Treating Pediatric Asthma According Guidelines.

Asthma is a common chronic inflammatory disorder of the lower respiratory airways in childhood. The management of asthma exacerbations and the disease control are major concerns for clinical practice. The Global Strategy for Asthma Management and Prevention, published by GINA, updated in 2017, the British Thoracic Society/Scottish Intercollegiate Guideline Network, revised in 2016, the National Institute for Health and Care Excellence asthma guideline consultation, available in 2017, are widely accepted documents, frequently implemented, with conflicting advices, and different conclusion on asthma definition and treatment. An International Consensus on Pediatric Asthma was carried out in 2012 by a Committee with expertise in the field, to critically review differences on current guidelines. In addition, the specific issue of treating severe and difficult asthma has been recently highlighted throughout the International European Respiratory Society/American Thoracic Society guidelines on severe asthma. The aim of this paper is to describe conventional treatments and some new therapeutic approaches to pediatric asthma according to guidelines, highlighting key aspects, and differences on proposed clinical recommendations for asthma management. Age specific therapy are proposed in steps, according to clinical severity and the level of disease control. If control is not achieved within 3 months, stepping-up should be considered; otherwise, if control is achieved after 3 months, stepping down may be considered. The most used drug classes of asthma medications are beta-2 adrenergic agonists, corticosteroids, and leukotriene modifiers. Intramuscolar triamcinolone has been used for severe asthma treatment. Chromones and xanthines have been extensively used in the past, but they have shown limits related to their efficacy and safety profile. Omalizumab, a monoclonal antibody against IgE, is an immunomodulatory biological agent, used as new drug in patients with confirmed IgE-mediated allergic asthma, only for patient's specific range of total IgE level. There are low evidences in the efficacy of metotrexate, as well as macrolide antibiotics in children with asthma. Antifungal agents are also not recommended in asthmatic patients. Non-pharmacological measures that may improve patient's quality of life should also be attempted. We conclude that treatment decisions on childhood asthma management should be critically made, pondering the differences suggested by agreed international consensus documents.

Respiratory epithelial imbalances in asthma pathophysiology.

The pathophysiology of asthma is complex and involves a number of factors including atopy and bronchial hyperreactivity. A strong body of evidence suggests that structural and functional respiratory epithelial alterations play a crucial role in both development and persistence of this condition. From the onset of symptoms the airways epithelium of asthmatic patients seems to be altered and unable to repair. The interactions between the epithelium and the underlying mesenchyma, which are jointly referred to as the epithelial-mesenchymal trophic unit (EMTU), are thought to result in a self-sustaining damage of the airways and, ultimately, in a chronic inflammatory scenario. A better understanding of the relationship occurring across EMTU, environmental noxae, and factors of susceptibility to epithelial damage is likely to pave the way to future new preventive and therapeutic strategies for this condition.

Risk factors for subclinical atherosclerosis in diabetic and obese children.

BACKGROUND: Increased carotid intima-media thickness (cIMT) is considered a marker of early-onset atherosclerosis and it seems to predict cardiovascular events both in obese and diabetic subjects. We aimed to evaluate early signs of atherosclerosis and investigate for predisposing factors in children and adolescents affected by type 1 diabetes (T1DM) or obesity, comparing them with healthy controls. METHODS: Out of 71 enrolled subjects (mean age 12.8 ± 2.3 years), 26 had T1DM and 24 were obese, while 21 age- and sex-matched subjects acted as controls. cIMT was measured using standardized methods. Serum glucose, insulin, cholesterol, triglycerides and C-reactive protein levels were evaluated. An oral glucose tolerance test (OGTT) was performed in obese subjects. RESULTS: Diabetic and obese individuals showed higher cIMT mean values than healthy controls (p < 0.005). cIMT of the three examined segments correlated positively with fasting glucose levels and negatively with units of insulin/kg/day administered in T1DM individuals. A positive correlation between insulin levels (basal and after oral glucose load) and cIMT of common, internal and external carotid artery was found in obese subjects (p < 0.03). High density cholesterol levels represented a protective factor for cIMT in this latter group of the study population. CONCLUSIONS: Our findings show that cIMT correlates with high insulin levels (a sign of insulin resistance) in obese patients and with high fasting glucose levels (a sign of relative insulin deficiency) in T1DM subjects, confirming the need of reducing hyperinsulinism and monitoring blood glucose levels in these subjects to prevent atherosclerosis.

New insights into childhood Vernal keratoconjunctivitis-associated factors.

