Neonatal sepsis and later development of atopy

Background: The role of infections on the development of atopy is still widely debated. We aimed to evaluate the effects of neonatal severe sepsis and consequent antibiotic treatment on the development of atopy and allergic diseases. Material and methods: A retrospective enrolment at school age of children with a clear history of neonatal sepsis (NS) was performed from registers of neonatal intensive care units. A normal control was assigned to each patient with sepsis. Thirty six cases with sepsis (18 males, 18 females) and 36 controls (21 males, 15 females) were selected (8.5±3.6 yrs). Physical examination and lung function evaluation were performed. Atopic status was verified by blood eosinophil count, total IgE serum level and skin prick tests (SPT). Results: SPT positivity for at least one allergen was present in 30% of subjects in both groups. No difference for all investigated parameters between groups and no influence by other factors such as familiarity or gender was observed. No correlation was associated to NS history. Conclusions: Neonatal sepsis, even if clinically severe and dramatic, could represent an event too limited and really precocious in life to influence the development of immune response. Furthermore, other factors, besides infections, may influence the atopic future of newborns (AU)

Neonatal sepsis and later development of atopy.

BACKGROUND: The role of infections on the development of atopy is still widely debated. We aimed to evaluate the effects of neonatal severe sepsis and consequent antibiotic treatment on the development of atopy and allergic diseases. MATERIAL AND METHODS: A retrospective enrollment at school age of children with a clear history of neonatal sepsis (NS) was performed from registers of neonatal intensive care units. A normal control was assigned to each patient with sepsis. Thirty six cases with sepsis (18 males, 18 females) and 36 controls (21 males, 15 females) were selected (8.5+/-3.6 yrs). Physical examination and lung function evaluation were performed. Atopic status was verified by blood eosinophil count, total IgE serum level and skin prick tests (SPT). RESULTS: SPT positivity for at least one allergen was present in 30% of subjects in both groups. No difference for all investigated parameters between groups and no influence by other factors such as familiarity or gender was observed. No correlation was associated to NS history. CONCLUSIONS: Neonatal sepsis, even if clinically severe and dramatic, could represent an event too limited and really precocious in life to influence the development of immune response. Furthermore, other factors, besides infections, may influence the atopic future of newborns.

Chromosome 7p linkage and GPR154 gene association in Italian families with allergic asthma.

BACKGROUND: Several genome scans have reported linkage of markers on chromosome 7p with asthma and related phenotypes in different populations. A fine mapping in Finnish and French-Canadian populations has associated the GPR154 gene (also known as G-protein-coupled receptor for asthma susceptibility, GPRA) with elevated IgE or asthma. OBJECTIVE: To confirm chromosome 7p linkage and candidate gene association in Italian families with atopic asthma. METHODS: In a two-phase approach, we first performed a linkage analysis of chromosome 7, and then a family-based association study on the GPR154 gene for allergic asthma phenotypes in the Italian population. RESULTS: The screening of 117 families with 19 microsatellite markers showed potential linkage for elevated IgE (P<0.002 at 22 cM from p-ter), asthma (P<0.005 at 44 cM), or atopy (P<0.005 at 54 cM). In the second phase of the present study, candidate gene GPR154, which is located in the phase one-linked region, was investigated in 211 families with seven single nucleotide polymorphisms (SNPs) that tag most haplotype variability, by the pedigree disequilibrium test. Elevated IgE levels were associated with two GPR154 gene SNPs (SNP 546333, P=0.0046; rs740 347, P=0.006), and with haplotypes in the global test (P=0.013). Haplotype analysis performed in nuclear families having at least 1 asthmatic parent showed a significant association with asthma (P=0.0173), atopy (P=0.0058), SPT (P=0.0025), and bronchial hyper reactivity (P=0.0163). CONCLUSION: These results support a susceptibility locus for asthma and related phenotypes on chromosome 7, and are in agreement with recent reports suggesting that a common susceptibility factor for atopic manifestations in asthma is likely conferred by the locus containing the GPR154 gene.

[Role of leukotriene antagonists in non-asthmatic disorders]. / Effetto degli antileucotrieni nella patologia non asmatica.

