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ObjectivesPalivizumab is a monoclonal antibody which can prevent infection with respiratory syncytial virus (RSV). Due to its high cost, it is recommended for high-risk infants only. We aimed to determine the proportion of infants eligible for palivizumab treatment in England who receive at least one dose.MethodsWe used the Hospital Treatment Insights database containing hospital admission records linked to hospital pharmacy dispensing data for 43/153 hospitals in England. Infants born between 2010 and 2016 were considered eligible for palivizumab if their medical records indicated chronic lung disease (CLD), congenital heart disease (CHD), or severe immunodeficiency (SCID), and they met additional criteria based on gestational age at birth and age at start of the RSV season (beginning of October). We calculated the proportion of infants who received at least one dose of palivizumab in their first RSV season, and modelled the odds of treatment according to multiple child characteristics using logistic regression models.ResultsWe identified 3,712 eligible children, of whom 2,479 (67%) had complete information on all risk factors. Palivizumab was prescribed to 832 of eligible children (34%). Being born at ConclusionIn England, palivizumab is not prescribed to the majority of children who are eligible to receive it. Doctors managing these infants might be unfamiliar with the eligibility criteria or are constrained by other considerations, such as cost.

The recruitment of neutrophils to the infected airway occurs early following respiratory syncytial virus (RSV) infection and high numbers of activated neutrophils in airway and blood is associated with the development of severe disease. Here, we investigated whether trans-epithelial migration across primary human airway epithelial cells (AECs) is sufficient and necessary for neutrophil activation during RSV infection. Using flow cytometry, we identified three populations of neutrophils in our in vitro model; those in suspension in basolateral and apical compartments and those that migrated and adhered to AECs. After 1h incubation, the number of adherent neutrophils was significantly greater following RSV infection compared to mock infected. We found that, when migration occurred, neutrophil expression of CD11b, CD62L, CD64, NE and MPO increased in all compartments. However, this did not occur when neutrophils were prevented from migrating. This suggests that the heightened neutrophil activation we detected in the basolateral compartment may be due to reverse migrating neutrophils, as has been suggested by clinical observations. Using live-cell fluorescent microscopy, we then profiled the early temporal and spatial movement and adherence of human neutrophils during migration. Our findings suggest three main phases of early neutrophil recruitment and behaviour in the airways during RSV infection, with neutrophil recruitment, activation and adherence to RSV infected AECs, with clustering, occurring within the first 20 minutes. This work and the model we developed could provide new insight into how neutrophil activation and a dysregulated neutrophil response to RSV mediates disease severity.Graphical AbstractBuilding on previous work of neutrophil function we propose 3 main phases of early neutrophil recruitment and behaviour in the airways during RSV infection. Phase 1. Initial chemotaxis and adherence: Here unstimulated circulating neutrophils expressing baseline levels of CD11b migrate across infected AECs in response to chemotactic signals in the apical supernatant. Some neutrophils remain adherent to the infected AECs. Phase 2: Activation and reverse migration: once on the apical side of the epithelium, neutrophils increase expression of CD11b and other activation associated markers, and some ‘activated’ neutrophils undergo reverse migration. Neutrophils with greater expression of CD11b are detected on the basolateral side Phase 3: Amplified chemotaxis and clustering: after 20 minutes, adherent neutrophils begin to rapidly cluster on RSV infected primary airway epithelial cells cultures, mediated by signalling from a dying neutrophil. Drawing created using BioRender.com.

Background Bronchiolitis caused by respiratory syncytial virus (RSV) is a major cause of mortality and morbidity in infants. Aim To describe RSV epidemiology in children in the community in a high-income setting. Methods We used stored blood samples from the United Kingdom Born in Bradford cohort study that had been collected at birth, age 1 and 2 years old, tested for IgG RSV postfusion F antibody and linked to questionnaires and primary and hospital care records. We used finite mixture models to classify children as RSV infected/not infected according to their antibody concentrations at age 1 and 2 years. We assessed risk factors for primary RSV infection at each age using Poisson regression models. Results The study cohort included 700 children with cord blood samples; 490 had additional blood samples taken at both ages 1 and 2 years old. Of these 490 children, 258 (53%; 95% confidence interval (CI): 48–57%) were first infected with RSV at age 1, 99 of whom (38%; 95% CI: 33–43%) had been in contact with healthcare during peak RSV season (November–January). Having older siblings, birth in October–June and attending formal childcare were associated with risk of RSV infection in infancy. By age 2, a further 164 of 490 children (33%; 95% CI: 29–38%) had been infected. Conclusion Over half of children experienced RSV infection in infancy, a further one third had evidence of primary RSV infection by age 2, and one in seven remained seronegative by their second birthday. These findings will inform future analyses to assess the cost-effectiveness of RSV vaccination programmes in high-income settings.

This study shows that the RSV-infected human airway drives changes in the behavior of human neutrophils, including increasing activation markers and delaying apoptosis, that result in greater airway damage and viral clearance., Respiratory syncytial virus (RSV) is a major cause of pediatric respiratory disease. Large numbers of neutrophils are recruited into the airways of children with severe RSV disease. It is not clear whether or how neutrophils enhance recovery from disease or contribute to its pathology. Using an in vitro model of the differentiated airway epithelium, we found that the addition of physiological concentrations of neutrophils to RSV-infected nasal cultures was associated with greater epithelial damage with lower ciliary activity, cilium loss, less tight junction expression (ZO-1), and more detachment of epithelial cells than is seen with RSV infection alone. This was also associated with a decrease in infectious virus and fewer RSV-positive cells in cultures after neutrophil exposure than in preexposure cultures. Epithelial damage in response to RSV infection was associated with neutrophil activation (within 1 h) and neutrophil degranulation, with significantly greater cellular expression of CD11b and myeloperoxidase and higher levels of neutrophil elastase and myeloperoxidase activity in apical surface media than in media with mock-infected airway epithelial cells (AECs). We also recovered more apoptotic neutrophils from RSV-infected cultures (>40%) than from mock-infected cultures (

