Respiratory manifestations of gastro-oesophageal reflux in children.

Gastro-oesophageal reflux disease (GORD) is a complex problem in children. Suspected respiratory manifestations of GORD, such as asthma, chronic cough and laryngitis, are commonly encountered in the paediatric practice, but continue to be entities with more questions than answers. The accuracy of diagnostic tests (ie, pH or pH-impedance monitoring, laryngoscopy, endoscopy) for patients with suspected extraoesophageal manifestations of GORD is suboptimal and therefore whether there is a causal relationship between these conditions remains largely undetermined. An empiric trial of proton pump inhibitors can help individual children with undiagnosed respiratory symptoms and suspicion of GORD, but the response to therapy is unpredictable, and in any case what may be being observed is spontaneous improvement. Furthermore, the safety of these agents has been called into question. Poor response to antireflux therapy is an important trigger to search for non-gastro-oesophageal reflux causes for patients' symptoms. Evidence for the assessment of children with suspected extraoesophageal manifestations of GORD is scanty and longitudinal studies with long-term follow-up are urgently required.

Tuberculosis care among refugees arriving in Europe: a ERS/WHO Europe Region survey of current practices.

No evidence exists on tuberculosis (TB) and latent TB infection (LTBI) management policies among refugees in European countries.A questionnaire investigating screening and management practices among refugees was sent to 38 national TB programme representatives of low and intermediate TB incidence European countries/territories of the WHO European Region.Out of 36 responding countries, 31 (86.1%) reported screening for active TB, 19 for LTBI, and eight (22.2%) reporting outcomes of LTBI treatment. Screening for TB is based on algorithms including different combinations of symptom-based questionnaires, bacteriology and chest radiography and LTBI screening on different combinations of tuberculin skin test and interferon-γ release assays. In 22 (61.1%) countries, TB and LTBI screening are performed in refugee centres. In 22 (61.1%) countries, TB services are organised in collaboration with the private sector. 27 (75%) countries answered that screening for TB is performed as per national and international guidelines, while 19 (52.7%) gave the same answer with regards to LTBI screening. Infection control measures are inadequate in several of the countries surveyed.There is need for improved coordination of TB screening in Europe to implement the End TB Strategy and achieve TB elimination.

IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis.

Dysregulated inflammasome activation contributes to respiratory infections and pathologic airway inflammation. Through basic and translational approaches involving murine models and human genetic epidemiology, we show here the importance of the different inflammasomes in regulating inflammatory responses in mice and humans with cystic fibrosis (CF), a life-threatening disorder of the lungs and digestive system. While both contributing to pathogen clearance, NLRP3 more than NLRC4 contributes to deleterious inflammatory responses in CF and correlates with defective NLRC4-dependent IL-1Ra production. Disease susceptibility in mice and microbial colonization in humans occurs in conditions of genetic deficiency of NLRC4 or IL-1Ra and can be rescued by administration of the recombinant IL-1Ra, anakinra. These results indicate that pathogenic NLRP3 activity in CF could be negatively regulated by IL-1Ra and provide a proof-of-concept evidence that inflammasomes are potential targets to limit the pathological consequences of microbial colonization in CF.

Ground zero: not asthma at all.

Upper airway obstruction is commonly misdiagnosed as asthma. We report on four children with recurrent respiratory symptoms who had been erroneously diagnosed as having asthma and who received anti-asthma medication for several years. The evaluation of spirometry tracing was neglected in all cases. Subglottic stenosis, tracheomalacia secondary to tracheo-esophageal fistula, double aortic arch, and vocal cord dysfunction were suspected by direct inspection of the flow-volume curves and eventually diagnosed. The value of clinical history and careful evaluation of spirometry tracing in children with persistent respiratory symptoms is critically discussed.

Cytophagic histiocytic panniculitis, hemophagocytic lymphohistiocytosis and undetermined autoimmune disorder: reconciling the puzzle.

Cytophagic histiocytic panniculitis is a rare disease, associated with either nonmalignant conditions or subcutaneous panniculitis-like T-cell lymphoma, and often also associated with hemophagocytic lymphohistiocytosis (HLH). We report the case of a 11-year-old boy with a history of secondary HLH who, after a local trauma, developed a painful, indurated plaque over the right thigh associated with relapsing HLH. Histopathologic findings from skin biopsy specimens revealed significant lobular panniculitis with benign histiocytes showing hemophagocytosis. High-dose intravenous methylprednisolone and cyclosporine A treatment was highly effective. A genetic study after a new, relapsing episode of HLH revealed an heterozygous missense mutation on STX 11 gene inherited from the mother.

Management of plastic bronchitis with nebulized tissue plasminogen activator: another brick in the wall.

Plastic bronchitis is a rare complication of a variety of respiratory diseases and congenital heart disease surgery, particularly Fontan procedure. Bronchial casts with rubber-like consistency develop acutely and may cause severe life-threatening respiratory distress. The management of plastic bronchitis is yet not well defined. Early intermittent, self-administered nebulization of tissue plasminogen activator was found to be effective in preventing deterioration of acute respiratory symptoms in a patient with primary ciliary dyskinesia and recurrent cast formation. Further investigation into new therapeutic strategies for this devastating disease is advocated.

Hypoxia promotes danger-mediated inflammation via receptor for advanced glycation end products in cystic fibrosis.

