Salpietro A

TLR2 and TLR4 gene polymorphisms and atopic dermatitis in Italian children: a multicenter study.

Background Genetic factors have an important role in atopic dermatitis (AD) predisposition. Toll like receptor (TLR) are important mediators between environment and immune system. There are incosnsitent studies about TLSR polymorphisms in AD. Objective This study examined whether single nucleotide polimorphisms (SNPs) in the genes for TLR2 and TLR4 could be associated with the AD phenotypes and with its clinical severity in a large group of Italian children. Methods 187 children with Ad and 150 healthy children were recruited. AD severity was assessed by SCORAD. TLR2 (A-16934T and R753Q polymorphisms) and TLR4 (D299G and T399I SNPs) were genotyped by PCR-RFLP. Results The frequency of the R753Q was significantly higher in AD children (16.0%) compared with controls (6.0%, P=0.004; OR2.99,95%CI 1.39–6.41; RR 1.46,95%CI 1.14–1.69). AD patients a significantly different frequency of the D299G SNP (14.9%) in comparison with the controls (6.6%, P = 0.01; OR 2.46, 95%CI 1.17–5.17; RR 2.24; 95%CI 1.15–4.45). Conclusion Children with AD may have a distinct genotype and the TLR-2 R753Q SNP was prevalent in a subset of patients with AD characterized by a more severe clinical picture.

Specific immunotherapy in children: the evidence.

Specific immunotherapy (SIT) is the only treatment able to not only act on the symptoms of allergy but also act on the causes. At present, SIT may be administered in two forms: subcutaneous (SCIT) and sublingual immunotherapy (SLIT). SCIT represents the standard modality of treatment while SLIT has recently been introduced into clinical practice and today represents an accepted alternative to SCIT. The main advantages of SIT that are lacking with drug treatment are long-lasting clinical effects and alteration of the natural course of the disease. This prevents the new onset of asthma in patients with allergic rhinitis and the onset of new sensitizations. The mechanism of action of both routes is similar; they modify peripheral and mucosal Th2-responses into a prevalent Th1-polarization with subsequent reduction of the allergic inflammatory reaction. Both have long-term effects for years after they have been discontinued, although for SLIT these evidences are insufficient To date several guidelines have defined indications, contraindications, side-effects, and clinical aspect for SCIT and SLIT. New forms of immunotherapy, allergen products and approaches to food allergy and atopic eczema represents the future of SIT.

Adenoids during childhood: the facts.

Adenoids are constantly exposed to viral and bacterial agents as well as to allergens. They play a major role in the upper airways immunity, being effector organs in both mucosal-type and systemic-type adaptive immunity. Because of both their immunological function and their specific location, adenoids are considered to be as reservoirs of viruses and bacteria. Reiterative infections may therefore contribute both to Eustachian tube dysfunction and to tissue hypertrophy. Nasal endoscopy is a key diagnostic tool to detect both adenoid hypertrophy and adenoiditis. Moreover, such a procedure may be very helpful in detecting bacterial biofilms that could justify the concomitant presence of recurrent episodes of otitis media, chronic and occult sinusitis in children. Even though the connection between allergies and adenoidal diseases is not completely clear, allergic diseases cause an inflammatory state that influences adenoidal tissue as well, configuring the picture of allergic adenoiditis, a condition in which adenoid tissue exhibit numerous IgE positive mast cells. Several studies are still needed to better understand the relationship between allergies and infections and the influence they play on adenoids during childhood.

