Atopic Dermatitis Phenotypes in Preschool and School-Age Children: A Latent Class Analysis.

BACKGROUND: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in childhood. Few data are available about AD phenotypes and their nationwide distribution. METHODS: We performed a cross-sectional multicenter study involving some of the main Italian pediatric allergy centers from 9 Italian cities. A structured questionnaire was administered to 371 children with AD. Patients were divided in 2 groups: preschool children (aged ≤5 years) and schoolchildren (aged 6-14 years). A latent class analysis was used to detect AD phenotypes and to investigate their association with risk factors and other atopic diseases. RESULTS: Latent class analysis identified 5 AD phenotypes in preschoolers ("moderate-severe AD, high comorbidity", 8%; "moderatesevere AD, low comorbidity", 35%; "mild AD, low comorbidity", 20%; "mild AD, respiratory comorbidity", 32%; "mild AD, food-induced comorbidity", 5%) and 4 AD phenotypes in schoolchildren ("moderate-severe AD, high comorbidity", 24%; "moderate-severe AD, low comorbidity", 10%; "mild AD, low comorbidity", 16%; "mild AD, respiratory comorbidity", 49%). Parental history of asthma and eczema, early day-care attendance, and exposure to molds were significantly associated with the "moderate-severe AD, high comorbidity" phenotype in preschool children (P<.05). The "moderate-severe AD" phenotypes were also associated with the highest burden in terms of medication use and limitations in daily activities. CONCLUSIONS: The detection of different AD phenotypes highlights the need for a stratified approach to the management of this complex disease and for further studies to predict the course of AD and to develop more efficient therapeutic strategies.

Atopic dermatitis phenotypes in preschool and school-age children: a latent class analysis

BACKGROUND: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease in childhood. Few data are available about AD phenotypes and their nationwide distribution. METHODS: We performed a cross-sectional multicenter study involving some of the main Italian pediatric allergy centers from 9 Italian cities. A structured questionnaire was administered to 371 children with AD. Patients were divided in 2 groups: preschool children (aged ≤5 years) and schoolchildren (aged 6-14 years). A latent class analysis was used to detect AD phenotypes and to investigate their association with risk factors and other atopic diseases. RESULTS: Latent class analysis identified 5 AD phenotypes in preschoolers ("moderate-severe AD, high comorbidity", 8%; "moderatesevere AD, low comorbidity", 35%; "mild AD, low comorbidity", 20%; "mild AD, respiratory comorbidity", 32%; "mild AD, food-induced comorbidity", 5%) and 4 AD phenotypes in schoolchildren ("moderate-severe AD, high comorbidity", 24%; "moderate-severe AD, low comorbidity", 10%; "mild AD, low comorbidity", 16%; "mild AD, respiratory comorbidity", 49%). Parental history of asthma and eczema, early day-care attendance, and exposure to molds were significantly associated with the "moderate-severe AD, high comorbidity" phenotype in preschool children (P<.05). The "moderate-severe AD" phenotypes were also associated with the highest burden in terms of medication use and limitations in daily activities. CONCLUSIONS: The detection of different AD phenotypes highlights the need for a stratified approach to the management of this complex disease and for further studies to predict the course of AD and to develop more efficient therapeutic strategies

ANTECEDENTES: La dermatitis atópica (DA) es la enfermedad crónica cutánea más frecuente en la infancia. Hay pocos datos disponibles sobre los diferentes fenotipos de DA y su distribución geográfica. MÉTODOS: Se realizó un estudio transversal multicéntrico en nueve de los principales centros italianos de alergia infantil. Se realizó un cuestionario a 371 con DA. Los pacientes fueron divididos en dos grupos: preescolares (<5 años) y escolares (6-14 años). Se empleó un análisis de clases latentes (ACL) para establecer los fenotipos de la DA y su asociación con factores de riesgo y otras enfermedades atópicas. RESULTADOS: El ACL identificó cinco fenotipos de DA en el grupo preescolar (8% DA moderada-severa con alta comorbilidad, 35% DA moderada-severa con baja comorbilidad, 20% DA leve con baja comorbilidad, 32% DA leve con patología respiratoria asociada, 5% DA leve con alergia alimentaria asociada) y cuatro fenotipos en escolares (24% DA moderada-severa con alta comorbilidad, 10% DA moderada-severa con baja comorbilidad, 16% DA leve con baja comorbilidad, 49% DA leve con patología respiratoria asociada). Los antecedentes familiares de asma y eccema, la asistencia temprana a guardería y la exposición a hongos se asociaron al fenotipo DA moderada-severa con alta comorbilidad en niños preescolares (p < 0,05). Los fenotipos moderados-severos requerían mayor uso de medicación y tenían mayores limitaciones para su actividad diaria. CONCLUSIONES: La clasificación de la DA en diferentes fenotipos implica la importancia de un tratamiento estratificado para esta compleja enfermedad así como la necesidad de estudios capaces de predecir el curso de la DA y con ello desarrollar estrategias de tratamiento más eficientes

