Age-dependent nasal immune responses in non-hospitalized bronchiolitis children.

Bronchiolitis in children is associated with significant rates of morbidity and mortality. Many studies have been performed using samples from hospitalized bronchiolitis patients, but little is known about the immunological responses from infants suffering from mild/moderate bronchiolitis that do not require hospitalization. We have studied a collection of nasal lavage fluid (NLF) samples from outpatient bronchiolitis children as a novel strategy to unravel local humoral and cellular responses, which are not fully characterized. The children were age-stratified in three groups, two of them (GI under 2-months, GII between 2-4 months) presenting a first episode of bronchiolitis, and GIII (between 4 months and 2 years) with recurrent respiratory infections. Here we show that elevated levels of pro-inflammatory cytokines (IL1ß, IL6, TNFα, IL18, IL23), regulatory cytokines (IL10, IL17A) and IFNγ were found in the three bronchiolitis cohorts. However, little or no change was observed for IL33 and MCP1, at difference to previous results from bronchiolitis hospitalized patients. Furthermore, our results show a tendency to IL1ß, IL6, IL18 and TNFα increased levels in children with mild pattern of symptom severity and in those in which non RSV respiratory virus were detected compared to RSV+ samples. By contrast, no such differences were found based on gender distribution. Bronchiolitis NLFs contained more IgM, IgG1, IgG3 IgG4 and IgA than NLF from their age-matched healthy controls. NLF from bronchiolitis children predominantly contained neutrophils, and also low frequency of monocytes and few CD4+ and CD8+ T cells. NLF from infants older than 4-months contained more intermediate monocytes and B cell subsets, including naïve and memory cells. BCR repertoire analysis of NLF samples showed a biased VH1 usage in IgM repertoires, with low levels of somatic hypermutation. Strikingly, algorithmic studies of the mutation profiles, denoted antigenic selection on IgA-NLF repertoires. Our results support the use of NLF samples to analyze immune responses and may have therapeutic implications.

Identifying and managing bronchiolitis.

Bronchiolitis is a common viral illness that affects the lower respiratory tract of infants and young children. The disease is characterized by wheezing and increased mucus production and can range from mild to severe in terms of respiratory distress. This article reviews the epidemiology, clinical presentation, and treatment of bronchiolitis.

Heliox delivered by high flow nasal cannula improves oxygenation in infants with respiratory syncytial virus acute bronchiolitis / Heliox administrado por cânula nasal de alto fluxo melhora a oxigenação em crianças com bronquiolite aguda por vírus sincicial respiratório

Abstract Objective: The objective of this study is to evaluate the hypothesis that use of heliox would result in improvement of gas exchange when used with high flow nasal cannula in infants with RSV acute bronchiolitis. Methods: All patients that met the inclusion criteria were randomized to either heliox (70:30) or air-oxygen mixture 30% via high flow nasal cannula at 8 L/min for a continuous 24 h. Measurements were taken at baseline, after 2 h, and at the end of the 24 h. Results: This prospective study included 48 patients. After 2 h of treatment with heliox, the oxygen saturation and PaO2 significantly improved when compared with the air-oxygen group, 98.3% vs. 92.9%, 62.0 mmHg vs. 43.6 mmHg (p = 0.04 and 0.01), respectively. Furthermore, PaO2/FiO2 ratio was significantly higher in the heliox group when compared with the air-oxygen group, 206.7 vs. 145.3. Nevertheless, CO2 showed better elimination when heliox was used, without significance. MWCA score dropped significantly in the heliox group, 2.2 points vs. 4.0 points in air-oxygen (p = 0.04), 2 h after starting the therapy. Conclusion: Transient improvement of oxygenation in infants with RSV acute bronchiolitis during the initial phase of the therapy is associated with heliox when provided with HFNC, may provide a precious time for other therapeutic agents to work or for the disease to resolve naturally, avoiding other aggressive interventions.

Resumo Objetivo: Avaliar a hipótese de que o uso da mistura heliox resultaria em melhoria da troca gasosa quando usado com cânula nasal de alto fluxo em crianças com bronquiolite aguda por VSR. Métodos: Todos os pacientes que atenderam aos critérios de inclusão foram randomizados para receber a mistura heliox (70:30) ou a mistura ar/oxigênio a 30% por meio da cânula nasal de alto fluxo a 8 L/min por 24 horas contínuas. As medições foram feitas no início, depois de duas horas e ao fim de 24 horas. Resultados: Fizemos um estudo prospectivo em que foram incluídos 48 pacientes. Após duas horas de tratamento com a mistura heliox, a saturação de oxigênio e a PaO2 apresentaram melhoria significativa em comparação com o grupo da mistura ar/oxigênio: 98,3% em comparação com 92,9%, 62,0 mmHg em comparação com 43,6 mmHg (p = 0,04 e 0,01), respectivamente. Além disso, a relação PaO2/FiO2 era significativamente mais alta no grupo da mistura heliox do que no grupo da mistura ar/oxigênio, 2.067 em comparação com 1.453. Contudo, o CO2 apresentou melhor eliminação quando a mistura heliox foi usada, sem relevância. O Escore MWCA caiu significativamente no grupo da mistura heliox, 2,2 pontos em comparação com 4,0 pontos da mistura ar/oxigênio (p = 0,04) duas horas após o início da terapia. Conclusão: A breve melhoria da oxigenação em crianças com bronquiolite aguda por VSR na fase inicial da terapia está associada à mistura heliox quando administrada pela CNAF e poderá fornecer um tempo precioso para outros agentes terapêuticos funcionarem ou para a própria doença se curar naturalmente e evitar outras intervenções agressivas.

