Filaggrin gene variants and atopic diseases in early childhood assessed longitudinally from birth

Bønnelykke K, Pipper CB, Tavendale R, Palmer CNA, Bisgaard H. Filaggrin gene variants and atopic diseases in early childhood assessed longitudinally from birth.
Pediatr Allergy Immunol 2010: 21: 954–961.
© 2010 John Wiley & Sons A/S Copenhagen Prospective Study on Asthma in Childhood (COPSAC) was one of the discovery cohorts of the association between eczema and variants in the filaggrin coding gene (FLG). Here, we study the FLG‐associated risk of asthma symptoms in early life and describe the temporal relationship in the development of the different FLG‐associated atopic outcomes: asthma, sensitization and eczema, assessed longitudinally from birth. A high‐risk cohort of 411 children was assessed in a prospective clinical study from birth to school‐age. Asthma, acute severe asthma exacerbations, sensitization and eczema were diagnosed prospectively by the investigators. FLG variants R501X and Del4 were determined in 382 Caucasians. Filaggrin variants increased risk of developing recurrent wheeze, asthma and asthma exacerbations (hazard ratio 1.82 [1.06–3.12], p = 0.03), which was expressed within the first 1.5 yr of life. Children with filaggrin variants had a marked and persistent increase in acute severe asthma exacerbations from 1 yr of age (incidence ratio 2.40 [1.19–4.81], p = 0.01) and increased risk of asthma by age 5 (odds ratio 2.62 [1.12–6.11], p = 0.03). FLG variants increased the risk of eczema, manifesting fully in the first year of life (point prevalence ratio for age 0–5 was 1.75 [1.29–2.37]; p‐value = 0.0003) contrasting the increased risk of specific sensitization by age 4 (odds ratio 3.52 [1.72–7.25], p = 0.0007) but not age 1.5. This study describes a FLG‐associated pattern of atopic diseases characterized by the early onset of asthma symptoms and eczema and later development of sensitization. The association of filaggrin variants with asthma suggests skin barrier dysfunction as a novel, and potentially modifiable, mechanism driving early childhood asthma.     

Does airway allergic inflammation pre‐exist before late onset wheeze in children?

Thavagnanam S, Williamson G, Ennis M, Heaney LG, Shields MD. Does airway allergic inflammation pre‐exist before late onset wheeze in children?
Pediatr Allergy Immunol 2010: 21: 1002–1007.
© 2010 John Wiley & Sons A/S Epidemiological studies show that some children develop wheezing after 3 yr of age which tends to persist. It is unknown how this starts or whether there is a period of asymptomatic inflammation. The aim of this study is to determine whether lower airway allergic inflammation pre‐exists in late onset childhood wheeze (LOCW). Follow‐up study of children below 5 yr who had a non‐bronchoscopic bronchoalveolar lavage (BAL) performed during elective surgery. The children had acted as normal controls. A modified ISAAC questionnaire was sent out at least 7 yr following the initial BAL, and this was used to ascertain whether any children had subsequently developed wheezing or other atopic disease (eczema, allergic rhinitis). Cellular and cytokine data from the original BAL were compared between those who never wheezed (NW) and those who had developed LOCW. Eighty‐one normal non‐asthmatic children were recruited with a median age of 3.2 . Of the 65 children contactable, 9 (16.7%) had developed wheeze, 11 (18.5%) developed eczema and 14 (22.2%) developed hay fever. In five patients, wheeze symptoms developed mean 3.3‐ yr (range: 2–5 yr) post‐BAL. Serum IgE and blood eosinophils were not different in the LOCW and NW, although the blood white cell count was lower in the LOCW group. The median BAL eosinophil % was significantly increased in the patients with LOCW (1.55%, IQR: 0.33 to 3.92) compared to the children who never wheezed, NW (0.1, IQR: 0.0 to 0.3, p = 0.01). No differences were detected for other cell types. There were no significant differences in BAL cytokine concentrations between children with LOCW and NW children. Before late onset childhood wheezing developed, we found evidence of elevated eosinophils in the airways. These data suggest pre‐existent airways inflammation in childhood asthma some years before clinical presentation.     