The purpose of this study was to test for detectable serum levels of antibodies usually associated with immune-related diseases in children with Vernal keratoconjunctivitis (VKC) and seek for their family history of allergies and autoimmune disorders. The association of human leukocyte antigens (HLA) with VKC was also investigated. We enrolled 181 VKC children and assessed total and specific IgE, antithyroglobulin (AbTG), antithyroidperoxidase (AbTPO), antitransglutaminase (tTG), and antinuclear antibodies (ANA) by standard procedures. Class I and II HLA typing was also carried out following standard protocols, and it was compared with that of healthy subjects. Patients were positive for AbTG (22%), AbTPO (14.6%), and ANA (15.8%), and AbTG positivity was associated with VKC severity (mean ocular score ± SD positive vs. negative: 6.56 ± 2.1 vs. 4.82 ± 2.1; p = 0.03). We found that 12.2% of VKC cases had a positive family history for psoriasis, 6.4% for other cases of VKC, and 5.2% for thyroiditis, while 50.2% of them were atopic. The expression of HLA class I B37 was significantly higher in VKC patients than in controls (7.1% vs. 2.1%, p = 0.04), although not confirmed after multiple antigens testing analysis. Our study suggests a role of common components associated with immune-based diseases in the clinical expression of VKC.

Association of interleukin-(IL)10 haplotypes and serum IL-10 levels in the progression of childhood immune thrombocytopenic purpura.

Derangement of genetic and immunological factors seems to have a pivotal role in the pathophysiology of immune thrombocytopenic purpura (ITP). We investigated interleukin(IL)-10 genetically determined expression in children with an acute progression of ITP (n=41) compared to young patients with chronic ITP (n=44) and healthy controls (n=60), and attempted to correlate IL-10 production with the course of the disease. We genotyped our study population for three single nucleotide polymorphisms at positions -1082 (A/G), -819 (C/T) and -592 (C/A) in the promoter region of the IL-10 gene. IL-10 levels were measured by enzyme-linked immunoassay. The IL-10 production in our study population was significantly higher in patients carrying the GCC haplotype than those bearing ACC and ATA haplotypes (6.9 ± 1.5 vs 3.6 ± 0.8 vs 3.3 ± 0.3, p=0.03). The serum concentration of IL-10 was significantly higher in patients with an acute course of their disease, who mainly carried the GCC haplotype (92%), compared to chronic subjects, bearing the non-GCC haplotypes, and controls [17 pg/mL (1.7-18) vs 3.5 pg/mL (0.6-11) vs 3 pg/mL (1-7), p<0.01)]. Our findings show that patients carrying the GCC-high producer IL-10 haplotype have an acute development of ITP and that IL-10 levels might represent a useful predictive biomarker of the disease course.

The role of post-transplantation cyclosporine treatment in the course of cystic fibrosis pulmonary disease: a case report.

We describe the case of a 44-year-old female cystic fibrosis (CF) patient (R334W/852del22) who presented symptoms of prolonged acute respiratory infections and recurrent episodes of pneumonia. Computed tomography (CT) scan images of the chest showed that the patient presented airway and parenchymal changes throughout both lungs. She also had decreased lung function performances. In March 2004, she underwent live-related donor renal transplant and started an immunosuppressive therapy with cyclosporine. CT scan images taken respectively 2 and 6 years after transplantation documented a progressive significant size reduction of structural lung damages in both lungs and clinical signs and symptoms of improvements.

A large deletion causes apparent homozygosity for the D1152H mutation in the cystic fibrosis transmembrane regulator (CFTR) gene.

We report the case of a patient with an apparent homozygosity for the D1152H mutation located in exon 18 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The parents had no personal history of cystic fibrosis (CF) and referred to our laboratory after the diagnosis of fetal bowel hyperechogenicity. The proband presented with meconium ileus and normal sweat chloride test. Sequencing of the CFTR exon 18 together with quantitative genomic assays, such as real-time PCR and the multiplex ligation probe amplification (MLPA) techniques, were performed and revealed that the father was heterozygous for the D1152H mutation and the mother carried a large deletion of the CFTR gene encompassing the genomic sequence including the same mutation. The child inherited D1152H from his father and the large deletion of the CFTR gene from his mother. We suggest that D1152H likely acts as a mild mutation with a dominant effect on the severe deletion of exon 18, considering that after 3 years of clinical examinations the child shows no classical signs and symptoms of CF. Not testing for large deletions in subjects with apparent homozygosity for a mutated CFTR allele could lead to the misidentification of CFTR mutation carrier status.

Clinical and laboratory characteristics of children positive for antiphospholipid antibodies.

