Pulmonary Outcomes in Children Born Extremely and Very Preterm at 11 Years of Age.

Background: There is increasing evidence of prematurity being a risk factor for long-term respiratory outcomes regardless the presence of bronchopulmonary dysplasia (BPD). Aim: To assess the effect of prematurity on respiratory outcomes in children born ≤32 weeks of gestational age at 11 years of age. Materials and Methods: Fifty five ex-preterm children (≤ 32 weeks of gestational age), born in Chieti between January 1, 2006 and December 31, 2007, performed lung function and diffusing capacity test (DLCO) at 11 years of age. Furthermore, allergy evaluation by skin prick test (SPT), eosinophil blood count and assessment of eosinophilic airways inflammation by exhaled nitric oxide (FeNO) were performed. The ex-preterm group was compared to an age- and sex-matched group of term children. Results: No difference for atopic and respiratory medical history was found between ex-preterm children and term controls, except for preschool wheezing that resulted more frequent in ex-preterm children. No difference neither in school-aged asthma frequency nor in lung function assessment at 11 years of age was found between the two groups. Lower DLCO values in ex-preterm children compared to term controls regardless the presence of BPD were found; furthermore, we showed a positive association between DLCO and gestational age. Eosinophil blood count, positive SPTs and FeNO values were similar between the two groups. Conclusions: Diffusing lung capacity was decreased in ex-preterm children at 11 years of age in the absence of lung function impairment and eosinophil airway inflammation, suggesting a non-eosinophilic pattern underlying pulmonary alterations. It could be desirable to include the diffusing capacity assessment in follow-up evaluation of all ex-preterm children.

Role of THRB, ARG1, and ADRB2 Genetic Variants on Bronchodilators Response in Asthmatic Children.

Background: An interindividual variability in response to short-acting bronchodilator drugs (short-acting inhaled ß2-agonists, SABA) exists and this is linked in part to genetic factors. The aim of this study was to verify the influence of single nucleotide polymorphisms (SNPs) of a previously studied gene (ADRB2) and of new candidate genes (THRB and ARG1) on the acute response to SABA in children with asthma. Methods: One hundred asthmatic children (mean age 9.6 ± 3.0 years, 77 boys) underwent allergological and lung function evaluations. Spirometry was performed before and after bronchodilation test (BD test). The ADRB2 region containing the Arg16Gly (rs1042713) and Gln27Glu (rs1042714) variants were amplified by polymerase chain reaction, whereas ARG1 rs2781659 (A>G) and THRB rs892940 (G>A) SNPs were genotyped by high-resolution melting (HRM) analysis. Results: Seventy-seven percent of children developed asthma in the first 6 years of life. Allergic sensitization was observed in 92% (total immunoglobulin G: 529.8 ± 477. kU/L). All patients exhibited respiratory allergy: 43% has multiple respiratory, 22% to single respiratory, and 27% multiple respiratory and food allergies. Fifty four percent children showed positive BD response (forced expiratory volume in 1 second [FEV1] > 12%). Presence of Arg/Gly or Gly/Gly genotypes in position 16 of ADRB2 was significantly associated to a worse BD response (post-BD FEV1: 108.68% ± 15.62% in Arg/Arg vs. 101.86% ± 14.03% in Arg/Gly or Gly/Gly patients, p = 0.02). No significant association was found between spirometric parameters before and after BD for the other three examined SNPs. Conclusion: The influence of genetic variability on responsiveness to drugs could become a key parameter to optimize a tailored therapy for young patients with asthma, especially if drug-resistance occurs.

An underestimated cause of chronic cough: The Protracted Bacterial Bronchitis.