Diagnostic relevance of IgE sensitization profiles to eight recombinant Phleum pratense molecules.

BACKGROUND: Grass pollen-related seasonal allergic rhinoconjunctivitis (SARg) is clinically heterogeneous in severity, comorbidities, and response to treatment. The component-resolved diagnostics disclosed also a high heterogeneity at molecular level. Our study aimed at analyzing the characteristics of the IgE sensitization to Phleum pratense molecules and investigating the diagnostic relevance of such molecules in childhood. METHODS: We examined 1120 children (age 4-18 years) with SARg. Standardized questionnaires on atopy were acquired through informatics platform (AllergyCARD™). Skin prick tests were performed with pollen extracts. Serum IgE to airborne allergens and eight P. pratense molecules (rPhl p 1, rPhl p 2, rPhl p 4, rPhl p 5b, rPhl p 6, rPhl p 7, rPhl p 11, rPhl p 12) were tested by ImmunoCAP FEIA. RESULTS: The analysis of IgE responses against eight P. pratense molecules showed 87 profiles. According to the number of molecules recognized by IgE, the more complex profiles were characterized by higher serum total IgE, higher grass-specific serum IgE, and higher number and degree of sensitization to pollens. The most frequent IgE sensitization profile was the monomolecular Phl p 1. Sensitization to Phl p 7 was a reliable biomarker of asthma, whereas Phl p 12 of oral allergy syndrome. Sensitization to Phl p 7 was associated with a higher severity of SARg, and complex profiles were associated with longer disease duration. CONCLUSIONS: In a large pediatric population, the complexity of IgE sensitization profiles against P. pratense molecules is related to high atopic features although useless for predicting the clinical severity. The detection of serum IgE to Phl p 1, Phl p 7, and Phl p 12 can be used as clinical biomarkers of SARg and comorbidities. Further studies in different areas are required to test the impact of different IgE molecular profiles on AIT response.

Ara h 6 sensitization in peanut allergy: friend, foe or innocent bystander?

The clinical role of Ara h 6 sensitization in peanut allergy is a current matter of debate. We investigated the role of Ara h 6 sensitization patterns in a sample of young adults from different Italian cities. Sera of 33 patients with specific IgE against Ara h 6 were selected. According to clinical symptoms upon peanut ingestion, patients were divided into severe reaction (SR) and mild-tolerant (MT) subgroups. While the SR group mainly showed sensitization patterns involving Ara h 2 and other major allergenic components, a previously undescribed association between Ara h 6 and Ara h 9 was found in the MT group. This pattern seems to be clustered in Mediterranean Italy and associated with Pru p 3 sensitization. This finding might shed a new light on the role of Ara h 6 sensitization in peanut allergy.

Endotypes of pollen-food syndrome in children with seasonal allergic rhinoconjunctivitis: a molecular classification.

BACKGROUND: Pollen-food syndrome (PFS) is heterogeneous with regard to triggers, severity, natural history, comorbidities, and response to treatment. Our study aimed to classify different endotypes of PFS based on IgE sensitization to panallergens. METHODS: We examined 1271 Italian children (age 4-18 years) with seasonal allergic rhinoconjunctivitis (SAR). Foods triggering PFS were acquired by questionnaire. Skin prick tests were performed with commercial pollen extracts. IgE to panallergens Phl p 12 (profilin), Bet v 1 (PR-10), and Pru p 3 (nsLTP) were tested by ImmunoCAP FEIA. An unsupervised hierarchical agglomerative clustering method was applied within PFS population. RESULTS: PFS was observed in 300/1271 children (24%). Cluster analysis identified five PFS endotypes linked to panallergen IgE sensitization: (i) cosensitization to ≥2 panallergens ('multi-panallergen PFS'); (ii-iv) sensitization to either profilin, or nsLTP, or PR-10 ('mono-panallergen PFS'); (v) no sensitization to panallergens ('no-panallergen PFS'). These endotypes showed peculiar characteristics: (i) 'multi-panallergen PFS': severe disease with frequent allergic comorbidities and multiple offending foods; (ii) 'profilin PFS': oral allergy syndrome (OAS) triggered by Cucurbitaceae; (iii) 'LTP PFS': living in Southern Italy, OAS triggered by hazelnut and peanut; (iv) 'PR-10 PFS': OAS triggered by Rosaceae; and (v) 'no-panallergen PFS': mild disease and OAS triggered by kiwifruit. CONCLUSIONS: In a Mediterranean country characterized by multiple pollen exposures, PFS is a complex and frequent complication of childhood SAR, with five distinct endotypes marked by peculiar profiles of IgE sensitization to panallergens. Prospective studies in cohorts of patients with PFS are now required to test whether this novel classification may be useful for diagnostic and therapeutic purposes in the clinical practice.

