Michael C McKean

British Thoracic Society guidelines for the management of community acquired pneumonia in children: update 2011

The British Thoracic Society first published management guidelines for community acquired pneumonia in children in 2002 and covered available evidence to early 2000. These updated guidelines represent a review of new evidence since then and consensus clinical opinion where evidence was not found. This document incorporates material from the 2002 guidelines and supersedes the previous guideline document.

Raised interleukin-17 is immunolocalised to neutrophils in cystic fibrosis lung disease

Interleukin (IL)-17 is pivotal in orchestrating the activity of neutrophils. Neutrophilic inflammation is the dominant pathology in cystic fibrosis (CF) lung disease. We investigated IL-17 protein expression in the lower airway in CF, its cellular immunolocalisation and the effects of IL-17 on CF primary bronchial epithelial cells. Immunohistochemistry was performed on explanted CF lungs and compared with the non-suppurative condition pulmonary hypertension (PH). Airway lavages and epithelial cultures were generated from explanted CF lungs. Immunoreactivity for IL-17 was significantly increased in the lower airway epithelium in CF (median 14.1%) compared with PH (2.95%, p = 0.0001). The number of cells staining positive for IL-17 in the lower airway mucosa was also increased (64 cells·mm−1 compared with 9 cells·mm−1 basement membrane, p = 0.0005) and included both neutrophils in addition to mononuclear cells. IL-17 was detectable in airway lavages from explanted CF lungs. Treatment of epithelial cultures with IL-17 increased production of IL-8, IL-6 and granulocyte macrophage colony-stimulating factor. In conclusion, immunoreactive IL-17 is raised in the lower airway of people with CF and localises to both neutrophils and mononuclear cells. IL-17 increases production of pro-neutrophilic mediators by CF epithelial cells, suggesting potential for a positive feedback element in airway inflammation.

Ceramide Is Increased in the Lower Airway Epithelium of People with Advanced Cystic Fibrosis Lung Disease

RATIONALE Ceramide accumulates in the airway epithelium of mice deficient in cystic fibrosis transmembrane conductance regulator, resulting in susceptibility to Pseudomonas aeruginosa infection and inflammation. OBJECTIVES To investigate quantitatively ceramide levels in the lower airway of people with cystic fibrosis compared with pulmonary hypertension, emphysema, and lung donors. METHODS Immunohistochemistry was performed on the lower airway epithelium of explanted lungs (eight cystic fibrosis, emphysema, and pulmonary hypertension, respectively) and eight donor lungs using ceramide, neutrophil elastase, and myeloperoxidase antibodies. High-performance liquid chromatography-mass spectrometry was performed on tissue from five lungs with cystic fibrosis and five with pulmonary hypertension. MEASUREMENTS AND MAIN RESULTS Staining for ceramide was significantly increased in the lower airway epithelium of people with cystic fibrosis (median, 14.11%) compared with pulmonary hypertension (3.03%; P = 0.0009); unused lung donors (3.44%; P = 0.0009); and emphysema (5.06%; P = 0.01). Ceramide staining was increased in emphysematous lungs compared with pulmonary hypertension (P = 0.0135) and unused donors (P = 0.0009). The number of neutrophil elastase- and myeloperoxidase-positive cells in the airway was positively correlated with the percentage of epithelium staining for ceramide (P = 0.001). Ceramide staining was significantly increased in lungs colonized with Pseudomonas aeruginosa (10.1%) compared with those not colonized (3.14%; P = 0.0106). Significantly raised levels of ceramides C16:0, C18:0, and C20:0 were detected by mass spectrometry in lungs with cystic fibrosis compared with pulmonary hypertension. Differences in C22:0 were not significant. CONCLUSIONS Immunoreactive ceramide is increased in the lower airway epithelium of people with advanced cystic fibrosis. Detected by mass-spectrometry ceramide species C16:0, C18:0, and C20:0 but not C22:0 are increased.

The oral corticosteroid-sparing effect of omalizumab in children with severe asthma

Objective To report the oral corticosteroid-sparing effect of omalizumab in children with severe asthma. Design 16-week therapeutic trial. Setting Tertiary paediatric asthma clinic. Patients 34 children with severe asthma maintained on oral prednisolone (median age 12 years; 15 children <12 years and 19 children ≥12 years). Interventions Fortnightly or monthly subcutaneous injections of omalizumab; the dose was calculated as per manufacturers instructions based on body weight and serum immunoglobulin E concentration. Main outcome measures Reduction in prednisolone dose; mini-Asthma Quality of Life Questionnaire (AQLQ); Childhood Asthma Control Test (ACT); forced expiratory volume in 1 s (FEV1). Results Median daily prednisolone dose reduced from 20 mg to 5 mg (n=34, p<0.0001), including seven children who stopped prednisolone completely. Mini-AQLQ score increased from 3.5 to 5.9 (n=24, p<0.0001). Childhood ACT score increased from 12 to 20 (n=23, p=0.0001). FEV1 increased from 2.10 to 2.25 litres (n=31, non-significant). The reduction in prednisolone dose and improvements in mini-AQLQ and childhood ACT were significant in children both under and over 12 years of age, with no differences in outcome detected between these two groups. Conclusions A 16-week therapeutic trial of omalizumab allowed a significant reduction in daily prednisolone dose and was associated with improvements in asthma control and quality of life in 34 children with severe asthma. Similar benefits were seen in children both above and below 12 years of age. These uncontrolled data are very encouraging. There is an urgent requirement for a multicentre randomised placebo-controlled trial of omalizumab in children with severe asthma, with reduction in oral corticosteroid dose as the primary outcome measure.