BACKGROUND: It is difficult to estimate the actual prevalence of antiphospholipid syndrome (APS) in the paediatric population since there are no standardised criteria. We aimed to assess clinical and laboratory characteristics of a cohort of children positive for antiphospholipid antibodies (aPL) to contribute to the understanding of the heterogeneous aPL-related features in childhood. MATERIALS AND METHODS: Forty-four patients with prolonged activated partial thromboplastin time were enrolled and assigned to group I ("transiently positive") or group II ("persistently positive"), based on the detection of elevated aPL plasma levels [lupus anticoagulant (LA), anticardiolipin (aCL), and anti-ß2-glycoprotein I (anti-ß2GPI) antibodies] on, respectively, one or more occasions, at least 12 weeks apart, by standard procedures. The clinical history and symptoms of all patients were recorded. RESULTS: Thirty-three (75%) patients were assigned to group I, while the other 11 (25%) formed group II. Major associated diseases in group I were urticarial vasculitis (21%), acute infections (18%) and thalassaemia (12%). Five subjects (15%) were asymptomatic. Four out of the 11 subjects (36%) in group II had thrombotic events; they were all persistently aPL-positive and two of them had concomitant systemic lupus erythematosus. The rate of detection of LA-positivity was not significantly different between the two groups (76% vs 91%, p>0.05), whereas the percentage of patients positive for overall aCL was higher in group II than in group I (54% vs 42%, respectively; p<0.05). Specifically, aCL IgG and anti-ß2GPI IgM subtypes were significantly more represented in group II than in group I (100% vs 62% and 75% vs 33%, respectively; p<0.05). DISCUSSION: Our study shows that aPL-positive children have different features that should be taken into account in the classification of criteria for paediatric APS.

Clinical significance of serum cytokine levels and thrombopoietic markers in childhood idiopathic thrombocytopenic purpura.

BACKGROUND: Biological markers useful for defining children with newly diagnosed immune thrombocytopenic purpura (ITP) who are likely to develop the chronic form of the disease are partially lacking. The purpose of this study was to assess the clinical role of both immunological and thrombopoietic markers in children with ITP and correlate their levels with different disease stages. MATERIALS AND METHODS: We enrolled 28 children with ITP at the onset of their disease, who were followed-up for a whole year and divided according to whether their disease resolved within the 12 months (n=13) or became chronic (n=15), 11 subjects with chronic ITP off therapy for at least 1 month at the time of enrolment, and 30 healthy matched controls. Serum levels of T helper type 1 and 2 and T regulatory-associated cytokines, such as interferon γ, tumour necrosis factor α, interleukin (IL) 2, IL6, IL10, and thrombopoietin were measured in all children using quantitative immunoenzymatic assays, while reticulated platelets were evaluated by flow cytometric analysis. RESULTS: Serum IL10 levels were significantly higher in patients with an acute evolution of ITP than in either healthy controls (p<0.001) or patients with chronic progression of ITP (p<0.05). Reticulated platelet count and thrombopoietin levels were significantly higher in ITP patients at the onset of their disease, whether with acute resolution or chronic progression, than in healthy subjects (p<0.01; p<0.001), but did not differ between the groups of patients. CONCLUSION: IL-10 seems to predict the clinical course of ITP, as it is significantly higher at the onset of disease in patients who obtain disease remission in less than 1 year.

Genotype-phenotype correlation in cystic fibrosis patients bearing [H939R;H949L] allele.

Cystic fibrosis (CF) is caused by CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations. We ascertained five patients with a novel complex CFTR allele, with two mutations, H939R and H949L, inherited in cis in the same exon of CFTR gene, and one different mutation per patient inherited in trans in a wide population of 289 Caucasian CF subjects from South Italy. The genotype-phenotype relationship in patients bearing this complex allele was investigated. The two associated mutations were related to classical severe CF phenotypes.

Asthma and endocrine disorders: shared mechanisms and genetic pleiotropy.

Asthma is a common inflammatory disease for which the cause is not yet known. Studies of the epidemiology and natural history of childhood asthma into adulthood demonstrate a change in gender prevalence with age. Hormones and inflammation may interact in asthma pathogenesis and determine its course. The same may be true for some endocrine disorders, including diabetes and obesity. Obesity plays a major role in the development of the metabolic syndrome and has been identified as an important risk factor for chronic diseases such as type 2 diabetes mellitus. The prevalence of asthma has paralleled the rise in obesity, suggesting that shared environmental factors could affect both conditions. In addition, endocrine diseases and asthma may share common genetic determinants. In the first part of this review we assess endocrine influences on asthma and overlaps between endocrine disorders and asthma while in the second part we explore the potential benefit of comparative genetic analyses between asthma and endocrine diseases.

