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[This corrects the article DOI: 10.1371/journal.pone.0170774.].

IntroductionRecent data suggest 8-52% of babies on the NICU have evidence of a viral respiratory tract infection (VRTI) (Ronchi 2014, Bennett 2012). These studies, and our own data, indicate babies with VRTIs spend twice as long in hospital and have significantly worse respiratory outcomes such as chronic lung disease and the need for home oxygen. There is little evidence exploring ways of reducing these infections in the NICU. Our recent survey demonstrates significant variation in UK NICU visiting practices and isolation policies for babies with RVTIs.AimTo establish the impact of visitor restriction on the incidence of NICU VRTIs.MethodsWe performed a retrospective study of all admissions between 2007 and 2013 at two large UK tertiary NICUs (13,300 bed days/year). Normal visiting policy included parents, family and friends. During the periods November to April of 2009, 2010 and 2011, in response to the H1N1 pandemic, we restricted visiting to parents/carers only. No other variations in practice occurred. We identified all babies positive for VRTIs. We used a Poisson generalised additive model (GAM), factoring in workload intensity and incidence of community VRTIs, to calculate the impact of these 3 winter restriction periods compared with normal visiting.ResultsThere were 100 PCR proven VRTIs in 93 babies during this period (16/yr). Rhinovirus (n = 71), RSV (n = 8) and H1N1 (n = 5) were the most common. The median gestation of infected babies was 29 weeks (IQR 26-34 Weeks) and 46% required an escalation of respiratory support. Two of five H1N1 positive babies died. The results from the GAM suggest there was a 39% reduction (P < 0.05) in VRTIs during restricted visiting periods compared to normal visiting (Incident Rate Ratio 0.61, 95% CI 0.38-0.99). Extrapolating this to the UK, based on the NHS NICU tariff, the extra bed days associated with VRTIs cost between pound sterling 7M and pound sterling 25M/year.ConclusionThis is the first study demonstrating a significant reduction in NICU VRTIs through restricting visiting practices. VRTIs are associated with significant neonatal respiratory morbidity and have short and long-term resource implications. We need to explore better ways of minimising the impact of VRTIs in this vulnerable population.

BackgroundRespiratory Syncythial Virus (RSV) is a common lower respiratory tract viral infection. RSV and a wide variety of other respiratory viruses are common triggers for bronchiolitis.AimTo determine the length of stay in infants with acute RSV bronchiolitis vs. Non-RSV.Materials and methodsA retrospective study was conducted at Hamad Medical Corporation (HMC). Infants and children ages 0 to 18 months hospitalised with acute bronchiolitis from October 2010 to March 2013 were included. The data collected: age at diagnosis, sex, direct fluorescent antibody (DFA) and length of stay.ResultsThe study included 838 infants, mean age 3.6( plus or minus 3.5) months, and boys constituted 60%. DFA was conducted on 770 infant, where 352 Were RSV positive (45.7%), 142 were RSV negative (18.4%) and other non-RSV viruses (Adenoviurs, RhinoVirus, InfluenzaVirus, Parainflenzavirus, and Bocavirus)276 (35.8%). The mean length of stay for RSV-positive was 8.03 days, 95% C. I. (7.26-8.79), and 6.94 days, 95% C. I. (5.89-8.00) for RSV-negative compared to 9.76 days, 95%C. I. (8.31-11.21) for other non-RSV. The p value was 0.723 when comparing the length of stay in infants who tested positive RSV to those tested negative RSV, while the p-value was (0.059)when comparing RSV-positive to other non-RSV viruses. There was a statistically significance difference in length of stay for RSV negative compared to other non-RSV viruses (p = 0.010).ConclusionsOur data showed, there is no difference in length of stay in infants hospitalised with RSV-positive bronchiolitis compared to the group with RSV-negative; however the length of stay was statistically significant longer with Non-RSV viruses compared to RSV-negative infection.