Wheeze in children: the impact of parental education on atopic and non‐atopic symptoms

de Meer G, Reijneveld SA, Brunekreef B. Wheeze in children: the impact of parental education on atopic and non‐atopic symptoms.
Pediatr Allergy Immunol 2010: 21: 823–830.
© 2009 John Wiley & Sons A/S There is conflicting evidence for the relationship between parental socioeconomic position and their children’s asthma. The aim of this study was to investigate relationships between parental education and respiratory symptoms in their children, distinguishing atopic and non‐atopic symptoms. A cross‐sectional survey among 3262 elementary school children (age 8–13) was performed; data on parental education were obtained for 3213 children. Parents completed a questionnaire on their child’s allergic and respiratory symptoms, and potential explanatory variables including family history, indoor environment, and the child’s medical history. Subsets of children were tested for atopy (n = 1983), lung function (n = 2325), and airway hyperresponsiveness (AHR) (n = 880). Logistic regression was used to assess relationships of health outcomes with parental education. A high parental education was associated with an increased risk of atopic sensitization to indoor allergens (OR 1.31, 95% CI 1.02; 1.69). Studied explanatory variables did not influence the relationship. In contrast, a high parental education protected children from wheeze (OR 0.77, 95% CI 0.61; 0.97). This only applied to non‐atopic wheeze (OR 0.65, 95% CI 0.43; 0.99) and not to atopic wheeze (OR 0.89, 95% CI 0.60; 1.31). The protection from non‐atopic wheeze in children of highly educated parents declined after adjustment for household smoking and breastfeeding (OR 0.96, 95% CI 0.58; 1.57). Similar results were observed for non‐atopic and atopic rhinitis. We conclude that children from highly educated parents are protected from non‐atopic respiratory symptoms, which is largely explained by a lower rate of household smoking and a higher rate of breastfeeding.     

Timing of infection and development of wheeze,eczema, and atopic sensitization during the first 2 yr of life: The KOALA Birth Cohort Study

Mommers M, Thijs C, Stelma F, Penders J, Reimerink J, van Ree R, Koopmans M. Timing of infection and development of wheeze, eczema, and atopic sensitization during the first 2 yr of life: The KOALA Birth Cohort Study.
Pediatr Allergy Immunol 2010: 21: 983–989.
© 2010 The John Wiley & Sons A/S To investigate if infections in pregnancy and very early in life present a risk for wheezing, eczema, or atopic sensitization in later infancy. A total of 2319 children enrolled before birth in the KOALA Birth Cohort Study were followed during their first 2 yr of life using repeated questionnaires. Information was obtained on common colds, fever, and diarrhea with fever as well as on wheeze and eczema at ages 3 and 7 months and 1 and 2 yr, respectively. Blood samples were collected from 786 children at age 2 yr for specific immunoglobulin E analyses. Children with a common cold [adjusted odds ratio (aOR) 2.03 95% CI 1.21–3.41] or fever episode (aOR 1.81 95% CI 1.10–2.96) in the first 3 months of life had a higher risk of new onset wheeze in the second year of life compared to children who had not. For children with diarrhea with fever in the first 3 months of life, the aOR for new onset wheeze in the second year of life was 3.94 (95% CI 1.36–11.40) compared to children without diarrhea. Infections becoming clinically manifest during the first 3 months of life may be a general marker for a wheezy phenotype.     

IL13 variants are associated with total serum IgE and early sensitization to food allergens in children with atopic dermatitis

Increased total and specific serum immunoglobulin E (IgE) levels are common characteristics of atopic diseases and their basal production is proposed to be under strong genetic control. Interleukin 13 (IL13) variants have been consistently associated with total serum IgE levels in white populations with a strongest association in non‐atopics. The aim of this study was to test the IL13 p.R130Q and c.1‐1111C>T variants in children with atopic dermatitis (AD) for associations with total serum IgE and early sensitization to common food and inhalant allergens and with asthma. We included 453 children with AD [participants of the Early Treatment of the Atopic Child (ETAC) study] that were followed from the age of 12–24 months for 3 yr. Total and specific IgE were determined at four time points. We genotyped the IL13 p.R130Q and c.1‐1111C>T variants by melting curve analysis. In children up to 4 yr of age, the 130Q allele was related to slightly higher total IgE levels compared to heterozygotes and 130R homozygotes. More importantly, both IL13 variants were significantly associated with sensitization to food allergens, with most significant results for sensitization to egg (p = 0.0001). Although early sensitization to hen’s egg represents a strong risk factor for subsequent sensitization to inhalant allergens and asthma, the investigated IL13 variants were not associated with these phenotypes at the age of 48–60 months. In summary IL13 variants contribute to elevated levels of total serum IgE in young atopic children and are strongly associated with sensitization to food allergens, particularly to hen’s egg. These findings suggest that IL13 variants play a major role not only in non‐cognate but also in allergen specific IgE synthesis.     