Nasal High-Mobility Group Box-1 Protein in Children with Allergic Rhinitis

Background: Allergic rhinitis (AR) is characterized by an inflammatory reaction. High-mobility group box-1 protein (HMGB1) has many characteristics similar to classic proinflammatory cytokines. No study has yet investigated its role in AR. The aim of this study was to measure HMGB1 levels in the fluid recovered from nasal lavage in children with untreated AR and in control subjects. Materials: The study was conducted on 104 AR subjects (48 males and 56 females, median age 10.3 ± 3.4 years) and 97 healthy children (42 males and 55 females) who were age-matched (median age 9.8 ± 4.1 years). Total serum immunoglobulin E, peripheral eosinophils and nasal symptoms assessed by visual analog scale (VAS) were considered. HMGB1 was measured using an ELISA assay. Results: HMGB1 levels in nasal lavage fluid were higher in AR children than in the control group (96.9 ± 19.3 vs. 9.27 ± 4.01 ng/ml; p < 0.001). There was a very strong relationship between HMGB1 levels and VAS values in AR children (r = 0.919). Considering the symptom severity assessed by VAS, there was a relationship between HMGB1 and VAS in all AR subgroups: more evident in the severe subgroup (r = 0.727). Conclusions: Nasal HMGB1 has significantly increased in children with AR and is significantly related to symptom severity.

A forced expiratory flow at 25-75% value >65% of predicted should be considered abnormal: A real-world, cross-sectional study

Forced expiratory volume in 1 second (FEV1) is considered an important parameter for asthma diagnosis and follow-up. However, it has been proposed that forced expiratory flow at 25-75% (FEF(25-75)) could be more sensitive than FEV1 to detect slight airways obstruction. In this regard, a cutoff FEF(25-75) value has been recently established in a group of asthmatic children: FEF(25-75) < 65% of predicted has been considered impaired. However, the considered population was specifically selected. Therefore, the aim of the present study was to confirm an FEF(25-75) cutoff value in a large cohort of asthmatic children. Seven hundred allergic children (493 male subjects; median age, 11 years) with controlled and partly controlled asthma were evaluated by performing spirometry and skin-prick tests. Three hundred thirteen (44.7%) patients had FEF(25-75%) values of <65% of predicted. Two predictors were significantly associated with impaired FEF(25-75) values: (i) sensitization to perennial allergens (adjusted odds ratio [OR(Adj)], 3.4) and (ii) FEV(1) ≤ 86% of predicted (OR(Adj), 3.8). This study, conducted in real life, could suggest that FEF(25-75) value of <65% of predicted may be considered abnormal.

HMGB1 levels in children with atopic eczema/dermatitis syndrome (AEDS)

