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Introduction: Montelukast has been proven to assure a protective effect against exercise-induced bronchoconstriction., Aim: To verify exactly when montelukast begins protection in asthmatic children by evaluating different time intervals between dosing and challenge., Methods: In a double blind, placebo-controlled, three day doses, crossover study, patients were randomized to receive in sequence treatment with either a placebo or montelukast and assigned to one of seven groups that were tested 1, 2, 3, 4, 5, 6 and 8 h after drug administration, respectively. For each group, the exercise challenge was always performed at the same hour on the first and third days of treatment., Results: Sixty-nine asthmatic children took part in the study. On day 3, the mean FEV(1) % fall from baseline was 25.54 (95% CI = 21.63/29.46) and 14.89 (95% CI = 11.85/17.92) for the placebo and active drug (p < 0.05), respectively. On day 1, the mean fall of FEV(1) was 28.20 (95% CI = 24.46/31.94) and 19.01 (95% CI = 15.71/22.31) for the placebo and montelukast (p < 0.05), respectively. Clinical protection was achieved in 21 (30%) and 33 (48%) subjects by montelukast on the first and third days, respectively., Conclusions: Montelukast assured protection against exercise-induced bronchoconstriction from the first through the eighth hour from the first day of treatment. However, individual susceptibility to protection was evident since some individuals were not protected at any time. We conclude that in clinical use individual responses to the drug should be carefully evaluated in the follow-up management., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Children living on farms have fewer allergies. It is unclear whether breastfeeding in different environments contributes to preventing allergies by exposing offspring to different cytokines that can modulate immune responses. The aim of this study was to quantify and compare levels of Transforming Growth Factor-beta1 (TGF-beta1) and Interleukin-10 (IL-10) in the colostrum and mature milk of mothers living in towns at sea level (references) and mothers on farms. Milk samples were collected within 3 days postpartum (colostrum) and at the first month of the baby's life (mature milk). Sixty-nine reference mothers and 45 farm mothers participated in the study. TGF-beta1 concentrations were significantly higher both in the colostrum (p < 0.05) and in mature milk (p < 0.05) of farm mothers. In the reference mothers, a significant decrease in TGF-beta1 concentrations was observed between colostrum (650, range 0-8000 pg/ml) and mature milk (250, range 0-8000 pg/ml) (p < 0.05). In farm mothers, TGF-beta1 concentrations were 1102 pg/ml (range 0-14,500) in colostrum and remained high in mature milk (821 pg/ml, range 0-14,650). IL-10 concentrations were higher in the mature milk of farm mothers (p < 0.05). No significant differences in IL-10 were observed between colostrum and mature milk in the control group (15 pg/ml, range 0-1800, and 0 pg/ml, range 0-230) or in farm mothers (9.5 pg/ml, range 0-1775, and 14.2 pg/ml, range 0-930), respectively. Exposure to a farm environment is associated with higher concentrations of TGF-beta1 and IL-10 in breast milk when compared to exposure to an urban environment. Higher cytokine concentrations in breast milk may influence early modulation of the development of an immune response, leading to a reduced prevalence of allergy-related diseases in farm children., ((c) 2010 John Wiley & Sons A/S.)

Conclusions: The results of this study suggest that atypical bacteria may be involved not only in acute upper airway diseases but also in recurrent infections requiring adenoidectomy and/or tonsillectomy. Therefore, their identification, followed by an appropriate treatment, should be considered., Objective: Although viruses and group A beta-haemolytic streptococci (GABHS) represent the most frequent bacterial aetiological agents of paediatric upper respiratory tract infections (URTIs), chlamydia and Mycoplasma pneumoniae have also been found in acute tonsillopharyngitis. Nevertheless their relevance in chronic or recurrent URTI has never been evaluated. This study aimed to further address the role of atypical bacteria in recurrent URTIs requiring adenoidectomy and tonsillectomy., Methods: Samples from 55 consecutive children who underwent adenoidectomy and/or tonsillectomy for recurrent or chronic URTI were cut transversely into smaller sections of 5 mm. Each section was pooled and assayed by specific PCR for viruses and bacteria., Results: Adenovirus was detected in 10 patients (18.2%), influenza A virus in one patient and influenza B virus in another. None of the other tested viruses was found. GABHS was found in 37 patients (67.3%). Moraxella catarrhalis and Haemophilus influenzae were detected in 30 patients (54.5%). M. pneumoniae was detected in 6 patients (10.9%) and C. pneumoniae was found in 10 patients (18.2%).