Urinary eosinophil protein X in children with asthma: Influence of atopy and airway infections

It has been suggested that urinary eosinophil protein X (U‐EPX) can be used to monitor bronchial inflammation in childhood asthma. However, the influence of atopy and airway infections is not well elucidated. To determine the clinical value of measuring U‐EPX in children with asthma and to evaluate the influence of atopy and airway infections, U‐EPX was measured in 170 children with asthma (mean age 69 months, range 12–179 months), in 79 children with lower or upper respiratory tract infections (mean age 41 months, range 1–165 months), and in 64 controls. U‐EPX was elevated in children with acute asthma (median 132 µg/mmol of creatinine, quartiles 77–195 µg/mmol of creatinine, n = 51, p < 0.001) and chronic asthma (median 93 µg/mmol of creatinine; quartiles 46–149 µg/mmol of creatinine, n = 119, p < 0.01) compared with controls (median 54 µg/mmol of creatinine; quartiles 40–89 µg/mmol of creatinine, n = 39). Atopic children had higher levels of U‐EPX than non‐atopics with acute asthma (median 155 µg/mmol of creatinine, quartiles 113–253 µg/mmol of creatinine, n = 27, vs. median 102 µg/mmol of creatinine, quartiles 56–168 µg/mmol of creatinine, n = 24, p < 0.05), as well as with chronic asthma (median 110 µg/mmol of creatinine, quartiles 65–162 µg/mmol of creatinine, n = 63, vs. median 60 µg/mmol of creatinine, quartiles 39–123 µg/mmol of creatinine, n = 56, p < 0.01). In chronic asthma, children without atopy had levels of U‐EPX similar to values of controls; levels were similar in symptomatic and asymptomatic patients, and not influenced by treatment with inhaled corticosteroids. Moreover, U‐EPX levels were higher in children with pneumonia (median 207 µg/mmol of creatinine, quartiles 111–280 µg/mmol of creatinine, n = 35, p < 0.001), laryngitis (median 109 µg/mmol of creatinine, quartiles 65–161 µg/mmol of creatinine, n = 24, p < 0.01), and rhinitis (median 172 µg/mmol of creatinine, quartiles 123–254 µg/mmol of creatinine, n = 19, p < 0.001) than in controls (median 62 µg/mmol of creatinine, quartiles 41–93 µg/mmol of creatinine, n = 64). There was significant overlap among all groups of children with disease, as well as between children with disease and controls. Hence, U‐EPX may reflect differences in eosinophil involvement and activation between children with atopic and non‐atopic asthma, but the individual spread within groups and the influence of airway infections limits the clinical value of U‐EPX in childhood asthma.     

Allergic sensitization is associated with rhinovirus‐, but not other virus‐, induced wheezing in children

Jartti T, Kuusipalo H, Vuorinen T, Söderlund‐Venermo M, Allander T, Waris M, Hartiala J, Ruuskanen O. Allergic sensitization is associated with rhinovirus‐, but not other virus‐, induced wheezing in children.
Pediatr Allergy Immunol 2010: 21: 1008–1014.
© 2010 John Wiley & Sons A/S Background: Data on the link between atopy and viral wheeze are limited. Aim: To evaluate the association between IgE sensitization and viral infection in wheezing children. Methods: This is an observational study in hospitalized wheezing children (n = 247; median age 1.6 ; interquartile range 1.1, 2.9). Eighteen respiratory viral infections were studied using all available methods. A specific immunoglobulin E (IgE) sensitization for common food and aeroallergens and other atopy‐related variables including total IgE, blood and nasal eosinophils, exhaled nitric oxide, eczema and atopic eczema, parental allergy and asthma, number of wheezing episodes, positive asthma predictive index or asthma and use of inhaled corticosteroid were correlated with specific viral etiology. Results: Atopy was closely associated with sole rhinovirus etiology (n = 58) but not with sole respiratory syncytial virus, sole enterovirus, sole human bocavirus, sole other virus, mixed viral, or virus negative etiology. The number of sensitizations was particularly associated with sole rhinovirus etiology (odds ratio 4.59; 95% confidence interval 1.78, 11.8; adjusted to age and sex), followed by aeroallergen sensitization (respectively; 4.18; 2.00, 8.72), total IgE level (2.06; 1.32, 3.21), food allergen sensitization (2.02; 1.08, 3.78), and nasal eosinophil count (1.52; 1.08, 2.13). Conclusions: According to our data, allergic sensitization is positively linked to rhinovirus‐, but not other virus‐, associated wheezing and calls attention for studies to test rhinovirus‐associated wheezing as a part of asthma risk indices.     

