The role of peripheral type 2 innate lymphoid cells in bronchiolitis.

Our aim was to detect type 2 innate lymphoid cells (ILC2s)-related cytokines of infants with bronchiolitis by using Elisa, Liquidchip technology and RT-PCR and investigated its correlation with bronchiolitis. We recruited 26 infants with bronchiolitis and 20 healthy infants as control from Xiangya Hospital. Compared to the control group, the serum levels of interleukin-5 (IL-5) [41.99 (21.11) vs 25.70 (19.64)], IL-9 [27.04 (37.51) vs 8.30 (0.54)], IL-13 [184.05 (132.81) vs 121.75 (176.13)], IL-33 [83.70 (46.69) vs 11.23 (55.31)] and thymic stromal lymphopoietin (TSLP) [31.42 (5.41) vs 28.76 (2.56)] were significantly increased in infants with bronchiolitis (P < 0.05), while the level of IgE had no significant difference between the two groups [19.05 (14.15) vs 14.85 (20.2), P > 0.05]. The mRNA expression of IL-17RB (9.83 ± 0.35 vs 9.19 ± 0.58), TSLP (16.98 ± 2.12 vs 15.07 ± 2.25), retinoid acid receptor related orphan receptor α (7.18 ± 0.71 vs 5.46 ± 1.09) and trans-acting T-cell-specific transcription factor 3 (4.86 ± 0.66 vs 4.19 ± 0.90) were significantly increased in infants with bronchiolitis versus the control group (P < 0.05), while there was no statistical significance for suppression of tumorigenicity 2 (5.59 ± 0.68 vs 5.41 ± 0.87, P > 0.05). Our findings suggested that ILC2s possibly play a specific role in immunopathology of bronchiolitis.

Transcriptome of airway neutrophils reveals an interferon response in life-threatening respiratory syncytial virus infection.

BACKGROUND: Neutrophils are the most abundant cell type infiltrating the airways during severe respiratory syncytial virus (RSV) infection. Their exact role in disease pathophysiology remains enigmatic. Therefore, we determined genome-wide RNA expression profiles of local and systemic neutrophils in RSV bronchiolitis to provide further insight into local neutrophil biology. METHODS: We performed a single-center analysis, in 16 infants, admitted to the pediatric intensive care unit with severe RSV bronchiolitis. Neutrophils were isolated from blood and tracheobronchial aspirates (sputum). After low input RNA sequencing, differential expression of genes was determined followed by gene set analysis. RESULTS: Paired transcriptomic analysis of airway versus blood neutrophils showed an inflammatory phenotype, characterized by NF-kB signaling and upregulated expression of IL-6 and interferon pathways. We observed distinct expression of neutrophil activation genes (TNFSF13B, FCER1G). DISCUSSION: Our data indicate that airway neutrophils regulate their function at the transcriptional level in response to viral infection. It also suggests that local interferon drives the neutrophil response of severe RSV bronchiolitis.

Differential lung inflammation and injury with tobacco smoke exposure in Wistar Kyoto and spontaneously hypertensive rats.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide and has been associated with periods of intense lung inflammation. The objective of this study was to characterize whether similar rat strains, possessing different genetic predispositions, might play a role in exacerbating the pathophysiology of COPD-like cellular and structural changes with progressive 12-week exposure to tobacco smoke (TS). Normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SH) rats were compared. MATERIALS AND METHODS: WKY and SH rats were exposed to filtered air or to tobacco smoke at a particulate concentration of 80 mg/m3 for 4, 8, or 12 weeks. Necropsy was performed 24 h after the last exposure to obtain cells by bronchoalveolar lavage for total cell and differential counts. Scoring of lung tissues and immunohistochemical staining for M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages were performed on paraffin-embedded lung sections. RESULTS AND DISCUSSION: With progressive exposure, TS-exposed SH rats demonstrated significant airspace enlargement, mucin production, and lung inflammation compared to their FA control and TS-matched WKY rats. Moreover, SH rats also demonstrated increased expression of the M1 marker in alveolar macrophages compared to FA control, as well as the M2 marker compared to controls and TS-exposed WKY rats. CONCLUSION: The progressive tobacco smoke exposure contributes to persistent lung injury and inflammation that can be significantly enhanced by rat strain susceptibility in the genesis of COPD.

Clinical and Th1/Th2 immune response features of hospitalized children with human rhinovirus infection.