Mannitol bronchial challenge test in asthmatic children.

Bronchial asthma is a chronic inflammatory disease characterized by bronchial obstruction, usually reversible spontaneously or after therapy, bronchial hyperreactivity and accelerated decrease of lung function that may possibly evolve into irreversible obstruction of the respiratory tract. Bronchial provocation tests can be used in order to assess the presence and degree of bronchial hyper reactivity. The recently introduced mannitol powder inhalation indirect test seems to have an interesting and promising role, especially in childhood, because of its high diagnostic specificity, easiness of execution and best standardization. In this study the authors focused on the significance and clinical use of mannitol bronchial challenge test in asthmatic children.

VITAMIN D AND BRONCHIAL INFLAMMATION IN ASTHMATIC CHILDREN.

The role of the vitamin D in calcium homeostasis and bone metabolism is well known. In recent years it has been recognized that in addition to the traditional functions, vitamin D modulates a variety of processes such as host defense, inflammation and immunity. Epidemiological data indicate that low levels of vitamin D in serum are associated with impaired lung function and increased incidence of inflammatory diseases, infectious diseases and cancer. The authors studied the correlation among vitamin D levels, allergic inflammation, lung function and control of asthma and found a significant decrease of FeNO values (p= 0.0018) in children with vitamin D levels>30 ng/ml. These findings confirm that vitamin D plays a major role in bronchial inflammation.

ß2-AGONISTS IN CHILDHOOD ASTHMA.

ß2-agonists reduce airflow limitation by improving airway diameter as a consequence of a direct action on airway smooth muscle. ß;2-agonists can be broadly classified according to their duration of action: short-acting ß2-agonists (SABAs), including albuterol, terbutaline and fenoterol, have pharmacodynamics half–lives between 2 and 6 h and long-acting ß2-agonists (LABAs), including salmeterol and formoterol, require twice daily treatment. SABAs are often used “as needed” for asthma exacerbations and before exercise in the presence of exercise-induced bronchospasm. LABAs provide longer symptom control, which is a particularly useful feature for preventing night-time symptoms. There are two main LABAs, salmeterol and formoterol. This review focused on the recent data published on this topic.

Airways allergic inflammation and L. reuterii treatment in asthmatic children.

Recently, it has been hypothesized that the oral administration of specific live probiotic strains may have therapeutic potential in the treatment of allergic inflammation. The aim of this study was to evaluate the effect of the oral L. reuteri DSM 17938 administration (1X108CFU), in airways allergic inflammation in mild persistent asthmatic children. In this DBPC randomized study we selected 50 children (6-14 years old), affected by mild persistent asthma (GINA step 2) and allergic to HDM. At the run-in period (T-2), the children were submitted to medical examination, prick tests for the main respiratory allergens, spirometry and children asthma control test (C-ACT). We selected only the children with well controlled asthma (C-ACT >19 and FEV1> 80%). After two weeks (T0) the children were allocated into two groups, the FeNO was measured and the breath condensate was collected. Group A children were treated with the placebo (5 drops per day) and Group B children with L. reuteri (108CFU =5 drops per day) for 60 days. After the treatment period (T1), all patients were evaluated by medical examination, C-ACT, spirometry, FeNO measurement and exaled breath condensate analysis. The FeNO values showed a significant reduction (p=0,045) in L. reuteri group but not in the placebo group at the end of the treatment (T1). Furthermore, the cytokines exam showed an increase in IL-10 levels (p less than 0.05) and a significant reduction in IL-2 levels (p less than 0.05) only in L. reuteri group at T1. No significant differences in FEV1 values and C-ACT score were found in both groups. In conclusion, these data showed that L. reuteri (108 CFU) was effective in reducing bronchial inflammation in asthmatic children. No significant effect was found on FEV1 values and C-ACT score, probably because we selected children with well controlled asthma.