IL‐17E but not IL‐17A is associated with allergic sensitization: results from the LISA study

Herberth G, Daegelmann C, Röder S, Behrendt H, Krämer U, Borte M, Heinrich J, Herbarth O, Lehmann I for the LISAplus study group. IL‐17E but not IL‐17A is associated with allergic sensitization: results from the LISA study.
Pediatr Allergy Immunol 2010: 21: 1086–1090.
© 2010 John Wiley & Sons A/S Functional studies have provided evidence for the importance of IL‐17A and IL‐17E in the regulation of immune responses. IL‐17A is involved in inflammation and IL‐17E is able to induce Th2 cytokine production and eosinophilia. By now it is not clear whether these cytokines correlate with specific IgE levels. The aim of our investigation was to analyse the relationship of these two cytokines to allergic sensitization in context of an epidemiological study. Within the Life style Immune System Allergy study (LISA), we analysed phytohemagglutinin (PHA)‐stimulated blood samples of 6 yr old children for the concentration of IL‐17A and IL‐17E and sera for levels of specific IgE. In total, data from 293 children were available for blood analysis and for the analysis of confounding factors for the allergic sensitization. Among the investigated children, 29% reacted against inhalant and 13.6% against food allergens, whereas 33.1% of children were sensitized to any allergen. IL‐17E was associated with high levels of any specific IgE (adjusted odds ratio (OR) 1.45, 95% confidence interval (CI) 1.11–1.90). Furthermore, children with high IL‐17E responses (>208.8 pg/ml) were sensitized to food and inhalant allergens (OR 1.45, 95% CI 1.02–2.07 and OR 1.35, 95% CI 1.03–1.77, respectively) and to Der p 1 (OR 1.55, 95% CI 1.12–2.15). In contrast, IL‐17A, in trend, was negatively associated to sensitization to timothy (p for trend=0.013) and rye (p for trend=0.026). Concluding IL‐17E production is linked to the amount of specific IgE antibodies in blood samples of 6 yr old children.     

The role of TNF‐α in eosinophilic inflammation associated with RSV bronchiolitis

Choi J, Callaway Z, Kim HB, Fujisawa T, Kim CK. The role of TNF‐α in eosinophilic inflammation associated with RSV bronchiolitis.
Pediatr Allergy Immunol 2010: 21: 474–479.
© 2009 John Wiley & Sons A/S The purpose of our study was to investigate whether tumor necrosis factor (TNF)‐α correlates with eosinophilic inflammation that occurs during a lower respiratory tract infection with the respiratory syncytial virus (RSV) in children. Sixty children with RSV bronchiolitis (RSV group) and 20 healthy children with no respiratory symptoms (Control group) were enrolled. We measured the nasal lavage fluid (NLF) Th2 cytokine (IL‐5), proinflammatory cytokine (TNF‐α, IL‐8), eosinophil‐active cytokine [granulocyte‐macrophage colony stimulating factor (GM‐CSF), IFN‐γ], and eosinophil‐active chemokine (eotaxin, regulated on activation normal T cell excreted and secreted) levels for both groups. We also measured serum eosinophil‐degranulation product (eosinophil‐derived neurotoxin; EDN, eosinophil cationic protein; ECP) levels from RSV group. TNF‐α, IL‐8, GM‐CSF, IFN‐γ, and eotaxin levels were significantly higher in the RSV group compared with the Control group. TNF‐α correlated with GM‐CSF (r = 0.87, p < 0.0001), IFN‐γ (r = 0.92, p < 0.0001), eotaxin (r = 0.64, p < 0.0001), and IL‐8 (r = 0.84, p < 0.0001). TNF‐α may have an important role in eosinophilic inflammation of airways in children with RSV bronchiolitis.     