Diagnosis of asthma in children

Children presenting with wheeze are likely to have either atopic asthma or episodic viral wheeze; distinguishing between these has important implications for management

A model of viral wheeze in nonasthmatic adults: symptoms and physiology

Episodic wheezing associated with viral infections of the upper respiratory tract (URT) is a common problem in young children but also occurs in adults. It is hypothesized that an experimental infection with human coronavirus (HCoV), the second most prevalent common cold virus, would cause lower respiratory tract (LRT) changes in adults with a history of viral wheeze. Twenty-four viral wheezers (15 atopic) and 19 controls (seven atopic) were inoculated with HCoV 229E and monitored for the development of symptoms, changes in airway physiology and provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (FEV1) (PC20). At baseline, viral wheezers were similar to controls in PC20 (mean+/-SD log2PC20: 5.1+/-1.9 and 5.8+/-1.4 g x L(-1), respectively) but had a lower FEV1 than controls (mean+/-SD 85.8+/-11.4 and 95.6+/-13.2% predicted, respectively p < 0.05). Nineteen viral wheezers and 11 controls developed colds. Viral wheezers with colds reported significantly more URT symptoms than controls (median scores (interquartile range): 24 (10-37) and 6 (4-15), respectively p = 0.014). Sixteen viral wheezers and no controls reported LRT symptoms (wheeze, chest tightness and shortness of breath). The viral wheezers with colds had small (3-4%) reductions in FEV1 and peak expiratory flow on days with LRT symptoms (days 3-6), but a progressive reduction in PC20 from baseline on days 2, 4 and 17 after inoculation (by 0.82, 1.35 and 1.82 doubling concentrations, respectively). The fall in PC20 affected both atopic and nonatopic subjects equally. There were no changes in FEV1 or PC20 in controls. An adult model of viral wheeze that is independent of atopy and therefore, of classical atopic asthma was established.

The evidence for high flow nasal cannula devices in infants.

High flow nasal cannula (HFNC) devices deliver an adjustable mixture of heated and humidified oxygen and air at a variable flow rate. Over recent years HFNC devices have become a frequently used method of non-invasive respiratory support in infants and preterm neonates that is generally popular amongst clinicians and nursing staff due to ease of use and being well tolerated by patients. Despite this rapid adoption relatively little is known about the exact mechanisms of action of HFNC however and only recently have data from randomised controlled trials started to become available. We describe the features of a modern HFNC device and discuss current knowledge about the mechanisms of action and results of clinical studies in preterm neonates and infants with bronchiolitis. We also highlight future areas of research that are likely to increase our understanding, inform best clinical practice and strengthen the evidence base for the use of HFNC.

Primary bronchial epithelial cell culture from explanted cystic fibrosis lungs.

ABSTRACT Lung disease is responsible for more than 95%% of morbidity and mortality in cystic fibrosis. The exact pathogenesis of cystic fibrosis lung disease remains poorly understood. Experimental models are therefore vital for use in research. Animal models and immortalized cell lines both have inherent limitations. Explanted lungs removed from people with cystic fibrosis at the time of transplantation represent a potentially valuable but technically and logistically challenging source of primary cystic fibrosis bronchial epithelial cells. In this study, pieces of segmental bronchus from explanted lungs were treated with patient-specific antimicrobials prior to isolation of bronchial epithelial cells. Cultured cells were characterized by their morphology under light microscopy, cytokeratin and hematoxylin-eosin staining, and electrophysiological profile. Primary bronchial epithelial cells were successfully cultured from 15 of 22 patients attempted. The cells exhibited typical epithelial morphology, staining for cytokeratin, lack of responsiveness to forskolin treatment, and remained viable after storage in liquid nitrogen. Seven unsuccessful cultures failed due to early infection with bacteria known to colonize the airways pretransplant. The results show that primary bronchial epithelial cell culture is possible from explanted cystic fibrosis lungs. This provides an important cellular model to elucidate the pathogenic mechanisms in cystic fibrosis lung disease and to investigate potential therapeutic targets.

An adult model of exclusive viral wheeze: inflammation in the upper and lower respiratory tracts

Background We have previously reported an experimental infection of young adults with a history of episodic and exclusive viral wheeze (EVW) using human coronavirus, in which 16 of 24 with EVW (15 atopic) and 11 of 19 healthy controls (seven atopic) developed a symptomatic cold with evidence of infection, but only those with EVW developed lower respiratory tract symptoms and increased airway responsiveness.

The ‘unified airway’: the RCPCH care pathway for children with asthma and/or rhinitis

Aims The Royal College of Paediatrics and Child Health (RCPCH) Science and Research Department was commissioned by the Department of Health to develop national care pathways for children with allergies: the asthma/rhinitis care pathway is the third such pathway. Asthma and rhinitis have been considered together. These conditions co-exist commonly, have remarkably similar immuno-pathology and an integrated management approach benefits symptom control. Method The asthma/rhinitis pathway was developed by a multidisciplinary working group and was based on a comprehensive review of evidence. The pathway was reviewed by a broad group of stakeholders including the public and was approved by the Allergy Care Pathways Project Board and the RCPCH Clinical Standards Committee. Results The pathway entry points are defined by symptom type and severity at presentation. Acute severe rhinitis and life-threatening asthma are presented as distinct entry routes to the pathway, recognising that initial care of these conditions requires presentation-specific treatments. However, the pathway emphasises that ideal long term care should take account of both conditions in order to achieve maximal improvements in disease control and quality of life. Conclusions The pathway recommends that acute presentations of asthma and/or rhinitis should be treated separately. Where both conditions exist, ongoing management should address the upper and lower airways. The authors recommend that this pathway is implemented locally by a multidisciplinary team (MDT) with a focus on creating networks. The MDT within these networks should work with patients to develop and agree on care plans that are age and culturally appropriate.