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Background Prenatal phthalate exposure has been suggested to alter immune responses and increase the risk of asthma, eczema and rhinitis. However, few studies have examined the effects in prospective cohorts and only one examined rhinitis. We therefore studied associations between maternal urinary concentrations of phthalate metabolites and asthma, eczema and rhinitis in offspring aged 5 years. Methods From 552 pregnant women in the Odense Child Cohort, we quantified urinary concentrations of 12 phthalate metabolites in third trimester. We assessed asthma, rhinitis and eczema in their offspring at age 5 years with a questionnaire based on the International Study of Asthma and Allergies in Childhood (ISAAC), and conducted logistic regression adjusting for relevant confounders. Results 7.4% of the children had asthma, 11.7% eczema and 9.2% rhinitis. Phthalate exposure was low compared to previous cohorts. No significant associations between prenatal phthalate exposure and asthma were found. Odds ratios (ORs) of child rhinitis with a doubling in ΣDiNP m and di-2-ethylhexyl phthalate metabolite (ΣDEHP m ) concentrations were, respectively, 1.15 (95% confidence interval (CI) 0.97,1.36) and 1.21 (CI 0.93,1.58). The OR of eczema when doubling ΣDiNP m was 1.24 (CI 1.00,1.55), whereas the OR of using medicine against eczema when doubling a di-ethyl phthalate (DEP) metabolite was 0.81 (CI 0.68,0.96). Conclusion The lack of association between maternal phthalate exposure and asthma in the offspring may be due to low exposure and difficulties in determining asthma in 5-year-olds. The higher odds of rhinitis may raise public concern but further research in larger cohorts of older children is warranted.

Background Asthma is the most common non-communicable disease in children. Prenatal exposure to perfluoroalkyl substances (PFASs), a group of persistent environmental chemicals with endocrine disrupting abilities, has been associated with immunomodulation and may contribute to the aetiology of asthma. We investigated the associations between prenatal exposure to five PFASs and asthma in 5-year-old children. Methods We studied 981 mother-child pairs within the Odense Child Cohort (OCC), Denmark. We measured perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA) in maternal serum donated in early pregnancy. A standardized questionnaire based on the International Study of Asthma and Allergies in Childhood (ISAAC) was used to assess wheeze, self-reported asthma and doctor-diagnosed asthma among children at age 5 years. Associations were examined using logistic regression analyses adjusting for parity, maternal educational level, maternal pre-pregnancy BMI, asthma predisposition and child sex. Results Among the 5-year-old children 18.6% reported wheeze and 7.1% reported asthma. We found no association between prenatal exposure to PFAS and doctor-diagnosed asthma or wheeze. Prenatal PFAS exposure was associated with self-reported asthma, although only significant for PFNA (OR = 1.84, 95% CI 1.03,3.23). Conclusion Our findings support the suggested immunomodulatory effects of PFASs, however, additional studies are warranted. In order to verify our findings, it is important to re-examine the children with postnatal measurements of serum PFAS concentrations and additional clinical diagnostic testing at an older age where an asthma diagnosis is more valid.