Chronic cough in childhood is associated with a high morbidity and decreased quality of life. Protracted bacterial bronchitis (PBB) seems to be the second most common cause of chronic cough in children under 6 years of age. Its main clinical feature is represented by wet cough that worsens when changing posture and improves after the introduction of antibiotics. Currently, the mainstay of PBB treatment is a 2-week therapy with a high dose of antibiotics, such as co-amoxiclav, to eradicate the infection and restore epithelial integrity. It is very important to contemplate this disease in a child with chronic cough since the misdiagnosis of PBB could lead to complications such as bronchiectasis. Clinicians, however, often do not consider this disease in the differential diagnosis and, consequently, they are inclined to change the antibiotic therapy rather than to extend it or to add steroids. Data sources of this review include PubMed up to December 2016, using the search terms "child," "chronic cough," and "protracted bacterial bronchitis."

Usefulness of molecular diagnosis in egg allergic children.

INTRODUCTION: Egg allergy is one of the most common food allergies in children. Egg white, including ovomucoid (OVM or Gal d 1) and ovalbumin (OVA or Gal d 2), is the major source of allergens. The aim of this study was to assess the role of Gal d 1 and Gal d 2 in predicting the risk of anaphylaxis caused by eggs in children, and to compare this new diagnostic tool with established methods of allergen-specific IgE detection. MATERIAL AND METHODS: One hundred and forty-eight children were divided into 2 groups according to a positive (group A, 33 children) or negative (group B, 115 children) history of anaphylaxis after ingestion/contact with eggs. All patients underwent an allergological evaluation by measurements of specific IgE against egg white: Gal d 1 and Gal d 2. RESULTS: Higher levels of Gal d 1, Gal d 2 and IgE against egg white were detected in group A compared to group B (p < 0.001). Although the area under the curve was similar for Gal d 1 and Gal d 2, egg white specific IgE showed a better sensitivity (85%) for a cut-off value ≥ 0.975 kUA/l, while Gal d 1 and Gal d 2 demonstrated a better specificity (90% and 80%, respectively) for cut-off values ≥ 1.460 kUA/l and ≥ 2.310 kUA/l, respectively. CONCLUSIONS: Egg white specific IgE showed a similar ability as Gal d 1 and Gal d 2 in differentiating children at risk for egg anaphylaxis, although Gal d 1 and Gal d 2 showed a better specificity.

Insulin resistance and lung function in obese asthmatic pre-pubertal children.

BACKGROUND: Recent findings have supposed that the underlying association between the increased prevalence of both asthma and obesity may be insulin resistance (IR). METHODS: Insulin and glucose serum levels were analyzed to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) for IR in 98 pre-pubertal children. Lung function and allergy status evaluation were performed. The study population was divided into four groups: (1) obese asthmatic children (ObA); (2) normal-weight asthmatic children (NwA); (3) normal-weight non-asthmatic children (Nw) and (4) obese non-asthmatic children (Ob). RESULTS: Forced expiratory volume in 1 s (FEV1) was slightly lower in obese subjects compared with normal-weight subjects and forced vital capacity (FVC) appeared lower in asthmatics, whereas between non-asthmatics subjects, it was lower in the obese group than in the normal-weight one. The post hoc analysis revealed a statistically significant reduction in FEV1, peak expiratory flow (PEF), forced expiratory flows (FEF) between 50% and 25% of the FVC (FEF50 and FEF25) between ObA and Nw and in FEV1, FVC, PEF, FEF50 and FEF25 between NwA and Nw, but no statistically significant differences of lung function parameters were observed between ObA and NwA. We found an inverse relationship between HOMA-IR and all spirometric parameters, although without any statistical significance. We also observed a significantly lower FVC in insulin-resistant children (HOMA-IR>95th percentile) (p=0.03). CONCLUSIONS: This study suggests that lung function could be early altered in obese children, already in pre-pubertal age. Although IR should not manifest its effects on lungs in pre-pubertal obese children, the prevention or treatment of obesity in the pre-pubertal period may prevent definitive negative effects on lungs.

Potential Teratogenic Effects of Clomiphene Citrate.

