Maintenance Therapy for Children and Adolescents with Asthma: Guidelines and Recommendations from the Emilia-Romagna Asthma (ERA) Study Group.

Asthma is the most frequent chronic disease of childhood, affecting up to 20% of children worldwide. The main guidelines on asthma maintenance therapy in pediatrics suggest different approaches and describe different stages of asthma to determine the most appropriate treatment. This project aims to summarize the most recent evidence regarding maintenance therapy for asthma in children and adolescents. A multidisciplinary panel of experts was asked clinical questions regarding the treatment of children and adolescents with asthma. Overall, 10 clinical questions were addressed, and the search strategy included accessing electronic databases and a manual search of gray literature published in the last 25 years. After data extraction and narrative synthesis of results, recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology. Results showed that the choice of medication depends on the severity of the child's asthma, phenotype, age, preference, and individual factors. In addition to medications, the identification of comorbidities and modifiable factors is crucial to obtaining good control. Asthma in children is heterogeneous, and its evolution varies over time. Since most recommendations for asthma management in childhood are extrapolated from clinical studies performed in adults, more clinical trials specifically designed for young children should be conducted.

Risk Factors Affecting Development and Persistence of Preschool Wheezing: Consensus Document of the Emilia-Romagna Asthma (ERA) Study Group.

Wheezing at preschool age (i.e., before the age of six) is common, occurring in about 30% of children before the age of three. In terms of health care burden, preschool children with wheeze show double the rate of access to the emergency department and five times the rate of hospital admissions compared with school-age asthmatics. The consensus document aims to analyse the underlying mechanisms involved in the pathogenesis of preschool wheezing and define the risk factors (i.e., allergy, atopy, infection, bronchiolitis, genetics, indoor and outdoor pollution, tobacco smoke exposure, obesity, prematurity) and the protective factors (i.e., probiotics, breastfeeding, vitamin D, influenza vaccination, non-specific immunomodulators) associated with the development of the disease in the young child. A multidisciplinary panel of experts from the Emilia-Romagna Region, Italy, addressed twelve key questions regarding managing preschool wheezing. Clinical questions have been formulated by the expert panel using the PICO format (Patients, Intervention, Comparison, Outcomes). Systematic reviews have been conducted on PubMed to answer these specific questions and formulate recommendations. The GRADE approach has been used for each selected paper to assess the quality of the evidence and the degree of recommendations. Based on a panel of experts and extensive updated literature, this consensus document provides insight into the pathogenesis, risk and protective factors associated with the development and persistence of preschool wheezing. Undoubtedly, more research is needed to improve our understanding of the disease and confirm the associations between certain factors and the risk of wheezing in early life. In addition, preventive strategies must be promoted to avoid children's exposure to risk factors that may permanently affect respiratory health.

Management of Preschool Wheezing: Guideline from the Emilia-Romagna Asthma (ERA) Study Group.

Preschool wheezing should be considered an umbrella term for distinctive diseases with different observable and measurable phenotypes. Despite many efforts, there is a large gap in knowledge regarding management of preschool wheezing. In order to fill this lack of knowledge, the aim of these guidelines was to define management of wheezing disorders in preschool children (aged up to 5 years). A multidisciplinary panel of experts of the Emilia-Romagna Region, Italy, addressed twelve different key questions regarding the management of preschool wheezing. Clinical questions have been formulated by the expert panel using the PICO format (Patients, Intervention, Comparison, Outcomes) and systematic reviews have been conducted on PubMed to answer these specific questions, with the aim of formulating recommendations. The GRADE approach has been used for each selected paper, to assess the quality of the evidence and the degree of recommendations. These guidelines represent, in our opinion, the most complete and up-to-date collection of recommendations on preschool wheezing to guide pediatricians in the management of their patients, standardizing approaches. Undoubtedly, more research is needed to find objective biomarkers and understand underlying mechanisms to assess phenotype and endotype and to personalize targeted treatment.

C5 and SRGAP3 Polymorphisms Are Linked to Paediatric Allergic Asthma in the Italian Population.