BackgroundTo clarify the characteristic and the duration of positive nucleic acid in children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including asymptomatic children.MethodsA total of 32 children confirmed with SARS-CoV-2 infection between January 24 and February 12, 2020 from four provinces in Western China were enrolled in this study and followed up until discharge and quarantine 14 days later.ResultsEleven children (34%) were asymptomatic, among whom six children had normal computed tomographic (CT) scan images. Age and gender were not associated with clinical symptoms or the results of CT scan in children infected with SARS-CoV-2. The concentrations of white blood cells and neutrophils were higher in children with asymptomatic infection than in children with clinical symptoms or CT abnormalities. Patients who presented with CT abnormalities had lower D-dimer or lower total bilirubin than those who had normal CT scan but clinical symptoms. All children recovered and no one died or was admitted to the pediatric intensive care unit (PICU). The mean duration of positive SARS-CoV-2 nucleic acid was 15.4 (SD=7.2) days and similar for both asymptomatic children and children with symptoms or CT abnormalities. We found a significant negative correlation between the lymphocyte count and the duration of positive nucleic acid test.ConclusionsChildren with asymptomatic infection should be quarantined for the same duration as symptomatic patients infected with SARS-CoV-2. The clinical significance and mechanism behind the negative correlation between the number of lymphocytes and the duration of positive SARS-CoV-2 needs further study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background: A serious adverse effect of corticosteroid therapy is adrenal suppression. Our aim was to identify genetic variants affecting susceptibility to corticosteroid-induced adrenal suppression. Methods: We enrolled children with asthma who used inhaled corticosteroids as part of their treatment from 25 sites across the UK (discovery cohort), as part of the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) study. We included two validation cohorts, one comprising children with asthma (PASS study) and the other consisting of adults with chronic obstructive pulmonary disorder (COPD) who were recruited from two UK centres for the Pharmacogenomics of Adrenal Suppression in COPD (PASIC) study. Participants underwent a low-dose short synacthen test. Adrenal suppression was defined as peak cortisol less than 350 nmol/L (in children) and less than 500 nmol/L (in adults). A case-control genome-wide association study was done with the control subset augmented by Wellcome Trust Case Control Consortium 2 (WTCCC2) participants. Single nucleotide polymorphisms (SNPs) that fulfilled criteria to be advanced to replication were tested by a random-effects inverse variance meta-analysis. This report presents the primary analysis. The PASS study is registered in the European Genome-phenome Archive (EGA). The PASS study is complete whereas the PASIC study is ongoing. Findings: Between November, 2008, and September, 2011, 499 children were enrolled to the discovery cohort. Between October, 2011, and December, 2012, 81 children were enrolled to the paediatric validation cohort, and from February, 2010, to June, 2015, 78 adults were enrolled to the adult validation cohort. Adrenal suppression was present in 35 (7%) children in the discovery cohort and six (7%) children and 17 (22%) adults in the validation cohorts. In the discovery cohort, 40 SNPs were found to be associated with adrenal suppression (genome-wide significance p−6), including an intronic SNP within the PDGFD gene locus (rs591118; odds ratio [OR] 7·32, 95% CI 3·15–16·99; p=5·8 × 10−8). This finding for rs591118 was validated successfully in both the paediatric asthma (OR 3·86, 95% CI 1·19–12·50; p=0·02) and adult COPD (2·41, 1·10–5·28; p=0·03) cohorts. The proportions of patients with adrenal suppression by rs591118 genotype were six (3%) of 214 patients with the GG genotype, 15 (6%) of 244 with the AG genotype, and 22 (25%) of 87 with the AA genotype. Meta-analysis of the paediatric cohorts (discovery and validation) and all three cohorts showed genome-wide significance of rs591118 (respectively, OR 5·89, 95% CI 2·97–11·68; p=4·3 × 10−9; and 4·05, 2·00–8·21; p=3·5 × 10−10). Interpretation: Our findings suggest that genetic variation in the PDGFD gene locus increases the risk of adrenal suppression in children and adults who use corticosteroids to treat asthma and COPD, respectively. Funding: Department of Health Chair in Pharmacogenetics.

Approximately 25% of the asthmatic children suffer from uncontrolled asthma despite regular use of inhaled corticosteroids (ICS).1 Variation within the 17q21 locus is the strongest genetic determinant for childhood‐onset asthma.2 Recently, the influence of this locus on treatment outcomes has been shown in several studies.3, 4 The Pharmacogenomics in Childhood Asthma (PiCA) consortium is a multiethnic consortium that brings together data from ≥14 000 asthmatic children/young adults from 12 different countries to study the pharmacogenomics of uncontrolled asthma despite treatment.5 In 14 PiCA populations (with over 4000 asthmatic patients), we studied the association between variation in the 17q21 locus, and asthma exacerbations despite ICS use. We specifically focused on rs7216389, a single nucleotide polymorphism (SNP) in the 17q21 locus strongly associated with childhood asthma and initially identified by Moffatt et al.2 Ten PiCA studies included patients with non‐Hispanic European origins, two included Hispanic patients, one African American, and one included East Asian patients. Additional details of the study populations can be found in the Data S1. Two outcomes were assessed: (i) asthma‐related hospitalizations/emergency department visit (ED) visits and (ii) short courses of oral corticosteroid (OCS) use reported by the parent/child at the study visit or based on completed study questionnaires. Age, gender, genotype data, and exacerbation data were available for 4529 steroid‐treated children and young adults (Table 1). Logistic regression analysis was used to assess the risk of exacerbations when carrying rs7216389. Due to potential heterogeneity between cohorts, the odds ratios (ORs) were meta‐analyzed with the inverse variance weighting method assuming random effects. See Data S1 for more detail.

Aim: International collaboration is needed to enable large-scale pharmacogenomics studies in childhood asthma. Here, we describe the design of the Pharmacogenomics in Childhood Asthma (PiCA) consortium. Materials & methods: Investigators of each study participating in PiCA provided data on the study characteristics by answering an online questionnaire. Results: A total of 21 studies, including 14,227 children/young persons (58% male), from 12 different countries are currently enrolled in the PiCA consortium. Fifty six percent of the patients are Caucasians. In total, 7619 were inhaled corticosteroid users. Among patients from 13 studies with available data on asthma exacerbations, a third reported exacerbations despite inhaled corticosteroid use. In the future pharmacogenomics studies within the consortium, the pharmacogenomics analyses will be performed separately in each center and the results will be meta-analyzed. Conclusion: PiCA is a valuable platform to perform pharmacogenetics studies within a multiethnic pediatric asthma population.

Researchers should ensure data processing is lawful , fair and transparent, and adheres to the 5 Rs: In order to use personal data for research, both the legal basis General Data Protection Regulation (GDPR) and the ethical basis (informed consent) need to be satisfied. Good research practice already meets most GDPR regulations. GDPR does permit ‘big data’ research, where this methodological approach is necessary and in general facilitates the conduct of research. In the case of research, data subjects are usually the research participants and data controllers are the researchers (but could include, for example, the clinical trials unit). If in doubt, contact your local data protection officer. The key relevant changes brought by the GDPR to research include its

Respiratory syncytial virus (RSV) is a major cause of paediatric respiratory disease. Large numbers of neutrophils are recruited into the airways of children with severe RSV disease. It is not clear whether or how neutrophils enhance recovery from disease or contribute to its pathology.Using an in vitro model of the differentiated airway epithelium, we found that addition of physiological concentrations of neutrophils to RSV infected nasal cultures was associated with greater epithelial damage with lower ciliary activity, cilia loss, less tight junction expression (ZO-1) and more detachment of epithelial cells than seen with RSV infection alone. This was also associated with a decrease in infectious virus and fewer RSV positive cells in cultures after neutrophil exposure compared to pre-exposure. Epithelial damage in response to RSV infection was associated with neutrophil activation (within 1h), and neutrophil degranulation with significantly greater cellular expression of CD11b, MPO and higher neutrophil elastase and myeloperoxidase activity in apical surface medias compared to that from mock-infected AECs. We also recovered more apoptotic neutrophils from RSV infected cultures (>40%), compared to The results of this study could provide important insights into the role of neutrophils in host response in the airway.

The PROteKT study tested the hypothesis that rosuvastatin can inhibit aminoglycoside-induced nephrotoxicity in children with Cystic Fibrosis (CF). This open label, parallel group, randomised controlled trial recruited children and young people aged 6 to 18 years with CF at 13 paediatric CF treatment centres in the UK. Participants were randomised equally to either receive oral rosuvastatin (10 mg once daily) or no intervention (control) throughout clinically indicated treatment with intravenous tobramycin. The primary outcome was the difference between the groups in mean fold-change in urinary Kidney Injury Molecule-1 (KIM-1). Fifty (rosuvastatin n = 23, control n = 27) participants were recruited between May 2015 and January 2017. Primary outcome data was available for 88% (rosuvastatin n = 20, control n = 24). The estimated mean treatment difference in the geometric mean-fold change of normalised KIM-1 was 1.08 (95% CI 0.87–1.35, p = 0.48). In total there were 12 adverse reactions, all mild, reported by five participants randomised to rosuvastatin, and one serious adverse event in each group. Whilst no protective effect of rosuvastatin was seen, there was a lower than expected level of nephrotoxicity in the cohort. Therefore, we can neither confirm nor refute the hypothesis that rosuvastatin protects against aminoglycoside nephrotoxicity.