Clomiphene citrate (CC) is the oldest drug used to regulate the process of ovulation. Considering the great use of CC over the last 40 years, it is important to understand the possible risks associated with its use. The aim of this review was to evaluate the possible teratogenic effects of CC, analyzing results obtained from animal and human studies. The pharmacokinetics of CC and possible mechanisms involved in teratogenesis are examined. Fetal exposure to CC is possible due to the long half-life of CC and its metabolites. Alarming data have emerged from animal studies, although controversial results come from human studies. There is some evidence regarding a possible association of CC exposure and fetal malformations, mainly neural tube defects and hypospadias, which would require further investigation in order to allow safer use of this useful drug.

Bronchial hyperresponsiveness to mannitol, airway inflammation and Asthma Control Test in atopic asthmatic children.

INTRODUCTION: The aim of this study was to evaluate the relationship between airway hyperresponsiveness (AHR) to mannitol and bronchial inflammation measured as exhaled nitric oxide (FeNO) and to assess whether asthma control correlates with AHR to mannitol and FeNO in atopic asthmatic children. MATERIAL AND METHODS: Allergy evaluation, the mannitol challenge test, FeNO levels and the Asthma Control Test (ACT) questionnaire were assessed in 40 children with intermittent and mild persistent allergic asthma. RESULTS: All the subjects showed positive AHR to mannitol. Pearson's correlation test revealed a significant inverse correlation between AHR (mannitol PD15) and FeNO (p = 0.020). There was also a significant positive correlation between ACT and PD15 (p = 0.020) and a significant negative correlation between ACT and FeNO levels (p = 0.003). The study population was divided into two groups according to FeNO levels (group A ≥ 16 ppb vs. group B < 16 ppb). In group A mannitol PD15 was significantly lower (p = 0.040) and ACT score values were significantly lower (p = 0.001) compared to group B. In group A, the ACT showed that 13.3% of subjects had well-controlled asthma, 80% had partially controlled asthma and 6.7% had uncontrolled asthma. In group B, the ACT showed that 72% of subjects had well-controlled asthma and 28% had partially controlled asthma. CONCLUSIONS: Our findings indicate that the degree of AHR to mannitol correlates with the degree of airway inflammation in asthmatic atopic children; moreover, better control of asthma correlates with a lower degree of AHR to both mannitol and FeNO.

Critical appraisal of Timothy grass pollen extract GRAZAX in the management of allergic rhinitis.

Allergic rhinitis is one of the most common diseases of adult and pediatric age, associated with grass pollen (GP) allergy in >50% cases, with a consistent impact on quality of life of affected patients. A grass allergen tablet, containing standardized extract derived from Timothy grass (Phleum pratense) pollen and ~15 µg major allergen P. pratense (rPhl p 5), may be the future of allergen-specific immunotherapy (IT) for GP allergy. The aim of this review was to critically evaluate the role of Timothy GP extract IT for the management of allergic rhinitis. For this purpose, we have tried to analyze potential mechanisms of action at the basis of Timothy GP extract, we have reviewed efficacy studies to establish potential benefits and clinical response, and we have also evaluated safety and tolerability profiles and patient focus perspective, such as quality of life, satisfaction and acceptability, and compliance to this IT.

Vitamin D supplementation modulates the immune system and improves atopic dermatitis in children.

BACKGROUND: Vitamin D seems to influence the evolution of atopic dermatitis (AD) in children. METHODS: We tested the vitamin D serum levels of 39 children with AD (AD group t0) and of 20 nonallergic healthy controls (C group). AD severity was evaluated using the AD scoring system (SCORAD index). Cytokine serum levels (IL-2, IL-4, IL-6, IFN-γ, TNF-α) and atopy biomarkers were also measured. The patients were then treated with vitamin D oral supplementation of 1,000 IU/day (25 mg/day) for 3 months. We then reevaluated the vitamin D serum levels, AD severity and cytokine serum levels in all of the treated children (AD group t1). RESULTS: The cross-sectional analysis on patients affected by AD (AD group t0) showed that the initial levels of all the tested cytokines except for TNF-α were higher than those of the healthy control group (C group), falling outside the normal range. After 3 months of supplementation the patients had significantly increased vitamin D levels (from 22.97 ± 8.03 to 29.41 ± 10.73 ng/ml; p = 0.01). A concomitant significant reduction of both the SCORAD index (46.13 ± 15.68 at the first visit vs. 22.57 ± 15.28 at the second visit; p < 0.001) and of all the altered cytokines (IL-2, IL-4, IL-6, IFN-γ) was also found. CONCLUSIONS: This study showed vitamin D supplementation to be an effective treatment in reducing AD severity in children through normalization of the Th1 and Th2 interleukin serum pattern.