Asthma is a complex and heterogeneous disease, caused by the interaction between genetic and environmental factors with a predominant allergic background in children. The role of specific genes in asthmatic bronchial reactivity is still not clear, probably because of the many common pathways shared with other allergic disorders. This study is focused on 11 SNPs possibly related to asthma that were previously identified in a GWAS study. The genetic variability of these SNPs has been analysed in a population of 773 Italian healthy controls, and the presence of an association between the polymorphisms and the asthma onset was evaluated performing genotyping analysis on 108 children affected with asthma compared with the controls. Moreover, a pool of 171 patients with only allergic rhinoconjunctivitis has been included in the case-control analysis. The comparison of allele frequencies in asthmatic patients versus healthy controls identified two SNPs-rs1162394 (p = 0.019) and rs25681 (p = 0.044)-associated with the asthmatic condition, which were not differentially distributed in the rhinoconjunctivitis group. The rs25681 SNP, together with three other SNPs, also resulted in not being homogenously distributed in the Italian population. The significantly higher frequency of the rs25681 and rs1162394 SNPs (located, respectively, in the C5 and SRGAP3 genes) in the asthmatic population suggests an involvement of these genes in the asthmatic context, playing a role in increasing the inflammatory condition that may influence asthma onset and clinical course.

Is there a relationship between joint hypermobility and gastrointestinal disorders in children?

BACKGROUND: The main aim of the study was to assess the association between joint hypermobility (JH) and gastrointestinal (GI) disorders in children. METHODS: All children aged 4-17 years attending the clinics of the participating Pediatric Gastroenterology Centres for functional GI disorders (FGIDs) and inflammatory bowel disease (IBD) were screened for joint laxity. JH diagnosis was inferred using the Beighton Score. JHS diagnosis was inferred based on the Brighton Criteria. Rome III Diagnostic Criteria were used to diagnose possible FGIDs. Ulcerative colitis and Crohn`s disease diagnoses were made according to the Porto Criteria. Age and sex- matched healthy children were enrolled as controls. RESULTS: One-hundred-seventy children with GI disorders (70 with FGIDs, 50 with Crohn`s disease, and 50 with ulcerative colitis) and 100 healthy controls were enrolled in the study. JH was reported in 7/70 (10%) children with FGIDs (p=0.26 compared to controls), 4/50 (8%) children with Crohn`s disease (p=0.21 compared to controls) and 15/50 (30%) children with ulcerative colitis (p=0.09 compared to controls; p=0.01 compared to FGIDs; p=0.01 compared to Crohn`s). CONCLUSIONS: JH is more prevalent in patients suffering from ulcerative colitis compared to the healthy general population, yet the difference did not reach statistical significance. Likely, a proportion of children with ulcerative colitis and JH may show connective tissue abnormalities. However, whether JH can be considered a possible feature of pediatric GI disorders deserves further investigation.

Cardiovascular issues in obstructive sleep apnoea in children: A brief review.

Obstructive sleep apnoea (OSA) is a very common disease with a prevalence that ranges from 1% to 6% in children. It is characterized by intermittent partial or complete occlusion of the upper airway during sleep, leading to recurrent arousals and disturbed sleep architecture, to neurocognitive disorders and alterations in homeostatic gas exchange. Cardiovascular complications may develop in children with OSA through various mechanisms including activation and dysregulation of the sympathetic nervous system, induction of pro-inflammatory and pro-oxidant status and increased risk of systemic hypertension. As the deleterious effects of OSA on the cardio-vascular system may start early in life, in this brief review we focused our attention both on early and late cardiological changes induced by apnoeic events in the paediatric population, by reviewing recent findings in the literature.

When the Cough Does Not Improve: A Review on Protracted Bacterial Bronchitis in Children.