Maturation of cytokine‐producing capacity from birth to 1 yr of age

Little is known about the immunologic maturation in the early stages of life. The aim of this study was to investigate maturation of immune system from birth to 1 yr of age and to compare immune functions between mothers and their children. Also the effect of atopy to the immune responses of children was examined. Cord blood samples (n = 228) and peripheral blood samples of children (n = 200) and their mothers (n = 208) 1 yr after birth were collected. Whole blood samples were stimulated for 24 and 48 h with Staphylococcal enterotoxin B (SEB), lipopolysaccharide (LPS) and the combination of phorbol ester and ionomycin (P/I). Production of TNF‐α, IFN‐γ, IL‐5, IL‐8 and IL‐10 was determined using ELISA. Significant mother‐to‐child correlation was detected in cytokine‐producing capacity at the age of 1 yr. TNF‐α (P/I, SEB and LPS stimulation), IFN‐γ (P/I and SEB), IL‐5 (P/I and SEB) and IL‐10 (P/I, SEB and LPS) producing capacity increased from birth to 1 yr of age. In general, stimulated cytokine responses were higher in mothers’ than in children’s blood samples, except in the case of P/I and LPS‐stimulated IL‐8, which were highest at birth. Maternal inhalation atopy was associated with increased cord blood IL‐5 (24 and 48 h) and IL‐10 (48 h) production following P/I stimulation. Also children of food atopic mothers expressed elevated cord blood IL‐10 (48 h, P/I) responses and decreased IFN‐γ/IL‐5 ratio (24 h, P/I). In addition, the production of IFN‐γ (24 and 48 h, P/I) and the IFN‐γ/IL‐5 ratio (24 h and 48 h, P/I) at the age of 1 yr was lower among children with food atopic mothers. In conclusion, our results suggest that both adaptive and innate immune responses increase from birth to 1 yr of age, but are still weak in comparison to adult responses. Cytokine responses of children begin to correlate with those of their mothers during the first year of life. Although only few associations were observed between atopy and cytokine‐producing capacity, our results suggest that children of atopic mothers express T_h2‐polarized cytokine pattern.     

Airway inflammation in probiotic‐treated children at 5 years

To cite this article: Kukkonen AK, Kuitunen M, Savilahti E, Pelkonen A, Malmberg P, Mäkelä M. Airway inflammation in probiotic‐treated children at 5 years. Pediatr Allergy and Immunol 2011; 22 : 249–251. Early treatment of new‐born high‐risk children with certain probiotic strains has reduced the risk of atopic eczema. Whether probiotics reduce risk for airway inflammation in long term is not known. We aimed at studying the effect of probiotic treatment during the six first months of life on airway inflammation at age 5 yr. In a randomized double‐blind allergy prevention trial between 2000 and 2007 in Helsinki, Finland, we gave a probiotic combination, plus pre‐biotics, or placebo, to 1018 children during 6 months from birth. At age 5, we measured exhaled nitric oxide (FE_NO) in a randomized sub‐population of 160 children. Allergic diseases and IgE‐sensitization were assessed in all infants. FE_NO did not differ between probiotic and placebo groups, median (interquartile range, IQR) 5.45 (4.3–7.3) vs. 5.70 (3.9–6.8) ppb, p = 0.22. FE_NO was elevated among those suffering from asthma during the first 5 yr than in healthy non‐sensitized children (p = 0.009). FE_NO correlated positively with serum total and allergen‐specific IgE concentrations. Early intervention with probiotics and pre‐biotics does not affect airway inflammation later in childhood.     

Early wheezing phenotypes and cognitive development of 3‐yr‐olds. Community‐recruited birth cohort study

Jedrychowski W, Perera FP, Jankowski J, Maugeri U, Mrozek‐Budzyn D, Mroz E, Flak E, Skarupa A, Edwards S, Lisowska‐Miszczyk I. Early wheezing phenotypes and cognitive development of 3‐yr‐olds. Community‐recruited birth cohort study.
Pediatr Allergy Immunol 2010: 21: 550–556.
© 2009 John Wiley & Sons A/S The main purpose of the study was to answer the question whether young children without clinical diagnosis of asthma but experiencing early wheezing disorders and therefore being at high risk of developing asthma may have cognitive deficits. In the ongoing birth cohort study wheezing symptoms were recorded postpartum over two first years of age and subsequently cognitive status of children at the age of 3 yr was assessed with the Bayley Mental Development Index (MDI). In the statistical analysis a wide range of modifying and confounding factors (maternal education, gender of children, prenatal exposure to lead and environmental tobacco smoke (ETS) were considered to assess the independent effect of early wheezing phenotypes on cognitive development of children. The MDI score correlated inversely with the number of wheezing days recorded over 24 months (r = ?0.13, p = 0.007), lead cord blood concentration (r = ?0.12, p = ?0.02), number of siblings (r = ?0.17, p = 0.0006) and the number of cigarettes smoked daily by other household members at home over the pregnancy period (r = ?0.18, p = 0.0002). While the children who experienced wheezing over the first year of age showed deficit of 2 MDI scores (beta coeff. = ?2.31, 95%CI: ?4.63 to 0.02), those with persistent wheezing had the score deficit of 4 points (beta coeff. = ?4.41, 95%CI: ?8.27 to ?0.55). To our knowledge, it is the first report in the iterature showing that early wheezing is associated the cognitive deficit in a community‐recruited very young children. Observed cognitive deficit in early wheezers may be caused by RSV infections or can be related to lower lung function attributed to persistent wheezing, which reducing oxygen supply would affect rapidly developing brain.     