RATIONALE: Hypoxia regulates the inflammatory-antiinflammatory balance by the receptor for advanced glycation end products (RAGE), a versatile sensor of damage-associated molecular patterns. The multiligand nature of RAGE places this receptor in the midst of chronic inflammatory diseases. OBJECTIVES: To characterize the impact of the hypoxia-RAGE pathway on pathogenic airway inflammation preventing effective pathogen clearance in cystic fibrosis (CF) and elucidate the potential role of this danger signal in pathogenesis and therapy of lung inflammation. METHODS: We used in vivo and in vitro models to study the impact of hypoxia on RAGE expression and activity in human and murine CF, the nature of the RAGE ligand, and the impact of RAGE on lung inflammation and antimicrobial resistance in fungal and bacterial pneumonia. MEASUREMENTS AND MAIN RESULTS: Sustained expression of RAGE and its ligand S100B was observed in murine lung and human epithelial cells and exerted a proximal role in promoting inflammation in murine and human CF, as revealed by functional studies and analysis of the genetic variability of AGER in patients with CF. Both hypoxia and infections contributed to the sustained activation of the S100B-RAGE pathway, being RAGE up-regulated by hypoxia and S100B by infection by Toll-like receptors. Inhibiting the RAGE pathway in vivo with soluble (s) RAGE reduced pathogen load and inflammation in experimental CF, whereas sRAGE production was defective in patients with CF. CONCLUSIONS: A causal link between hyperactivation of RAGE and inflammation in CF has been observed, such that targeting pathogenic inflammation alleviated inflammation in CF and measurement of sRAGE levels could be a useful biomarker for RAGE-dependent inflammation in patients with CF.

Macronodular hepatosplenic tuberculosis.

Hepatosplenic involvement is a rare manifestation of abdominal tuberculosis in children. We describe the case of a 7-year-old girl with persistent fever, cough, and hepatosplenomegaly. Typical lesions were shown in the liver and spleen by ultrasound and computed tomography. Colonoscopy showed a nodular, ulcerated mass that partially obstructed the cecum. Microbiological and histopathological findings of intestinal and liver biopsy confirmed the clinical suspicion of tuberculosis.

Endpoints in respiratory diseases.

A wide range of outcome measures or endpoints has been used in clinical trials to assess the effects of treatments in paediatric respiratory diseases. This can make it difficult to compare treatment outcomes from different trials and also to understand whether new treatments offer a real clinical benefit for patients. Clinical trials in respiratory diseases evaluate three types of endpoints: subjective, objective and health-related outcomes. The ideal endpoint in a clinical trial needs to be accurate, precise and reliable. Ideally, the endpoint would also be measured with minimal risk and across all ages, easy to perform, and be inexpensive. As for any other disease, endpoints for respiratory diseases must be viewed in the context of the important distinction between clinical endpoints and surrogate endpoints. The association between surrogate endpoints and clinical endpoints must be clearly defined for any disease in order for them to be meaningful as outcome measures. The most common endpoints which are used in paediatric trials in respiratory diseases are discussed. For practical purposes, diseases have been separated into acute (bronchiolitis, acute viral-wheeze, acute asthma and croup) and chronic (asthma and cystic fibrosis). Further development of endpoints will enable clinical trials in children with respiratory diseases with the main objective of improving prognosis and safety.

Montelukast sodium for exercise-induced asthma.

Exercise is the most common trigger of bronchospasm in children with asthma. Exercise-induced bronchoconstriction (EIB) occurs in up to 90% of individuals with asthma who are not under antiinflammatory treatment and in about 40% of those with allergic rhinitis. EIB may be an overwhelming problem in childhood and adolescence, when physical activity is a prominent component of daily life. The importance for those with asthma to maintain regular physical activity is recognized by asthma guidelines, which include the recommendation of full participation in sporting activities in their goals for the management of asthma. Cysteinyl leukotrienes, which are derivatives of the 5-lipoxygenase pathway of arachidonic acid metabolism, are important mediators of airway allergic inflammation and have a role in the pathogenetic mechanism of EIB. Montelukast sodium (Singulair, Merck & Co.) is a selective and orally active leukotriene receptor antagonist with demonstrated activity for treating asthma and allergic rhinitis. The effect of this drug in the prevention of EIB has been evaluated in a variety of studies in adults as well as in children. Both single-dose and regular-treatment studies showed that montelukast provides effective protection against EIB. Furthermore, chronic treatment with montelukast does not induce tolerance to the bronchoprotective effect over time. This aspect is particularly relevant for children, who tend to be active at frequent and irregular intervals throughout the day, and who therefore may benefit from around-the-clock pharmacologic protection.

Foreign body aspiration in children.

BACKGROUND: The aim was to investigate the role of physical and radiological findings before bronchoscopy in the diagnosis of foreign body aspiration (FBA). METHODS: We retrospectively reviewed the clinical records for 82 patients (mean age 26.4 +/- 21.4 months, range 9 months to 13.5 years; 49 males) with a history suggestive of foreign body aspiration. RESULTS: The presence of a foreign body in the airways was confirmed in 70 children (85.4%) (mean age 25 +/- 14.1 months, 45 boys). Of the 70 children, 63 patients (90%) were under 3 years of age, with a peak incidence during the second year. Of the 70 foreign bodies retrieved, 46 (60%) were vegetable and 35 (76%) of these were nuts. In 42% of the patients the foreign body was located in the right bronchial tree. The most frequent physical findings observed in our patients were persistent cough (75%), localized decreased breath sound (62.8%) and localized wheezing (30%). The clinical triad (concomitant cough, localized wheezing and decreased breath sound) was present in 11 patients (15.7%). All clinical findings had a high positive predictive value with poor sensitivity. In 11 patients (20%) chest X-rays were normal. Five foreign bodies (9.1%) were radiopaque. The most frequent radiological findings observed were localized air trapping (43.6%), followed by atelectasis (40%). The diagnostic sensitivity was 80% and the specificity 33% for the presence of a single positive radiological finding. CONCLUSIONS: Our study confirmed that clinical symptoms and radiological findings before bronchoscopy have a low diagnostic value in children with a history of FBA.