Chronic cough is defined as a daily cough that persists longer than 4 weeks. Protracted bacterial bronchitis (PBB) is a common cause of chronic wet cough in preschool children with no symptoms or signs of other specific causes, and resolution usually follows a 2-week course of an appropriate oral antibiotic. The diagnosis is mainly clinical; generally, no instrumental examinations are necessary. The most common bacteria found in the bronchoalveolar lavage (BAL) of subjects with PBB include Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. Nowadays, there is no certain evidence of the role of viruses in PBB pathogenesis even though different types of viruses have been detected in BAL from children with PBB. Airway malacia is commonly found in children with PBB; conversely, there is no correlation with any type of immunodeficiency. Amoxicillin-clavulanate acid is the most commonly used antibiotic, as first-line, prolonged therapy (longer than 2 weeks) is sometimes required to cough resolution. When the wet cough does not improve despite prolonged antibiotic treatment, an underlying disease should be considered. Moreover, there are several hypotheses of a link between PBB and bronchiectasis, as recent evidences show that recurrent PBB (>3 episodes/years) and the presence of H. influenzae infection in the lower airways seem to be significant risk factors to develop bronchiectasis. This underlines the importance of a close follow-up among children with PBB and the need to consider chest computerized tomography (CT) in patients with risk factors for bronchiectasis. In this brief review, we summarize the main clinical and pathogenetic findings of PBB, a disease that may be related to a relevant morbidity and decreased quality of life during the pediatric age.

Airway Clearance Management with Vaküm Technology in Subjects with Ineffective Cough: A Pilot Study on the Efficacy, Acceptability Evaluation, and Perception in Children with Cerebral Palsy.

Background: In the medical complexity of a children with cerebral palsy, impaired airway clearance represents a major problem, leading to significative respiratory morbidity and mortality. Its management is difficult because of limited cooperation and poor tolerance to invasive treatments. Free Aspire® (FA) is a device designed to remove bronchial secretions noninvasively, without generating cough. Methods: The aim of our pilot prospective study is to assess the efficacy and acceptability of FA in removing airway obstruction in subjects with cerebral palsy and ineffective cough. We enrolled 11 subjects. At enrollment and after 3, 6, and 12 months, we collected data regarding health care resources use for respiratory exacerbations, perceived efficacy, and acceptability of treatment. Results: We observed a reduction in emergency room (ER) accesses, home pharmacological treatment, hospitalizations number, and hospital stay length. In particular after 12 months we observed a reduction of 74% in ER accesses and home pharmacological treatment, 38% in hospitalizations number, and 17% in hospital stay length for respiratory exacerbations. The 100% of caregivers considered the treatment effective and simple to use and noted an improvement in subjects' general condition. They also reported good treatment tolerance of subjects, with an overall good compliance. Conclusion: The study demonstrates that FA is an effective device for the removal of bronchial secretions, with a positive caregivers' perception, that favored a good long-term compliance.

Asthma and Food Allergy: Which Risks?

Over the past few decades, an increase in the prevalence of asthma and food allergy has been observed in the pediatric population. In infants, food sensitization, particularly to egg, has increased the risk of developing allergic asthma. This is even more likely if sensitization to food allergens occurs early within the first few years of life. It is indeed known that both diseases may be present simultaneously in the pediatric population, but coexistence may negatively influence the severity of both conditions by increasing the risk of life-threatening asthmatic episodes as well as food-related anaphylaxis. Therefore, an accurate clinical and phenotype characterization of this high-risk group of children with both asthma and food allergy and a more aggressive management might lead to reducing related morbidity and mortality. The aim of this review is to provide an updated overview on the close link between food allergy and asthma and their negative mutual influence.

A pediatric disease to keep in mind: diagnostic tools and management of bronchiectasis in pediatric age.

Bronchiectasis in pediatric age is a heterogeneous disease associated with significant morbidity.The most common medical conditions leading to bronchial damage are previous pneumonia and recurrent lower airway infections followed by underlying diseases such as immune-deficiencies, congenital airway defects, recurrent aspirations and mucociliary clearance disorders.The most frequent symptom is chronic wet cough. The introduction of high-resolution computed tomography (HRCT) has improved the time of diagnosis allowing earlier treatment.However, the term "bronchiectasis" in pediatric age should be used with caution, since some lesions highlighted with HRCT may improve or regress. The use of chest magnetic resonance imaging (MRI) as a radiation-free technique for the assessment and follow-up of lung abnormalities in non-Cystic Fibrosis chronic lung disease is promising.Non-Cystic Fibrosis Bronchiectasis management needs a multi-disciplinary team. Antibiotics and airway clearance techniques (ACT) represent the pillars of treatment even though guidelines in children are lacking. The Azithromycin thanks to its antinflammatory and direct antimicrobial effect could be a new strategy to prevent exacerbations.

Free-Aspire: A new device for the management of airways clearance in patient with ineffective cough.