To the Editor, Atopic eczema/dermatitis syndrome (AEDS) is a chronic relapsing-remitting inflammatory skin disorder beginning usually in early childhood, characterized by a skin barrier dysfunction resulting in epidermal damage and altered permeability to allergens and microbes (1). Depending on whether there is an association with or without immunoglobulin (Ig)E sensitization, AEDS may be defined as atopic (aAEDS) or nonatopic (naAEDS), respectively. However, it is currently unclear whether aAEDS and naAEDS are really two different diseases or whether AEDS starts in early infancy as naAEDS phenotype without evidence of IgE sensitization and then progresses through allergic sensitization to the IgE-associated phenotype (aAEDS). Moreover, in infants, the progression from AEDS to other forms of allergic diseases (e.g., rhinitis and asthma), usually referred to as the ‘atopic march’, as well as their relationships with one other, seems more complicated than a simple evolution of one condition into another and one which does not always follow the classic sequential pattern of these illnesses (1). Although the exact etiology of AEDS remains unknown, both genetic and environmental factors have been proposed to play crucial pathogenetic roles. However, various factors including immunological abnormalities have been suggested to contribute to the pathogenesis and development of AEDS. In this regard, we recently studied serum interleukin (IL)-17, IL-23, and IL-10 levels in 181 children with AEDS (99 males, 82 females; mean age: 8.31 3.21 years), and we found significantly higher levels of IL-17 and IL-23 and significantly lower levels of IL-10 than in a healthy control group. Moreover, serum IL-17 and IL-23 levels, but not IL-10 levels, were significantly higher in aAEDS than in naAEDS subtypes. Additionally, this immune biomarker phenotype significantly correlated with score atopic dermatitis (SCORAD) values. Interestingly, in the aAEDS subjects, we found a concomitant association of atopic diseases such as asthma and rhinitis, and higher serum IL-17 and IL-23 levels than in children with nonallergic sensitization (naAEDS) (2). To add new data on a ‘double-face’ disease, we, firstly, investigated the levels of high-mobility box 1 (HMGB1), an inflammatory marker belonging to the alarmin family, in the patients’ sera frozen of our previous study (2). High-mobility group box (HMGB) 1, is implicated as a mediator of both infectious and non-infectious inflammatory conditions. Extracellular HMGB1 acts as an endogenous danger signal and binds to Toll-like receptor (TLR) 2, TLR4, receptor for advanced glycation end products (RAGE), and chemokine receptors. Recent studies suggest that the elevated levels of extracellular HMGB1 have been implicated in association with several disease states, including sepsis, and autoimmune disease such as arthritis, meningitis, ischemia– reperfusion injury, cancer, psoriasis, and local inflammation. Furthermore, although several studies have assessed the role of HMGB1 in immune-mediated tissue-damaging responses (3, 4) of some allergic diseases (asthma and rhinitis), to date, no data have been reported in children with AEDS (5, 6) and only a few data in mice (7, 8). In this report, we analyzed the HMGB1 levels in both patients with naAEDS and patients with aAEDS, the relationship between serum HMGB1 levels and clinical severity of the disease, and, finally, the HMGB1 levels in different allergic phenotypes such as aAEDS plus allergic sensitization, aAEDS plus rhinitis, aAEDS plus asthma, and aAEDS plus rhinitis and asthma. Moreover, we investigated the relationship between HMGB1 and IL-17/IL-23 axis and IL-10. HMGB1 levels (IBL Shino Test Corporation, Hamburg, Germany) were determined through ELISA according to the manufacturer’s instructions. The data collected were statistically analyzed using a statistical computer software SPSS, version 15.0 (IBM. Statistical Package for the Social Sciences. 2009). A p value of <0.05 was considered to be statistically significant. Statistical analysis was performed with ANOVA test and relative post hoc vs. control. Mean and standard deviations were calculated for the variables, and t-test was employed for the comparisons. For the attributes, percentages were calculated first, and then, v2 test was used for comparisons. Correlations between HMGB1 levels and serum total IgE levels and between SCORAD index and serum IL-17, IL-23, and IL-10 levels were calculated using Spearman’s correlation coefficient. Clinical and laboratory findings of all patients are shown in Table 1. Although no difference was found between aAEDS and naAEDS subtypes (serum HMGB1 levels 19.73 1.68 ng/ml vs. 19.27 3.16 ng/ml, respectively, p = 0.208), serum

Body mass index is related with bronchial function and reversibility in children with allergic rhinitis and asthma.

Several studies have outlined a possible relationship between an increased body mass index and respiratory allergic diseases, such as asthma and rhinitis. The aim of the study was to analyse the relationship between BMI and lung function, including bronchodilation test, in allergic children. The study included 153 children (103 males, mean age 12.8 years) with allergic rhinitis and mild asthma. All subjects were evaluated performing skin prick test, spirometry, and bronchodilalation test. BMI values were in the normal range as well as lung function. BMI significantly related with FEV1, FVC values and FEV1/FVC ratio both before and after bronchodilation. In conclusion, this study provides the first evidence that BMI is negatively related with bronchial reversibility in children with allergic rhinitis and asthma. As reversibility is related with bronchial inflammation, this finding might underline a link between overweight and allergic inflammation.