Mycoplasma pneumoniae infection with rhabdomyolysis in a child.

We report the history of a seven year-old male boy with cough and fever, who developed rhabdomyolysis concomitant with Mycoplasma pneumoniae infection. The association between this organism and the muscular injury is rarely described in paediatric patients. This case then thus emphasizes that even seemingly mild M. pneumoniae airway infections may be complicated by invalidating neuromuscular sequelae.

Usefulness of nBos d 4, 5 and nBos d 8 Specific IgE Antibodies in Cow's Milk Allergic Children.

PURPOSE: The aim of study was to assess the value of recombinants in predicting the degree of symptoms in children with and without anaphylaxis to cow's milk. METHODS: The study included 79 children (70±40 months) referred to the Allergological Unit of the Pediatric Department between the years 2008-2012. Group A was composed of 17 children (78±49.6 months) with anaphylaxis after ingestion of milk. Group B was composed of 62 children (73.1±38.6 months) without a history of anaphylaxis, but with less severe symptoms (gastrointestinal and/or skin symptoms). All patients from Group B had a positive open challenge with cow's milk. All patients underwent an allergic evaluation and blood samples were collected to test for IgE to recombinans of milk (nBos d 4, 5, 8). RESULTS: A significant difference in nBos d 8 emerged with higher levels in Group A (median [IQR]=2.80 [0.91-16.1]) than B (0.65 [0.24-1.67]; P=0.006), whereas there were no statistically significant differences for nBos d 4 and 5. The recombinants' sum was higher in Group A than B: 8.39 [2.72-41.39] vs 3.04 [1.85-7.31] kUA/L; P=0.044. The recombinant nBos d 8 was superior to the other recombinants in identifying children at risk for anaphylaxis, with an area under the curve of 0.718 (95% CI, 0.57-0.86, P=0.006). Considering a cutoff of 1.8 kUA/L, nBos d 8 had the most favorable sensitivity and specificity ratio (sensitivity=0.65, specificity=0.77) with an odd ratio of 6.02 (95% C.I: 1.89-19.23). CONCLUSIONS: This study suggested 2 phenotypes of allergic children, "high-anaphylaxis-risk" and "milder-risk". These types can be differentiated through measuring the level of IgE to nBos d 8.

Evaluation of association between airway hyperresponsiveness, asthma control test, and asthma therapy assessment questionnaire in asthmatic children.