A 3-year-old girl with Spinal Muscular Atrophy type I presented with a right pneumonia. On physical examination pulmonary auscultation revealed an asymmetry of breath sounds between the 2 hemithoraces, owing to decreased breath sounds in the right hemithorax. Blood tests were normal. The initial working diagnosis was a suspected area of mucus accumulation. A treatment with Free Aspire was started. Within a few days, the girl was discharged with a normal physical examination and X-ray study result. Spinal Muscular Atrophy is a rare neuromuscular disorder characterized by loss of motor neurons and progressive muscle wasting. Cough in these patients result ineffective. Free-Aspire is an electromedical machine for removing bronchoalveolar secretions. The case show that Free Aspire in patients with ineffective cough and impaired removal of secretions is a safe and effective device for the removal of bronchial secretions and could be an another help in the management of airway clearance.

Association of autoimmune thyroiditis and celiac disease with Juvenile Polyposis due to 10q23.1q23.31 deletion: Potential role of PI3K/Akt pathway dysregulation.

Juvenile Polyposis (JP) is a rare hereditary condition characterized by diffuse hamartomatous gastrointestinal polyposis, associated with a significantly increased risk of neoplastic transformation. Most of the cases are caused by SMAD and BMPR1A mutations, while 10q23 microdeletions, encompassing both PTEN and BMPR1A oncogenes, are extremely rare, typically associated with more aggressive JP, and extraintestinal features overlapping with PTEN Hamartoma Tumor Syndrome. We present the first case of a young female with multiple autoimmune disorders (i.e. thyroiditis and celiac disease), associated with JP, cardiac defects and epilepsy, who carries a de novo heterozygous 10q23.1q23.31 deletion. The dysregulation of the PI3K/Akt pathway is advanced as the putative mechanism connecting autoimmune, malformative and neoplastic disorders. A literature review of clinical manifestation, gene alterations and the treatment of patients with 10q23 deletion is also provided, highlighting the importance of comprehensive, long-term, multi-disciplinary management, aimed at early identification and treatment of both intestinal and extraintestinal disorders.

A New Formulation of an Old Drug: A Potential New Therapy in the Management of Oral cGvHD.

Oral chronic graft versus host disease (cGVHD) is often refractory to systemic therapies. Additional topical treatment is commonly required. The potency of the agent, the vehicle and formulation in which it is delivered are all critical factors in determining the effectiveness of topical therapies. High potency of budesonide, combined with its very low bioavailability when absorbed through mucosal surfaces, increased the potential role in topical application for oral cGVHD. Viscous formulation increases mucosal contact time resulting in a greater decrease in mucosal inflammation. This short communication suggests that oral viscous budesonide should be considered as a potential new therapy in the management of oral cGVHD.

Esophageal Inlet Patch: An Under-Recognized Cause of Symptoms in Children.

OBJECTIVES: To determine the incidence of inlet patch (IP) and to assess the clinical and pathological features, role of the diagnostic workup in treatment decision making, efficacy of medical and endoscopic therapy, and natural history in a pediatric population. STUDY DESIGN: Consecutive patients aged <18 years (n = 1000) undergoing esophagogastroduodenoscopy were enrolled prospectively. Biopsy specimens were obtained from IPs and the proximal and distal esophagus, stomach, and duodenum. Multichannel intraluminal impedance and pH monitoring (MII-pH) was performed in all symptomatic patients. Symptomatic patients were treated with proton pump inhibitors for 8 weeks, and IP ablation by argon plasma coagulation (APC) was performed in unresponsive patients. RESULTS: The endoscopic incidence of IP was 6.3%, with a cumulative missing rate of 5.8%. Thirty-five of the 63 patients (56%) were asymptomatic, 11 (17%) had symptoms clearly related to the underlying digestive disorder, and 17 (27%) had chronic IP-related symptoms. MII-pH was positive in 10 of the 28 symptomatic patients. All 17 patients with IP-related symptoms were unresponsive to proton pump inhibitors and were treated with APC, and all had achieved complete remission by the 3-year follow-up. Patients with underlying disorders were successfully treated with medical therapy, and asymptomatic patients remained symptom-free, with no endoscopic or histological changes seen at the 3-year follow-up. CONCLUSION: IP is an under-recognized cause of symptoms in children with unexplained esophageal and respiratory symptoms. MII-pH and bioptic sampling are needed to exclude entities mimicking IP symptoms and to direct therapy. APC is safe and effective for treating IP-related symptoms.

