ObjeCtivesTo systematically review studies investigating the prevalence of antibiotic resistance in urinary tract infections caused by Escherichia coli in children and, when appropriate, to meta-analyse the relation between previous antibiotics prescribed in primary care and resistance. Design anD Data analysisSystematic review and meta-analysis. Pooled percentage prevalence of resistance to the most commonly used antibiotics in children in primary care, stratified by the OECD (Organisation for Economic Co-operation and Development) status of the study country. Random effects meta-analysis was used to quantify the association between previous exposure to antibiotics in primary care and resistance. Data sOurCesObservational and experimental studies identified through Medline, Embase, Cochrane, and ISI Web of Knowledge databases, searched for articles published up to October 2015.eligibility Criteria fOr seleCting stuDies Studies were eligible if they investigated and reported resistance in community acquired urinary tract infection in children and young people aged 0-17. Electronic searches with MeSH terms and text words identified 3115 papers. Two independent reviewers assessed study quality and performed data extraction. results 58 observational studies investigated 77 783 E coli isolates in urine. In studies from OECD countries, the pooled prevalence of resistance was 53.4% (95% confidence interval 46.0% to 60.8%) for ampicillin, 23.6% (13.9% to 32.3%) for trimethoprim, 8.2% (7.9% to 9.6%) for co-amoxiclav, and 2.1% (0.8 to 4.4%) for ciprofloxacin; nitrofurantoin was the lowest at 1.3% (0.8% to 1.7%). Resistance in studies in countries outside the OECD was significantly higher: 79.8% (73.0% to 87.7%) for ampicillin, 60.3% (40.9% to 79.0%) for co-amoxiclav, 26.8% (11.1% to 43.0%) for ciprofloxacin, and 17.0% (9.8% to 24.2%) for nitrofurantoin. There was evidence that bacterial isolates from the urinary tract from individual children who had received previous prescriptions for antibiotics in primary care were more likely to be resistant to antibiotics, and this increased risk could persist for up to six months (odds ratio 13.23, 95% confidence interval 7.84 to 22.31). COnClusiOnsPrevalence of resistance to commonly prescribed antibiotics in primary care in children with urinary tract infections caused by E coli is high, particularly in countries outside the OECD, where one possible explanation is the availability of antibiotics over the counter. This could render some antibiotics ineffective as first line treatments for urinary tract infection. Routine use of antibiotics in primary care contributes to antimicrobial resistance in children, which can persist for up to six months after treatment.

The inflammatory response to lung infections must be tightly regulated, enabling pathogen elimination while maintaining crucial gas exchange. Using recently described “depletion of regulatory T cell” (DEREG) mice, we found that selective depletion of regulatory T cells (Tregs) during acute respiratory syncytial virus (RSV) infection enhanced viral clearance but increased weight loss, local cytokine and chemokine release, and T-cell activation and cellular influx into the lungs. Conversely, inflammation was decreased when Treg numbers and activity were boosted using interleukin-2 immune complexes. Unexpectedly, lung (but not draining lymph node) Tregs from RSV-infected mice expressed granzyme B (GzmB), and bone marrow chimeric mice with selective loss of GzmB in the Treg compartment displayed markedly enhanced cellular infiltration into the lung after infection. A crucial role for GzmB-expressing Tregs has not hitherto been described in the lung or during acute infections, but may explain the inability of children with perforin/GzmB defects to regulate immune responses to infection. The effects of RSV infection in mice with defective immune regulation closely parallel the observed effects of RSV in children with bronchiolitis, suggesting that the pathogenesis of bronchiolitis may involve an inability to regulate virus-induced inflammation.