Background Evidence suggests that early life infections, presence of older siblings and furred pets in the household affect the risk of developing allergic diseases through altered microbial exposure. Recently, low gut microbial diversity during infancy has also been linked with later development of allergies. We investigated whether presence of older siblings, furred pets and early life infections affected gut microbial communities at 9 and 18 months of age and whether these differences were associated with the cumulative prevalence of atopic symptoms of eczema and asthmatic bronchitis at 3 years of age. Bacterial compositions and diversity indices were determined in fecal samples collected from 114 infants in the SKOT I cohort at age 9 and 18 months by 16S rRNA gene sequencing. These were compared to the presence of older siblings, furred pets and early life infections and the cumulative prevalence of diagnosed asthmatic bronchitis and self-reported eczema at 3 years of age. Results The number of older siblings correlated positively with bacterial diversity ( p  = 0.030), diversity of the phyla Firmicutes ( p  = 0.013) and Bacteroidetes ( p  = 0.004) and bacterial richness ( p  = 0.006) at 18 months. Further, having older siblings was associated with increased relative abundance of several bacterial taxa at both 9 and 18 months of age. Compared to the effect of having siblings, presence of household furred pets and early life infections had less pronounced effects on the gut microbiota. Gut microbiota characteristics were not significantly associated with cumulative occurrence of eczema and asthmatic bronchitis during the first 3 years of life. Conclusions Presence of older siblings is associated with increased gut microbial diversity and richness during early childhood, which could contribute to the substantiation of the hygiene hypothesis. However, no associations were found between gut microbiota and atopic symptoms of eczema and asthmatic bronchitis during early childhood and thus further studies are required to elucidate whether sibling-associated gut microbial changes influence development of allergies later in childhood.

The use of complementary/alternative medicine (CAM) is increasing. The aim was to characterise the use of CAM among patients in a paediatric department. All patients (aged 0-18 years), out-patients or hospitalised, in contact with the Department of Paediatrics, Odense University Hospital during a 2 week period in the autumn of 2001 were asked to participate. In total, 622 (92%) patients participated. The data were collected in an interviewer administered questionnaire during a short structured interview with the patient and parents. CAM was divided into herbal medicine (herbal drugs or dietary supplements) (HM), alternative therapy (AT) (i.e. acupuncture) or chiropractic (CHI). Of all patients, 53% had tried CAM at least once and 23% had tried CAM within the last month (15% HM, 7% AT and 2% CHI). There was no correlation between use of CAM and gender, age or if the patient was out-patient or hospitalised. The users were pre-school children. HM (Bio-Strath and Echinacea) was especially used to strengthen the immune system. Among AT, reflexological treatment was the most popular treatment. The most frequent users of CAM were patients with asthma, eczema or allergy plus patients suffering from gastrointestinal diseases or hospitalised for observation. More than 50% of the users experienced positive effects and 6% had side-effects from AM. Of the CAM users, 11% or 2% of the total paediatric population used CAM instead of conventional medicines. Of the paediatric patients, 53% had tried complementary/alternative medicine, which was used as a supplement to conventional medicine although we did not know how long it was used. Paediatric patients should be interviewed about their use of complementary/alternative medicine with regard to side-effects, interactions or lack of compliance with conventional medicine.

Background Surfactant Protein D (SP‐D) is a pattern recognition molecule belonging to the family of collectins expressed in multiple human organ systems, including the lungs. Previous studies have shown that SP‐D levels in bronchoalveolar lavage samples decrease and serum levels increase in patients suffering from asthma, possibly due to a combination of induced SP‐D synthesis and decreased air–blood barrier integrity. The aims of this study were to investigate whether serum levels of SP‐D and common variants in the SP‐D gene were associated with asthma in adolescents and young adults. Methods Prospective observational study including 449 adolescents and young adults (age 11–27 years) previously diagnosed with asthma during a 2‐year period from 2003 to 2005 (0–16 years). At follow‐up from 2016 to 2017, 314 healthy controls with no history of asthma were recruited. Serum SP‐D was analyzed on samples obtained at baseline as well as samples obtained at follow‐up. SP‐D genotyping was performed for rs721917, rs2243639, and rs3088308. Results No differences were found in mean levels of sSP‐D and SFTPD genotype among subjects with current asthma, no current asthma, and controls. Serum SP‐D and SFTPD genotype were not associated with any clinical parameters of asthma. Furthermore, baseline sSP‐D was not associated with asthma at follow‐up. Conclusion Serum surfactant protein D and common SP‐D gene variants were not associated with asthma in Danish adolescents and young adults with mild to moderate asthma. Serum surfactant protein D did not demonstrate any value as a clinical biomarker of asthma.

