Carlo Capristo

Fractional Exhaled Nitric Oxide (FENO), Lung Function and Airway Hyperresponsiveness in Naïve Atopic Asthmatic Children

Background. Measurement of fractional exhaled nitric oxide (FENO) is a noninvasive, simple, well‐tolerated, and reproducible marker of airway inflammation. Asthmatic children with normal respiratory function could be affected by airway inflammation. The aim of this study was to assess the correlation between FENO and bronchial hyperesponsiveness (BHR) to methacholine, and between FENO and lung function in atopic children with intermittent asthma. Methods. Thirty‐seven children (21 male), aged 7.2–14.4 years (median: 10.9 years), suffering from mild intermittent atopic asthma with a physician‐diagnosed history of wheezing and/or chest tightness were studied. None had taken anti‐asthmatic therapy for at least three months before the study. No child had symptoms of respiratory tract infection in the month before the study. All subjects underwent FENO measurement, pulmonary function testing and the methacholine provocation tests. Results. The mean percentages of FEV1 and FEF25–27 were 91.9 ± 10.5 and 88.3 ± 11.8, respectively. The mean FENO was 62.2 ± 39.2 ppb and PC20 methacholine was 0.93 mg/ml ± 0.54. Significant correlations were identified between FENO and FEV1 (p < 0.0059, r = 0.468) and between FENO and FEF25–75 (p < 0.0098, r = 0.439). There was no correlation between FENO and logPC20 (p = 0.14). Conclusions. A single FENO measurement is probably of scarce prognostic and predictive value and it is not surprising to find discordance with BHR. We suggest that FENO measurement could represent a good marker of airway inflammation also in naïve atopic children with intermittent asthma. Repeated measurements over time are probably necessary to understand better the clinical implications of the data obtained in this study.

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.

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.

Probiotics and atopic dermatitis. A new strategy in atopic dermatitis

Over the last few decades, the prevalence of atopic dermatitis has been increasing from 2% to 100%, with 90% of cases within 5 years of age versus 6% between 6 and 10 years and 2% after 10 years, and environmental factors may possibly play an important role in this increase as in other atopic diseases. Many findings suggest an important role of atopy in atopic dermatitis; moreover, 40% of children with atopic dermatitis have food allergy and the removal of the food allergen from the patients diet leads to a significant clinical improvement. In a possible scenario, IgE-bearing dendritic cells are likely to process allergens acquired in the gastrointestinal tract, circulate to the skin and activate local T cells. Cultures of beneficial live microorganisms characteristic of the commensal microflora are administered with probiotic functional foods in order to provide a microbial challenge for the maturation of gut-associated lymphoid tissue, which the infant often lacks. The probiotic effects are attributed to normalisation of the increased intestinal permeability and balancing gut microecology, improvement of the immunological defence barrier (IgA) of the intestine, alleviation of the intestinal inflammatory response, and downregulation of proinflammatory cytokines characteristic of local and systemic allergic inflammation.

Leukotriene modifiers in the treatment of asthma in children

Asthma is one of the most common respiratory disorders in clinical practice, affecting up to 13% of people worldwide. Inflammation is the most important component of asthma and inhaled corticosteroids (ICS) are recommended as the first line controller treatment for patients of all ages. Treatment with corticosteroids is often unable to fully control asthma symptoms and progression. Recently, leukotrienes have come to the forefront of research as they have been found play a pivotal role in the airway inflammatory process, and specific drugs have been developed to target them. Cysteiny leukotriene antagonists (LTRAs) have recently emerged as important therapeutic options that show a large potential clinical utility. Three specific LTRAs are licensed for clinical use: montelukast, zafirlukast and pranlukast, although montelukast is the only drug approved in the paediatric age range. It is well tolerated (although adverse effects such as headaches, abdominal pain, rashes, angioedema, pulmonary eosinophilia and arthralgia have been reported) and shows many positive effects in asthmatic patients. Current Global Initiative for Asthma guidelines recommend LTRAs as: (1) a second choice treatment to ICS for patients with mild persistent asthma, (2) an add-on therapy to reduce the dose of ICS in patients with moderate or severe asthma, due to the different and complementary mechanisms of action of these agents. LTRAs may be particularly appropriate choices in a number of clinical situations, including the following: patients with concomitant rhinitis; patients with viral-induced wheeze; patients with exercise-induced bronchoconstriction (EIB) and, in children aged 2-5 years, to reduce the frequency of asthma exacerbations.

Bioavailable Vitamin D in Obese Children: The Role of Insulin Resistance.

CONTEXT Studies examining vitamin D levels in association with childhood obesity usually do not consider the effect of insulin on vitamin D-binding protein and do not calculate the unbound, bioavailable vitamin D. OBJECTIVE This study aimed to evaluate in a group of children 1) the concentrations of both total 25-hydroxyvitamin D and bioavailable fraction, and 2) the potential role of insulin resistance in modulating the concentrations of bioavailable vitamin D. Design, Setting, and Patients or Other Participants: This was a cross-sectional study at a University Pediatric Department in which 63 obese children and 21 lean controls were enrolled. MAIN OUTCOME MEASURES Total 25-hydroxyvitamin D and vitamin D-binding protein were measured, two single-nucleotide polymorphisms in the coding region of the vitamin D-binding protein (rs4588 and rs7041) were studied, and the vitamin D bioavailable fraction was calculated. RESULTS Obese children showed total 25-hydroxyvitamin D levels lower compared with nonobese children (21.3 ± 6.7 ng/mL vs 29.6 ± 11.7 ng/mL; P = .0004). Bioavailable 25-hydroxyvitamin D levels were not different among the two groups (3.1 ± 1.6 ng/mL vs 2.6 ± 1.2 ng/mL; P > .05). Insulin-resistant children showed higher bioavailable levels of 25-hydroxyvitamin D compared with noninsulin-resistant children (3.4 ± 1.4 ng/mL vs 2.0 ± 0.9 ng/mL; P = .013) and an inverse correlation between insulin resistance and vitamin D-binding protein was found (r:= -0.40; P = .024). CONCLUSIONS Obese children present levels of bioavailable 25-hydroxyvitamin D similar to those of normal-weight children due to reduced concentration of vitamin D-binding protein. The insulin resistance could play a role in this reduced concentration.