This study aimed to assess the clinical characteristics and T-helper 1 (Th1)/Th2 profile of human rhinovirus (HRV) infection in children with bronchiolitis and pneumonia, compared with the respiratory syncytial virus (RSV). In September 2013 to August 2014, 335 nasopharyngeal aspirates from children below 14 with bronchiolitis and pneumonia were screened for HRV and 13 other respiratory viruses by PCR or reverse transcription PCR. Interferon (IFN)-γ, interleukin (IL)-2, IL-4, IL-6, IL-10, and tumor necrosis factor (TNF)-α were detected by multiplex enzyme-linked immunosorbent assay. HRVs were found in 66 cases (19.7%), including 35 bronchiolitis and 31 pneumonia cases. Compared with the RSV alone group, children with pneumonia had more frequent wheezing episodes in HRV (Pa = .001) and HRV + non-RSV (Pb = .002) groups, and fever in the HRV (Pf = .004) and HRV + RSV (Pg = .005) groups. Among patients with bronchiolitis, cases with HRV alone were more likely to present in winter than those with RSV alone (Pi = .010) and HRV + non-RSV (Pj = .014), and less numerous in summer compared with HRV + non-RSV (Ph = .005). Children with HRV alone were more susceptible to have a history of eczema than RSV alone among bronchiolitis (Pc < .001) and pneumonia (Pe = .033) cases. HRV bronchiolitis cases had increased IL-4/IFN-γ and decreased TNF-α/IL-10 ratios, compared with HRV pneumonia counterparts. HRV is a major non-RSV pathogen causing hospitalization in children with bronchiolitis and pneumonia and induces an imbalanced Th1/Th2 response in bronchiolitis. Compared with RSV infection, HRV bronchiolitis and pneumonia differ significantly regarding wheezing episodes, susceptibility to eczema, fever occurrence, and seasonal prevalence.

Immune recovery following bronchiolitis is linked to a drop in cytokine and LTC4 levels.

BACKGROUND: Bronchiolitis is the main cause of hospitalization of children younger than 1 year; however, the immune mechanism of bronchiolitis is not completely understood. The aim of this study was to analyze the recovery of immune response after a bronchiolitis episode. METHODS: Forty-nine infants hospitalized with bronchiolitis diagnosis were enrolled. Nasopharyngeal aspirates (NPAs) were processed. Twenty-seven pro-inflammatory biomarkers linked to innate immunity, inflammation, and epithelial damage, as well as nitrites and lipid mediators, were evaluated in the NPA supernatant by ELISA (enzyme-linked immunosorbent assay) and Luminex. Also, 11 genes were analyzed in NPA cells by quantitative PCR. RESULTS: A widespread statistically significant decline of multiple pro-inflammatory parameters and cytokines were detected in the recovery period after respiratory infection: interferon-α2 (IFNα2), IFNγ, interleukin-10 (IL-10), IL-1ß, IL-8, IFN-γ-inducible protein-10, vascular endothelial growth factor, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α (MIP-1α), and MIP-1ß. Supporting these results, a decreased nuclear factor-κB gene expression was observed (P = 0.0116). A significant diminution of cysteinyl leukotriene C4 (LTC4) soluble levels (P = 0.0319) and cyclooxygenase-2 (COX-2) gene expression were observed in the recovery sample. In children classified by post-bronchiolitis wheezing, LTC4 remains elevated in the NPA supernatant. CONCLUSIONS: After bronchiolitis, cytokines and biomarkers linked to innate immune response in NPA decrease significantly in the recovery period accompanied by a drop in LTC4 levels; however, this reduction was lower in infants with post-bronchiolitis wheezing.

Temporal trend of hospitalizations for acute bronchiolitis in infants under one year of age in brazil between 2008 and 2015 / Tendência temporal das hospitalizações por bronquiolite aguda em lactentes menores de um ano no brasil entre 2008 e 2015