BACKGROUND: Achieving asthma control is a major challenge in children, otherwise symptoms perception remain poor especially at this age. The aim of this study is to evaluate the relationship between Asthma Control Test (ACTTM), Asthma Therapy Assessment Questionnaire (ATAQTM) and exercise-induced bronchospasm (EIB). METHODS: We studied 80 asthmatic children. Airways hyperresponsiveness (AHR) was assessed by exercise-induced bronchospasm (Balke Protocol). Asthma control was evaluated using two questionnaires in all subjects: ACT (composed by Childhood-ACT and ACT) and ATAQ. In addition the use of short acting beta 2 agonist agents (SABAs) was assessed for each patient. Non-parametric variables were compared by Chi Square Test. Binomial logistic regression was performed to estimate the two questionnaires Odds Ratio (OR) in finding AHR. RESULTS: We have found that ATAQ has a sensitivity and a specificity of 0.72 and 0.45 respectively; instead, ACT has a sensitivity and a specificity of 0.5 and 0.39 respectively in evaluating AHR. Patients with uncontrolled asthma according to ATAQ revealed a significant higher percentage of AHR compared with ACT (72% vs 50%, p < 0.01).Confirming this finding, patients declaring uncontrolled asthma to ATAQ have a significantly higher percentage (34%) of frequent SABAs use than the group with uncontrolled asthma to ACT (21%) (p <0.01).Binomial logistic regression shows how a test revealing uncontrolled asthma is associated with the increasing odds of having AHR according to ATAQ (OR = 3.8, p = 0.05), not to ACT (OR = 0.2, p = 0.1). CONCLUSIONS: Our results show that ATAQ reflects AHR and asthma control better than ACT. Children with uncontrolled asthma according to ATAQ have higher odds of having AHR and use of rescue medications (SABAs) compared to patients declaring uncontrolled asthma according to ACT. However both questionnaires are not sufficient alone to fully evaluate asthma control in children and it is always necessary to perform functional tests and investigate patients lifestyle, drug use and other important data that a simple questionnaire is not able to point out.

Sensitization to timothy grass pollen allergenic molecules in children.

BACKGROUND: Grass pollens are significant elicitors of IgE-mediated allergic disease in the world and timothy (Phleum pratense) is one of the most important pollens of the family. Molecular and biochemical characterization of Phleum pratense has revealed several allergen components: rPhl p 1 and rPhl p 5 have been shown to be "Species Specific Allergens", while the profilin rPhl p 12 and the calcium-binding protein rPhl p 7 are the principal Cross-Reactive components. METHODS: In this study the pattern of sensitization to rPhl p 1, rPhl p 5, rPhl p 7 and rPhl p 12 was analyzed in children with asthma and/or rhinoconjunctivitis and grass pollen allergy, in order to evaluate the frequency of sensitization to allergenic molecules of Phleum pratense among pediatric subjects allergic to grass pollen in a Mediterranean population. The correlation of sensitization to these Phleum allergenic molecules with IgE against grass pollen extract and its variation according to age and level of IgE against grass pollen extract were evaluated. RESULTS: IgE against to rPhl p 1 were found in 99% (205/207) of patients, to rPhl p 5 in 67% (139/207), to rPhl p 12 in 32% (66/207) and to rPhl p 7 only in 5% (10/207).Sensitization only to "Species Specific" (rPhl p1, rPhl p5) allergenic molecules of Phleum pratense was detected in 65% (135/207) of children. Our data show the predominant role of rPhl p 1 in pediatric populations as the most relevant sensitizing allergen detectable at all ages and at all levels of timothy grass pollen-specific IgE antibodies, while the importance of rPhl p 5 rises with the increase of patients' age and with grass pollen IgE levels. CONCLUSIONS: The assessment of sensitization to grass pollen allergenic molecules could help develop a better characterization of allergic sensitization in grass pollen allergy in children, which may be different in every patient. It could also enable clinicians to give more specific and effective immunotherapy, based on allergenic molecule sensitization.

Montelukast versus inhaled corticosteroids in the management of pediatric mild persistent asthma.

International guidelines recommend the use of inhaled corticosteroids (ICSs) as the preferred therapy, with leukotriene receptor antagonists (LTRAs) as an alternative, for the management of persistent asthma in children. Montelukast (MLK) is the first LTRA approved by the Food and Drug Administration for the use in young asthmatic children.Therefore, we performed an analysis of studies that compared the efficacy of MLK versus ICSs. We considered eligible for the inclusion randomized, controlled trials on pediatric populations with Jadad score > 3, with at least 4 weeks of treatment with MLK compared with ICS.Although it is important to recognize that ICSs use is currently the recommended first-line treatment for asthmatic children, MLK can have consistent benefits in controlling asthmatic symptoms and may be an alternative in children unable to use ICSs or suffering from poor growth. On the contrary, low pulmonary function and/or high allergic inflammatory markers require the corticosteroid use.