IntroductionThe symptoms of cow’s milk protein allergy (CMPA) in infancy can be non-specific which may delay a correct diagnosis and cause adverse clinical outcomes. The diagnosis of non-IgE-mediated CMPA is particularly complex as it involves a 2 to 4 week elimination diet followed by oral food challenge (OFC). The Cow’s Milk-related Symptom Score (CoMiSS) is a clinical resource for primary healthcare providers which aims to increase awareness of CMPA symptoms to facilitate an earlier diagnosis. The aim of the present study is to assess if the CoMiSS can be used as a potential diagnostic tool in infants with suspected CMPA.Methods and analysisExclusively formula-fed infants aged 0–6 months presenting with symptoms suggestive of CMPA will be included in this prospective, multicentre trial which will be conducted in 10 centres in China. All infants will commence a 2-week trial of an amino acid-based formula (AAF) while eliminating all cow milk protein from their diets. After the AAF treatment period, infants will undergo an open OFC in hospital with standard cow’s milk formula, followed by an open home challenge for another 2 weeks. Clinical symptoms will be documented on standardised symptom scorecards. The CoMiSS will be determined at study entry (CoMiSS 1, before the start of the AAF), after 2 weeks (CoMiSS 2, before the OFC) and after a further period of 2 weeks or when symptoms suggestive of CMPA reappear (CoMiSS 3). Weight and length will be measured at each visit. The difference between CoMiSS 1 and 2 as a predictor of the OFC outcome will also be assessed. The diagnostic accuracy of the baseline CoMiSS will be calculated.Ethics and disseminationThe study was approved by the Hunan Children’s Hospital Medical Ethics Committee, Hunan, China. The findings of this trial will be submitted for publication in a peer-reviewed journal in paediatric nutrition or gastroenterology. Abstracts will be submitted to the relevant national and international conferences.Trial registration number NCT03004729; Pre-results.

Background Microfibrillar‐associated protein 4 (MFAP4) is an extracellular matrix protein belonging to the fibrinogen‐related protein superfamily, which plays multifaceted roles in innate immunity and normal endothelial function. It has been proposed that MFAP4 promotes the development of asthma in vivo and proasthmatic pathways of bronchial smooth muscle cells in vitro. The aim of this study was to investigate the significance of serum MFAP4 in adolescents and young adolescents with persistent asthma. Methods Prospective, observational study including adolescents and young adults (age 11‐27 years) previously diagnosed with asthma during childhood 2003 to 2005 (0‐15 years) at the four pediatric outpatient clinics in the Region of Southern Denmark (n = 449). Healthy controls were recruited at follow‐up (n = 314). Detection of serum MFAP4 was performed by AlphaLISA technique. Results Current asthma was associated to a 14% higher mean level of serum MFAP4 compared with controls (expβ 1.14, 95% confidence intervals [CI], 1.05‐1.23) and a 6% higher mean level compared with subjects with no current asthma (expβ 1.06, 95% CI, 0.99‐1.13). No association was found at follow‐up between serum MFAP4 and self‐reported atopic symptoms (other than asthma), Asthma Control Test‐score, fractional exhaled nitric oxide (FeNO), nor to flow rate at 1 second, forced vital capacity, and forced expiratory flow 25% to 75%, response to short‐acting beta 2 agonist or mannitol. Conclusions We found a significantly higher mean level of serum MFAP4 in adolescent and young adults with mild to moderate asthma compared with healthy controls but no association to FeNO and lung function nor to the response to short‐acting beta 2 agonist or mannitol. The result supports the hypothesis that MFAP4 plays a role in the pathogenesis of asthma although the marker did not demonstrate any obvious potential as an asthma biomarker in adolescents and young adults with asthma. To understand the possible proasthmatic functions of MFAP4, further investigation in specific asthma phenotypes and the underlying molecular mechanisms is warranted. This is the first clinical study investigating the significance of serum microfibrillar‐associated Protein 4 (MFAP4) in adolescents and young adults with asthma. The study reveals an association between the extracellular matrix protein MFAP4 and current asthma in a comprehensively characterized population of adolescents and young adults previously diagnosed with asthma during childhood. The study supports previous findings from experimental in vitro and in vivo studies hypothesizing that MFAP4 plays a role in the pathogenesis of asthma.