ABSTRACT Objective: To evaluate the trend of hospitalization for acute bronchiolitis in infants under one year of age, in the past eight years and after the implementation of the palivizumab immunization program in Brazil. Methods: The study is a retrospective analysis of data on infants younger than one year of age, who were hospitalized with acute bronchiolitis between 2008 and 2015 in Brazil. The Brazilian National Health System database was used. The rates of hospitalization in the pre-implementation (2008-2012) and post-implementation (2014-2015) periods of the palivizumab immunization program were evaluated. The total number of admissions in the same period was used as a comparison. Results: Between January 2008 and December 2015, 263,679 hospitalizations for bronchiolitis were recorded in infants younger than one year of age, 60% represented by boys. The incidence of hospitalization for bronchiolitis increased by 49% over this period (8.5 to 12.7 per 1,000 inhabitants per year). Between 2013 and 2014, the incidence rate of hospitalization for acute bronchiolitis decreased by 8% (12.5 to 11.5 per 1,000 inhabitants per year). However, in the second year of the program, hospitalization rate increased again by 10% (12.7 per 1,000 inhabitants per years). Conclusions: Acute bronchiolitis presented increasing rates of hospitalization over the study period. Hospitalization incidence for acute bronchiolitis declined one year after the implementation of palivizumab but increased again in the second year of the program.

RESUMO Objetivo: Avaliar a tendência de hospitalização por bronquiolite aguda (BA) em lactentes menores de um ano de idade nos últimos oito anos no Brasil e, secundariamente, após a implementação do programa de imunização por palivizumabe. Métodos: Análise retrospectiva dos dados de lactentes menores de um ano de idade, hospitalizados com diagnóstico de BA entre 2008 e 2015 no Brasil, utilizando o banco de dados do Sistema Único de Saúde (SUS). Foram avaliadas as taxas de hospitalização nos períodos pré-implementação (2008-2012) e pós-implementação (2014-2015) do programa de imunização por palivizumabe. O número total de internações no mesmo período foi utilizado como comparação. Resultados: Entre janeiro de 2008 e dezembro 2015 foram registradas 263.679 internações por bronquiolite em lactentes menores de um ano de idade, 60% representado por meninos. A incidência de hospitalização por bronquiolite aumentou em 49% ao longo desse período (8,5 para 12,7 por mil ­habitantes/­ano). Entre 2013 e 2014, a taxa de incidência de hospitalização por BA diminuiu 8% (12,5 para 11,5 por mil habitantes/ano). Porém, no segundo ano do programa, a taxa de internação aumentou novamente em 10% (12,7 por mil habitantes/ano). Conclusões: A BA apresentou taxas de hospitalização crescente ao longo do período estudado. A incidência de hospitalizações de BA apresentou declínio um ano após a implementação de palivizumabe e retornou à tendência crescente no segundo ano do programa.

Methylation Landscape of RUNX3 Promoter Region as a Predictive Marker for Th1/Th2 Imbalance in Bronchiolitis.

BACKGROUND The methylation status of RUNX3 promoter region, its impact on RUNX3 gene expression, and Th1/Th2 imbalance are unknown in bronchiolitis. This study aimed to explore the predictors of bronchiolitis developing into asthma. MATERIAL AND METHODS The methylation status of RUNX3 promoter was assessed using Illumina HiSeq platform method. The relative RUNX3 mRNA levels in PBMCs were measured by qRT-PCR. Serum IL-4 and IFN-γ concentrations were measured by ELISA. RESULTS A series of sites with significantly higher levels of methylation as compared to their corresponding controls were identified, including 24 sites in group Ba vs. group Cn, 13 sites in group Ba vs. group Ca, 7 sites in group Ba vs. group Bn, 16 sites in group Bn vs. group Cn, 11 sites in group Ca vs. group Cn, and 23 sites in group B vs. group C; P<0.05. The relative mRNA levels in group Ba were significantly lower than those in groups Cn, Ca, Bn; P<0.05. The serum IL-4 concentrations in group Ba were significantly higher than those in group Cn; P<0.05. The serum IFN-γ concentrations in group Ba were significantly lower than those in groups Cn, Ca, Bn; P<0.05. Correlation analysis showed that differentially methylated RUNX3 promoter region sites were significantly negatively correlated with levels of relative RUNX3 mRNA and IFN-γ, and were significantly positively correlated with IL-4 levels. CONCLUSIONS The methylation status of RUNX3 promoter region plays a role in Th1/Th2 imbalance by silencing RUNX3 gene expression, which can serve as predictive marker for the development of bronchiolitis into asthma.

[Lower lymphocyte response in severe cases of acute bronchiolitis due to respiratory syncytial virus]. / Menor respuesta linfocitaria en casos graves de bronquiolitis aguda por virus respiratorio sincitial.