Genotype-phenotype correlation in cystic fibrosis patients bearing [H939R; H949L] allele

Cystic fibrosis (CF) is caused by CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations. We ascertained five patients with a novel complex CFTR allele, with two mutations, H939R and H949L, inherited in cis in the same exon of CFTR gene, and one different mutation per patient inherited in trans in a wide population of 289 Caucasian CF subjects from South Italy. The genotype-phenotype relationship in patients bearing this complex allele was investigated. The two associated mutations were related to classical severe CF phenotypes.

Lactobacillus reuteri modulates cytokines production in exhaled breath condensate of children with atopic dermatitis.

We measured the concentration of interferon-gamma and interleukin-4 in the exhaled breath condensate of children with atopic and nonallergic dermatitis receiving a probiotic supplementation (Lactobacillus reuteri ATCC 55730) or placebo for 8 weeks. We demonstrated that the levels of these cytokines increased and decreased respectively only in atopic subjects receiving active treatment. Our data suggest that the oral administration of a specific probiotic strain in patients with atopic dermatitis can modulate in vivo the cytokine pattern at a different site from intestine.

Sleep-disordered breathing in obese children: the southern Italy experience.

BACKGROUND: The association of obesity with sleep-associated respiratory disturbances, which has traditionally been described as a problem in adults, actually originates in childhood. We sought an association between sleep-disordered breathing (SDB) and overweight and/or obesity in a large cohort of school- and preschool-aged children in Southern Italy. METHODS: One thousand two hundred seven children (612 girls and 595 boys; mean age 7.3 years) were screened by self-administered questionnaires. According to answers, subjects were divided into three groups: nonsnorers (NS), occasional snorers (OS), and habitual snorers (HS). All HS, who also failed an oximetry study at home, underwent polysomnographic monitoring for the definition of SDB. BMI was calculated according to Italian growth charts. RESULTS: A total of 809 subjects (67.0%) were eligible for the study. Of them, 44 subjects (5.4%) were classified as HS, 138 (17.0%) as OS, and 627 (77.5%) as NS. Fourteen subjects (1.7%) were given a diagnosis of obstructive sleep apnea syndrome (OSAS). Sixty-four subjects (7.9%) were defined as obese, 121 (14.9%) as overweight, and 624 (77.2%) as normal weight. The frequency of HS was significantly higher in obese subjects than in overweight and normal-weight subjects (12.5% vs 5.8% vs 4.6%, respectively; P = .02), whereas the frequency of OSAS was 1.6% in normal-weight, 1.6% in overweight, and 3.1% in obese subjects (P = not significant). CONCLUSIONS: Our findings in a large sample of Italian children suggest that obesity is associated with snoring.

Treatment of severe vernal keratoconjunctivitis with 1% topical cyclosporine in an Italian cohort of 197 children.

The purpose of our study was to verify the efficacy of prolonged cycles of 1% topical cyclosporine in improving severe form of vernal keratoconjunctivitis (VKC) in childhood and investigate for factors affecting the response to therapy. We conducted an open trial involving 197 children with severe VKC, who received topical cyclosporine 1% for 4 months. Ocular subjective symptoms (SS) and objective signs (OS) were scored in all children at entry, 2 wks and 4 months. Skin prick tests and microscope endothelial cells evaluation were also performed; serum immunoglobulin E and cyclosporine levels were assessed. The mean score values for severity of SS and OS were significantly decreased after 2 wks and 4 months, compared with those at entry (p < 0.001) in all children. Cyclosporine serum levels were neither detectable at the end of therapy, nor were endothelial corneal cells damaged. Patients who started the therapy at the beginning of the disease and/or received long-term regimen of treatment with cyclosporine had a faster improvement of ocular signs and symptoms, compared with all other patients. Our findings suggest that 1% cyclosporine concentration administrated topically at the beginning of the disease and for a long-term period might be the most effective treatment to control symptoms and local inflammation in severe forms of VKC in childhood.

Association between DEFB1 gene haplotype and herpes viruses seroprevalence in children with acute lymphoblastic leukemia.