Asthma is a heterogeneous group of conditions that result in recurrent, reversible bronchial obstruction. Although the disease can start at any age, the first symptoms occur during childhood in most cases. Asthma has a strong genetic component, and genome-wide association studies have identified variations in several genes that slightly increase the risk of disease. Asthma is often associated with increased susceptibility to infection with rhinoviruses and with changes in the composition of microbial communities colonising the airways, but whether these changes are a cause or consequence of the disease is unknown. There is currently no proven prevention strategy; however, the finding that exposure to microbial products in early life, particularly in farming environments, seems to be protective against asthma offers hope that surrogates of such exposure could be used to prevent the disease. Genetic and immunological studies point to defective responses of lung resident cells, especially those associated with the mucosal epithelium, as crucial elements in the pathogenesis of asthma. Inhaled corticosteroids continue to be the mainstay for the treatment of mild and moderate asthma, but limited adherence to daily inhaled medication is a major obstacle to the success of such therapy. Severe asthma that is refractory to usual treatment continues to be a challenge, but new biological therapies, such as humanised antibodies against IgE, interleukin 5, and interleukin 13, offer hope to improve the quality of life and long-term prognosis of severe asthmatics with specific molecular phenotypes.

Asthma is a heterogeneous group of conditions that result in recurrent, reversible bronchial obstruction. Although the disease can start at any age, the first symptoms occur during childhood in most cases. Asthma has a strong genetic component, and genome-wide association studies have identified variations in several genes that slightly increase the risk of disease. Asthma is often associated with increased susceptibility to infection with rhinoviruses and with changes in the composition of microbial communities colonising the airways, but whether these changes are a cause or consequence of the disease is unknown. There is currently no proven prevention strategy; however, the finding that exposure to microbial products in early life, particularly in farming environments, seems to be protective against asthma offers hope that surrogates of such exposure could be used to prevent the disease. Genetic and immunological studies point to defective responses of lung resident cells, especially those associated with the mucosal epithelium, as crucial elements in the pathogenesis of asthma. Inhaled corticosteroids continue to be the mainstay for the treatment of mild and moderate asthma, but limited adherence to daily inhaled medication is a major obstacle to the success of such therapy. Severe asthma that is refractory to usual treatment continues to be a challenge, but new biological therapies, such as humanised antibodies against IgE, interleukin 5, and interleukin 13, offer hope to improve the quality of life and long-term prognosis of severe asthmatics with specific molecular phenotypes.

Introduction and ObjectivesAcute exacerbations are a major cause of morbidity and mortality in COPD and current treatments are not very effective. Histone deacetylase 2 (HDAC2) is deficient in stable COPD and is likely to be a mechanism of corticosteroid resistance. It is not known whether impaired HDAC2 activity is an important mechanism in COPD exacerbations.Methods9 subjects with GOLD stage II COPD, 10 smokers and 11 non-smokers were infected with rhinovirus 16. Macropahges from induced sputum and bronchoalveolar lavage (BAL) were collected before and following rhinovirus infection and HDAC2 activity measured. Virus load and inflammatory markers were measured in sputum supernantants.ResultsAt baseline there were no differences in HDAC2 activity in sputum or BAL macrophages between the groups. Following infection HDAC2 activity in the smoking controls and non-smoking controls did not change significantly from baseline (Figure 1). In the COPD subjects there was a trend towards reduced HDAC2 activity in both sputum (ANOVA P = 0.064) and BAL macrophages (Paired t test P = 0.098). Sputum HDAC activity was significantly lower in the COPD subjects compared to non-smokers on days 5 and 42 (P < 0.05), and there was a trend towards lower levels of HDAC in BAL macrophages at infection compared to the non-smokers (P = 0.095) and smokers (P = 0.059) (Figure 1).[Figure]Lower sputum macrophage HDAC2 activity at baseline was associated with greater sputum virus load (r = -0.82, P = 0.022) and higher sputum levels of neutrophil elastase (r = -0.81, P = 0.022) and TNF- alpha (r = -0.79, P = 0.028).HDAC2 activity in BAL macrophages at infection correlated inversely with peak NL virus load (r = -0.8, P = 0.0096), peak sputum GM-CSF (r = -0.67, P = 0.0499), TNF- alpha (r = -0.72, P = 0.03), neutrophil elastase (r = -0.67, P = 0.0499) and sputum nitrite levels (r = -0.78, P = 0.0125).ConclusionsFollowing rhinovirus infection HDAC2 activity in airway macrophages is reduced and relates to airway inflammatory markers. Restoring HDAC activity is a potential therapeutic option for COPD exacerbations.