Expression of and responses to CD2 and CD3 in 18‐month‐old children with and without atopic dermatitis

We hypothesize that atopy is associated with a reduced T‐cell function early in life and an imbalance in cytokine production. The purpose of this study was to investigate the expression of and responses to CD2 and CD3 in children who did or did not develop atopic dermatitis early in life. The expression of CD2 and CD3 was analyzed by flow cytometry, and proliferation of CD2 and CD3 was studied by ³H‐thymidine incorporation in phytohaemagglutinin (PHA)‐ and anti‐CD3‐stimulated peripheral blood mononuclear cells (PBMC) of 18‐month‐old children, 25 with and 29 without atopic dermatitis. Exogenous interleukin (IL)‐2 was added to compensate for possible functional differences in accessory cells. Anti‐CD3‐induced secretion of IL‐4, IL‐5, IL‐6, IL‐10, IL‐13, and interferon‐γ (IFN‐γ) was analyzed by enzyme‐linked immunosorbent assay (ELISA). Atopy was associated with a low proportion of CD2⁺ lymphocytes. Responsiveness to PHA, which activates lymphocytes partly via the sheep erythrocyte receptor, CD2, was reduced in the allergic children. The anti‐CD3‐induced proliferation declined more rapidly with antibody dilution in the allergic than in the non‐allergic children. Atopic dermatitis was associated with high levels of anti‐CD3‐stimulated IL‐5 secretion. The IL‐4/IL‐10 and IL‐4/IFN‐γ ratios were higher in children with elevated total immunoglobulin E (IgE) levels. Skin prick test‐negative children with eczema produced higher levels of IL‐10 than skin prick test‐positive children. In conclusion, atopic children have a reduced T‐cell function. Atopic dermatitis is associated with increased IL‐5 production, while high total IgE levels are associated with high IL‐4/IFN‐γ and IL‐4/IL‐10 ratios.     

Establishing the diagnosis of peanut allergy in children never exposed to peanut or with an uncertain history: a cross‐Canada study

Ben‐Shoshan M, Kagan R, Primeau M‐N, Alizadehfar R, Turnbull E, Harada L, Dufresne C, Allen M, Joseph L, St. Pierre Y, Clarke A. Establishing the diagnosis of peanut allergy in children never exposed to peanut or with an uncertain history: a cross‐Canada study.
Pediatr Allergy Immunol 2010: 21: 920–926.
© 2010 John Wiley & Sons A/S The diagnosis of peanut allergy (PA) can be complex especially in children never exposed to peanut or with an uncertain history. The aim of the study is to determine which diagnostic algorithms are used by Canadian allergists in such children. Children 1–17 yrs old never exposed to peanut or with an uncertain history having an allergist‐confirmed diagnosis of PA were recruited from the Montreal Children’s Hospital (MCH) and allergy advocacy organizations. Data on their clinical history and confirmatory testing were compared to six diagnostic algorithms: I. Skin prick test (SPT) ≥8 mm or specific IgE ≥5 kU/l or positive food challenge (+FC); II. SPT ≥8 or IgE ≥15 or +FC; III. SPT ≥13 or IgE ≥5 or +FC; IV. SPT ≥13 or IgE ≥15 or +FC; V. SPT ≥3 and IgE ≥5 or IgE ≥5 or +FC; VI. SPT ≥3 and IgE ≥15 or IgE ≥15 or +FC. Multivariate logistic regression analysis was used to identify factors associated with the use of each algorithm. Of 497 children recruited, 70% provided full data. The least stringent algorithm, algorithm I, was applied in 81.6% (95% CI, 77–85.6%) of children and the most stringent, algorithm VI, in 42.6% (95% CI, 37.2–48.1%).The factor most associated with the use of all algorithms was diagnosis made at the MCH in those never exposed to peanut. Other factors associated with the use of specific diagnostic algorithms were higher paternal education, longer disease duration, and the presence of hives, asthma, eczema, or other food allergies. Over 18% (95% CI, 14.4–23.0%) of children were diagnosed with PA without fulfilling even the least stringent diagnostic criteria.     