Introduction Several vaccines for respiratory syncytial virus (RSV) are under development. Designing an effective vaccination programme for RSV requires information about the relative contribution of risk factors for severe RSV symptoms. Aim To inform preventive strategies in Europe by quantifying the contribution of key child, family and health service risk factors to the burden of RSV hospital admissions in young children. Methods We constructed a birth cohort study of all singleton children born in Scotland between October 2009 and September 2012 using linkage between birth registration, maternity, vaccination and hospital admission records, with follow-up until the age of 3 years. RSV-confirmed hospital admissions were defined using linkage to national laboratory surveillance data. We estimated hospital admission rates per 1,000 child years and length of stay according to each risk factor. Cox proportional hazard regression models were used to estimate adjusted hazard ratios. Results There were 5,185 RSV admissions among the 169,726 children in the cohort: 48.6% of admissions occurred before the age of 6 months, and 29.6% after the age of 1 year. Children born prematurely, small for gestational age, between July and December, with chronic conditions, older siblings, mothers Conclusion Future RSV vaccination programmes must protect children throughout early childhood. Vaccination and/or interventions to reduce transmission by older siblings could substantially reduce RSV hospital admissions.

In December 2019, an infectious disease, caused by a novel coronavirus, emerged in Wuhan City, China. The disease was later named coronavirus disease 2019 (COVID-19) and the virus causing it was named the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid spread of COVID-19 worldwide has brought great challenges to local and global public health security and health systems. On March 12, 2020, the World Health Organization (WHO) declared the coronavirus outbreak a global pandemic and raised the risk of a global SARS-CoV-2 outbreak to “very high” (1-6). COVID-19, and its pathogen SARS-CoV-2, represent a novel infectious disease and all populations are therefore susceptible to infection. Its basic reproductive number R0 has been estimated at 3.3 (range 1.4 to 6.5), which is similar to SARS and much higher than Middle East respiratory syndrome (MERS) or influenza (7-10). By April 15, around two million confirmed cases had been reported over 200 countries worldwide. The exact number of patients under the age of 18 remains unknown, but their percentage among all cases is estimated to be less than 2% (11,12). Evidence indicates that the family cluster is the main source of COVID-19 infection for children (13). In contrast to adults, most infected children are asymptomatic or have only mild clinical manifestations. The existing COVID-19 clinical practice guidelines for public health policies have mostly focused on the prevention, diagnosis and treatment in adults, with little attention paid to children. Few of them are based on evidence from systematic reviews (14). Based on the above considerations, an international multidisciplinary working group developed this rapid advice guideline for management of children with COVID-19 using the methods and process proposed by the WHO and GRADE working group (15-17). We present the following article in accordance with the RIGHT reporting checklist (available at http://dx.doi.org/10.21037/atm-20-3754).

Respiratory syncytial virus (RSV) bronchiolitis is the most common cause of infant hospital admissions, but there is limited understanding of the mechanisms of disease, and no specific antiviral treatment. Using a novel in vitro primary transepithelial neutrophil migration model and innovative imaging methods, we show that RSV infection of nasal airway epithelium increased neutrophil transepithelial migration and adhesion to infected epithelial cells, which is associated with epithelial cell damage and reduced ciliary beat frequency, but also with a reduction in infectious viral load.Following migration, RSV infection results in greater neutrophil activation, degranulation and release of neutrophil elastase into the airway surface media compared to neutrophils that migrated across mock-infected nasal epithelial cells. Blocking of the interaction between the ligand on neutrophils (the β2-integrin LFA-1) for intracellular adhesion molecule (ICAM)-1 on epithelial cells reduced neutrophil adherence to RSV-infected cells and epithelial cell damage to pre-infection levels, but did not reduce the numbers of neutrophils that migrated or prevent the reduction in infectious viral load.These findings have provided important insights into the contribution of neutrophils to airway damage and viral clearance, which are relevant to the pathophysiology of RSV bronchiolitis. This model is a convenient, quantitative preclinical model that will further elucidate mechanisms that drive disease severity and has utility in antiviral drug discovery.

M.catarrhalis adherence to the respiratory epithelium is implicated in the pathogenesis of infections and exacerbations of chronic obstructive pulmonary disease (COPD). However, the earliest interaction with the ciliated epithelium in COPD has not been explored. Therefore, we investigated early M.catarrhalis infection of healthy and COPD epithelium. Adherence of M.catarrhalis to healthy and COPD epithelium cultured at air fluid interface was evaluated using high speed video and confocal microscopy and epithelial invasion was quantified by killing extracellular bacteria with imipenem. The effect of apical fluid from cultures on M.catarrhalis growth and biofilm was evaluated. M.catarrhalis bound instantly to the tips of rapidly moving cilia of healthy and COPD cultures, with increasing aggregation of bacteria onto initially bound bacteria. At 15 minutes after infection, 27% of 7 healthy and 5 COPD cultures had bacteria attached to ciliary tips and beat frequency reduced from 9.8±0.5Hz to 8.4±0.4Hz, p=0.029 and 9.4±0.6Hz to 8.1±0.3Hz, p=0.022, respectively, n=10areas/culture. At 24 hours intracellular epithelial uptake of M.catarrhalis was lower in healthy cultures than in COPD (9.8±6.8x102cfu/ml, n=7 healthy vs 2.2±1.3x105cfu/ml, n=4 COPD), p=0.049, confirmed by Z-stack imaging. Preliminary data indicates that apical fluid from ciliated cultures, n=10 reduces growth and biofilm formation of M.catarrhalis by up to 70%. Our results suggest that initial interaction of M.catarrhalis with the respiratory tract involved immediate and strong binding to the tips of rapidly moving cilia that impairs ciliary function. This was followed by intracellular penetration of bacteria which was greater in COPD cultures.

Two meetings, one sponsored by the Wellcome Trust in 2012 and the other by the Global Virology Foundation in 2013, assembled academic, public health and pharmaceutical industry experts to assess the challenges and opportunities for developing antivirals for the treatment of respiratory syncytial virus (RSV) infections. The practicalities of clinical trials and establishing reliable outcome measures in different target groups were discussed in the context of the regulatory pathways that could accelerate the translation of promising compounds into licensed agents. RSV drug development is hampered by the perceptions of a relatively small and fragmented market that may discourage major pharmaceutical company investment. Conversely, the public health need is far too large for RSV to be designated an orphan or neglected disease. Recent advances in understanding RSV epidemiology, improved point-of-care diagnostics, and identification of candidate antiviral drugs argue that the major obstacles to drug development can and will be overcome. Further progress will depend on studies of disease pathogenesis and knowledge provided from controlled clinical trials of these new therapeutic agents. The use of combinations of inhibitors that have different mechanisms of action may be necessary to increase antiviral potency and reduce the risk of resistance emergence.