INTRODUCTION: Acute bronchiolitis (AB) of the infant has a serious outcome in 6-16% of the hospital admitted cases. Its pathogenesis and evolution is related to the response of the T lymphocytes. The objective of the present study is to determine if the lower systemic lymphocytic response is related to a worse outcome of AB in hospitalised infants. PATIENTS AND METHOD: Retrospective observational-analytical study of cases-controls nested in a cohort of patients admitted due to RSV-AB between the period from October 2010 to March 2015. Those with a full blood count in the first 48hours of respiratory distress were included. Infants with underlying disease, bacterial superinfection, and premature infants <32 weeks of gestation were excluded. The main dichotomous variable was PICU admission. Other variables were: gender, age, post-menstrual age, gestational and post-natal tobacco exposure, admission month, type of lactation, and days of onset of respiratory distress. Lymphocyte counts were categorised by quartiles. Bivariate analysis was performed with the main variable and then by logistic regression to analyse confounding factors. RESULTS: The study included 252 infants, of whom 6.6% (17) required PICU admission. The difference in mean±SD of lymphocytes for patients admitted to and not admitted to PICU was 4,044±1755 and 5,035±1786, respectively (Student-t test, P<.05). An association was found between PICU admission and lymphocyte count <3700/ml (Chi-squared, P=.019; OR: 3.2) and it was found to be maintained in the logistic regression, regardless of age and all other studied factors (Wald 4.191 P=.041, OR: 3.8). CONCLUSIONS: A relationship was found between lymphocytosis <3700/ml in the first days of respiratory distress and a worse outcome in previously healthy infants <12 months and gestational age greater than 32 weeks with RSV-AB.

The Changes of Th17/Treg and Related Cytokines: IL-17, IL-23, IL-10, and TGF-ß in Respiratory Syncytial Virus Bronchiolitis Rat Model.

Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and hospitalization that lead to high morbidity and mortality among young infants. T helper 17 (Th17) cells and regulatory T cells (Tregs) play essential roles in the pathogenesis of autoimmune, cancer, and inflammatory diseases. However, whether changes in T-cell subsets are related to the systemic immune responses in RSV-caused bronchiolitis merit further investigation. Three-week-old Sprague Dawley (SD) rats were randomly divided into the normal control (NC) and RSV bronchiolitis (RSV-B) groups. An RSV-B model was successfully established using nasal drip containing RSV. Furthermore, pathological changes in the lung tissues were observed using hematoxylin and eosin staining. Flow cytometry determined the levels of Th17 and Treg subsets. The related cytokines were measured using enzyme-linked immunosorbent assay (ELISA). The expression levels of related transcription factors, such as RORγt and FOXP3, were examined using real-time quantitative PCR and western blot analysis. The RSV-B group exhibited pulmonary interstitial hyperemia and edema, inflammatory cell infiltration, wide alveolar septa, and bronchial collapse and deformation. The percentage of Th17 cells in RSV-B group was about 2.3 fold higher than that of NC group, and the concentration of IL-17, IL-23 and RORγt was higher than in NC group. In contrast, the percentage of Treg cells in the RSV-B group was approximately 0.7 fold lower than that in the NC group, and the levels of IL-10, TGF-ß, and FOXP3 in the RSV-B group were lower than those in the NC group. The above results were statistically significant. The changes of Th17/Treg, and their associated cytokines, specific transcription factors, are present in RSV bronchiolitis model rats, which may play an important role in the pathogenesis of RSV bronchiolitis.

Advanced Role of Neutrophils in Common Respiratory Diseases.

Respiratory diseases, always being a threat towards the health of people all over the world, are most tightly associated with immune system. Neutrophils serve as an important component of immune defense barrier linking innate and adaptive immunity. They participate in the clearance of exogenous pathogens and endogenous cell debris and play an essential role in the pathogenesis of many respiratory diseases. However, the pathological mechanism of neutrophils remains complex and obscure. The traditional roles of neutrophils in severe asthma, chronic obstructive pulmonary diseases (COPD), pneumonia, lung cancer, pulmonary fibrosis, bronchitis, and bronchiolitis had already been reviewed. With the development of scientific research, the involvement of neutrophils in respiratory diseases is being brought to light with emerging data on neutrophil subsets, trafficking, and cell death mechanism (e.g., NETosis, apoptosis) in diseases. We reviewed all these recent studies here to provide you with the latest advances about the role of neutrophils in respiratory 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.

The Helminth-Derived Immunomodulator AvCystatin Reduces Virus Enhanced Inflammation by Induction of Regulatory IL-10+ T Cells.