Effects of silicone expanders and implants on echocardiographic image quality after breast reconstruction.

BACKGROUND: Use of silicone expanders and implants is the most common breast reconstruction technique after mastectomy. Postmastectomy patients often need echocardiographic monitoring of potential cardiotoxicity induced by cancer chemotherapy. The impairment of the echocardiographic acoustic window caused by silicone implants for breast augmentation has been reported. This study investigates whether the echocardiographic image quality was impaired in women reconstructed with silicone expanders and implants. METHODS: The records of 44 consecutive women who underwent echocardiographic follow-up after breast reconstruction with expanders and implants at the authors' institution from January of 2000 to August of 2012 were reviewed. The population was divided into a study group (left or bilateral breast expanders/implants, n=30) and a control group (right breast expanders/implants, n=14). The impact of breast expanders/implants on echocardiographic image quality was tested (analysis of covariance model). RESULTS: Patients with a breast expander/implant (left or bilateral and right breast expanders/implants) were included. The mean volume of the breast devices was 353.2±125.5 cc. The quality of the echocardiographic images was good or sufficient in the control group; in the study group, it was judged as adequate in only 50 percent of cases (15 patients) and inadequate in the remaining 15 patients (p<0.001). At multivariable analysis, a persistent relationship between device position (left versus right) and image quality (p=0.001) was shown, independent from other factors. CONCLUSIONS: Silicone expanders and implants in postmastectomy left breast reconstruction considerably reduce the image quality of echocardiography. This may have important clinical implications, given the need for periodic echocardiographic surveillance before and during chemotherapy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Parity as predictor of early hypertension during menopausal transition.

OBJECTIVES: Studies regarding the effects of parity on blood pressure in later life produced conflicting results. The aim of our study is to analyse whether parity influences the prevalence of hypertension in perimenopausal and postmenopausal women. METHODS: One thousand perimenopausal and postmenopausal women (mean age 55.2 ±â€Š5.4 years) were enrolled with a median follow-up of 63.0 months. The study sample consisted of patients who self-referred, in 1998-2009, to the BenEssere Donna Clinic, dedicated to menopause-related disorders. RESULTS: One hundred and twenty-two (12.2%) women were nulliparous and 878 (87.8%) had at least one child. Thirty-four (27.9%) women among nulliparous and 326 (37.1%) among parous were hypertensive at baseline (P = 0.046) and 812 women (81.2%) were in their postmenopausal period. Univariate analysis showed that women with one or more children were at higher risk of being hypertensive [odds ratio (OR): 1.529; 95% confidence interval (CI): 1.006-2.324; P = 0.047]. Likewise, multivariate analysis revealed that parity (OR: 2.907; 95% CI: 1.290-6.547; P = 0.010), BMI (OR: 1.097; 95% CI: 1.048-1.149; P < 0.001) and family history of hypertension (OR: 3.623; 95% CI: 2.231-5.883; P < 0.001) were independently related to hypertension at baseline. In a subanalysis of 640 initially normotensive women, 109 (17.0%) patients developed hypertension after follow-up, without a statistically significant association with parity (13.6% in nulliparous versus 17.6% in parous; P = 0.362). Consistently, parity showed no relationship with the incidence of hypertension during follow-up (OR: 1.350; 95% CI: 0.707-2.579; P = 0.363). CONCLUSION: For the first time in a population of White perimenopausal and postmenopausal women, parity was demonstrated to be independently associated with early hypertension during menopausal transition. Conversely, postmenopausal hypertension was not related with parity.

Lung function outcome at school age in very low birth weight children.