A systematic review of food protein–induced enterocolitis syndrome from the last 40 years

OBJECTIVE To provide a complete, exhaustive summary of current literature relevant to food protein-induced enterocolitis syndrome (FPIES). DATA SOURCES Data have been extracted from PubMed and Science Direct databases. STUDY SELECTIONS Following the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines, a literature search for peer-reviewed journal articles in English through January 1975 with updates through October 2016 was conducted. Relevant publications were reviewed that included pediatric and adult populations. Information on the study design, sample, intervention, comparators, outcome, timeframe, and risk of bias were abstracted for each article. RESULTS Of 135 reviewed reports, 52 were included in this systematic review. In accordance with the age at onset, clinical features, and offending foods, it is possible to distiguish different types of FPIES. An immune systemic involvement can occur in patients with FPIES. In addition to the most common causative foods (cows milk, soy, and rice), any food can potentially cause FPIES. Although specific diagnostic tests are not available, open food challenge remains the gold standard for FPIES diagnosis. Moreover, because of the lack of randomized clinical trials and of use of different adopted methods, confounding factors might mask critical findings, leading to poor knowledge of this pleiotropic clinical entity. CONCLUSION Multicenter studies are needed to better develop an evidence-based approach to pathophysiology, prevalence, diagnosis, and natural history of the disease.

High mobility group box 1: Biomarker of inhaled corticosteroid treatment response in children with moderate-severe asthma

BACKGROUND High mobility group box 1 (HMGB1) is abnormally expressed in serum and sputum of patients with allergic asthma. OBJECTIVE The aim of this study was to investigate the role of HMGB1 as guidance for treatment management of children with asthma. METHODS Thirty children with asthma and 44 healthy children were enrolled. The patients were classified according to Global Initiative for Asthma Guideline disease severity criteria. Sputum HMGB1 levels and lung function index (percentage forced expiratory volume in 1 second [FEV1%]) were recorded in the cohort study at baseline (T0) and after 3 (T3) and 6 (T6) months of inhaled corticosteroids (ICS) treatment. RESULTS Sputum HMGB1 levels were significantly higher in all the patients with asthma (p < 0.001). An inverse correlation between sputum HMGB1 levels and pulmonary function parameters was observed only in the children with moderate asthma (T0: FEV1%, r = -0.9891, p < 0.001; T3: FEV1%, r = -0.6763, p < 0.001; T6: FEV1%, r = -0.5419, p < 0.05) and in the children with severe asthma (T0: FEV1%, r = -0.8696, p < 0.001; T3: FEV1%, r = -0.6477, p < 0.05; T6: FEV1%, r = -0.8627, p < 0.001). After ICS treatment, a significant decrease of sputum HMGB1 levels was noted in moderate (T0 [93.44 ± 20.65 ng/mL] versus T3 [77.96 ± 1.81 ng/mL] versus T6 [67.75 ± 3.01 ng/mL]; p < 0.0001) and in the children with severe asthma (T0 [130.3 ± 7.48 ng/mL] versus T3 [156.9 ± 1.09 ng/mL] versus T6 [116.08 ± 4.77 ng/mL]; p < 0.0001) data are mean ± standard deviation, respectively. The area under the receiver operating characteristic curve, performed to define the diagnostic profile of sputum HMGB1 levels in identifying the children with asthma, was 0.713. CONCLUSION In addition to the findings that HMGB1 is a sensitive biomarker of allergic asthma in children, our data demonstrated a significant correlation between the decrease of HMGB1 levels and a successful treatment response.

Mode of delivery and risk for development of atopic diseases in children.

Atopic diseases are a major public health problem worldwide, and several factors are thought to contribute to this rapid increase. The observed association between mode of delivery and risk of atopy in childhood has had a great deal of interest during the past few decades. In fact, even during delivery, exposure to antigens can index immune system in newborn, which induces the release of biologically active molecules, which are polarizing immune responses toward the T-helper 2 atopic profile. However, to date, studies on the relationship between mode of delivery and atopy have produced conflicting findings. The aim of this review was to summarize what is known about the relationship between mode of delivery and risk of atopic diseases in children. A literature search of electronic databases was undertaken for the major studies published from 1994 to today. The databases searched were PubMed, EMBASE, Medline, and Cochrane Library. The following key words were used: mode of delivery, cesarean section, vaginal delivery, atopy, and atopic diseases.