We describe a child who had anaphylactic hypersensitivity to imiglucerase therapy for Gaucher disease. Treatment was stopped and symptoms returned. After immune desensitization to imiglucerase using a rush protocol, the patient was able to resume treatment and has not had further hypersensitivity complications to date.

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.

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

The epidemiology of the genetic sublineages of human metapneumovirus (hMPV) and their clinical relevance are not fully understood. We compared hMPV genotypes isolated in the province of Bolzano in Northern Italy with strains from nearby Italian and Austrian regions by sequencing of NP- and L-gene fragments. Our results suggest that similar strains cycle through adjacent geographic areas, with the respective subtypes replacing each other on a seasonal basis.

Asthma is a multifactorial disease influenced by genetic and environmental factors. In the past decade, several loci and >100 genes have been found to be associated with the disease in at least one population. Among these loci, region 12q13-24 has been implicated in asthma etiology in multiple populations, suggesting that it harbors one or more asthma susceptibility genes. We performed linkage and association analyses by transmission/disequilibrium test and case-control analysis in the candidate region 12q13-24, using the Sardinian founder population, in which limited heterogeneity of pathogenetic alleles for monogenic and complex disorders as well as of environmental conditions should facilitate the study of multifactorial traits. We analyzed our cohort, using a cutoff age of 13 years at asthma onset, and detected significant linkage to a portion of 12q13-24. We identified IRAK-M as the gene contributing to the linkage and showed that it is associated with early-onset persistent asthma. We defined protective and predisposing SNP haplotypes and replicated associations in an outbred Italian population. Sequence analysis in patients found mutations, including inactivating lesions, in the IRAK-M coding region. Immunohistochemistry of lung biopsies showed that IRAK-M is highly expressed in epithelial cells. We report that IRAK-M is involved in the pathogenesis of early-onset persistent asthma. IRAK-M, a negative regulator of the Toll-like receptor/IL-1R pathways, is a master regulator of NF- kappa B and inflammation. Our data suggest a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicate IRAK-M as a potential target for therapeutic intervention against 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.

The use of inhaled beta2-agonists delivered by a metered-dose inhaler (MDI) with a holding chamber (spacer) actually is considered the best treatment for childhood acute asthma. However, its use in daily practice still seems rather limited. The aim of this study was to investigate, using a questionnaire, the use of a nebulizer or MDI as the first-line method for delivering inhaled beta2-agonists in children with acute asthma. A questionnaire was developed and distributed to 22 pediatric departments and to 131 family pediatricians (FPs) in northeast Italy. We showed that in the hospitals the episodes of acute asthma usually were treated with bronchodilators administered by wet nebulization (95.45%). This was the case also for FPs (70.9%). However, 29.1% of FPs usually advised the use of an MDI/holding chamber to children with acute asthma. Despite the established efficacy of inhaled beta2-agonists administrated with an MDI compared with wet nebulization in acute asthma, this practice still is rather limited. The use of wet nebulization was more evident in hospital settings compared with community medicine. Emergency room visits may represent a missed opportunity to promote an effective method of delivering bronchodilators in childhood asthma.

The interleukin-1 cluster on human chromosome 2q12-2q14 harbors various promising candidate genes for asthma and other inflammatory diseases. We conducted a systematic association study with single-nucleotide polymorphisms (SNPs) located in candidate genes situated in this cluster. Single-marker, two-locus and three-locus haplotype analysis of SNPs yielded several significant results (p < 0.05-0.0021) for the human IL1RN gene encoding the IL-1 receptor antagonist protein, an antiinflammatory cytokine that plays an important role in maintaining the balance between inflammatory and antiinflammatory cytokines. These findings were replicated and confirmed in an independent Italian family sample in which significant, although weaker, association with asthma was detected. A sequencing approach to the coding region of the human IL1RN gene revealed additional DNA variants, from which a selection was also associated with the disease in German and Italian samples. Calculation of the linkage disequilibrium for the human IL1RN gene showed strong linkage disequilibrium for nearly all analyzed SNPs. Further haplotype analysis indicated that six SNPs are sufficient for tagging all haplotypes with a prevalence of more than 1%. The most frequent haplotype constructed from these SNPs was 1.4-fold overtransmitted in the German family sample.

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.

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.

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.

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.

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.

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.

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.

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.