with disease exacerbations. Recent data suggest that common bacteria may also be involved, but this should be confirmed. Although current information is considerable, improvements in detection methodologies, as well as the wide variation in respect to location, time and populations, underline the need for additional studies that should also take into account interacting factors.

Childhood asthma and infection: virus-induced exacerbations as determinants and modifiers.

Respiratory infections have been implicated in the origin and exacerbation of asthma in a variety of ways; however, systemisation of this knowledge in a way helpful for disease management remains suboptimal. Several conceptual issues need to be taken into account: the fact that the effects of an infection may vary according to genetic background, the current immune status of the host, and parallel environmental stimuli, in addition to the particular infectious agent itself. Moreover, childhood is a very special period because of the continuous processes taking place, such as neural, immune and respiratory maturation. Epidemiological studies have convincingly demonstrated that the majority of asthma exacerbations, in both adults and children, follow viral upper respiratory tract infections. Asthma exacerbations are still often unresponsive to current asthma treatment, and new therapeutic approaches are required. This review presents current knowledge on the associations between infection and exacerbation of established asthma with respect to definitions, epidemiology, mechanisms and treatment.

Exhaled breath temperature increases during mild exacerbations in children with virus-induced asthma.

BACKGROUND: Exhaled breath temperature (EBT) has been suggested as a non-invasive surrogate marker of airway inflammation in asthma. The aim of the study was to evaluate differences in EBT between periods of controlled disease and during exacerbations in children with virus-induced asthma. METHODS: Twenty-nine children (aged 6-14 years) with a history of intermittent, virus-induced asthma were included in this case-control study. Cases presented with a common cold and/or mild exacerbation of asthma, while controls were free of asthmatic or common cold symptoms during the previous 6 weeks. A baseline questionnaire was obtained. Atopy assessment, central temperature and a spirometric measurement were recorded. EBT was measured with a new device (Delmedica, Singapore). A nasal wash (for identification of common respiratory viruses) was obtained. RESULTS: Twenty-four children (12 from each group) completed the study. Groups were homogeneous with respect to baseline characteristics. PCR revealed the presence of a virus in 3 out of 17 controls and 10 out of 12 cases (17.6 and 83.3%, respectively, p = 0.002). The most commonly identified virus was rhinovirus (3/3 controls and 7/10 cases, p = 0.02). EBT values were significantly higher for cases (34.91 +/- 0.62 degrees C) compared to controls (34.18 +/- 1.1 degrees C, p = 0.032). No important differences were observed in the increase rate of EBT (Deltae degrees T) between groups. CONCLUSIONS: Changes in airway inflammation during virus-induced asthma exacerbations are reflected in EBT changes. These preliminary data suggest a possible role of EBT measurements in the assessment of airway inflammation in children with virus-induced asthma.

The multinational birth cohort of EuroPrevall: background, aims and methods.

BACKGROUND/AIM: The true prevalence and risk factors of food allergies in children are not known because estimates were based predominantly on subjective assessments and skin or serum tests of allergic sensitization to food. The diagnostic gold standard, a double-blind placebo-controlled food provocation test, was not performed consistently to confirm suspected allergic reactions in previous population studies in children. This protocol describes the specific aims and diagnostic protocol of a birth cohort study examining prevalence patterns and influential factors of confirmed food allergies in European children from different regions. METHODS: Within the collaborative translational research project EuroPrevall, we started a multi-center birth cohort study, recruiting a total of over 12 000 newborns in nine countries across Europe in 2005-2009. In addition to three telephone interviews during the first 30 months, parents were asked to immediately inform the centers about possible allergic reactions to food at any time during the follow-up period. RESULTS: All children with suspected food allergy symptoms were clinically evaluated including double-blind placebo-controlled food challenge tests. We assessed sensitization to different food allergens by measurements of specific serum immunoglobulin E and skin prick tests, collect blood, saliva or buccal swabs for genetic tests, breast milk for measurement of food proteins/cytokines, and evaluate quality-of-life and economic burden of families with food allergic children. CONCLUSIONS: This birth cohort provides unique data on prevalence, risk factors, quality-of-life, and costs of food allergies in Europe, leading to the development of more informed and integrated preventative and treatment strategies for children with food allergies.

Budesonide and formoterol inhibit inflammatory mediator production by bronchial epithelial cells infected with rhinovirus.

BACKGROUND: Rhinoviruses (RVs) are responsible for the majority of acute asthma and chronic obstructive pulmonary disease (COPD) exacerbations. RVs infect the lower airways and induce the production of pro-inflammatory and remodelling-associated mediators. Budesonide (BUD) and formoterol (FORM) synergize in controlling asthma and COPD exacerbations; however, their effects on virus-induced inflammation and remodelling are less known. OBJECTIVE: We investigated whether BUD and FORM synergize in suppressing RV-induced inflammation and remodelling in the airways. METHODS: In vitro models of RV infection of BEAS-2B and primary normal human bronchial epithelial (NHBE) cells were used. We assessed the effects of individual and combined drugs administered post-infection, at a clinically relevant concentration range (10(-6)-10(-10) m), on the production of CCL5, CXCL10, CXCL8, IL-6 and the remodelling-associated VEGF and bFGF, using ELISA and RT-PCR. RESULTS: BUD effectively suppressed RV-mediated induction of all mediators studied, in a concentration-dependent manner. FORM alone suppressed the production of CXCL8 and bFGF. The combination of BUD and FORM had concentration-dependent, additive or synergistic effects in the suppression of RV-induced CCL5, CXCL8 and CXCL10 in both cell types as well as VEGF in NHBE only. Combination treatment also resulted in an enhanced suppression of RV-induced IL-6, and CCL5 at the mRNA level as compared with BUD or FORM alone. CONCLUSION: BUD and FORM suppress RV-induced chemokines and growth factors in bronchial epithelial cells in a concentration-dependent, synergistic or additive manner. These data further support the combined use of BUD and FORM in asthma and COPD and intensification of this therapy during exacerbations.