Effectiveness of nebulized hypertonic saline and epinephrine in hospitalized infants with bronchiolitis.

The objective of the study is to verify effects of nebulized 3% saline hypertonic solution (HS) in comparison to normal saline (NS) in addition to epinephrine in hospitalized children with bronchiolitis. Infants were randomly assigned either to receive every 6 hours nebulized NS (group I) or 3% HS (group II) in addition to epinephrine (1.5 mg) and to conventional treatment. The main endpoints of this study were the length of stay (LOS) in hospital and the clinical response score (CSS). Patients presented a significant decrease in CSS from the first through the third day of treatment, present in the first group but even more evident in the second group (p=0.0001). Comparison between group I and II data shows significant decrease in CSS in the 3% HS-treated patients both at the second (p<0.005) and at the third day of treatment (p<0.005). Infants in the NS control group had a mean LOS of 5.6±1.6 days, whereas children treated with 3% HS were discharged with a LOS of 4.9±1.3 days, reaching a significant decrease in stay (p<0.05). In hospitalized patients bronchiolitis nebulized 3% HS and epinephrine significantly decreased symptoms and LOS as compared to 0.9% NS and epinephrine.

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 percent) compared with controls (6.0 percent, P =0.004; OR2.99, 95 percent CI 1.39-6.41; RR 1.46, 95 percent CI 1.14-1.69). AD patients a significantly different frequency of the D299G SNP (14.9 percent) in comparison with the controls (6.6 percent, P = 0.01; OR 2.46, 95 percent CI 1.17–5.17; RR 2.24; 95 percent 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.

Evaluation of bronchial hyperreactivity with mannitol dry powder challenge test in a paediatric population with intermittent allergic asthma or allergic rhinitis.

We evaluated the bronchial hyperreactivity (BHR) with a new bronchial challenge test, mannitol dry powder, in a paediatric population with intermittent allergic asthma or allergic rhinitis who did not respond to an exercise challenge test. We selected 50 children, aged 9-16 years, with intermittent allergic bronchial asthma (Group 1) or allergic rhinitis without clinical manifestation of asthma for at least 12 months (Group 2). All patients performed the following tests in three different days (≥ 48 hours apart): Day 1: exhaled nitric oxide (FeNO) determination followed by baseline spirometry and reversibility to inhaled beta2-agonists; Day 2: exercise challenge test followed by FeNO determination; Day 3: mannitol challenge test followed by FeNO determination. Forty children completed the study. Eighteen subjects of Group 1 (90 percent) and 5 subjects of Group 2 (25 percent) resulted positive to the mannitol test. Positive mannitol challenge subjects showed no statistically significant differences compared to negative subjects as regard baseline spirometry, reversibility to salbutamol and response to the exercise challenge test, but they had significantly higher FeNO values. In conclusion, the mannitol challenge test can be a diagnostic tool more useful than the exercise challenge test to identify BHR in a paediatric population with intermittent allergic asthma or allergic rhinitis because it is better reproducible, quick and easy to perform and well tolerated.

Effectiveness of Ischia thermal water nasal aerosol in children with seasonal allergic rhinitis: a randomized and controlled study.

Allergic rhinitis is characterized by local inflammation. Nasal lavage may be a useful treatment, however, there are few studies on this topic. This study aims to evaluate the effects of Ischia thermal water nasal irrigation on allergic rhinitis symptoms and airway inflammation during the period of natural exposure to Parietaria pollen in children with allergic rhinitis and intermittent asthma. Forty allergic children were randomly divided into two groups: the first group (Group 1) practiced crenotherapy with thermal water aerosol for 15 days per month, for three consecutive months, the control group (Group 2) was treated with 0.9% NaCl (isotonic) solution. In addition, all children were treated with cetirizine (0.5 gtt./kg/day once daily). Nasal symptom assessment, including Total Symptom Score (TSS), spirometry, and exhaled nitric oxide (FeNO) were considered before the treatment (T0), at the end of the treatment (T1) and again 2 weeks after the end of the treatment (T2). The study was registered in the Clinical Trials.gov (NCT01326247). Thermal water significantly reduced both TSS and FeNO levels and there was a significant relationship between reduction of nasal symptoms and FeNO values at the end of treatment with thermal water. In conclusion, this study shows that nasal crenotherapy with the hypermineral chloride-sodium water of Ischia was effective in children with seasonal allergic rhinitis based on the sensitivity to Parietaria. These results demonstrate that this natural treatment may be effective in a common and debilitating disease such as the allergic rhinitis.