Early exposure to paracetamol or to antibiotics and eczema at school age: Modification by asthma and rhinoconjunctivitis

Garcia‐Marcos L, González‐Díaz C, Garvajal‐Urueña I, Pac‐Sa MR, Busquets‐Monge RM, Suárez‐Varela MM, Batlles‐Garrido J, Blanco‐Quirós A, Varela ÁL.‐S., García‐Hernández G, Aguinaga‐Ontoso I. Early exposure to paracetamol or to antibiotics and eczema at school age: modification by asthma and rhinoconjunctivitis.
Pediatr Allergy Immunol 2010.
© 2010 John Wiley & Sons A/S The association between early exposure to paracetamol or to antibiotics and eczema is conflicting. This study aims to know whether the early exposure to those drugs is associated with eczema at school age, and whether the strength of the association is modified by the presence of asthma or rhinoconjunctivitis. Children aged 6–7 (n = 13908) from the International Study of Asthma and Allergies in Childhood in Spain provided data about current asthma, rhinoconjunctivitis and eczema. Parent‐reported information was also obtained on paracetamol and antibiotic consumption during the first year of life. Logistic regression analysis with eczema as outcome and including exposure to paracetamol or to antibiotics, together with possible confounders, was carried out in the whole sample of children and in five different strata: no respiratory symptom and any respiratory symptom further subdivided into: asthma with rhinoconjunctivitis, asthma without rhinoconjunctivitis and rhinoconjunctivitis without asthma. In the whole sample, exposure to paracetamol was associated with eczema (aOR 1.56 [1.36–1.80]) as was antibiotic consumption (aOR 1.66 [1.43–1.92]). These associations did not substantially change after additionally adjusting for the other drug. A similar pattern was found among children without respiratory symptoms. In children with symptoms, adjusting for the other drug modified the association with paracetamol (aOR from 1.32 [1.03–1.71] to 1.09 [0.83–1.43]) but did not change that with antibiotics (aOR from 1.80 [1.38–2.35] to 1.81 [1.37–2.39]). Early exposure to paracetamol or to antibiotics is associated with an increased prevalence of eczema at school age. Asthma and/or rhinoconjunctivitis substantially modifies this association.     

Effects of treating helminths during pregnancy and early childhood on risk of allergy‐related outcomes: Follow‐up of a randomized controlled trial

Background

Helminth infections, common in low‐income countries, may protect against allergy‐related disease. Early exposure may be a key. In the Entebbe Mother and Baby Study, treating helminths during pregnancy resulted in increased eczema rates in early childhood. We followed the cohort to determine whether this translated to increased asthma rates at school age.

Methods

This randomized, double‐blind, placebo‐controlled trial, conducted in Entebbe, Uganda, had three interventions. During pregnancy, women were randomized, simultaneously, to albendazole vs placebo and to praziquantel vs placebo. Their children were independently randomized to quarterly albendazole vs placebo from age 15 months to 5 years. We here report follow‐up to age 9 years. Primary outcomes at 9 years were recent reported wheeze, skin prick test positivity (SPT) to common allergens and allergen‐specific IgE positivity to dust mite or cockroach. Secondary outcomes were doctor‐diagnosed asthma and eczema rates between 5 and 9 years, recent eczema, rhinitis and urticaria at 9 years, and SPT and IgE responses to individual allergens.

Results

2507 pregnant women were enrolled; 1215 children were seen at age nine, of whom 1188 are included in this analysis. Reported wheeze was rare at 9 years (3.7%) while SPT positivity (25.0%) and IgE positivity (44.1%) were common. There was no evidence of a treatment effect for any of the three interventions on any of the primary outcomes.

Conclusions

Prenatal and early‐life treatment of helminths, in the absence of change in other exposures, is unlikely to increase the risk of atopic diseases later in childhood in this tropical, low‐income setting.     

What lessons can be learned about asthma phenotypes in children from cohort studies?

‘Phenotyping’ asthma by multivariate analyses and more recently by unsupervised analysis has been performed in children cohorts. We describe the key findings that have emerged from these cohorts. It would appear that there are three wheeze phenotypes in children of preschool age: the mild episodic viral wheeze phenotype; the multitrigger atopic wheeze; and, less often encountered, the severe non‐atopic wheeze. Early onset of allergy in asthma (more prevalent in boys) is associated with poor prognosis unlike the severe non‐atopic wheeze phenotype which has a female predominance. The prognosis of the severe non‐atopic wheeze depends on time of onset (early or late) of allergic expression. At school age, the risk of severe asthmatic exacerbations is associated with eosinophil predominant inflammation frequently related to allergic asthma, whereas neutrophil inflammation is associated with moderate‐to‐severe asthma with poorer lung function. Nevertheless, allergic asthma is also a heterogeneous disease with a severe allergic phenotype strongly associated with atopic dermatitis and very high eosinophil‐driven inflammatory markers. Further studies are required to find non‐invasive biological markers in very young children to better define wheezing phenotypes associated with an elevated risk of developing severe asthma with a view to personalizing treatment.     