It has been shown that the leukotriens play a role in the pathobiologic process of allergic asthma and wheezing due to infection. Their specific role in other respiratory disorders or in other diseases is not yet fully understood. A recent consensus has elaborated the guidelines for the treatment of asthma in the paediatric age. According to these guidelines, the leukotriene-antagonists are recommended as a possible alternative to inhaled corticosteroids in the long-term treatment of mild persistent asthma. The association of antileukotrienes with the usual classical therapy led to a great improvement in the treatment of the most severe forms of the disease. Moreover, a growing number of disorders such as allergic rhinitis, chronic urticaria, atopic dermatitis and nasal polyposis seem to benefit from the use of these new drugs. In allergic rhinitis, the most common allergic disorder, the leukotrienes seem to be, together with histamine, important mediators of both the early and late stage of the allergic reaction. They seem to be responsible for the vasodilation and therefore for the nasal obstruction. There is a production of leukotrienes also in chronic urticaria, which is more frequent in adults, and in atopic dermatitis, which usually has its onset in the paediatric age. This paper summarizes the results of several clinical trials evaluating the therapeutical efficacy and safety of the leukotriene-antagonists. Despite the promising results, further studies are however necessary on a greater number of patients before recommending the use of this type of drug in this kind of disorders.

Chronic treatment with inhaled corticosteroids does not modify leptin serum levels.

AIM: To assess the influence of a short-term treatment with low-dose inhaled corticosteroids on leptin serum levels. PATIENTS: 14 prepubertal children, mean age 5.1 +/- 2.4 years, treated with inhaled fluticasone propionate 100 microg b.d. and 16 prepubertal children, mean age 8.3 +/- 1.3 years, treated with inhaled budesonide 200 microg b.d. METHODS: All children underwent a CRH test with evaluation of leptin, cortisol and ACTH levels before and after 3 months of treatment. RESULTS: Fluticasone group: no difference was found between basal cortisol level, delta and area under the curve (AUC) before and after treatment, though cortisol peak was significantly lower following treatment. Basal ACTH level, peak and AUC were significantly lower after treatment. Budesonide group: no statistically significant difference in any of the parameters regarding cortisol and ACTH secretion was observed before and after treatment. No significant changes in basal serum leptin levels and AUC were observed following treatment in both groups. Furthermore no significant variation in leptin level was observed during both CRH tests. DISCUSSION: Leptin secretion does not seem to be affected by low-dose inhaled corticosteroids; moreover leptin does not seem to be involved in the response of the HPA axis to stress.

Systemic activity of inhaled corticosteroid treatment in asthmatic children: corticotrophin releasing hormone test.

BACKGROUND: A study was undertaken to assess the function of the hypothalamic-pituitary-adrenal axis (HPA) in a group of asthmatic children before and after treatment with inhaled corticosteroids. METHODS: Thirty prepubertal patients of mean (SD) age 6.7 (1.8) years were treated with inhaled corticosteroids. All children underwent a corticotrophin releasing hormone (CRH) test with evaluation of serum cortisol and adrenocorticotrophin hormone (ACTH) levels before and after 3 months of treatment. Twenty four hour urine samples were also collected to measure free cortisol (UFC) excretion. RESULTS: Subjects showed no difference between basal serum cortisol levels (mean change -18; 95% CI -41 to 5; p=0.118) and delta (peak minus basal) levels (mean change -13; 95% CI -38 to 12; p=0.308) before and after treatment, whereas the peak cortisol level (mean change -31; 95% CI -55 to -7; p=0.013) and area under the curve (AUC) (mean change -175; 95% CI -288 to -63; p=0.003) after CRH were significantly lower following treatment. Basal, peak and AUC ACTH were significantly lower after treatment (p<0.05, p=0.004 and p=0.003, respectively), while delta ACTH was similar before and after treatment ((mean change -12; 95% CI - 31 to -7; p=0.199). No significant reduction in 24 hour UFC was observed after the treatment period (before 14.9 (7.1), after 15.0 (11.6); mean change 0.1, 95% CI -5.2 to 5.4; p=0.967). No correlation was found between UFC and any of the parameters of cortisol excretion following the CRH test, either before or after treatment. CONCLUSIONS: These data suggest that, at the dosage and for the treatment period used, inhaled steroids do not seem to suppress the HPA axis in the majority of patients. The CRH test may be more sensitive than 24 hour UFC and morning plasma cortisol levels in evaluating systemic activity of inhaled corticosteroid treatment.