LncRNA MEG3 ameliorates respiratory syncytial virus infection by suppressing TLR4 signaling.

Maternally expressed gene 3 (MEG3), a long noncoding RNA (lncRNA) has been dysregulated in various tumors. However, the expression level and functional role of MEG3 in the progression of respiratory syncytial virus (RSV) infection remains to be elucidated. The present study quantified the expression level of MEG3 in the nasopharyngeal (NPA) samples of RSV­infected patients and in BEAS­2B cells infected with RSV. The findings of the present study demonstrated that the expression level of lncRNA MEG3 was reduced in the NPA samples of RSV­infected patients and in BEAS­2B cells infected with RSV. In vitro transfection revealed increased mRNA expression levels of toll­like receptor 4 (TLR4), tumor necrosis factor­α (TNFα) and interleukin (IL)­8 following RSV infection in BEAS­2B cells. Additionally, ectopic expression of MEG3 reduced the expression level of TLR4, subsequently suppressing the mRNA expression levels of TNFα and IL­8, indicating the protective role of MEG3 in the process of RSV infection. It is of note, that RSV infection­induced p38 mitogen activated protein kinase (MAPK) and nuclear factor­κB (NF­κB) activation was partly abolished by overexpression of MEG3. In conclusion, to the best of our knowledge, the present study provided the first evidence that lncRNA MEG3 expression level was reduced in the NPA samples of patients with RSV infection and RSV­infected cells. Additionally, it was demonstrated that MEG3 protected human airway epithelial cells from RSV infection, primarily by suppressing TLR4­dependent p38 MAPK and NF­κB signaling.

Thymic stromal lymphopoietin, IL-33, and periostin in hospitalized infants with viral bronchiolitis.

Much attention has recently been focused on thymic stromal lymphopoietin (TSLP), IL-33, and periostin in allergic disease, but less is known about their role in viral bronchiolitis.The aim of the study was to investigate whether infants exhibit enhanced nasal airway secretion of TSLP, IL-33, and periostin during natural respiratory viral bronchiolitis compared to healthy controls.In total, 213 infants < 2 years of age, hospitalized with bronchiolitis from October/2013 to April/2016 were enrolled alongside 45 healthy infants. Nasopharyngeal aspirates (NPA) were screened for respiratory viruses by the polymerase chain reaction. TSLP, IL-33, and periostin were measured in NPAs. Clinical data were recorded.At least 1 virus was detected in 186 (87.3%) hospitalized infants: 149 (70%) respiratory syncytial virus (RSV); 42 (19.7%) rhinovirus (HRV); 16 (7.5%) parainfluenza virus (PIV); 9 (4.2%) adenovirus; 10 (4.7%) bocavirus; and 7 (3.3%) metapneumovirus (hMPV). Infants with bronchiolitis had higher levels of TSLP (P = .02), IL-33 (P<.001), and periostin (P = .003) than healthy controls.Detectable levels of TSLP and periostin were more frequent in virus-positive than in virus-negative patients (P = .05). TSLP and IL-33 were also more common in coinfections, mainly RSV and HRV, than in single-infections (P < .05). No patient with bronchiolitis but with negative viral detection had detectable levels of nasal TSLP or IL-33. Infants with hospital stay ≥5 days were more likely to have detectable levels of nasal TSLP and periostin after adjusting by age (P = .01).Bronchiolitis by common respiratory viruses is associated with elevated nasal levels of TSLP, IL-33, and periostin, factors known to be important in the development of Th2-response. Respiratory viruses in early life might shift immune responses toward Th2, involving asthma, and allergic diseases.

Neutrophil infiltration and activation in bronchiolitic airways are independent of viral etiology.