Interleukin (IL-) 10 is a pleiotropic cytokine with broad immunosuppressive functions, particularly at mucosal sites such as the intestine and lung. Here we demonstrate that infection of BALB/c mice with respiratory syncytial virus (RSV) induced IL-10 production by CD4+ and CD8+ T cells in the airways at later time points (e.g. day 8); a proportion of these cells also co-produced IFN-γ. Furthermore, RSV infection of IL-10−/− mice resulted in more severe disease with enhanced weight loss, delayed recovery and greater cell infiltration of the respiratory tract without affecting viral load. In addition, IL-10−/− mice had a pronounced airway neutrophilia and heightened levels of pro-inflammatory cytokines and chemokines in the bronchoalveolar lavage fluid. Notably, the proportion of lung T cells producing IFN-γ was enhanced, suggesting that IL-10 may act in an autocrine manner to dampen effector T cell responses. Similar findings were made in mice treated with anti-IL-10R antibody and infected with RSV. Therefore, IL-10 inhibits disease and inflammation in mice infected with RSV, especially during recovery from infection.

IntroductionCombined inhaled long-acting beta-agonists and corticosteroids (LABA+ICS) are costly. They are recommended in severe or very severe chronic obstructive pulmonary disease (COPD). They should not be prescribed in mild or moderate disease. In COPD ICS are associated with side-effects including risk of pneumonia. We quantified appropriateness of prescribing and examined the risks and costs associated with overuse. MethodsData were extracted from the electronic and paper records of 41 London general practices (population 310,775) including spirometry, medications and exacerbations. We classified severity, assessed appropriateness of prescribing using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for 2009, and performed a sensitivity analysis using the broader recommendations of the 2011 revision.Results3537 patients had a diagnosis of COPD. Spirometry was recorded for 2458(69%). 709(29%) did not meet GOLD criteria. 1749(49%) with confirmed COPD were analysed: 8.6% under-treated, 38% over-treated. Over-prescription of ICS in GOLD stage I or II (n=403, 38%) and in GOLD III or IV without exacerbations (n=231, 33.6%) was common. An estimated 12 cases (95%CI 7-19) annually of serious pneumonia were likely among 897 inappropriately treated. 535 cases of overtreatment involved LABA+ICS with a mean per patient cost of £553.56/year (€650.03). Using the broader indications for ICS in the 2011 revised GOLD guideline 25% were still classified as over-treated. The estimated risk of 15 cases of pneumonia (95%CI 8-22) in 1074 patients currently receiving ICS would rise by 20% to 18 (95%CI 9.8-26.7) in 1305 patients prescribed ICS if all with GOLD grade 3 and 4 received LABA+ICS. ConclusionOver-prescription of ICS in confirmed COPD was widespread with considerable potential for harm. In COPD where treatment is often escalated in the hope of easing the burden of disease clinicians should consider both the risks and benefits of treatment and the costs where the benefits are unproven.

SummaryBackgroundAntimicrobial resistance is a serious threat to public health, with most antibiotics prescribed in primary care. General practitioners (GPs) report defensive antibiotic prescribing to mitigate perceived risk of future hospital admission in children with respiratory tract infections. We developed a clinical rule aimed to reduce clinical uncertainty by stratifying risk of future hospital admission.Methods8394 children aged between 3 months and 16 years presenting with acute cough (for ≤28 days) and respiratory tract infection were recruited to a prognostic cohort study from 247 general practitioner practices in England. Exposure variables included demographic characteristics, parent-reported symptoms, and physical examination signs. The outcome was hospital admission for respiratory tract infection within 30 days, collected using a structured, blinded review of medical records.Findings8394 (100%) children were included in the analysis, with 78 (0·9%, 95% CI 0·7%–1·2%) admitted to hospital: 15 (19%) were admitted on the day of recruitment (day 1), 33 (42%) on days 2–7; and 30 (39%) on days 8–30. Seven characteristics were independently associated (p<0·01) with hospital admission: age <2 years, current asthma, illness duration of 3 days or less, parent-reported moderate or severe vomiting in the previous 24 h, parent-reported severe fever in the previous 24 h or a body temperature of 37·8°C or more at presentation, clinician-reported intercostal or subcostal recession, and clinician-reported wheeze on auscultation. The area under the receiver operating characteristic (AUROC) curve for the coefficient-based clinical rule was 0·82 (95% CI 0·77–0·87, bootstrap validated 0·81). Assigning one point per characteristic, a points-based clinical rule consisting of short illness, temperature, age, recession, wheeze, asthma, and vomiting (mnemonic STARWAVe; AUROC 0·81, 0·76–0·85) distinguished three hospital admission risk strata: very low (0·3%, 0·2–0·4%) with 1 point or less, normal (1·5%, 1·0–1·9%) with 2 or 3 points, and high (11·8%, 7·3–16·2%) with 4 points or more.InterpretationClinical characteristics can distinguish children at very low, normal, and high risk of future hospital admission for respiratory tract infection and could be used to reduce antibiotic prescriptions in primary care for children at very low risk.FundingNational Institute for Health Research (NIHR).