Aminoglycosides are commonly used for the treatment of pulmonary exacerbations in patients with cystic fibrosis (CF). However, they are potentially nephrotoxic. This prospective observational cohort study aimed to investigate the potential validity of two urinary renal biomarkers, Kidney Injury Molecule-1 (KIM-1) and Neutrophil Gelatinase-associated Lipocalin (NGAL), in identifying aminoglycoside-induced nephrotoxicity in children with CF. Children and young adults up to 20 years of age with a confirmed diagnosis of CF were recruited from ten United Kingdom hospitals. Participants provided urine samples for measurement of KIM-1 and NGAL concentrations, at baseline, at regular outpatient appointments, and before, during and after exposure to clinically-indicated treatment with the aminoglycoside tobramycin. 37/158 patients recruited (23.4%) received at least one course of IV tobramycin during the study. The median peak fold-change during tobramycin exposure for KIM-1 was 2.28 (IQR 2.69) and 4.02 (IQR 7.29) for NGAL, in the absence of serum creatinine changes. Baseline KIM-1 was positively associated with cumulative courses of IV aminoglycosides (R2 = 0.11; β = 0.03; p

Aminoglycoside antibiotics, in particular gentamicin and tobramycin, are still commonly used in paediatric clinical practice. These drugs cause nephrotoxicity, which particularly affects the proximal tubule epithelial cells due to selective endocytosis and accumulation of aminoglycosides via the multi-ligand receptor megalin. Recent epidemiological studies, using more widely accepted definitions of acute kidney injury (AKI), have suggested that AKI may occur in between 20 and 33 % of children exposed to aminoglycosides. A consensus set of phenotypic criteria for aminoglycoside-induced nephrotoxicity have recently been published. These are specifically designed to provide robust phenotyping for pharmacogenomic studies, but they can pave the way for standardisation for all clinical studies. Novel renal biomarkers, in particular kidney injury molecule-1, identify aminoglycoside-induced proximal tubular injury earlier than traditional markers and have shown promise in observational studies. Further studies need to demonstrate a clear association with clinically relevant outcomes to inform translation into clinical practice. Extended interval dosing of aminoglycosides results in a reduction in nephrotoxicity, but its use needs to become more widespread. Inhibition of megalin-mediated endocytosis by statins represents a novel approach to the prevention of aminoglycoside-induced nephrotoxicity which is currently being evaluated in a clinical trial. Recommendations for future directions are provided.

Background Poor nutrition occurs frequently in people with cystic fibrosis and is associated with other adverse outcomes. Oral calorie supplements are used to increase total daily calorie intake and improve weight gain. However, they are expensive and there are concerns they may reduce the amount of food eaten and not improve overall energy intake. This is an update of a previously published review. Objectives To establish whether in people with cystic fibrosis, oral calorie supplements: increase daily calorie intake; and improve overall nutritional intake, nutritional indices, lung function, survival and quality of life. To assess adverse effects associated with using these supplements. Search methods We searched the Cochrane Cystic Fibrosis Trials Register comprising references from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We contacted companies marketing oral calorie supplements. Last search: 18 October 2016. Selection criteria Randomised or quasi-randomised controlled trials comparing use of oral calorie supplements for at least one month to increase calorie intake with no specific intervention or additional nutritional advice in people with cystic fibrosis. Data collection and analysis We independently selected the included trials, assessed risk of bias and extracted data. We contacted the authors of included trials and obtained additional information for two trials. Main results We identified 21 trials and included three, reporting results from 131 participants lasting between three months and one year. Two trials compared supplements to additional nutritional advice and one to no intervention. Two of the included trials recruited only children. In one trial the risk of bias was low across all domains, in a second trial the risk of bias was largely unclear and in the third mainly low. Blinding of participants was unclear in two of the trials. Also, in one trial the clinical condition of groups appeared to be unevenly balanced at baseline and in another trial there were concerns surrounding allocation concealment. There were no significant differences between people receiving supplements or dietary advice alone for change in weight, height, body mass index, z score or other indices of nutrition or growth. Changes in weight (kg) at three, six and 12 months respectively were: mean difference (MD) 0.32 (95% confidence interval (CI) -0.09 to 0.72); MD 0.47 (95% CI -0.07 to 1.02 ); and MD 0.16 (-0.68 to 1.00). Total calorie intake was greater in people taking supplements at 12 months, MD 265.70 (95% CI 42.94 to 488.46). There were no significant differences between the groups for anthropometric measures of body composition, lung function, gastro-intestinal adverse effects or activity levels. Moderate quality evidence exists for the outcomes of changes in weight and height and low quality evidence exists for the outcomes of change in total calories, total fat and total protein intake as results are applicable only to children between the ages of 2 and 15 years and many post-treatment diet diaries were not returned. Evidence for the rate of adverse events in the treatment groups was extremely limited and judged to be of very low quality Authors' conclusions Oral calorie supplements do not confer any additional benefit in the nutritional management of moderately malnourished children with cystic fibrosis over and above the use of dietary advice and monitoring alone. While nutritional supplements may be used, they should not be regarded as essential. Further randomised controlled trials are needed to establish the role of short-term oral protein energy supplements in people with cystic fibrosis and acute weight loss and also for the long-term nutritional management of adults with cystic fibrosis or advanced lung disease, or both.

AIM: To develop and test a new tool to assess the avoidability of adverse drug reactions that is suitable for use in paediatrics but which is also applicable to a variety of other settings.METHODS: The study involved multiple phases. Preliminary work involved using the Hallas scale and a modification of the existing Hallas scale, to assess two different sets of adverse drug reaction (ADR) case reports. Phase 1 defined, modified and refined a new tool using multidisciplinary teams. Phase 2 involved the assessment of 50 ADR case reports from a prospective study of paediatric inpatients by individual assessors. Phase 3 compared assessments with the new tool for individuals and groups in comparison to the 'gold standard' (the avoidability outcome set by a panel of senior investigators: an experienced clinical pharmacologist, paediatrician and pharmacist).MAIN OUTCOME MEASURES: Inter-rater reliability (IRR), measure of disagreement and utilization of avoidability categories.RESULTS: Preliminary work-Pilot phase: results for the original Hallas cases were fair and pairwise kappa scores ranged from 0.21 to 0.36. Results for the modified Hallas cases were poor, pairwise kappa scores ranged from 0.06 to 0.16. Phase 1: on initial use of the new tool, agreement between the two multidisciplinary groups was found on 13/20 cases with a kappa score of 0.29 (95% CI -0.04 to 0.62). Phase 2: the assessment of 50 ADR case reports by six individual reviewers yielded pairwise kappa scores ranging from poor to good 0.12 to 0.75 and percentage exact agreement (%EA) ranged from 52-90%. Phase 3: Percentage exact agreement ranged from 35-70%. Overall, individuals had better agreement with the 'gold standard'.CONCLUSION: Avoidability assessment is feasible but needs careful attention to methods. The Liverpool ADR avoidability assessment tool showed mixed IRR. We have developed and validated a method for assessing the avoidability of ADRs that is transparent, more objective than previous methods and that can be used by individuals or groups.