BACKGROUND: Hospitalization with bronchiolitis is linked to the development of early childhood chronic wheeze and asthma. Viral etiology and severity of inflammation are potential contributing factors. Previously we observed reduced airway neutrophil infiltration in breastfed bronchiolitic infants, with a corresponding reduction in disease severity. This study aimed to examine whether respiratory viral etiology and co-infection alters the pattern of neutrophil influx, and the inflammatory mediator profile, resulting in epithelial damage in bronchiolitis. METHODS: Nasopharyngeal aspirates (NPAs) collected from hospitalized infants were assessed for viruses, soluble protein, cellular infiltrate, interleukin (IL)-6, -8, and myeloperoxidase (MPO). RESULTS: NPAs were collected from 228 bronchiolitic and 14 non-bronchiolitic infants. In the bronchiolitic cohort, human rhinovirus was most prevalent (38%), followed by respiratory syncytial virus (36%), adenovirus (10%), and human metapneumovirus (6%), with 25% positive for viral co-infections and 25% negative for all screened viruses. Viral-induced bronchiolitis was associated with increased cellular infiltrate and protein, above control, and virus-negative infants (P < 0.05). Cellular infiltrate correlated to IL-6, -8, and MPO (r = 0.331, 0.669, and 0.661; P < 0.01). Protein, IL-6, -8, and MPO differed significantly between viral groups; however, the majority of marker values for all groups fall within an overlapping, indistinguishable range, precluding their use as biomarkers of viral etiology. No significant difference was found between single and viral co-infections for any parameter. CONCLUSION: Bronchiolitic infants presenting with a detectable respiratory virus during hospitalization demonstrated elevated markers of airway tissue inflammation and injury. In this cohort, viral etiology did not discernibly modulate chemokine-mediated neutrophil infiltration and activation. Pediatr Pulmonol. 2017;52:238-246. © 2016 Wiley Periodicals, Inc.

Differential lower airway dendritic cell patterns may reveal distinct endotypes of RSV bronchiolitis.

RATIONALE: The pathogenesis of respiratory syncytial virus (RSV) bronchiolitis in infants remains poorly understood. Mouse models implicate pulmonary T cells in the development of RSV disease. T cell responses are initiated by dendritic cells (DCs), which accumulate in lungs of RSV-infected mice. In infants with RSV bronchiolitis, previous reports have shown that DCs are mobilised to the nasal mucosa, but data on lower airway DC responses are lacking. OBJECTIVE: To determine the presence and phenotype of DCs and associated immune cells in bronchoalveolar lavage (BAL) and peripheral blood samples from infants with RSV bronchiolitis. METHODS: Infants intubated and ventilated due to severe RSV bronchiolitis or for planned surgery (controls with healthy lungs) underwent non-bronchoscopic BAL. Immune cells in BAL and blood samples were characterised by flow cytometry and cytokines measured by Human V-Plex Pro-inflammatory Panel 1 MSD kit. MEASUREMENTS AND MAIN RESULTS: In RSV cases, BAL conventional DCs (cDCs), NK T cells, NK cells and pro-inflammatory cytokines accumulated, plasmacytoid DCs (pDCs) and T cells were present, and blood cDCs increased activation marker expression. When stratifying RSV cases by risk group, preterm and older (≥4 months) infants had fewer BAL pDCs than term born and younger (<4 months) infants, respectively. CONCLUSIONS: cDCs accumulate in the lower airways during RSV bronchiolitis, are activated systemically and may, through activation of T cells, NK T cells and NK cells, contribute to RSV-induced inflammation and disease. In addition, the small population of airway pDCs in preterm and older infants may reveal a distinct endotype of RSV bronchiolitis with weak antiviral pDC responses.

Viral bronchiolitis in young infants: new perspectives for management and treatment / Bronquiolite viral em neonatos jovens: novas perspectivas para manejo e tratamento

Abstract Objective: The aim of this review was to address advances in management and treatment of acute viral bronchiolitis in infants. Sources: A systematic review search was made including all articles published in English between 2010 and 2017, and available in the electronic databases PubMed and Cochrane Central Register of Controlled Trials (CENTRAL) and specialized register of the Acute Respiratory Infections Group (Cochrane review group). The following MESH terms in English were included, using different Boolean operators for the search strategy: "bronchiolitis, viral," "diagnosis," "epidemiology," "etiology," "therapy," "virology," "prevention and control," "respiratory syncytial virus, human." Additional filters were used. Summary of findings: Few effective interventions are recommended for the management of RSV bronchiolitis in young infants. The main goal is to ensure an adequate oxygen supplementation and fluid balance whenever deemed necessary. Hypertonic saline nebulization is helpful only for hospitalized infants. Numerous antiviral drugs and specific vaccines for RSV are under evaluation and foretell advances in disease management in the near future. Conclusion: A number of promising new technologies are advancing in the field. Until new interventions became feasible, early detection and modification of preventable risk factors is essential to improve outcomes.