Prevalence of and factors associated with current asthma symptoms in school children aged 6–7 and 13–14 yr old in Bogotá, Colombia

This cross‐sectional study of children aged 6–7 years and adolescents aged 13–14 years in Bogotá, Colombia, assessed the prevalence of asthma symptoms and their associations with dietary, health, and behavioral habits. This study is part of the International Study of Asthma and Allergies in Childhood (ISAAC)‐phase III. Asthma prevalence among the children was assessed using a parental self‐administered written questionnaire (WQ), and among adolescents using a WQ together with a video questionnaire (VQ). Associations were estimated with bivariate and multivariate analysis. The study found that the 6–7 year age‐group were more likely to report current asthma symptoms than the 13–14 year age‐group (10.4% [WQ] vs. 8.6% [WQ] and 8.0% [VQ], respectively). Factors associated with current asthma symptoms among the 6–7 year age‐group included higher maternal education (OR = 1.7, [95% CI 1.2–2.6], p = 0.007), a cat in the home during the last year (OR = 1.5, [95% CI 1.0–2.3], p = 0.036), watching TV 1–2 hours/day (OR = 2.1, [95% CI 1.2–3.9], p = 0.013), and medication with acetaminophen in the first and most recent year of life (OR = 1.8, [95% CI 1.3–2.4], p < 0.001; OR = 2.2, [95% CI 1.7–2.8], p < 0.001, respectively) or antibiotics in the first year of life (OR = 1.9, [95% CI 1.4–2.5], p < 0.001). Among the 13–14 year age‐group, factors associated with current asthma symptoms included medication with acetaminophen during the last year (OR = 1.8, [95% CI 1.4–2.3], p < 0.001); cereal, milk, and fruit consumption 3 or more times weekly (OR = 1.5, [95% CI 1.1–1.9], p = 0.010; OR = 0.8, [95% CI 0.6–1.0], p = 0.046; OR = 0.6, [95% CI 0.4–1.0], p = 0.031, respectively). Overall, compared with that in other Latin American centers, asthma prevalence in Bogotá is close the lower estimates. However, associations with dietary, health, and behavioral habits need further study to assess their complex relationship with asthma.     

Interleukin‐4 receptor polymorphisms in asthma and allergy: relation to different disease phenotypes

Aim: Inheritance and genetic factors are supposed to influence susceptibility to asthma and allergy. We tested if single nucleotide polymorphisms (SNPs) in the IL4R gene were associated with susceptibility to such diseases, or if they were related to the phenotypic presentation of asthma and allergic rhinoconjunctivitis (ARC). Methods: Three hundred and nine 12‐ to 13‐year‐old children were included. Six SNPs in the IL4R were analysed in response to current allergic disease, and to presentation of specific asthma and ARC phenotypes. Questionnaires were used to determine allergic disease status, and skin prick tests to evaluate sensitization to common airborne allergens. Results: Less eczema was seen in individuals with the AA‐genotype of rs2057768, and less ARC among those with the AA‐genotype of rs2107356, especially ARC associated with sensitization to pollen. The AA‐genotype of rs2057768 and the TT genotype of rs3024632 were associated with a specific asthma phenotype. Conclusion: Variations within the IL4R gene are associated with allergic diseases in children, preferably with eczema and disease phenotypes of ARC and asthma.     

Clostridium difficile,atopy and wheeze during the first year of life

Differences have been suggested to occur in the composition of intestinal microflora from allergic and non‐allergic children. In this study we used a semi‐quantitative enzyme‐linked immunosorbent assay (ELISA) for the measurement of Clostridium difficile‐specific immunoglobulin G (IgG) (CDIgG). CDIgG was excellent in differentiating between adults with or without Cl. difficile colitis (absorbance levels, positive vs. negative controls: geometric mean (GM) 0.301, 95% CI: 0.289–0.314 vs. GM 0.167, 95% CI: 0.155–0.181; mean difference 1.8‐fold, 95% CI: 1.65–1.95; p < 0.0001). We used this technique to investigate whether there are any differences between atopic wheezy infants and non‐atopic non‐wheezy controls. In a prospective cohort study (n = 390) 10 patients were identified at 1 year of age (atopic, history of recurrent wheeze) and matched (gender, month of birth, exposure to Der p 1, Fel d 1 and Can f 1) with a control group of infants (non‐atopic, no history of wheeze). The patients had significantly higher Cl. difficile‐specific IgG absorbance levels (GM 0.298, 95% CI: 0.249–0.358) compared with controls (GM 0.235, 95% CI: 0.201–0.274; mean difference 1.27‐fold, 95% CI: 1.07–1.50; p = 0.01). These results suggest that there may be differences in the composition of intestinal microflora between allergic and non‐allergic infants at 1 year of age, with allergic children having higher Cl. difficile IgG antibody levels.