AimsTo comprehensively investigate the incidence, nature and risk factors of adverse drug reactions (ADRs) in a hospital-based population of children, with rigorous assessment of causality, severity and avoidability, and to assess the consequent impact on children and families. We aimed to improve the assessment of ADRs by development of new tools to assess causality and avoidability, and to minimise the impact on families by developing better strategies for communication.Review methodsTwo prospective observational studies, each over 1 year, were conducted to assess ADRs in children associated with admission to hospital, and those occurring in children who were in hospital for longer than 48 hours. We conducted a comprehensive systematic review of ADRs in children. We used the findings from these studies to develop and validate tools to assess causality and avoidability of ADRs, and conducted interviews with parents and children who had experienced ADRs, using these findings to develop a leaflet for parents to inform a communication strategy about ADRs.ResultsThe estimated incidence of ADRs detected in children on admission to hospital was 2.9% [95% confidence interval (CI) 2.5% to 3.3%]. Of the reactions, 22.1% (95% CI 17% to 28%) were either definitely or possibly avoidable. Prescriptions originating in the community accounted for 44 out of 249 (17.7%) of ADRs, the remainder originating from hospital. A total of 120 out of 249 (48.2%) reactions resulted from treatment for malignancies. Off-label and/or unlicensed (OLUL) medicines were more likely to be implicated in an ADR than authorised medicines [relative risk (RR) 1.67, 95% CI 1.38 to 2.02;p p = 0.830). For children who had been in hospital for > 48 hours, the overall incidence of definite and probable ADRs based on all admissions was 15.9% (95% CI 15.0 to 16.8). Opiate analgesic drugs and drugs used in general anaesthesia (GA) accounted for > 50% of all drugs implicated in ADRs. The odds ratio of an OLUL drug being implicated in an ADR compared with an authorised drug was 2.25 (95% CI 1.95 to 2.59;p ConclusionThe Adverse Drug Reactions In Children (ADRIC) programme has provided the most comprehensive assessment, to date, of the size and nature of ADRs in children presenting to, and cared for in, hospital, and the outputs that have resulted will improve the management and understanding of ADRs in children and adults within the NHS. Recommendations for future research: assess the values that parents and children place on the use of different medicines and the risks that they will find acceptable within these contexts; focusing on high-risk drugs identified in ADRIC, determine the optimum drug dose for children through the development of a gold standard practice for the extrapolation of adult drug doses, alongside targeted pharmacokinetic/pharmacodynamic studies; assess the research and clinical applications of the Liverpool Causality Assessment Tool and the Liverpool Avoidability Assessment Tool; evaluate, in more detail, morbidities associated with anaesthesia and surgery in children, including follow-up in the community and in the home setting and an assessment of the most appropriate treatment regimens to prevent pain, vomiting and other postoperative complications; further evaluate strategies for communication with families, children and young people about ADRs; and quantify ADRs in other settings, for example critical care and neonatology.FundingThe National Institute for Health Research Programme Grants for Applied Research programme.

Background Bronchiolitis caused by respiratory syncytial virus (RSV) is the most common reason for hospital admissions in infants. The community burden of RSV is less well understood. We used a unique dataset linking serial serological data, questionnaires, and routinely collected health records to undertake the first community-based serological survey of RSV in England. Methods We used stored blood samples, tested for immunoglobulin G RSV postfusion F antibody, linked to questionnaires and primary and secondary care records from the Born in Bradford cohort study, collected at birth, and ages 1 and 2 years. We used finite mixture models to classify children as RSV infected or not infected according to their antibody concentrations. We fitted multivariable Poisson regression models with robust error variances to identify factors associated with increased risk of primary RSV infection at ages younger than 1 year and 1–2 years. Findings The study included 490 children. By their first birthday, 258 children (53%, 95% CI 48–57%) had serological evidence of past RSV infection, 99 (38%) of whom contacted health-care services during peak RSV season (November–January) due to a respiratory tract infection. Having older siblings (adjusted risk ratio [aRR] 1·52, 95% CI 1·21–1·92, comparing one to no older siblings), Pakistani ethnicity (1·31, 1·04–1·65, compared with White British), blood sample taken outside October–December (1·74, 1·35–2·24 for January–March and 1·60, 1·23–2·08 for April–June, compared with October–December), and attending formal childcare (1·40, 1·12–1·75, compared with no formal childcare) were predictive of RSV infection in infancy. A further 164 children (33%, 95% CI 29–38%) were newly infected at ages 1–2 years, 58 (35%) of whom had contact with health-care services. 14% (95% CI 11–17%) had no evidence of RSV infection by age 2 years. Interpretation Around half of children are infected with RSV during the first year of life, and one in seven children remain unexposed after their second year. Our findings will inform future analyses to assess the cost-effectiveness of RSV vaccination programmes. Our novel approach reusing stored blood samples and linked data present a time-efficient and cheap method for future serological surveys of RSV. Funding Wellcome Trust Seed Award In Science (grant reference number 207673/Z/17/Z).

Summary Background Poorer socioeconomic circumstances have been linked with worse outcomes in cystic fibrosis. We assessed whether a relation exists between social deprivation and individual's clinical and health-care outcomes. Methods We did a longitudinal registry study of the UK cystic fibrosis population younger than 40 years (8055 people with 49 337 observations for weight, the most commonly collected outcome, between Jan 1, 1996, and Dec 31, 2009). We assessed data for weight, height, body-mass index, percent predicted forced expiratory volume in 1 s (%FEV 1 ), risk of Pseudomonas aeruginosa colonisation, and the use of major cystic fibrosis treatment modalities. We used mixed effects models to assess the association between small-area deprivation and clinical and health-care outcomes, adjusting for clinically important covariates. We give continuous outcomes as mean differences, and binary outcomes as odds ratios, comparing extremes of deprivation quintile. Findings Compared with the least deprived areas, children from the most deprived areas weighed less (standard deviation [SD] score −0·28, 95% CI −0·38 to −0·18), were shorter (–0·31, −0·40 to −0·21, and had a lower body-mass index (–0·13, −0·22 to −0·04), were more likely to have chronic P aeruginosa infection (odds ratio 1·89, 95% CI 1·34 to 2·66), and have a lower %FEV 1 (–4·12 percentage points, 95% CI −5·01 to −3·19). These inequalities were apparent very early in life and did not widen thereafter. On a population level, after adjustment for disease severity, children in the most deprived quintile were more likely to receive intravenous antibiotics (odds ratio 2·52, 95% CI 1·92 to 3·17) and nutritional treatments (1·78, 1·44 to 2·20) compared with individuals in the least deprived quintile. Patients from the most disadvantaged areas were less likely to receive DNase or inhaled antibiotic treatment. Interpretation In the UK, children with cystic fibrosis from more disadvantaged areas have worse growth and lung function compared with children from more affluent areas, but these inequalities do not widen with advancing age. Clinicians consider deprivation status, as well as disease status, when making decisions about treatments, and this might mitigate some effects of social disadvantage. Funding Medical Research Council (UK).

Aims To investigate parents' views and experiences of direct reporting of a suspected ADR in their child. Methods We audio-recorded semi-structured qualitative interviews with parents of children with suspected ADRs. Our sample included parents with (n = 17) and without (n = 27) previous experience of submitting a Yellow Card. Results Parents in both groups described poor awareness of the Yellow Card Scheme. Parents who had participated in the Yellow Card Scheme were generally happy to report their child's ADR via the Scheme and valued the opportunity to report concerns independently of health practitioners. They expressed motivations for reporting that have not previously been described linked to the parental role, including how registering a concern about a medicine helped to resolve uncomfortable feelings about their child's ADR. Parents who had not previously submitted a Yellow Card expressed uncertainty about the legitimacy of their involvement in reporting and doubts about the value of the information that they could provide. Conclusion Promoting wider participation in pharmacovigilance schemes will depend on raising public awareness. Additionally, our findings point to the need to empower lay people to submitting reports and to reassure them about the value of their reports.