Resumo Objetivo: Abordar avanços no manejo e no tratamento de bronquiolite viral aguda em neonatos. Fontes: Uma pesquisa de análise sistemática foi feita e incluiu todos os artigos publicados em inglês entre 2010 e 2017 e disponíveis nas bases de dados eletrônicas PubMed, no Registro Central de Ensaios Controlados (Central) da Cochrane e no registro especializado do Grupo de Infecções Respiratórias Agudas (grupo de revisão Cochrane). Os seguintes termos MESH em inglês foram incluídos na abordagem com diferentes operadores booleanos para a estratégia de pesquisa: "bronquiolite, viral", "diagnóstico", "epidemiologia", "etiologia", "terapia", "virologia", "prevenção e controle", "vírus sincicial respiratório, humano". Foram usados filtros adicionais. Resumo dos achados: Poucas intervenções efetivas são recomendadas para o manejo da bronquiolite por VSR em neonatos jovens. O principal objetivo é garantir uma suplementação de oxigênio adequada e equilíbrio de fluidos sempre que considerado necessário. A nebulização de solução salina hipertônica ajuda apenas em casos de neonatos hospitalizados. Vários medicamentos antivirais e vacinas específicas contra VSR estão em fase de avaliação e predizem avanços no manejo da doença no futuro próximo. Conclusão: Várias novas tecnologias promissoras avançam no campo. Até que as novas intervenções se tornem viáveis, a detecção precoce e a modificação de fatores de risco de prevenção são fundamentais para melhorar os resultados.

Lack of association between viral load and severity of acute bronchiolitis in infants / Falta de associação entre carga viral e gravidade da bronquiolite aguda em lactentes

ABSTRACT Objective: To investigate the correlation between respiratory syncytial viral load and length of hospitalization in infants with acute wheezing episodes. Methods: This was a two-year, cross-sectional study of infants ≤ 12 months of age with bronchiolitis at the time of admission to a tertiary hospital. For the identification of respiratory viruses, nasopharyngeal secretions were collected. Samples were analyzed (throughout the study period) by direct immunofluorescence and (in the second year of the study) by quantitative real-time PCR. We screened for three human viruses: rhinovirus, respiratory syncytial virus, and metapneumovirus. Results: Of 110 samples evaluated by direct immunofluorescence, 56 (50.9%) were positive for a single virus, and 16 (14.5%) were positive for two or more viruses. Among those 72 samples, the most prevalent virus was respiratory syncytial virus, followed by influenza. Of 56 samples evaluated by quantitative real-time PCR, 24 (42.8%) were positive for a single virus, and 1 (1.7%) was positive for two viruses. Among those 25 samples, the most prevalent virus was again respiratory syncytial virus, followed by human rhinovirus. Coinfection did not influence the length of the hospital stay or other outcome s. In addition, there was no association between respiratory syncytial virus load and the length of hospitalization. Conclusions: Neither coinfection nor respiratory syncytial viral load appears to influence the outcomes of acute bronchiolitis in infants.

RESUMO Objetivo: Investigar a correlação entre a carga viral do vírus sincicial respiratório e o tempo de internação hospitalar em lactentes com episódios de sibilância aguda. Métodos: Este foi um estudo transversal de dois anos envolvendo lactentes de até 12 meses de idade com bronquiolite no momento da internação em um hospital terciário. Para a identificação dos vírus respiratórios foram coletadas secreções nasofaríngeas. As amostras foram analisadas (por todo o período do estudo) por imunofluorescência direta e (no segundo ano do estudo) por PCR quantitativa em tempo real para três vírus humanos (rinovírus, vírus sincicial respiratório e metapneumovírus). Resultados: Das 110 amostras avaliadas por imunofluorescência direta, 56 (50,9%) foram positivas para um único vírus, e 16 (14,5%) foram positivas para dois ou mais vírus. Nessas 72 amostras, o vírus mais prevalente foi o vírus sincicial respiratório, seguido por influenza. Das 56 amostras avaliadas por PCR quantitativa em tempo real, 24 (42,8%) foram positivas para um único vírus, e 1 (1,7%) foi positiva para dois vírus. Nessas 25 amostras, o vírus mais prevalente foi o vírus sincicial respiratório, seguido por rinovírus humano. A coinfecção não influenciou o tempo de internação ou outros desfechos. Além disso, não houve associação entre a carga viral de vírus sincicial respiratório e o tempo de internação. Conclusões: A coinfecção e a carga viral do vírus sincicial respiratório não parecem influenciar os desfechos em lactentes com bronquiolite aguda.

Bronchiolitis: Analysis of 10 consecutive epidemic seasons.

