Higher oxygen saturation with hydroxyurea in paediatric sickle cell disease.

INTRODUCTION: Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and reduced life expectancy. Hydroxyurea (HU) has been shown to reduce the frequency and severity of vaso-occlusive episodes in SCD. Hypoxaemia and intermittent nocturnal oxygen desaturations occur frequently in children with SCD and contribute to the associated morbidity, including risk of cerebrovascular disease. OBJECTIVE: To evaluate the effect of HU on oxygen saturation (SpO2) overnight and on daytime SpO2 spot checks in children with SCD. METHODS: A retrospective review of children with SCD and respiratory problems who attended two UK tertiary sickle respiratory clinics and were treated with HU. Longitudinal data were collected from 2 years prior and up to 3 years after the commencement of HU. RESULTS: Forty-three children, 23 males (53%) with a median age of 9 (range 1.8-18) years were included. In the 21 children who had comparable sleep studies before and after starting HU, mean SpO2 was higher (95.2% from 93.5%, p=0.01) and nadir SpO2 was higher (87.2% from 84.3%, p=0.009) when taking HU. In 32 of the children, spot daytime oxygen saturations were also higher (96.3% from 93.5%, p=0.001). CONCLUSION: Children with SCD had higher oxygen saturation overnight and on daytime spot checks after starting HU. These data suggest HU may be helpful for treating persistent hypoxaemia in children with SCD pending more evidence from a randomised clinical trial

Disordered microbial communities in asthmatic airways.

A rich microbial environment in infancy protects against asthma [1], [2] and infections precipitate asthma exacerbations [3]. We compared the airway microbiota at three levels in adult patients with asthma, the related condition of COPD, and controls. We also studied bronchial lavage from asthmatic children and controls.We identified 5,054 16S rRNA bacterial sequences from 43 subjects, detecting >70% of species present. The bronchial tree was not sterile, and contained a mean of 2,000 bacterial genomes per cm(2) surface sampled. Pathogenic Proteobacteria, particularly Haemophilus spp., were much more frequent in bronchi of adult asthmatics or patients with COPD than controls. We found similar highly significant increases in Proteobacteria in asthmatic children. Conversely, Bacteroidetes, particularly Prevotella spp., were more frequent in controls than adult or child asthmatics or COPD patients.The results show the bronchial tree to contain a characteristic microbiota, and suggest that this microbiota is disturbed in asthmatic airways

Inflammatory phenotype and steroid responsiveness in children with severe asthma

Introduction The pathology of paediatric severe therapy resistant asthma (STRA) and the mechanisms of steroid resistance are little studied. Hypotheses STRA is a T H2 driven eosinophilic disease and submucosal inflammation, specifically airway smooth muscle (ASM) eosinophil and mast cell infiltration predict steroid responsiveness Methods 52 STRA children, mean age 12.2 (6.5-17.3) years underwent an asthma control test (ACT), spirometry (forced expiratory volume in 1 second, FEV1), fractional exhaled nitric oxide at 50ml/sec (FeNO), sputum induction and bronchoscopy, bronchoalveolar lavage (BAL) and endobronchial biopsy (EB), and received a single dose of intramuscular triamcinolone. All tests (apart from bronchoscopy) were repeated 4 weeks later. Steroid response was assessed in four ways, (1) normalisation or improvement by ~ 50% in ACT, (2) normalisation or improvement of ~15% in FEV1. (3) normalisation of FeNO «24ppb) and (4) normalisation of sputum eosinophil % «2.5%). EB were assessed for inflammation and airway remodelling using image analysis. Luminex was used to quantify cytokines in sputum and BAL supernatants. In addition, 7 mild/moderate asthmatics (MA) and 16 controls underwent bronchoscopy, BAL and EB. Results STRA was eosinophilic, not neutrophilic as reported in adults. There was little evidence in sputum supernatant, BAL and EB of T H2 cytokines, with no significant difference between STRA, mild-moderate asthmatics and non-asthmatic controls. Steroid response was difficult to predict, but indicators of a poor response were atopy, eosinophilia (blood and EB), increased EB CD4+ count, ASM mast cells and RBM thickening. The adult criteria for steroid response were only applicable to 50% of STRA children. Conclusions Airway eosinophilia not neutrophilia predominates in childhood STRA. The mechanism of eosinophilia is obscure, and does not involve conventional signature T H2 cytokines, both findings in contrast to adult severe asthma. Thus therapies targeting T H2 cytokines may be inappropriate for the majority of children with STRA. A paediatric definition of steroid responsiveness needs to be developed.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Pediatric severe asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines

BACKGROUND: The pathology of pediatric severe therapy-resistant asthma (STRA) is little understood. OBJECTIVES: We hypothesized that STRA in children is characterized by airway eosinophilia and mast cell inflammation and is driven by the T(H)2 cytokines IL-4, IL-5, and IL-13. METHODS: Sixty-nine children (mean age, 11.8 years; interquartile range, 5.6-17.3 years; patients with STRA, n = 53; control subjects, n = 16) underwent fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), and endobronchial biopsy. Airway inflammation, remodeling, and BAL fluid and biopsy specimen T(H)2 cytokines were quantified. Children with STRA also underwent symptom assessment (Asthma Control Test), spirometry, exhaled nitric oxide and induced sputum evaluation. RESULTS: Children with STRA had significantly increased BAL fluid and biopsy specimen eosinophil counts compared with those found in control subjects (BAL fluid, P < .001; biopsy specimen, P < .01); within the STRA group, there was marked between-patient variability in eosinophilia. Submucosal mast cell, neutrophil, and lymphocyte counts were similar in both groups. Reticular basement membrane thickness and airway smooth muscle were increased in patients with STRA compared with those found in control subjects (P < .0001 and P < .001, respectively). There was no increase in BAL fluid IL-4, IL-5, or IL-13 levels in patients with STRA compared with control subjects, and these cytokines were rarely detected in induced sputum. Biopsy IL-5(+) and IL-13(+) cell counts were also not higher in patients with STRA compared with those seen in control subjects. The subgroup (n = 15) of children with STRA with detectable BAL fluid T(H)2 cytokines had significantly lower lung function than those with undetectable BAL fluid T(H)2 cytokines. CONCLUSIONS: STRA in children was characterized by remodeling and variable airway eosinophil counts. However, unlike in adults, there was no neutrophilia, and despite the wide range in eosinophil counts, the T(H)2 mediators that are thought to drive allergic asthma were mostly absent