Background: Genetic variation may partly explain heterogeneity in response to asthma treatment . Recently, the P harmacogenomics i n C hildhood A sthma (PiCA) consortium was initiated to perform large-scale pharmacogenomics studies. Aims: To describe the characteristics of the asthmatic children currently included in PiCA and to assess treatment response definitions within this growing consortium. Methods: An online survey including questions about data collection, patient characteristics and outcome phenotypes was send to the 20 studies included in the PiCA consortium. Results: In total, 14,634 children/young adults (up to 25 years) from 11 different countries are enrolled in the PiCA consortium. Preliminary analysis of patients showed that 60% of the patients are male. PiCA is ethnically diverse: 47% Caucasians, 25% Latinos, 14% Asians, 9% African-Americans, 2% have mixed/other-ethnicity and 3% is unknown. PiCA currently includes data of 2,056 severe asthmatics. Furthermore, PiCA has data of 8,907 short acting β 2 -adrenergic agonist (SABA) users, 7,908 ICS users, 2,054 leukotriene modifier (LTM) users and 1,543 users of long acting β 2 -adrenergic agonists (LABA). Ninety-five percent of the studies have information regarding asthma exacerbations and lung function measurements and 80% have data on asthma symptoms. Discussion: The children within the PiCA consortium are a reflection of the global heterogeneous pediatric asthma population. Different outcome measures reflect different dimensions of asthma. By classifying three commonly used outcome measures using data that are available within the PiCA consortium, we will be able to study distinct response phenotypes in relation to genetics and clinical factors.

A number of medications do not have a licence, or label, for use in the paediatric age group nor for the specific indication for which they are being used in children. Over recent years, mycophenolate mofetil has increasingly been used off-label (i.e. off-licence) in adults for a number of indications, including autoimmune conditions; progressively, this wider use has been extended to children. This review summarizes current use of mycophenolate mofetil (MMF) in children, looking at how MMF works, the pharmacokinetics, the clinical conditions for which it is used, the advantages it has when compared with other immunosuppressants and the unresolved issues remaining with use in children. The review aims to focus on off-label use in children so as to identify areas that require further research and investigation. The overall commercial value of MMF is limited because it has now come off patent in adults. Given the increasing knowledge of the pharmacodynamics, pharmacokinetics and pharmacogenomics demonstrating the clinical benefits of MMF, new, formal, investigator-led studies, including trials focusing on the use of MMF in children, would be of immense value.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Use of off-label and unlicensed medicines in children is associated with a higher risk of adverse drug reactions (ADRs). • Spontaneous reporting systems such as the UK Yellow Card Scheme run by the Medicines and Healthcare Products Regulatory Agency (MHRA) are important in identifying signals of ADRs. • Up to 95% of all ADRs are not reported, despite current MHRA advice to report all suspected paediatric ADRs. WHAT THIS STUDY ADDS • Despite under-reporting, the Yellow Card Scheme receives more than 2000 reports per year on patients

Bronchiolitis is the commonest cause of lower respiratory tract infection in children under the age of 1 year [1]. Most cases are caused by respiratory syncytial virus (RSV), of which there are 2 serotypes, A and B. Serotype A is the most common serotype found in United Kingdom (UK) seasonal epidemics, although proportions vary annually [2]. The clinical manifestations of RSV infection range from mild upper respiratory tract symptoms, to severe lower respiratory tract infection presenting as low-grade fever that can progress over several days to coughing, wheezing, shortness of breath, and difficulty with feeding. Although some infants with bronchiolitis have clinical symptoms beyond the lungs including otitis media, myocardial failure, seizures, and hepatitis, [3] whether these extrapulmonary manifestations are due to RSV infection itself or to secondary effects is not fully understood. RSV RNA has been detected outside the lungs in cerebrospinal fluid [4], myocardium [5], and liver [6]. Human RSV is transmitted by inhalation of aerosolized virus droplets to the airway epithelium [7], a major site for viral replication. Infection is followed by cytokine release and airway inflammation [8, 9]. The surface glycoproteins RSV F and G facilitate binding of the virus [10, 11] to their target cells whereas RSV N protein is located inside the virion, tightly bound to the genome. In vitro, RSV has been shown to infect epithelial cells [12]), alveolar macrophages [13], dendritic cells [14, 15], and bone marrow stromal cells [16]. Infection of the epithelial cells promotes the release of cytokines [17–19] and the recruitment of inflammatory cells [17]. Neutrophils are recruited early in the course of infection and represent >80% of the inflammatory cell infiltrate in bronchoalveolar lavage (BAL) at the peak of the patient’s clinical symptoms [17]. Neutrophils in the airways are highly activated [20], release cytokines [21–24], and have delayed apoptosis [25, 26]. However, how they influence RSV clearance or viral replication within the human airway remains largely unknown. The aim of this study was to determine whether RSV directly interacts with, or indeed infects, infant neutrophils in the lung and peripheral circulation, by measuring RSV protein and gene transcript expression in neutrophils from the blood and BAL of infants with severe RSV bronchiolitis.

Background Child development in developing countries is often evaluated using assessment tools created for 'Western' settings. Recent work has demonstrated that, for certain developmental milestones, 'Western' tools may be inaccurate as they include items unfamiliar to children of different cultural settings. Methods We used qualitative methods to gather information about normal development in an African setting. Ten village and two professional focus group discussions (FGDs) were conducted. We used purposive sampling methods to recruit groups of mothers, grandmothers and men in four areas of Southern Malawi for village FGDs. Separate FGDs were carried out with professionals working in areas relating to child development. A thematic content analysis established main patterns and themes and dissemination of results and continued feedback allowed for respondent validation and reflection of results. The information then gathered was used to create questions for a revised Malawian developmental assessment tool. Results Social and gross motor milestones were the main focus of interest for village and professional FGDs with the latter creating new language and fine motor concepts. Social milestones highlighted included 'duties and chores', 'sharing' and 'taking up leadership roles'. Language milestones included 'reporting events' and 'shrugging to indicate no' and fine motor milestones included 'peeling bananas', 'sorting maize' and 'making patterns with bottle tops'. Intelligence was described in relation to social and community integrity rather than 'Western' concepts of numeracy and literacy. Conclusions Concepts, ideas and language relating to normal development in a sub-Saharan African setting have been gathered in this study. These have been used to create items for a more culturally appropriate developmental assessment tool.

Background: In respiratory syncytial virus (RSV) bronchiolitis, neutrophils account for >80% of cells recovered from the airways in bronchoalveolar lavage (BAL) fluid. This study investigated neutrophil activation and Toll-like receptor (TLR) expression in the blood and lungs of infants with severe RSV bronchiolitis. Methods: BAL fluid and (blood) samples were collected from 24 (16) preterm and 23 (15) term infants ventilated with RSV bronchiolitis, and 12 (8) control infants. Protein levels and mRNA expression of CD11b, myeloperoxidase (MPO) and TLRs 2, 4, 7, 8 and 9 were measured in neutrophils. Results: Blood neutrophils had more CD11b in preterm and term infants with RSV bronchiolitis than control infants (p