Seizures and type 1 diabetes mellitus: current state of knowledge.

In this review, we will try to analyze the possible coexistence between epilepsy or seizures and type 1 diabetes mellitus (T1DM), in order to establish if there is more than a casual association, and to investigate possible mechanisms underlying this link. Anti-glutamic acid decarboxylase antibodies (GAD-Abs) have been associated with T1DM and a great number of neurological diseases such as epilepsy. Epilepsy can be a feature of a large variety of autoimmune or inflammatory disorders. GAD-Abs can have a role at the basis of the possible link between epilepsy and T1DM, although their real pathogenetic mechanism in neurological diseases is still unknown. Metabolic conditions such as hypoglycemia and hyperglycemia, common problems in diabetic patients, may be also implicated, even if their underlying mechanism is minimally understood.

Growth failure in children with cystic fibrosis.

Poor linear growth and inadequate weight gain are very common problems in cystic fibrosis (CF) children. The most important factors involved in growth failure are undernutrition or malnutrition, chronic inflammation, lung disease, and corticosteroid treatment. Nutritional support and pharmacological therapy with recombinant human growth hormone are essential for a good management of children with CF, although these children are shorter and lighter than healthy children, and despite the catch-up growth observed after diagnosis, deficit in length/height and weight continues to be seen until adulthood. Early diagnosis is essential to ensure better nutritional status and growth, potentially associated with better respiratory function and prognosis. The aims of this review are try to explain etiology and pathogenetic mechanisms of growth failure in CF children and clarify their role in the disease morbidity and in clinical outcome, especially in relation to progressive decline of pulmonary function.

Relationship between exercise-induced bronchospasm (EIB) and asthma control test (ACT) in asthmatic children.

OBJECTIVE: Evaluate the relationship between Asthma Control Test™ (ACT) and exercise-induced bronchospasm (EIB) in 81 asthmatic children. METHODS: EIB was assessed in every patient by Balke protocol and asthma control was evaluated by ACT. Patients were divided into three groups: Group A (30 patients) with complete asthma control (ACT score = 25), Group B (37 patients) with partial asthma control (ACT score = 21-24), and Group C (14 patients) with poor asthma control (ACT score < 20). RESULTS: About 36% (11/30) of patients in Group A (with complete asthma control) tested positive for EIB, whereas 21% (8/37) in Group B (with partial asthma control) and 28% (4/14) in Group C (with poor asthma control) exhibited EIB. The percentage of positive EIB was very similar between the three groups with no differences between controlled, partially controlled, and uncontrolled asthma. Statistical evaluation by χ(2)-test between complete (ACT score = 25) and not complete asthma control (ACT score < 24) confirmed a statistically significant difference (p < .01) between the obtained data. CONCLUSIONS: It must be stated that ACT alone is not sufficient to evaluate asthma control in children correctly because it fails to detect EIB in a significant percentage of subjects.

Topiramate-induced weight loss: a review.

BACKGROUND: Weight loss can occur during topiramate (TPM) treatment and it should be evaluated by clinicians, especially in children, whose growth could be compromised. In international literature, the reported body weight loss incidences linked to TPM therapy vary widely and, in some cases, are very conflicting. AIMS: The aims of this review are to quantify TPM-induced weight loss, analyze the pathogenetic mechanisms and evaluate its clinical implications in patients with epilepsy. RESULTS: The amount of weight loss appears to be related to some factors such as the duration of the treatment and a high baseline body mass index (BMI), while the role of daily dosage and gender of patients is controversial. The mechanism through which TPM may induce weight loss is still unclear. INTERPRETATION: TPM is able to induce weight loss, especially in high baseline BMI patients, not strictly depending on daily dosage and perhaps not influenced by gender. This makes TPM a good choice, especially in obese patients suffering from seizures. However, TPM can make nutritionally vulnerable children or adult patients, with epilepsy associated with other neuropsychiatric diseases, who cannot voluntarily increase their caloric intake.