Bronchiolitis is the leading cause of hospitalization in infants under 12 months. Our aims were to analyze epidemiological characteristics of infants with bronchiolitis over 10 consecutive seasons and to evaluate whether there are any clinical differences between infants hospitalized for bronchiolitis during epidemic peak months and infants in non-peak months. We enrolled consecutive enrolled 723 previously healthy term infants hospitalized at the Paediatric Emergency Department, "Sapienza" University of Rome over the period 2004-2014. Fourteen respiratory viruses were detected from nasopharyngeal aspirates by molecular methods. Clinical and demographic data were extracted from clinical charts. Viruses were detected in 351 infants (48.5%): RSV in 234 (32.4%), RV in 44 (6.1%), hBoV in 11 (1.5%), hMPV in 12 (1.6%), co-infections in 39 (5.4%), and other viruses in 11 (1.5%). Analyzing the 10 epidemic seasons, we found higher incidence for bronchiolitis every 4 years with a peak during the months December-January. Infants hospitalized during peak months had lower family history for asthma (P = 0.003), more smoking mothers during pregnancy (P = 0.036), were slightly higher breastfed (0.056), had lower number of blood eosinophils (P = 0.015) and had a higher clinical severity score (P = 0.017). RSV was detected mostly during peak months, while RV was equally distributed during the seasons. We found some variations in bronchiolitis incidence during epidemics, and discriminative characteristics in infants hospitalized for bronchiolitis during peak months and in non-peak months, that might reflect two different populations of children. Pediatr Pulmonol. 2016;51:1330-1335. © 2016 Wiley Periodicals, Inc.

Respiratory syncytial virus seasonality in Brazil: implications for the immunisation policy for at-risk populations

Respiratory syncytial virus (RSV) infection is the leading cause of hospitalisation for respiratory diseases among children under 5 years old. The aim of this study was to analyse RSV seasonality in the five distinct regions of Brazil using time series analysis (wavelet and Fourier series) of the following indicators: monthly positivity of the immunofluorescence reaction for RSV identified by virologic surveillance system, and rate of hospitalisations per bronchiolitis and pneumonia due to RSV in children under 5 years old (codes CID-10 J12.1, J20.5, J21.0 and J21.9). A total of 12,501 samples with 11.6% positivity for RSV (95% confidence interval 11 - 12.2), varying between 7.1 and 21.4% in the five Brazilian regions, was analysed. A strong trend for annual cycles with a stable stationary pattern in the five regions was identified through wavelet analysis of the indicators. The timing of RSV activity by Fourier analysis was similar between the two indicators analysed and showed regional differences. This study reinforces the importance of adjusting the immunisation period for high risk population with the monoclonal antibody palivizumab taking into account regional differences in seasonality of RSV.

Flt3 ligand improves the innate response to respiratory syncytial virus and limits lung disease upon RSV reexposure in neonate mice.

Respiratory syncytial virus (RSV) causes severe bronchiolitis in infants worldwide. The immunological factors responsible for RSV susceptibility in infants are poorly understood. Here, we used the BALB/c mouse model of neonatal RSV infection to study the mechanisms leading to severe disease upon reexposure to the virus when adults. Two major deficiencies in neonatal lung innate responses were found: a poor DCs mobilization, and a weak engagement of the IFNI pathway. The administration of Flt3 ligand (Flt3-L), a growth factor that stimulates the proliferation of hematopoietic cells, to neonates before RSV-infection, resulted in increased lung DC number, and reconditioned the IFNI pathway upon RSV neonatal infection. Besides, neonates treated with Flt3-L were protected against exacerbated airway disease upon adult reexposure to RSV. This was associated with a reorientation of RSV-specific responses toward Th1-mediated immunity. Thus, the poor lung DCs and IFNI responses to RSV in neonates may be partly responsible for the deleterious long-term consequences revealed upon adult reexposure to RSV, which could be prevented by Flt3-L treatment. These results open new perspectives for developing neonatal immuno-modulating strategies to reduce the burden of bronchiolitis.

Adenovirus species C detection in children under four years of age with acute bronchiolitis or recurrent wheezing.

BACKGROUND: Lower respiratory tract viral infection is an important cause of morbidity and mortality in children worldwide. Among viral etiological agents the human Adenovirus (AdV) has been associated to mild or severe respiratory tract infection. OBJECTIVE: To detect the presence of human Adenovirus (AdV) in children with acute bronchiolitis or recurrent wheezing, describing their clinical features and determining Adenovirus species and AdV association to Respiratory Syncytial Virus (RSV), Human Metapneumovirus (MPV) and Parainfluenza virus (PIV). STUDY DESIGN: A total of 155 children bellow 48 months of age with acute bronchiolitis or recurrent wheezing were investigated for the presence of AdV, RSV, MPV and PIV in nasopharyngeal aspirate, by real-time PCR method. RESULTS: AdV, predominantly of species C, has been detected as the unique pathogen (AdVi) or in association to other pathogens (AdVa.), in 39/155 samples. Crackles were more frequent in children with AdV. RSVi was detected predominantly in children with acute bronchiolitis while AdVi and AdVa were detected more frequently in patients with recurrent wheezing. CONCLUSION: A small outbreak of AdV species C was observed in 2012 and 2013. AdV was detected more frequently in children with recurrent wheezing while RSVi was more frequent in infants with acute bronchiolitis.

Risk factors for bronchiolitis hospitalization during the first year of life in a multicenter Italian birth cohort.