Secular trend in body height of schoolchildren in Northeast Attica, Greece.

AIM: To examine the secular trend for body height in schoolchildren in Northeast Attica, Greece. METHODS: In 2005 we studied the growth of 4,131 Greek schoolchildren (2,054 boys) aged 5.5-12.6 years. The data were compared with those of a study performed in 1994/95. We also studied the growth of 236 immigrant schoolchildren (95 boys and 141 girls). RESULTS: For boys in the present study mean height (SD) was 135.6 (11.0) vs 133.8 (10.4) cm in the 1994/95 study, p < 0.001, and for girls of the present study mean height was 135.2 (11.7) vs 133.3 (10.8) cm in 1994/95, p < 0.001. The increase in height was present at almost all ages. There was a significant difference in height between Greek and immigrant boys, 135.6 (11.0) cm and 133.0 (10.2) cm, respectively, p < 0.05. However, there was no significant difference in height between Greek and immigrant girls, 135.2 (11.7) and 133.8 (12.4) cm, respectively. CONCLUSION: A secular trend in height is still taking place in Greek schoolchildren that is mostly attributed to an increase in height from early life.

A case-control study of the relation between plasma selenium and asthma in European populations: a GAL2EN project.

BACKGROUND: There is evidence that selenium levels are relatively low in Europe and may be falling. Low levels of selenium or low activity of some of the enzymes dependent on selenium have been associated with asthma. METHODS: The GA(2)LEN network has organized a multicentre case-control study in Europe to assess the relation of plasma selenium to asthma. The network compared 569 cases in 14 European centres with a diagnosis of asthma and reporting asthma symptoms in the last 12 months with 576 controls from the same centres with no diagnosis of asthma and no asthmatic symptoms in the last 12 months. RESULTS: All cases and controls were selected from the same population defined by age and place of residence. Mean plasma selenium concentrations among the controls ranged from 116.3 microg/l in Palermo to 67.7 microg/l in Vienna and 56.1 microg/l among the children in Oslo. Random effects meta-analysis of the results from the centres showed no overall association between asthma and plasma selenium [odds ratio (OR)/10 microg/l increase in plasma selenium: 1.04; 95% confidence interval (CI): 0.89-1.21] though there was a significantly protective effect in Lodz (OR: 0.48; 95% CI: 0.29-0.78) and a marginally significant adverse effect in Amsterdam (OR: 1.68; 95% CI: 0.98-2.90) and Ghent (OR: 1.35; 95% CI: 1.03-1.77). CONCLUSION: This study does not support a role for selenium in protection against asthma, but effect modification and confounding cannot be ruled out.

Mechanisms of virus-induced asthma exacerbations: state-of-the-art. A GA2LEN and InterAirways document.

Viral infections of the respiratory tract are the most common precipitants of acute asthma exacerbations. Exacerbations are only poorly responsive to current asthma therapies and new approaches to therapy are needed. Viruses, most frequently human rhinoviruses (RV), infect the airway epithelium, generate local and systemic immune responses, as well as neural responses, inducing inflammation and airway hyperresponsiveness. Using in vitro and in vivo experimental models the role of various proinflammatory or anti-inflammatory mediators, antiviral responses and molecular pathways that lead from infection to symptoms has been partly unravelled. In particular, mechanisms of susceptibility to viral infection have been identified and the bronchial epithelium appeared to be a key player. Nevertheless, additional understanding of the integration between the diverse elements of the antiviral response, especially in the context of allergic airway inflammation, as well as the interactions between viral infections and other stimuli that affect airway inflammation and responsiveness may lead to novel strategies in treating and/or preventing asthma exacerbations. This review presents the current knowledge and highlights areas in need of further research.

Synergistic effects of fluticasone propionate and salmeterol on inhibiting rhinovirus-induced epithelial production of remodelling-associated growth factors.

BACKGROUND: Rhinoviruses (RV), the major trigger of acute asthma exacerbations, are able to infect bronchial epithelium and induce production of pro-inflammatory, but also angiogenic and pro-fibrotic mediators. Fluticasone propionate (FP) and salmeterol (S) are clinically effective and act synergistically in controlling persistent asthma; however, their effect on virus-associated asthma is less clear. AIM: The aim of this study was to assess the individual and combined effects of FP and S on RV-induced epithelial production of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2). METHODS: Bronchial epithelial cells (BEAS-2B) were exposed in vitro to RV and were subsequently treated with FP and S, at physiologically relevant concentrations, alone or in combination. VEGF and FGF-2 were measured in the supernatants of these cultures using ELISA. RESULTS: FP was able to reduce RV-induced VEGF production in a dose-dependent manner. S also induced a smaller reduction; addition of both factors inhibited VEGF synergistically. FGF-2 production was not inhibited by either FP or S alone, but was significantly reduced when both substances were present in the culture. CONCLUSION: This study demonstrates that FP and S may synergistically inhibit the production of angiogenic and/or pro-fibrotic factors that are induced after RV infection of BEAS-2B and are implicated in airway remodelling, suggesting that this combination may represent an important therapeutic option on virus-induced asthma.