Background Rhinoconjunctivitis is a global health problem and one of the most common chronic conditions in children. Development of rhinoconjunctivitis depends on both genetic and environmental factors. Many studies have investigated rhinoconjunctivitis, but only few studies have evaluated the risk factors for non-allergic rhinoconjunctivitis in children finding family history of atopic diseases and gender to be of importance. The aim of this study was to investigate possible risk factors in early life for rhinoconjunctivitis, allergic as well as non-allergic, in adolescence. Methods The children in the Danish Allergy Research Center cohort were examined eight times from birth to 14 years of age. Visits included questionnaire-based interview, clinical examination, skin prick test and specific IgE. We used univariate and multivariate logistic regression to investigate the relationship between early-life risk factors and the development of rhinoconjunctivitis, allergic as well as non-allergic, in adolescence. Results Follow-up rate at 14-years was 66.2%. The prevalence of rhinoconjunctivitis was 32.8%. Family history of atopic diseases (aOR 2.25), atopic dermatitis (aOR 3.24), food allergy (aOR 3.89), early sensitization to inhalant and food allergens (aOR 2.92 and aOR 3.13) and male gender (aOR 1.90) were associated with allergic rhinoconjunctivitis but not with non-allergic rhinoconjunctivitis. Early environmental tobacco exposure was inversely associated with rhinoconjunctivitis (aOR 0.42), allergic (aOR 0.47) as well as non-allergic (aOR 0.43). Conclusion Different patterns of associations were revealed when stratifying rhinoconjunctivitis in allergic and non-allergic suggesting that allergic rhinoconjunctivitis and non-allergic-rhinoconjunctivitis are different phenotypes.

Commentary on: Tromp II Kiefte-de Jong JC Lebon A . The introduction of allergenic foods and the development of reported wheezing and eczema in childhood: the Generation R study. Arch Pediatr Adolesc Med 2011 ; 165 : 933 - 8 .

Background and Aims When investigating and treating asthma in children, diagnosing must be precise and valid. There is a need for studies researching asthma in children showing how to use registry‐based, epidemiological data. We examined the feasibility and validity of using anti‐asthmatic drug prescription data to identify children with asthma and assessed medication patterns in children with and without confirmed asthma. Methods We used population‐based Danish prescription data and hospital discharge registries to identify all children aged 0 to 14 years who had redeemed at least one prescription for an inhaled anti‐asthmatic drug. Individual asthma cases were validated by hospital discharge information and by their treating general practitioners according to international asthma guidelines. Results In total, 2053 children, out of a population of 20181, had redeemed at least one prescription of any inhaled anti‐asthmatic drug. The positive predictive value (PPV) of having two different asthma medications prescribed in 1 year was 80.2% for presence of true asthma, with a sensitivity of 59%. Corresponding estimates of PPV/sensitivity of at least one prescription for an inhaled corticosteroid (ICS) were 79% and 58%, respectively, while the true asthma PPV with at least one LABA prescription increased to 97%. Among children with confirmed asthma, one‐third had not used Beta2‐agonist therapy as part of their treatment. Conversely, among children without confirmed asthma, 40% were prescribed a minimum of two prescriptions for any kind of inhaled anti‐asthmatic drug, and 12% and 9% used an ICS or Leukotriene receptor antagonist, respectively. Conclusions Anti‐asthmatic drug prescription data could be used to identify children with true asthma, with reasonable accuracy. The observed pattern of anti‐asthmatic medication usage among children with and without confirmed asthma suggests that there is room for therapeutic improvement.