BACKGROUND: Respiratory Syncytial Virus (RSV) is one of the main causes of respiratory infections during the first year of life. Very premature infants may contract more severe diseases and 'late preterm infants' may also be more susceptible to the infection. The aim of this study is to evaluate the risk factors for hospitalization during the first year of life in children born at different gestational ages in Italy. METHODS: A cohort of 33-34 weeks gestational age (wGA) newborns matched by sex and age with two cohort of newborns born at 35-37 wGA and > 37 wGA were enrolled in this study for a three-year period (2009-2012). Hospitalization for bronchiolitis (ICD-9 code 466.1) during the first year of life was assessed through phone interview at the end of the RSV season (November-March) and at the completion of the first year of life. RESULTS: The study enrolled 2314 newborns, of which 2210 (95.5 %) had a one year follow-up and were included in the analysis; 120 (5.4 %) were hospitalized during the first year of life for bronchiolitis. Children born at 33-34 wGA had a higher hospitalization rate compared to the two other groups. The multivariate analysis carried out on the entire population associated the following factors with higher rates for bronchiolitis hospitalization: male gender; prenatal treatment with corticosteroids; prenatal exposure to maternal smoking; singleton delivery; respiratory diseases in neonatal period; surfactant therapy; lack of breastfeeding; siblings <10 years old; living in crowded conditions and/or in unhealthy households and early exposure to the epidemic RSV season. When analysis was restricted to preterms born at 33-34 wGA the following variables were associated to higher rates of bronchiolitis hospitalization: male gender, prenatal exposure to maternal smoking, neonatal surfactant therapy, having siblings <10 years old, living in crowded conditions and being exposed to epidemic season during the first three months of life. CONCLUSION: Our study identified some prenatal, perinatal and postnatal conditions proving to be relevant and independent risk factors for hospitalization for bronchiolitis during the first year of life. The combination of these factors may lead to consider palivizumab prophylaxis in Italy.

Co-immunization with virus-like particle and DNA vaccines induces protection against respiratory syncytial virus infection and bronchiolitis.

This study demonstrates that immunization with non-replicating virus-like particle (FFG VLP) containing RSV F and G glycoproteins together with RSV F DNA induced T helper type 1 antibody responses to RSV F similar to live RSV infection. Upon RSV challenge 21weeks after immunization, FFG VLP vaccination induced protection against RSV infection as shown by clearance of lung viral loads, and the absence of eosinophil infiltrates, and did not cause lung pathology. In contrast, formalin-inactivated RSV (FI-RSV) vaccination showed significant pulmonary eosinophilia, severe mucus production, and extensive histopathology resulting in a hallmark of pulmonary pathology. Substantial lung pathology was also observed in mice with RSV re-infections. High levels of systemic and local inflammatory cytokine-secreting cells were induced in mice with FI-RSV but not with FFG VLP immunization after RSV challenge. Therefore, the results provide evidence that recombinant RSV FFG VLP vaccine can confer long-term protection against RSV without causing lung pathology.

[Determination of the frequency of human bocavirus and other respiratory viruses among 0-2 years age group children diagnosed as acute bronchiolitis]. / Bronsiyolit tanisi alan 0-2 yas grubu çocuklarda insan bokavirusu ve diger solunum viruslarinin sikliginin arastirilmasi.