OBJECTIVE: The aim of this study was to assess pulmonary function and its predictors in very low birth weight (birth weight ≤1,500 g) children (VLBWc) with or without bronchopulmonary dysplasia (BPD), born at gestational age ≤32 weeks at a single tertiary center during 1996-1999, after the introduction of surfactant therapy. METHODS: Of the 120 surviving VLBW children, 48 (40%) VLBWc (22 with prior-BPD) at age 8.5 ± 1.0 years and 46 age-matched controls (8.8 ± 1.4 years) born at term, underwent lung function study. RESULTS: Adjusted values (z-score) of forced vital capacity (z-FVC), forced expiratory volume in 1 sec (z-FEV1), forced expiratory flow 25-75% (z-FEF25-75), carbon monoxide lung diffusion capacity (z-DLCO), and DLCO/alveolar volume (z-DLCO/VA) were significantly lower than controls (mean difference, 95% CI: -1.35, -1.81 to -0.90, P < 0.001; -1.31, -1.73 to -0.90, P < 0.001; -0.87, -1.29 to -0.46, P < 0.001; -0.98, -1.72 to -0.23, P < 0.001; -0.70, -1.22 to -0.18, P < 0.05; respectively). Residual volume (z-RV) and RV/total lung capacity (RV/TLC) ratio (%) were significantly higher in VLBWc than controls (mean difference, 95% CI: 1.06, 0.44 to 1.68, P < 0.001; 9.54%, 5.73 to 13.3%, P < 0.001; respectively). No differences were found in lung function between VLBWc (no-BPD vs. BPD) with the exception of a significant higher RV/TLC ratio in the BPD-subgroup (mean difference, 95% CI: 7.0%, 0.4 to 13%, P = 0.03). Lung function abnormalities were found in 30 (63%) VLBWc with evidence of airway obstruction and diffusing capacity impairment. A weak relationship was observed between gestational age with z-FVC (r = 0.30, P = 0.04), birth weight with z-FEV1 (r = 0.30, P = 0.04) and RV/TLC ratio (r = -0.49, P = 0.001). The duration of oxygen treatment correlated negatively with the z-DLCO/Va (r = -0.5, P = 0.02). No differences were found in FeNO levels between VLBWc and controls. CONCLUSION: VLBWc at school age showed lung function abnormalities characterized by airway obstruction, hyperinflation, and diffusion impairment. Neonatal lung damage together with preterm birth may play a role in worsening the functional respiratory outcome.

Long term prognostic value of subclinical carotid and femoral arterial wall lesions in patients with ST-elevation-myocardial infarction having percutaneous coronary intervention.

The presence of clinical peripheral arterial disease (PAD) is associated with an increased risk for adverse cardiovascular outcomes in patients with coronary artery disease. However, there are few data regarding the impact of the presence and degree of the subclinical PAD on outcomes in patients with coronary artery disease. The aim of this study was to assess prospectively the grade of subclinical PAD in the setting of patients who underwent primary percutaneous coronary intervention for the prediction of intermediate- and long-term clinical outcomes. A total of 971 consecutive patients without histories of clinical PAD who under went primary percutaneous coronary intervention for ST-segment elevation myocardial infarction were included in a prospective follow-up. Subclinical PAD severity was blindly assessed on the basis of an ultrasound arterial morphologic classification defined with the assessment of wall carotid and femoral artery bifurcations. This classification included 4 increasing classes of subclinical carotid and femoral arterial wall lesions, and the total group was divided accordingly. Death and major cardiovascular and cerebrovascular events were evaluated. During a median follow-up period of 40 months, a total of 109 patients (11.2%) died, 9 (2.8%) in class I, 12 (3.1%) in class II, 37 (23.7%) in class III, and 51 (49.0%) in class IV (p <0.001). On multivariate analysis, mortality in class IV was sevenfold higher (hazard ratio [HR] 7.34, 95% confidence interval [CI] 3.3 to 16.33, p <0.001) compared to class I and was also increased in class III (HR 5.38, 95% CI 2.42 to 11.92, p <0.001). Similar results were obtained for major adverse cardiovascular and cerebrovascular events in class IV (HR 7.50, 95% confidence interval 5.36 to 10.50, p <0.0001), class III (HR 6.44, 95% CI 4.45 to 9.32, p <0.001), and class II (HR 1.73, 95% CI 1.23 to 2.43, p = 0.002). In conclusion, ultrasound arterial morphologic classification may be applied in patients with ST-segment elevation myocardial infarctions who undergo primary percutaneous coronary intervention and can stratify patients for poor clinical outcomes during long-term follow-up.