Pulmonary rehabilitation (PR) is one of the most effective treatments for COPD but not widely available. Uptake is poor and completion rates are low. In this integrated PR service we report on effectiveness, attendance, and completion of twice weekly rolling recruitment and once weekly cohort recruitment programmes in two hospital and five community PR sites. The hospital and two of the community programmes were 'rolling' recruitment twice weekly for 8 weeks. Three community programmes ran in once weekly cohorts for 8 weeks. Predictors of attendance, completion and effectiveness were sought. 1114 eligible COPD patients were referred. 812 (73%) attended assessment, 656 (59%) started and 441 (40%) completed. Significant improvements were seen in incremental shuttle walk test (ISWT) (mean 68.3 m; 95%CI 59.3-77.4), Chronic Respiratory Questionnaire self-report dyspnoea scale (CRQ-SR) (0.94; 0.80-1.07), Hospital Anxiety and Depression Scale anxiety (0.9; 0.5-1.2) and depression (1.1; 0.8-1.4) components, exceeding the minimum clinically important difference for ISWT and CRQ-SR. Twice weekly compared with once weekly programmes showed similar improvement. Patients were less likely to complete if they were deprived (4(th) quintile of deprivation 0.56; 0.33-0.94, 5(th) quintile 0.57; 0.34-0.85), reported MRC dyspnoea scale 4 (0.61; 0.37-0.97) or 5 (0.39; 0.16-0.93), or had been referred by their general practitioner (0.42; 0.24-0.74) (pseudo R(2) 0.103). PR is effective for COPD in real-world practice achieving results comparable to trials. Low rates of attendance and completion of PR were not explained by demographic characteristics, disease severity, psychological morbidity and source of referral despite the large number of participants.

Human trials of formaldehyde-inactivated respiratory syncytial virus (FI-RSV) vaccine in 1966–1967 caused disastrous worsening of disease and death in infants during subsequent natural respiratory syncytial virus (RSV) infection. The reasons behind vaccine-induced augmentation are only partially understood, and fear of augmentation continues to hold back vaccine development. We now show that mice vaccinated with FI-RSV show enhanced local recruitment of conventional CD4 + T cells accompanied by a profound loss of regulatory T cells (Tregs) in the airways. This loss of Tregs was so complete that additional depletion of Tregs (in transgenic depletion of regulatory T-cell mice) produced no additional disease enhancement. Transfer of conventional CD4 + T cells from FI-RSV–vaccinated mice into naive RSV-infected recipients also caused a reduction in airway Treg responses; boosting Tregs with IL-2 immune complexes failed to restore normal levels of Tregs or to ameliorate disease. However, delivery of chemokine ligands (CCL) 17/22 via the airway selectively recruited airway Tregs and attenuated vaccine-augmented disease, reducing weight loss and inhibiting local recruitment of pathogenic CD4 + T cells. These findings reveal an unexpected mechanism of vaccine-induced disease augmentation and indicate that selective chemoattraction of Tregs into diseased sites may offer a novel approach to the modulation of tissue-specific inflammation.

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