Acute bronchiolitis, mostly seen in infants and younger children, is a lower respiratory tract infection frequently caused by viral agents. We aimed to determine the frequency of a broad panel of respiratory viruses including human bocavirus (HBoV) and to assess the clinical characteristics of acute bronchiolitis in a group of children under 24 months of age. A total of 62 children (45 male, 17 female; age range: 0-2 years) with the initial diagnosis of acute bronchiolitis and 33 healthy children (21 male, 12 female; age range: 0-2 years) as control group who were admitted to the Pediatrics Department of Mersin University Hospital, southern Turkey, from January to July 2010 were included in the study. Nasopharyngeal aspirates were collected from the study groups and the detection of respiratory viruses [respiratory syncytial virus (RSV) A & B; rhinovirus (RV); human metapneumovirus (hMPV) A & B; influenza virus type A [H1N1, H3N2, H1N1v], B & C; parainfluenza virus (PIV) type 1, 2, 3 & 4A/B; adenovirus (AdV); HBoV; coronavirus (CoV 229E); enterovirus (EV)], were performed by using a commercial system namely CLART®Pneumovir (Clinical Array Technology, Genomica, Spain) based on the principle of multiplex polymerase chain reaction (M-PCR) and DNA microarray. Demographic features, clinical and laboratory findings of the patients, treatment protocols and the relationship between the length of hospitalization and the viral agents determined were also evaluated. Of the 62 samples collected from bronchiolitis cases, at least one virus was detected in 52 (83.9%) and viral co-infections were detected in 31 (50%) of them. Including the co-infections, RSV was the most commonly identified virus (n= 21; 33.9%), followed by influenza A [H1N1] (n= 18; 29%), RV (n= 18; 29%), hMPV (n= 13; 21%), PIV (n= 10; 16.1%), AdV (n= 5; 8%), HBoV (n= 3; 4.8%) and EV (n= 1; 1.6%). Of the 33 samples from healthy children, at least one virus was detected in 21 (63.6%) and viral co-infections were detected in seven (21.2%) samples. Including the co-infections, the most commonly detected virus was RV (n= 10; 30.3%), followed by influenza A [H1N1] (n= 6; 18.1%), AdV (n= 6; 18.1%), RSV (n= 4; 12.1%) and PIV (n= 3; 9%), however HBoV and hMPV were not detected in the control group. The differences of demographic features (age, gender, history of atopy, exposure of smoking, length of breast-feeding, presence of school-age sibling) and frequency of virus detection (83.9% and 63.6%, respectively) between the patient and control groups were not statistically significant (p> 0.05). The most common complaints of patients on admission were cough (100%), runny nose (82.3%) and respiratory difficulty (71%), whereas fever was present in 21 (33.9%) patients. The most common findings on physical examination were prolonged expirium (98.4%), rhonchi (98.4%), rales (80.6%), tachypnea (71%) and tachycardia (67.7%). Pulmonary graphies revealed that diffuse air trappings were more common in virus-associated bronchiolitis (36/52; 69.2%) cases, on the other hand infiltrations were more common (6/10; 60%) in patients who were virus-negative (p< 0.05). The demographic features, clinical and laboratory findings, clinical severity scores, hospitalization rates and duration of hospitalizations in bronchiolitis cases did not show statistically significant differences between the viral agents (p> 0.05 for each parameter). However the rates of antibiotic and steroid use in hospitalized patients (24/34 and 5/34, respectively) were significantly higher than those of outpatients (7/28 and 0/28, respectively) (p= 0.001 and p= 0.03). Our data indicated a high rate (~84%) of respiratory viruses in children with bronchiolitis in the Mersin province and the detection of hMPV (21%) and HBoV (4.8%) only in the patient group encouraged their roles in the etiology of acute brochiolitis. It was concluded that viral etiology should be investigated in selected cases to prevent unnecessary antibiotic treatment and to initiate appropriate antiviral therapy when necessary.

Adenovirus species C is associated with chronic suppurative lung diseases in children.

BACKGROUND: The role of human adenoviruses (HAdVs) in chronic respiratory disease pathogenesis is recognized. However, no studies have performed molecular sequencing of HAdVs from the lower airways of children with chronic endobronchial suppuration. We thus examined the major HAdV genotypes/species, and relationships to bacterial coinfection, in children with protracted bacterial bronchitis (PBB) and mild bronchiectasis (BE). METHODS: Bronchoalveolar lavage (BAL) samples of 245 children with PBB or mild (cylindrical) BE were included in this prospective cohort study. HAdVs were genotyped (when possible) in those whose BAL had HAdV detected (HAdV(+)). Presence of bacterial infection (defined as ≥10(4) colony-forming units/mL) was compared between BAL HAdV(+) and HAdV negative (HAdV(-)) groups. Immune function tests were performed including blood lymphocyte subsets in a random subgroup. RESULTS: Species C HAdVs were identified in 23 of 24 (96%) HAdV(+) children; 13 (57%) were HAdV-1 and 10 (43%) were HAdV-2. An HAdV(+) BAL was significantly associated with bacterial coinfection with Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae (odds ratio [OR], 3.27; 95% confidence interval, 1.38-7.75; P = .007) and negatively associated with Staphylococcus aureus infection (P = .03). Young age was related to increased rates of HAdV(+). Blood CD16 and CD56 natural killer cells were significantly more likely to be elevated in those with HAdV (80%) compared with those without (56.1%) (P = .027). CONCLUSIONS: HAdV-C is the major HAdV species detected in the lower airways of children with PBB and BE. Younger age appears to be an important risk factor for HAdV(+) of the lower airways and influences the likelihood of bacterial coinfection.

Systematic review of montelukast's efficacy for preventing post-bronchiolitis wheezing.