The role of house dust mite elimination in the management of childhood asthma: an unresolved issue.

Indoor allergens are likely to be direct environmental causes of asthma and mite exposure, and sensitization is the most important environmental risk factor for childhood asthma in temperate zones. Analagous to occupational asthma, allergen avoidance in asthmatic children sensitized and exposed to mite allergens is associated with a reduction in airway hyperresponsiveness and symptoms associated with improvement in lung function. The long-term effect of this strategy needs to be prospectively evaluated considering both the timing and duration of exposure, as well as the timing and duration of removal. In order to be successful, it is important to achieve and maintain a major reduction on allergen levels, for a long period of time.

Linkage to atopy on chromosome 19 in north-eastern Italian families with allergic asthma.

BACKGROUND: Allergic asthma is a multifactorial disease for which there is a widely assessed, although poorly understood, genetic involvement. Genome-wide screens reported evidence for linkage of allergic asthma-related phenotypes to several chromosomal locations. Markers on chromosome 19 have been linked to allergic asthma phenotypes in different populations in independent studies. OBJECTIVE: The aim of this study was to perform a genetic linkage analysis on chromosome 19 to search for DNA markers linked to phenotypes related to allergic asthma. METHODS: Using non-parametric multipoint linkage analysis on a total of 22 random DNA markers in 2 stages, a sample of 111 families (542 subjects) from north-eastern Italy, recruited through an asthmatic allergic proband, was investigated. Phenotypes examined were: clinical asthma, total serum elevated IgE, skin prick test positivity, bronchial hyper-responsiveness, and atopy defined as skin prick test positivity and/or elevated IgE. Simulation studies were performed to confirm the significance of the results. RESULTS: A novel linkage of atopy and skin prick test positivity to marker D19S601 (19q13.3) was found. Modest evidence for linkage of atopy, skin prick test positivity, and IgE was also found to marker D19S591 (19p13.3). Simulation analysis for atopy gave an NPL-Z > 3.326 in 2 replicates out of 1000 (P = 0.002) for D19S601, and an NPL-Z > 2.56 in 16 replicates out of 1000 (P = 0.016) for D19S591. CONCLUSIONS: On chromosome 19, suggestive linkage of atopy and skin prick test positivity with marker D19S601 (19q13.3) and modest evidence of linkage of marker D19S591 (19p13.3) to the atopic phenotypes investigated were found. These results suggest that these regions may contain susceptibility loci associated to atopic phenotypes.

Chromosome 14 linkage analysis and mutation study of 2 serpin genes in allergic asthmatic families.

BACKGROUND: Genome and chromosome screens reported DNA markers on chromosome 14 linked to allergic asthma or intermediate phenotypes in several populations. OBJECTIVE: We sought to perform a linkage study on chromosome 14 and a further association study on candidate genes mapped in the region found to be linked to allergic asthma or intermediate phenotypes. METHODS: The study consisted of a sample of 189 families (847 genotyped individuals) from a restricted geographic area in northeastern Italy. The subjects were characterized for the following phenotypes: allergic asthma, total serum IgE levels, skin prick test responses, and bronchial hyperresponsiveness (BHR) to methacholine. Genotyping was done with 14 DNA markers and 4 polymorphisms in the genes encoding alpha(1)-anti-trypsin and alpha(1)-antichymotrypsin (ACT). RESULTS: Multipoint analysis indicated a potential linkage of BHR with marker D14S617 (nonparametric linkage z score = 2.32, P =.01). Transmission disequilibrium of Thr -15Ala in the gene encoding ACT was observed with all the phenotypes investigated: allergic asthma, BHR, total IgE levels, or skin prick test responses (P =.041,.02,.0053, or.026, respectively). CONCLUSION: Chromosome 14 screening and transmission disequilibrium testing on the gene encoding ACT suggest that it or a closely located gene may be involved in susceptibility to allergic asthma in the Italian population.