Recent studies investigated the role of an unusual immune response to infective agents in the etiology of acute lymphoblastic leukemia (ALL) in children. Human beta-defensin-1 (hBD-1) is an anti-microbial peptide of the innate immune system, which exerts a killing role against pathogens. In the present study, three polymorphisms have been genotyped, namely, -52G/A, -44C/G and -20G/A, of DEFB1 gene, coding for hBD-1, in 40 ALL patients and 40 healthy children, and tested for an association between genetic variants of the protein and seroprevalence of antibodies for herpes viruses. The seroprevalence of cytomegalovirus (CMV), herpes simplex viruses (HSV) and Epstein-Barr virus (EBV) IgG antibodies in leukemic children was higher than that in controls (CMV: 61.5 vs. 27.3%, p = .008; HSV: 50 vs. 24.2%, p = .04; EBV: 61.3 vs. 46.2%, p = ns, respectively). Carriers of the GCA haplotype were found to have a significantly higher rate of immunization against CMV and HSV in ALL children compared to controls (CMV: 68 vs. 29%, p = .006; HSV: 56 vs. 26%, p = .04, respectively). No such observation was made when we analyzed the immunization against Epstein-Barr virus (EBV) by GCA haplotype in case and controls (58 vs. 40%, p = ns). These findings suggest that leukemic patients carrying untranslated variants of hBD-1 display a higher susceptibility to herpes viruses infections than controls.

Adequacy and tolerance to ass's milk in an Italian cohort of children with cow's milk allergy.

BACKGROUND: The therapy for cow's milk proteins allergy (CMPA) consists in eliminating cow's milk proteins (CMP) from the child's diet. Ass's milk (AM) has been recently considered as substitute of CMP. This prospective study investigated tolerance and nutritional adequacy of AM in children with CMPA from Southern Italy. METHODS: Thirty children (aged 6 months to 11 years) with suspected CMPA were enrolled. They underwent skin prick tests and bouble-blind, placebo controlled food challenge to CMP. After confirming the diagnosis of CMPA, patients received fresh AM in a open challenge. Specific serum CMP and AM IgE, and biochemical parameters in blood were also assessed. Auxological evaluations were performed in all subjects at entry (T0) and after 4-6 months (T1) of AM intake. RESULTS: Twenty-five children resulted elegible for the study, and 24 out of 25 subjects (96%) tolerated AM at the food challenge. Auxological data resulted improved by the end of the study in all patients, while blood biochemical parameters did not vary during the follow-up. CONCLUSION: Our data confirm the high rate of AM tolerability in children with moderate symptoms of CMPA. Moreover, we found that AM seems to have nutritional adequacy in subjects with a varied diet.

Exhaled breath condensate cytokines and pH in pediatric asthma and atopic dermatitis.

Some studies have proposed exhaled breath condensate (EBC) as a noninvasive tool for monitoring airway inflammation in children. Moreover, atopic dermatitis (AD) has been considered a risk factor for the development of asthma. This study was designed to assess the EBC pH and the exhaled concentration of cytokines produced by T-helper (Th) 1, Th2, and T regulatory cells in asthmatic children and AD and to verify if their concentrations are affected by a short course of treatment with inhaled corticosteroids (ICS). We assessed the mean levels of pH, interferon (IFN) gamma, interleukin (IL)-4, and IL-10 in EBC of children with asthma (n=20) and AD (n=12) and healthy controls (n=20) by enzyme-linked immunosorbent assay (ELISA). Variations of pH and cytokine concentration in response to ICS (flunisolide, 500 microg/day, for 2 weeks), were also investigated in asthmatic patients. We found that the mean condensate pH value in patients with asthma and AD was significantly lower when compared with that of controls (6.9+/-0.2 and 7.0+/-0.2 versus 7.4+/-0.4; p<0.0001) and it significantly increased in asthmatic patients after treatment (7.2+/-0.2 versus 6.9+/-0.2; p=0.003). In addition, the IL-4/IFN-gamma ratio was significantly higher in children with asthma and in those with AD when compared with controls (9.72+/-2.00 and 9.70+/-2.0 versus 8.04+/-2.6; p<0.001) and that it decreased in asthmatic patients after ICS (6.4+/-5.4 versus 9.72+/-2.00; p<0.01). We observed that exhaled IL-10 levels were significantly higher in children with asthma compared with those of controls (18.8+/-8.9 versus 4.2+/-1.0; p<0.002). IL-10 did not significantly increase after treatment with steroids. No such finding was documented in children with AD. Our data suggest that EBC IL-10 levels are different in asthmatic patients compared with healthy children, but they are insensitive markers in monitoring therapy with ICS. Moreover, children with AD show an EBC pH and an exhaled pattern of Th2/Th1 cytokines similar to that of asthmatic patients.