IntroductionThere is very little data available on the impact that respiratory viral infections (RVI) have on neonatal morbidity and mortality in the UK.AimsDefine the epidemiology and impact of RVIs in a UK NICU population.MethodsWe conducted a retrospective case review of all NICU patients, at two large tertiary centres, with multiplex PCR confirmed RVIs between 2007 and 2013. Additionally, suspect/proven RVIs were identified in a local population (Nottingham area, 2 large teaching hospitals).Results15,907 respiratory samples were analysed by PCR with 7941 positive (50%) of which 52% were in children. 806 samples from NICU patients (76334 inpatient days) yielded 158 (19.6%) positives in 90 babies (median gestation 29 weeks, IQR 26-34). There were no differences in the number of RVIs between Spring/Summer (n = 46) and Autumn/Winter (n = 44) periods. 71% of babies positive for RVIs had rhinovirus, 8% RSV and 6% H1N1. Almost half of all infected babies required escalation of respiratory support especially those <28 weeks gestation who required ventilation or ECMO (38%). Three babies died, one with rhinovirus and 2 (of 5 infected) with H1N1. 35% of preterm infants required home oxygen.DiscussionThis is the largest UK series detailing RVIs in NICU patients. Although RVIs are uncommon, our study demonstrates significant associated morbidity, especially with rhinovirus, and significant mortality during the H1N1 pandemic. Subclinical RVIs can occur in the NICU1 and coupled with our data suggests we need to explore better ways of minimising the impact of RVIs in this vulnerable population.ReferenceBennett, et al. J Peds 2012; 161(5):814-18

Rhinovirus (RV) infection is the most common cause of asthma exacerbations (AE), however mechanisms are poorly understood. Conventional sampling techniques such as bronchoalveolar lavage dilute many cytokines below limits of detection and consequently it has not been possible to measure key mediators of Th1, Th2 and Th17 pathways during virus-induced AE's. In addition, IL-33, an epithelial-derived alarmin, has recently been shown to be essential for mouse virus-induced airway hyperresponsiveness, however the relationship between IL-33 and exacerbations in human asthma remains unknown. Using the human model of experimental RV induced AE along with novel techniques to sample upper and lower airway mucosal lining fluid (MLF) we investigated the roles of IL-33 and several other prominent cytokines in virus-induced AE's.Methods32 mild-to-moderate asthmatics and 14 healthy subjects were inoculated nasally with RV-16. Symptom scores were recorded daily. Bronchoscopies were performed 2 weeks prior to inoculation and on d4 post-inoculation. Novel techniques to sample MLF called 'bronchosorption' and 'nasosorption' were performed. Cytokines were measured in both bronchial and nasal samples at baseline and on d4 with further nasal sampling on days 2, 3, 5, 7, 10 and 42.ResultsIn asthma, nasal IL-4, -5, -13, -17, -33, and IFN- gamma levels were significantly increased during infection compared to baseline (all P<0.001). IL-33 and Th2 cytokines but not IFN- gamma or IL-17 were increased in asthma compared to healthy subjects (P<0.01). In the asthmatic lung, relationships between bronchial IL-33 (P<0.05), IL-13 (p<0.05), IL-5 (p=0.059) and chest symptom scores were observed. Bronchial levels of these cytokines correlated with nasal levels during infection (p<0.05) whilst baseline nasal levels of Th2 cytokines correlated strongly with infection levels (p<0.001).ConclusionSampling MLF permits the direct measurement of previously undetectable mediators across multiple inflammatory pathways. Increased IL-33 and Th2 induction are associated with increased AE severity. IL-33 correlated strongly with Th2 cytokine levels and may represent a novel target for the treatment of virus-induced AE's. In addition, nasal Th2 inflammation correlated with bronchial levels whilst baseline levels predicted the magnitude of Th2 induction during the AE. Therefore it may be possible to use nasosorption to guide therapy with anti-IL-5 and anti-IL-13 mAb treatments.