Streptococcus pneumoniae (the pneumococcus) is estimated to cause approximately 1 million deaths per year in children in the developing world.1 The pneumococcus is the primary cause of pneumonia and meningitis in children in the developing world1 and is the leading cause of community-acquired bacteremia in children in sub-Saharan Africa.2 The burden of invasive pneumococcal disease (IPD) has increased in areas with a high prevalence of HIV infection.3 In South Africa, the disease incidence in children younger than 2 years of age has been shown to be 73 per 100,000 children per year in HIV-uninfected children compared with 3036 per 100,000 children per year in HIV-infected children.4 Chemokines (or chemoattractant cytokines) are subdivided into 4 distinct subfamilies (CC, CXC, CX3C, and C) depending on the arrangement and number of the conserved N-terminal cysteine molecules. The CC chemokines (also called β chemokines) have the first 2 cysteine molecules adjacent, include regulated on activation normal T cells expressed and secreted (RANTES or CCL5), monocyte chemotactic protein-1 (MCP-1 or CCL2), macrophage inflammatory protein-1α (MIP-1α or CCL3) and MIP-1β (CCL4), and they preferentially attract monocytes and/or macrophages and eosinophils. The CXC chemokines (also called α chemokines) have the first 2 cysteine molecules separated by an amino acid, which includes interleukin (IL)-8 (or CXCL8), growth-related oncogene (GROα or CXCL1), and epithelial cell–derived neutrophil activating peptide (ENA-78 or CXCL5), and they preferentially attract neutrophils.5,6 Interferon-γ (IFNγ) has been demonstrated to modulate the release of chemokines in pneumococcal cell wall–stimulated mouse microglia differentially, supporting the view that activated microglia are a major intrinsic source of central nervous system (CNS) chemokine production and that IFNγ potentially regulates this microglial chemokine response pattern.7 Because chemokines are specific for particular cell types, the ratio and concentration of different chemokines in different body compartments determine the composition of the different cell types within the particular compartment. To understand the host response, IPD, more fully, it is important to gain insight into the production and regulation of chemokines at local sites of inflammation. The HIV coreceptor CCR5 also acts as a receptor for CCL3, CCL4, and CCL5, and receptor binding and CCR5-dependent inhibition of HIV infection are induced by CCL8.8 CCR2b, the receptor for CCL2 (and CCL7, CCL8, and CCL13) is also a coreceptor for HIV and is expressed on peripheral blood lymphocytes and monocytes and/or macrophages.9 In HIV infection, CC chemokines induce an inflammatory response attracting noninfected target cells to the site of active viral replication and also induce intracellular signaling that enhances viral replication.10 The aims of this study were to investigate the chemokine response to IPD in children with pneumonia and meningitis and to examine the influence of HIV infection on the chemokine response, pneumococcal bacterial loads, and outcome.

Objective To assess risks for parental depression following the diagnosis of cystic fibrosis (CF) in a child. Study design Matched cohort study in NW England; 45 parental couples with a child diagnosed with CF were compared with 45 control couples matching for age, sex, and position in the family of the index child. The Beck Depression Inventory (BDI-II) with a clinical cut-off ≥13 for dysphoria (mild depression) was the main outcome. A stratified analysis was conducted using the Mantel-Haenszel risk-ratio estimator ( RR MH ) with eight strata for each of the matching variable combinations. Results Heterogeneity was found within the dataset. Parents with a child with CF ≤9 months of age at baseline had an elevated prospective risk of depression (mothers RR MH [95% confidence interval(CI)] = 2·6[1·05,6·42], fathers RR MH [95%CI] = 2·26 [0·97,5·28]). The absence of a group effect for depression at follow-up after adjusting for the matching (mothers RR MH [95%CI] = 1·1 [0·59,2·05], fathers RR MH [95%CI] = 1·42 [0·66,3·08]) masked this heterogeneity. Conclusion This hypothesis-generating finding suggests that parents may be more vulnerable to depression when their child is diagnosed with a life-shortening condition during the first few months of life. Mood in parents of infants diagnosed early needs to be monitored longitudinally and preventative strategies devised.

We have previously shown high rates of co-infection with Respiratory Syncytial Virus (RSV) and human Metapneumovirus (hMPV) in infants with severe bronchiolitis at our institution in 2000-2002, and that co-infection was associated with increased disease severity. In this study, we have attempted to identify differences in intubated infants with severe RSV infection with and without hMPV co-infection. Here we show that RSV+/hMPV+ were clinically symptomatic for longer than RSV+/hMPV- infants, but that no differences in airway total cell concentration, differential cell count or cytokine/chemokine concentrations were detectable.

Background: RSV is a common infection during infancy; nearly all children will be infected by the age of 2 years. Although the majority have a self-limiting mild infection, 1-3% of all infants require admission to hospital during their first winter. These children have an abundance of neutrophils (>80% of bronchoalveolar lavage cells) within their airways. We have previously shown that RSV can enter neutrophils, both in vitro and ex vivo , but does not productively replicate. However, the extent to which RSV neutrophilia is protective versus pathogenic is unclear. Objective: To explore the neutrophil host response to RSV, hypothesising that neutrophils contribute to the pulmonary innate antiviral response. Methods: An in vitro model of RSV and neutrophil interaction was established. Following validation of this model, confirming presence of the virus within the neutrophil by confocal microscopy, gene microarray experiments were carried out. Results: RSV induced significant change in neutrophil gene expression with over 1000 differentially expressed genes being identified. Following data quality assessments, pathway analysis was performed revealing that a significant number of antiviral pathways were being activated. Validation using real time RT-PCR has confirmed differential expression within a number of these pathways Conclusions: We have shown for the first time that following RSV entry, a robust antiviral response is mounted by the neutrophil, which includes both modulation of interferon responses and up regulation of pathways inhibiting viral replication. These findings reveal the contribution of neutrophils to the innate immune response in the airway during viral infection.

Background To better understand the relative effects of infection with nontuberculous mycobacteria and Gram negative bacteria on lung function decline in cystic fibrosis, we assessed the impact of each infection in a Danish setting. Methods Longitudinal registry study of 432 patients with cystic fibrosis contributing 53,771 lung function measures between 1974 and 2014. We used a mixed effects model with longitudinally structured correlation, while adjusting for clinically important covariates. Results Infections with a significant impact on rate of decline in %FEV1 were Mycobacterium abscessus complex with − 2.22% points per year (95% CI − 3.21 to − 1.23), Burkholderia cepacia complex − 1.95% (95% CI − 2.51 to − 1.39), Achromobacterxylosoxidans − 1.55% (95% CI − 2.21 to − 0.90), and Pseudomonas aeruginosa − 0.95% (95% CI − 1.24 to − 0.66). Clearing M. abscessus complex was associated with a change to a slower decline, similar in magnitude to the pre-infection slope. Conclusions In a national population we have demonstrated the impact on lung function of each chronic CF pathogen. M. abscessus complex was associated with the worst impact on lung function. Eradication of M. abscessus complex may significantly improve lung function., Graphical abstract Effect on lung function of chronic infection from onset to end stage lung disease in Danish cystic fibrosis patients.

This chapter describes our longitudinal registry studies examining the effect of social deprivation on longitudinal clinical outcomes, healthcare use and employment opportunities in people with cystic fibrosis (CF). Because CF is genetically determined, this offers an opportunity to investigate the impact of deprivation on health and social outcomes, in a chronic condition without a socio-economic gradient in incidence. It helps in understanding how and when health inequalities are generated, in a chronic disease of childhood onset. The analyses show that children and adults with CF from more disadvantaged areas in the UK have worse growth and lung function compared with people from more affluent areas. These inequalities appear early, but do not widen with advancing age in the UK. In terms of use and access to treatments in the British National Health Service (NHS), more disadvantaged CF patients are more likely to receive antibiotic and nutritional treatments, after adjusting for disease severity, but less likely to receive inhaled therapies such as DNase. This inequality becomes more evident after transition to adult care. In adults with CF, greater deprivation, disease severity, and time in hospital all reduce employment chances. We discuss the implications of these findings for public health policy and care in cystic fibrosis.