Respiratory Syncytial Virus (RSV) is a major pathogen causing low respiratory tract disease (bronchiolitis), primarily in infants. Helminthic infections may alter host immune responses to both helminths and to unrelated immune triggers. For example, we have previously shown that filarial cystatin (AvCystatin/Av17) ameliorates allergic airway inflammation. However, helminthic immunomodulators have so far not been tested in virus-induced disease. We now report that AvCystatin prevents Th2-based immunopathology in vaccine-enhanced RSV lung inflammation, a murine model for bronchiolitis. AvCystatin ablated eosinophil influx, reducing both weight loss and neutrophil recruitment without impairing anti-viral immune responses. AvCystatin also protected mice from excessive inflammation following primary RSV infection, significantly reducing neutrophil influx and cytokine production in the airways. Interestingly, we found that AvCystatin induced an influx of CD4+ FoxP3+ interleukin-10-producing T cells in the airway and lungs, correlating with immunoprotection, and the corresponding cells could also be induced by adoptive transfer of AvCystatin-primed F4/80+ macrophages. Thus, AvCystatin ameliorates enhanced RSV pathology without increasing susceptibility to, or persistence of, viral infection and warrants further investigation as a possible therapy for virus-induced airway disease.

Effects of ceftaroline on the innate immune and on the inflammatory responses of bronchial epithelial cells exposed to cigarette smoke.

The tobacco smoking habit interferes with the innate host defence system against infections. Recurrent infections accelerated the functional respiratory decline. The present study assessed the effects of ceftaroline on TLR2 and TLR4 and on pro-inflammatory responses in airway epithelial cells (16HBE cell line and primary bronchial epithelial cells) with or without cigarette smoke extracts (CSE 10%). TLR2, TLR4, LPS binding and human beta defensin 2 (HBD2) were assessed by flow cytometry, NFkB nuclear translocation by western blot analysis, IL-8 and HBD2 mRNA by Real Time PCR; the localization of NFkB on the HBD2 and IL-8 promoters by ChiP Assay. CSE increased TLR4, TLR2 expression, LPS binding and IL-8 mRNA; CSE decreased HBD2 (protein and mRNA), activated NFkB and promoted the localization of NFkB on IL-8 promoter and not on HBD2 promoter. Ceftaroline counteracted the CSE effect on TLR2 expression, on LPS binding, on IL-8 mRNA, HBD2 and NFkB in 16HBE. The effects of ceftaroline on HBD2 protein and on IL-8 mRNA were confirmed in primary bronchial epithelial cells. In conclusion, ceftaroline is able to counteract the effects of CSE on the innate immunity and pro-inflammatory responses modulating TLR2, LPS binding, NFkB activation and activity, HBD2 and IL-8 expression in bronchial epithelial cells.

Cytokine responses in primary and secondary respiratory syncytial virus infections.

BACKGROUND: Primary respiratory syncytial virus (RSV) infections are characterized by high levels of IL-8 and an intense neutrophilia. Little is known about the cytokine responses in secondary infections. Preschool children experiencing RSV secondary infections were recruited from the siblings of infants admitted to hospital with RSV acute bronchiolitis. METHODS: Fifty-one infants with acute bronchiolitis (39 RSV positive, 12 RSV negative) and 20 age-matched control infants were recruited. In addition, seven older siblings of infants from the RSV-positive cohort and confirmed RSV infection were recruited. Samples of nasal secretions were obtained using a flocked swab, and secretions extracted using centrifugation. Cytokine bead array was used to obtain levels of interleukin (IL)-17A, IL-8, IL-6, IL-21, and tumor necrosis factor-α. RESULTS: Levels of IL-8 and IL-6 were significantly lower in the RSV-positive siblings compared with the RSV-positive infants. There were no significant differences between levels of the other cytokines in the primary and secondary infections. CONCLUSION: The very high levels of IL-8 and IL-6 response characteristic of the primary RSV infection was not observed in secondary RSV-positive infections and this did not appear to be due to a global reduction in cytokine production.

Human Respiratory Syncytial Virus: Role of Innate Immunity in Clearance and Disease Progression.