Linkage analysis of chromosome 12 markers in Italian families with atopic asthmatic children.

We investigated 116 Italian atopic families (560 individuals) for linkage with 13 DNA markers on chromosome 12. All the subjects were phenotyped for asthma, total serum IgE, bronchial hyperresponsiveness, skin-prick positivity to common aeroallergens, and atopy. A relative location map of the markers was prepared from Centre d'Etude du Polymorphisme Humain families. Affected sib pair multipoint linkage methods were used to perform the statistical analyses. We report suggestive linkage for asthma with markers on chromosome 12. The region of interest centers around marker D12S390 (maximum logarithm of odds [mlod] = 2.81; p = 0.003). These results provide additional support that asthma susceptibility factors are located on chromosome 12q.

Cat sensitivity: 7-yr audit in children attending a paediatric allergy clinic in North Italy.

Sensitivity to cats and exposure to cat allergen is a common cause of asthma exacerbation in children. To date, there is no data on the prevalence of cat sensitivity in children living in North Italy. Therefore, a 7-yr survey was performed in patients attending an allergy clinic for the first time. Skin prick tests (SPT) for perennial allergens and for pollens relevant to the region were performed in 4,957 children attending the outpatient clinic 1992-1998. A questionnaire on present or past cat ownership was presented to all cat-skin prick test positive children. An evaluation of cat ownership on the general population was made by telephone interview on a random sample of 1,268 families living in the same area. With a 3-mm wheal as a positive cut-off 439 (8.85%) children had a positive SPT to cats. Of these 103 (23.4%) had a cat at home and 336 (76.6%) never had a cat in the house. With a greater positive cut-off(a wheal diameter > or =4 mm) 140 (2.8%) showed a positive SPT to cats of these 35 (25%) had a cat at home and 105 (75%) had only an indirect exposure to the pet. Of the telephone interviewed families; 16% stated they had a cat at home. Cat sensitivity is less prevalent in Italy, in this hospital based population, compared with other European countries and this is in agreement with a lower rate of cat ownership. Cat sensitivity was three times more frequent in children who never had a cat at home, than in children living with cats, when the selected positive cut-off was either a wheal diameter of 3 mm or > or =4 mm. Thus in a population with a low prevalence of cat ownership public exposure seems to be more important than domestic exposure for the development of sensitivity.

Candidate genes and a genome-wide search in Italian families with atopic asthmatic children.

To identify genetic factors for susceptibility to atopy and asthma in childhood, 1,083 subjects were identified, mainly from the Veneto region and Bolzano province in North-east Italy, of whom 817 were from 172 families with at least two affected people, 189 were sporadic cases, and 77 unrelated controls. All the subjects were characterized for clinical asthma (asthma), total serum IgE (IgE), skin prick test (SPT) reactivity to common aeroallergens and bronchial hyperresponsiveness (BHR) to methacoline test. Atopy was defined as SPT positivity and/or increased IgE levels. Several candidate genes were investigated, and genome-wide linkage analysis was been initiated. The high affinity IgE receptor beta chain (FcepsilonRIbeta) locus showed significant allele sharing in affected sib-pairs for BHR and for SPT positivity. Lymphotoxin alpha (Ltalpha) gene Ncol mutation showed a suggestive linkage with atopy, and the LTalphaNcol 2/2 genotype was found to be associated with increased total IgE levels in all females. No evidence for linkage or association of any phenotype to the tumour necrosis factor alpha (TNFalpha) - 308 mutation or to the interleukin 4 receptor alpha (IL-4Ralpha) Q576R mutation was found. BHR, asthma and increased IgE were found to be linked to X and Y long arm pseudoautosomal region (PAR2) markers. Initial data were also collected from linkage analysis with chromosome 12, 14, and 19, DNA markers. Non-parametric multipoint analysis provides preliminary evidence for linkage of asthma with D12S390, of atopy with D19S601, and of BHR with D14S617. These results suggest that several genetic factors contribute to different allergic asthma phenotypes in the population investigated.