Objective To determine whether oral protein energy supplements, used long term in children with cystic fibrosis who are moderately malnourished, improve nutritional and other outcomes. Design Multicentre randomised controlled trial.Setting Seven specialist paediatric cystic fibrosis centres and their associated shared care clinics and seven smaller paediatric cystic fibrosis clinics. Participants 102 children with cystic fibrosis, aged between 2 and 15 years, who were moderately malnourished. Interventions Oral protein energy supplements in addition to usual dietary advice compared with dietary advice alone, for 12 months. Main outcome measure Change in body mass index centile over one year. Results Use of supplements was not associated with a change in body mass index centile (mean difference 2.99 centile points, 95% confidence interval −2.70 to 8.68) or other nutritional and spirometric outcomes in this group of children. Conclusions Long term use of oral protein energy supplements did not result in an improvement in nutritional status or other clinical outcomes in children with cystic fibrosis who were moderately malnourished. Oral protein energy supplements should not be regarded as an essential part of the management of this group of children. Trial registration ISRCTN: 95744468.

Cystic fibrosis (CF) is the most common life limiting genetic disorder of white populations. There are over 6000 patients in the UK with this condition and at least 30 000 in the USA.1 This review focuses on the challenges of diagnosis, clinical complications, and management of children with CF. CF is a multisystem disorder with a wide spectrum of clinical manifestations, and patients may present to a range of medical specialists. Table 1 lists some of the clinical features, which may lead to a presentation of CF. The diagnosis can be confirmed by sweat and/or genetic testing. In 2001, the UK’s Department of Health announced that newborn screening for CF would be introduced nationally and it is likely that this will be implemented by 2006. By identifying infants with CF at an early age, newborn screening will have a considerable impact on the investigation of children with suspected CF. However, in most areas of the country, for many years there will be a large cohort of children and adults with CF who have not been diagnosed as part of a neonatal screening programme and who will need to be investigated by sweat and/or genetic testing. Sweat testing will also continue to play a role in the investigation of the infant where the screening tests suggest CF. View this table: Table 1 Presentation of cystic fibrosis (CF) Sweat chloride > 60 mmol/l is considered diagnostic of CF. Values of sweat chloride of 40–60 mmol/l are considered highly suggestive of CF, and in this situation the sweat test should be repeated and/or genetic testing conducted. Although in CF patients there is a fall in sweat chloride with age, the magnitude of this fall is not sufficient to cause diagnostic confusion, if these criteria are used.2 Sweat sodium measurements are less reliable as concentrations of 60–80 …

Background. Respiratory syncytial virus (RSV) bronchiolitis in infants is characterized by a massive neutrophilic infiltrate into the airways. Chemokines direct migration of leukocytes and contribute to the pathogenesis of RSV disease. However, little is known about pulmonary chemokine responses to RSV in humans. Our aim was to characterize the production of chemokines in the lungs of infants with RSV bronchiolitis and how this production changes over time. Methods. Chemokine mRNA and the concentration of chemokines were measured in nonbronchoscopic bronchoalveolar lavage (BAL) samples from infants with RSV bronchiolitis and from control infants. In infants with RSV bronchiolitis, changes in the concentrations of chemokines during the 7 days after intubation and between the days of intubation and extubation were examined. Results. The production of chemokines within the lower respiratory tract was shown in all patients with RSV bronchiolitis. CXC chemokines (particularly CXCL10/interferon-inducible protein 10 and CXCL8/interleukin-8) were found to be the most abundant, but CC chemokines (CCL2/monocyte chemotactic protein 1 and CCL3/ macrophage inflammatory protein‐1a) were also present. Concentrations of some of these chemokines remained elevated over the course of the illness, whereas others decreased steadily. No differences in the concentrations were found between the days of intubation and extubation. Conclusions. CXC chemokines predominate within the RSV-infected lung. Much of this response comes from inflammatory cells within the lower respiratory tract. Chemokine response patterns vary over time, possibly indicating different cellular sources for individual chemokines in the RSV-infected lung. Respiratory syncytial virus (RSV) bronchiolitis is the most prevalent serious lower respiratory tract infection in infants !1 year of age. Approximately 2% of all infants require admission to the hospital when they have this illness, and 2%‐3% of those admitted require mechanical ventilation [1‐3]. In this subgroup of infants with severe RSV bronchiolitis, preterm babies are overrepresented [4]. In recent years, there has been much interest in the immunopathogenesis of RSV bronchiolitis, and a number of animal models have been de

The association between severe bronchiolitis and dual infection by human metapneumovirus (hMPV) and human respiratory syncytial virus (hRSV) was investigated in !2-year-old infants with bronchiolitis who were admitted to the hospital during the 2001–2002 winter season. hMPV in nasopharyngeal aspirate and/or cells and fluid collected by nonbronchoscopic bronchoalveolar lavage was detected by reverse transcriptase-polymerase chain reaction (RT-PCR). hRSV was detected in nasopharyngeal aspirate and/or cells and fluid collected by nonbronchoscopic bronchoalveolar lavage by enzyme immunoassay, tissue culture, and RT-PCR. Dual infection with hMPV and hRSV confers a 10-fold increase in relative risk (RR) of admission to a pediatric intensive-care unit for mechanical ventilation (RR, 10.99 [95% confidence interval, 5.0–24.12]; P < .001, by Fisher exact test). Dual infection by hMPV and hRSV is associated with severe bronchiolitis.

Objective: To investigate the validity and reliability of computerised acoustic analysis in the detection of abnormal respiratory noises in infants. Methods: Blinded, prospective comparison of acoustic analysis with stethoscope examination. Validity and reliability of acoustic analysis were assessed by calculating the degree of observer agreement using the κ statistic with 95% confidence intervals (CI). Results: 102 infants under 18 months were recruited. Convergent validity for agreement between stethoscope examination and acoustic analysis was poor for wheeze (κ = 0.07 (95% CI, −0.13 to 0.26)) and rattles (κ = 0.11 (−0.05 to 0.27)) and fair for crackles (κ = 0.36 (0.18 to 0.54)). Both the stethoscope and acoustic analysis distinguished well between sounds (discriminant validity). Agreement between observers for the presence of wheeze was poor for both stethoscope examination and acoustic analysis. Agreement for rattles was moderate for the stethoscope but poor for acoustic analysis. Agreement for crackles was moderate using both techniques. Within-observer reliability for all sounds using acoustic analysis was moderate to good. Conclusions: The stethoscope is unreliable for assessing respiratory sounds in infants. This has important implications for its use as a diagnostic tool for lung disorders in infants, and confirms that it cannot be used as a gold standard. Because of the unreliability of the stethoscope, the validity of acoustic analysis could not be demonstrated, although it could discriminate between sounds well and showed good within-observer reliability. For acoustic analysis, targeted training and the development of computerised pattern recognition systems may improve reliability so that it can be used in clinical practice.

The first and most crucial stage in performing a comprehensive search of the literature is to formulate a clearly defined question, which can easily be translated into an effective search strategy. The next stage is to choose the most appropriate information resource. There are many resources available, some of which provide access to summaries of pre-appraised high-quality information. These resources should be searched initially and can be interrogated simply by using one or two key terms taken from the search strategy developed. If this approach fails to retrieve any relevant material then more general medical databases should be sought. General medical databases such as MEDLINE provide access to primary research articles. These require more complex interrogation, using many terms from the devised search strategy to maximize the number of relevant hits.