Infants often develop reactive airway diseases subsequent to respiratory syncytial virus (RSV) bronchiolitis. Cysteinyl leukotrienes (cysLTs), a class of lipid mediators that have been implicated in the pathogenesis of allergic rhinitis and asthma, are released during RSV infection, thereby contributing to the pathogenic changes in airway inflammation. Many pediatric patients, especially those of very young age, continue to have recurrent episodes of lower airway obstruction after bronchiolitis treatment. This study was to systematically review and assessed the efficacy of montelukast for preventing wheezing in patients with post-bronchiolitis. The Cochrane library, PubMed, China National Knowledge Infrastructure (CNKI) periodical databases were screened for studies related to use of montelukast for preventing post-bronchiolitis wheezing published up to 31 December 2012. Randomized controlled trials (RCTs) and quasi-RCTs using montelukast alone as an active intervention in infants up to 24 months of age with post-bronchiolitis were selected. Two authors independently extracted data and assessed trial quality using the recommendations published by the Cochrane Collaboration. The meta-analyses were performed using the Cochrane statistical package RevMan5.0.0. Four trials, containing 1430 infants with confirmed diagnosis of acute bronchiolitis, were analyzed. Patients were administered montelukast at post-bronchiolitis. Three trials showed no effects of montelukast on reducing the incidence of recurrent wheezing risk ratios (RR = 0.78, 95% CI: 0.55-1.12, p = 0.17), while two trials found that montelukast did reduce the frequency of recurrent wheezing and another two trials demonstrated no effects of montelukast on symptom-free days. The pooled montelukast treatment group showed no significant effect on reducing the usage of corticosteroids, as compared to the placebo group (RR = 1.11, 95% CI: 0.85-1.44, p = 0.45). Two trials showed that montelukast significantly decreased serum eosinophil-derived neurotoxin levels, as compared to the control group. In general, the side effects of rash, vomiting, and insomnia caused by montelukast occurred in 1.5% of patients analyzed. The recent evidences indicate that montelukast may reduce the frequency of post-bronchiolitic wheezing without causing significant side effects but that it has no effects on decreasing incidences of recurrent wheezing, symptom-free days, or the associated usage of corticosteroid in post-bronchiolitis patients. The small number of enrolled participants and the inability to pool all clinical outcomes precludes us from making solid recommendations.

Adenovirus respiratory infection in hospitalized children in Hong Kong: serotype-clinical syndrome association and risk factors for lower respiratory tract infection.

Lower respiratory tract infections (LRTI) caused by adenovirus can be severe with resultant chronic pulmonary sequelae. More than 50 serotypes have been recognized; however, the exact association of serotype with clinical phenotype is still unclear. There have been no reports on the adenovirus serotype pattern in Hong Kong, and their relationships with disease manifestations and complications are not known. Clinical and epidemiological data on 287 children (<6 years old) admitted with adenovirus respiratory infections from 2001 to 2004 were reviewed. Common presenting symptoms included fever (97.9 %) and cough and rhinitis (74 %). Extra-pulmonary manifestations were present in 37.3 %. The clinical picture mimicked bacterial infection for its prolonged high fever and neutrophilic blood picture. Forty-two patients (14.6 %) had LRTI, either pneumonia or acute bronchiolitis, but none had severe acute respiratory compromise. Children aged 1 to 2 years old were most at risk for adenovirus LRTI (adjusted p = 0.0165). Serotypes 1 to 7 could be identified in 93.7 % of the nasopharyngeal specimens, with serotypes 2 and 3 being the most prevalent. Different serotypes showed predilection for different age groups and with different respiratory illness association. The majority of acute bronchiolitis (71.4 %) were associated with serotype 2 infection, and this association was statistically significant (p < 0.0001). Serotype 3 infection accounted for over half of the pneumonia cases (57-75 %) in those aged 3-5 years old. Only one patient developed mild bronchiectasis after serotype 7 pneumonia. Children aged 1 to 2 years old were the at-risk group for adenovirus LRTI, but respiratory morbidity was relatively mild in our locality. There was an apparent serotype-respiratory illness association.

Antiviral effects of modified dingchuan decoction against respiratory syncytial virus infection in vitro and in an immunosuppressive mouse model.

ETHNOPHARMACOLOGICAL RELEVANCE: Modified dingchuan decoction (MDD) is used in traditional Chinese medicine for the treatment of cough, chronic bronchitis, asthma and viral pneumonia. AIM OF THE STUDY: To investigate antiviral potentials of MDD in respiratory syncytial virus (RSV) infected mice. MATERIALS AND METHODS: MDD and each component were evaluated for antiviral efficacy against RSV in vitro in cell culture. Mice were were treated with cyclophosphamide and infected with RSV. Then, treatments with MDD at doses of 1.75 g/kg, 3.5 g/kg and 7.0 g/kg, respectively, were oral administrated daily for 5 days after challenge. The levels of Eotaxin, IL-4 and IFN-γ in serum and lung tissue were detected by ELISA, viral loads in lung tissues were detected by RFQ-PCR while expressions of NF-κB and TLR4 mRNA were also detected by RFQ-PCR. RESULTS: A selective index of >36.8 (2.5 times greater than that observed for ribavirin) was determined in the in vitro studies for this herbal medicine. MDD exhibited significant antiviral and anti-inflammatory effects on decreasing levels of Eotaxin, IL-4 and IFN-γ in serum and lung tissue, inhibiting pneumonia, decreasing lung viral loads and reversaling RSV-induced inflammation through down-regulation of TLR4 and NF-κB mRNA expression in the lung tissue of RSV-infected mice. CONCLUSIONS: MDD could exhibit antiviral and anti-inflammatory effects on RSV-infected mice as a suppressor of Eotaxin, IL-4 and IFN-γ. These effects appeared to be mediated by inhibitions of TLR4 and NF-κB activation. Therefore, MDD could provide an effective therapeutic approach for RSV and its subsequent viral bronchitis.