High-dose inhaled flunisolide versus budesonide in the treatment of acute asthma exacerbations in preschool-age children.

The role of inhaled corticosteroids in asthma exacerbation is debated. We compared high doses of nebulized budesonide versus high doses of nebulized flunisolide, in association with a short-acting beta-2-agonist, in the treatment of moderate asthma exacerbation in preschool children. In this randomized, parallel group, simple blind study, 46 children aged between 3 and 5 years affected by an acute moderate asthma attack were treated with nebulized flunisolide (Group 1) 40 microg/kg twice daily for 7 days and then 20 microg/kg twice daily for 14 days, or with nebulized budesonide (Group 2) 0.5 mg twice daily for 7 days then 0.25 mg twice daily for 15 days. Inhaled salbutamol (MDI+ spacer - 200 microg 4 times daily) was administered during the first 3 days of the study and then as needed. At T0, T7 and T21 days, airway resistances were evaluated with the forced oscillation technique before and after inhalation of inhaled salbutamol (200 mcg). Parents recorded symptoms and drug use on a diary card. Forty children completed the study. Airway resistances were significantly reduced at T7 (p< 0.01 flunisolide; p< 0.05 budesonide) and T21 (p< 0.05 flunisolide; p< 0.05 budesonide) versus T0 in both groups, although at T7 the reduction occurred faster in group 1 than in group 2 (p<0.01). During the first 7 days of treatment, symptom scores decreased in both groups; however, the decrease was greater in group 1 (p< 0.05). High doses of inhaled flunisolide and budesonide are both effective in the management of moderate asthma exacerbations in pre-school-age children, but the flunisolide therapeutic effect was faster than budesonide.

Atopy and house dust mite sensitization as risk factors for asthma in children.

BACKGROUND: Recent evidence suggests that asthma is not invariably related to atopy. The aim of this study was to evaluate the frequency of atopy, asthma and sensitization to eight common allergens in a large group of children with allergic symptoms. METHODS: 1426 children referred to our Paediatric Asthma and Allergy Center because of allergic symptoms were examined. Bronchial asthma, allergic rhino-conjunctivitis, food allergy and atopic dermatitis were diagnosed with standardized methods. Atopy was diagnosed if at least one skin test was positive. RESULTS: Of the 1426 children examined, 629 (44%) were atopic and 769 (56%) were non-atopic. Asthma was diagnosed in the same proportion (i.e., 64%) of atopic and non-atopic children. However, after division into age groups, non-atopic asthma was significantly more prevalent (chi2 = 8.46) in children between 0 and 3 years old (group 1). On the other hand, atopy was significantly associated with asthma only in group 3 (odds ratio 1.85). Furthermore, a significant association with asthma symptoms was found for house dust mite (HDM) in group 3 (odds ratio 4.8). CONCLUSIONS: Asthma is related to atopy in pre-selected children only from the age of 7 years. House dust mite sensitization seems to be an important determinant of asthma in these "older" children.

Corticosteroid-sparing effect of chromoglycate sodium and nedocromil.

The most appropiate management for bronchial asthma is the control of airway inflammation. Corticosteroids are the most effective anti-inflammatory drugs available, but they have a number of side effects; most of these are dose-dependent. In children, asthma control should be accomplished with low steroid doses possibly given by inhalation. In a double-bind placebo-controlled crossover study a group of children with mild to moderate asthma received NED 16 mg/day or BDP 400 mug/day. Values for FEV(1), PEF, symptoms use ofbronchodilators overlapped, whereas bronchial hyper-responsiveness assessed by histamine bronchoprovocation challenge was better with BDP than NED. In another case, one boy with high bronchial hyper-reactivity assessed by provocation test with hypertonic solution, experienced a significant improvement only after 2 weeks of therapy with Deflazacort (2 mg/Kg/day) followed by 4 months on combined treatment with NED (16 mg/day) and BDP (300 mu/day). Authors conclude that NED could have a steroidsparing effect over long-term use.