IntroductionDefective rhinovirus (RV) induced interferon (IFN)- beta and IFN- lambda production has been reported in primary human bronchial epithelial cells (HBECs) and peripheral blood mononuclear cells (PBMCs) from asthmatics. The mechanisms of defective IFN induction in asthma are unknown. Virus infection can induce IFNs through Toll like Receptors (TLR)3, TLR4 and TLRs7-9 and TLR agonists have been identified as potential therapeutic options for asthma. The role of these TLRs in IFN induction in asthma is unclear.ObjectiveTo investigate IFN responses to TLR stimulation in HBECs and PBMCs from atopic asthmatic and non-asthmatic individuals.MethodsHBECs and PBMCs from atopic asthmatic and non-asthmatic subjects were stimulated with agonists to TLR3, TLR4 & TLRs7-9 and type I and III IFN responses assessed by qPCR and ELISA.ResultsTLR3 and TLR7, but not TLR4, 8 or 9, stimulation induced IFN protein and mRNA expression in HBECs and PBMCs. IFNs induced were IFN- beta and predominantly type III IFN- lambda in HBECs and type I (- alpha and - beta ) with no IFN- lambda in PBMCs. TLR function was not defective in asthmatic compared to non-asthmatic subjects.ConclusionsTLR3 & TLR7 were the predominant TLRs involved in IFN induction in HBECs and PBMCs. Defective IFN induction to TLR agonists was not observed in these well controlled asthmatic subjects. TLR3/7 agonists could be effective in inducing IFNs in more severe/less well controlled asthmatics who may have deficient virus induced IFN production.

Most isolates of human rhinovirus, the common cold virus, replicate more robustly at the cool temperatures found in the nasal cavity (33–35 °C) than at core body temperature (37 °C). To gain insight into the mechanism of temperature-dependent growth, we compared the transcriptional response of primary mouse airway epithelial cells infected with rhinovirus at 33 °C vs. 37 °C. Mouse airway cells infected with mouse-adapted rhinovirus 1B exhibited a striking enrichment in expression of antiviral defense response genes at 37 °C relative to 33 °C, which correlated with significantly higher expression levels of type I and type III IFN genes and IFN-stimulated genes (ISGs) at 37 °C. Temperature-dependent IFN induction in response to rhinovirus was dependent on the MAVS protein, a key signaling adaptor of the RIG-I–like receptors (RLRs). Stimulation of primary airway cells with the synthetic RLR ligand poly I:C led to greater IFN induction at 37 °C relative to 33 °C at early time points poststimulation and to a sustained increase in the induction of ISGs at 37 °C relative to 33 °C. Recombinant type I IFN also stimulated more robust induction of ISGs at 37 °C than at 33 °C. Genetic deficiency of MAVS or the type I IFN receptor in infected airway cells permitted higher levels of viral replication, particularly at 37 °C, and partially rescued the temperature-dependent growth phenotype. These findings demonstrate that in mouse airway cells, rhinovirus replicates preferentially at nasal cavity temperature due, in part, to a less efficient antiviral defense response of infected cells at cool temperature. Significance Rhinovirus is the most frequent cause of the common cold, as well as one of the most important causes of asthma exacerbations. Most rhinovirus strains replicate better at the cooler temperatures found in the nasal cavity than at lung temperature, but the underlying mechanisms are not known. Using a mouse-adapted virus, we found that airway epithelial cells supporting rhinovirus replication initiate a more robust antiviral defense response through RIG-I–like receptor (RLR)–dependent interferon secretion and enhanced interferon responsiveness at lung temperature vs. nasal cavity temperature. Airway cells with genetic deficiencies in RLR or type I interferon receptor signaling supported much higher levels of viral replication at 37 °C. Thus, cooler temperatures can enable replication of the common cold virus, at least in part, by diminishing antiviral immune responses.