Human respiratory syncytial virus (HRSV) infections have worldwide records. The virus is responsible for bronchiolitis, pneumonia, and asthma in humans of different age groups. Premature infants, young children, and immunocompromised individuals are prone to severe HRSV infection that may lead to death. Based on worldwide estimations, millions of cases were reported in both developed and developing countries. In fact, HRSV symptoms develop mainly as a result of host immune response. Due to inability to establish long lasting adaptive immunity, HRSV infection is recurrent and hence impairs vaccine development. Once HRSV attached to the airway epithelia, interaction with the host innate immune components starts. HRSV interaction with pulmonary innate defenses is crucial in determining the disease outcome. Infection of alveolar epithelial cells triggers a cascade of events that lead to recruitment and activation of leukocyte populations. HRSV clearance is mediated by a number of innate leukocytes, including macrophages, natural killer cells, eosinophils, dendritic cells, and neutrophils. Regulation of these cells is mediated by cytokines, chemokines, and other immune mediators. Although the innate immune system helps to clear HRSV infection, it participates in disease progression such as bronchiolitis and asthma. Resolving the mechanisms by which HRSV induces pathogenesis, different possible interactions between the virus and immune components, and immune cells interplay are essential for developing new effective vaccines. Therefore, the current review focuses on how the pulmonary innate defenses mediate HRSV clearance and to what extent they participate in disease progression. In addition, immune responses associated with HRSV vaccines will be discussed.

Human T-cell Lymphotropic Virus Type-1 (HTLV-1)-associated Bronchioloalveolar Disorder Presenting with Mosaic Perfusion.

Human T-cell lymphotropic virus type-1 (HTLV-1)-associated bronchioloalveolar disorder (HABA) is a specific state with chronic and progressive respiratory symptoms caused by bronchiolar or alveolar disorder characterized by smoldering adult T-cell leukemia or the HTLV-I carrier state. We herein report a rare case of HABA with an initial presentation of mosaic perfusion in the lung. The diagnosis was made according to the results of a flow cytometry analysis of the bronchoalveolar lavage fluid and pathological findings. Clinicians must be careful to recognize that mosaic perfusion may be a radiological finding of HABA.

Intranasal nanoemulsion-based inactivated respiratory syncytial virus vaccines protect against viral challenge in cotton rats.

Respiratory Syncytial Virus is a leading cause of bronchiolitis and pneumonia in infants, the elderly and individuals with compromised immune systems. Despite decades of research, there is currently no available vaccine for RSV. Our group has previously demonstrated that intranasal immunization of mice with RSV inactivated by and adjuvanted with W805EC nanoemulsion elicits robust humoral and cellular immune responses, resulting in protection against RSV infection. This protection was achieved without the induction of airway hyper-reactivity or a Th2-skewed immune response. The cotton rat Sigmodon hispidus has been used for years as an excellent small animal model of RSV disease. Thus, we extended these rodent studies to the more permissive cotton rat model. Intranasal immunization of the nanoemulsion-adjuvanted RSV vaccines induced high antibody titers and a robust Th1-skewed cellular response. Importantly, vaccination provided sterilizing cross-protective immunity against a heterologous RSV challenge and did not induce marked or severe histological effects or eosinophilia in the lung after viral challenge. Overall, these data demonstrate that nanoemulsion-formulated whole RSV vaccines are both safe and effective for immunization in multiple animal models.

Respiratory syncytial virus human experimental infection model: provenance, production, and sequence of low-passaged memphis-37 challenge virus.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in children and is responsible for as many as 199,000 childhood deaths annually worldwide. To support the development of viral therapeutics and vaccines for RSV, a human adult experimental infection model has been established. In this report, we describe the provenance and sequence of RSV Memphis-37, the low-passage clinical isolate used for the model's reproducible, safe, experimental infections of healthy, adult volunteers. The predicted amino acid sequences for major proteins of Memphis-37 are compared to nine other RSV A and B amino acid sequences to examine sites of vaccine, therapeutic, and pathophysiologic interest. Human T- cell epitope sequences previously defined by in vitro studies were observed to be closely matched between Memphis-37 and the laboratory strain RSV A2. Memphis-37 sequences provide baseline data with which to assess: (i) virus heterogeneity that may be evident following virus infection/transmission, (ii) the efficacy of candidate RSV vaccines and therapeutics in the experimental infection model, and (iii) the potential emergence of escape mutants as a consequence of experimental drug treatments. Memphis-37 is a valuable tool for pre-clinical research, and to expedite the clinical development of vaccines, therapeutic immunomodulatory agents, and other antiviral drug strategies for the protection of vulnerable populations against RSV disease.