Neutrophilic Cells in Sputum of Allergic Asthmatic Children

Airway inflammation is regarded as a central feature of asthma and is mostly sustained by eosinophilic infiltrate. Recent studies have shown that a co-activation of eosinophil- and neutrophil-dependent inflammatory mechanisms might explain why some asthmatics do not respond to conventional asthma therapy. The aim of our study is to determine whether neutrophilic inflammation was involved in 55 allergic children with mild-moderate persistent asthma and the relationship with the response to steroid treatment. Before the sputum analysis, all children underwent spirometry with the reversibility test, and were divided into two groups on the basis of the response (such as >12% of baseline FEV1): group 1 positive and group 2 negative. Eosinophil cationic protein concentrations were measured by radioimmunoassay and neutrophyl myeloperoxidase (MPO) concentrations were measured by an MPO-EIA. Ten healthy children of comparable ages served as control group. Total IgE, FEV1 and FEV/FVC values were similar in both groups. The sputum macrophage count was higher in controls than in allergic asthmatics, but there was no difference between groups 1 and 2 (59.6% vs 18.3% and 17%; p≤ 0.005). Sputum neutrophils were significantly higher in group 2 both vs controls (62% vs 34%; p≤ 0.005) and vs group 1 (62% vs 37%; p≤ 0.005). Our data suggest that neutrophils are involved in airway allergic inflammation in mild-moderate persistent childhood asthma and a high neutrophil count in sputum may be related to a lower responsiveness to inhaled corticosteroids.

Resveratrol plus carboxymethyl-β-glucan reduces nasal symptoms in children with pollen-induced allergic rhinitis

Abstract Objective: Allergic rhinitis (AR) is caused by an IgE-mediated inflammatory reaction consequent to the exposure to causal allergen. Resveratrol is a natural non-flavonoid polyphenol, exerting anti-inflammatory activity; β-glucan is a polysaccharide with immuno-modulatory properties. Thus, this study aimed to investigate whether these combined compounds are able of relieving nasal symptoms in children with AR due to pollen allergy. Research design and methods: The present study was conducted as placebo-controlled, double-blinded, and randomized. Globally, 68 children (36 males; mean age 7.9 years) were treated with resveratrol plus β-glucan or placebo (the diluent of active drug) two sprays (100 µL/spray) in each nostril three times/day for 2 months. Nasal symptoms, including itching, sneezing, rhinorrhea, and obstruction, were assessed at baseline and after treatment. Use of rescue medication, such as cetirizine syrup, was also evaluated. Clinical trial registration: ClinicalTrials.gov identifier: NCT02130440. Results: Children treated with active drug achieved a significant reduction in all nasal symptoms: itching (p = 0.0001), sneezing (p = 0.0009), rhinorrhea (p = 0.009), and obstruction (0.002) as well as antihistamine use (p = 0.003). Placebo did not affect nasal complaints and cetirizine use. The intergroup analysis showed that active treatment was significantly superior to placebo about reduction of AR symptoms and rescue medication use. Conclusions: The present preliminary study firstly showed that intranasal resveratrol plus carboxymethyl-β-glucan is capable of significantly improving nasal symptoms in children with pollen-induced AR.

Expanding the phenotype of RTTN varations: a new family with primary microcephaly, severe growth failure, brain malformations and dermatitis

Primary autosomal recessive microcephaly (MCPH) is a developmental disorder characterized by prenatal onset of abnormal brain growth. MCPH occurs both alone and as part of a broad range of neurodevelopmental syndromes with or without cortical malformations and growth retardation. Here we report a consanguineous Moroccan family with two siblings affected by severe primary microcephaly, failure to thrive, congenital dermatitis and severe developmental delay. Brain magnetic resonance imaging showed lissencephaly of frontal lobes and periventricular heterotopia of the gray matter. We performed both Comparative Genomic Hybridization array and whole exome sequencing (WES) analyses of the kindred. No quantitative defects were detected. However, WES identified a new homozygous missense variation in the penultimate nucleotide of exon 23 of RTTN gene (c.2953A>G;pArg985Gly). cDNA sequencing revealed two abnormal spliced products, one lacking only exon 23 and the other lacking exons 22 and 23 (out‐of‐frame). RTTN is a protein involved in cilia structure and function. Homozygous mutations in RTTN gene have been described in bilateral diffuse isolated polymicrogyria and, more recently, in microcephalic primordial dwarfism (PD). We found a novel homozygous mutation in RTTN associated with microcephalic PD as well as complex brain malformations and congenital dermatitis, thus expanding the phenotypic spectrum of both RTTN‐associated diseases and ciliary dysfunction.

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 μg/kg twice daily for 7 days and then 20 μg/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 μg 4 times daily) was administered during the first 3 days of the study and then as needed. At TO, 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.