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Background: A specific diagnosis of a lower respiratory viral infection is often difficult despite frequent clinical suspicion. This low diagnostic yield may be improved by use of sensitive detection methods and biomarkers., Methods: The prevalence, clinical predictors and inflammatory mediator profile of respiratory viral infection in serious acute respiratory illness were investigated. Sequential bronchoalveolar lavage (BAL) fluids from all patients hospitalised with acute respiratory illness over 12 months (n=283) were tested for the presence of 17 respiratory viruses by multiplex PCR assay and for newly discovered respiratory viruses (bocavirus, WU and KI polyomaviruses) by single-target PCR. BAL samples also underwent conventional testing (direct immunoflorescence and viral culture) for respiratory virus at the clinician's discretion. 27 inflammatory mediators were measured in a subset of the patients (n=64) using a multiplex immunoassay., Results: 39 respiratory viruses were detected in 37 (13.1% of total) patients by molecular testing, including rhinovirus (n=13), influenza virus (n=8), respiratory syncytial virus (n=6), human metapneumovirus (n=3), coronavirus NL63 (n=2), parainfluenza virus (n=2), adenovirus (n=1) and newly discovered viruses (n=4). Molecular methods were 3.8-fold more sensitive than conventional methods. Clinical characteristics alone were insufficient to separate patients with and without respiratory virus. The presence of respiratory virus was associated with increased levels of interferon gamma-inducible protein 10 (IP-10) (p<0.001) and eotaxin-1 (p=0.017) in BAL., Conclusions: Respiratory viruses can be found in patients with serious acute respiratory illness by use of PCR assays more frequently than previously appreciated. IP-10 may be a useful biomarker for respiratory viral infection.

Community acquired respiratory viruses (CARVs) are increasingly recognized as serious threats to lung transplant recipients. While CARVs such as respiratory syncytial virus, parainfluenza, influenza, and adenovirus usually cause self-limited illnesses in immunocompetent subjects, infections in the transplant recipient can be dramatic. As transplant recipients live longer and diagnostic methods improve, the burden of CARVs will undoubtedly increase. Because of limited therapeutic options, some patients may succumb to CARV infections, while many survivors develop chronic allograft dysfunction. Recognition of this latter phenomenon has implicated CARVs in the pathogenesis of bronchiolitis obliterans.

Bronchiolitis obliterans syndrome (BOS) is the major obstacle to long-term survival after lung transplantation, in part because its pathogenesis is poorly understood and treatment options are limited. To identify unique risk factors for BOS and death, we performed a retrospective cohort study on 259 consecutive adult lung transplant recipients over a 5-year period. The demographic and clinical characteristics of this population were analyzed for an association between BOS or death and potential risk factors, including community-acquired respiratory viral (CARV) infections, acute rejection, and cytomegalovirus pneumonitis. Respiratory syncytial virus, parainfluenza, influenza, and adenovirus accounted for 21 CARV infections. Univariate and multivariate time-dependent Cox regression analyses demonstrated that this CARV group was more likely to develop BOS, death, and death from BOS. Furthermore, these trends were more pronounced in patients with evidence of lower respiratory tract-CARV (lower-CARV) infections. Notably, the CARV and lower-CARV infections were risk factors for BOS, death, and death from BOS distinct from the risk attributable to acute rejection. Identification of CARV and lower-CARV infections as BOS and mortality risk factors has important clinical implications and may provide insight into disease pathogenesis and accelerate the development of novel treatment strategies to modify post-CARV BOS.

The concept that airway inflammation leads to airway disease has led to a widening search for the types of cellular and molecular interactions responsible for linking the initial stimulus to the final abnormality in airway function. It has not yet been possible to integrate all of this information into a single model for the development of airway inflammation and remodeling, but a useful framework has been based on the behavior of the adaptive immune system. In that paradigm, an exaggeration of T-helper type 2 (Th2) over Th1 responses to allergic and nonallergic stimuli leads to airway inflammatory disease, especially asthma. In this review, we summarize alternative evidence that the innate immune system, typified by actions of airway epithelial cells and macrophages, may also be specially programmed for antiviral defense and abnormally programmed in inflammatory disease. Furthermore, this abnormality may be inducible by paramyxoviral infection and, in the proper genetic background, may persist indefinitely. Taken together, we propose a new model that highlights specific interactions between epithelial, viral, and allergic components and so better explains the basis for airway immunity, inflammation, and remodeling in response to viral infection and the development of long-term disease phenotypes typical of asthma and other hypersecretory airway diseases.

A protective immune response to a respiratory viral infection requires a series of coordinated cellular and molecular responses. We have previously demonstrated that increased expression of airway epithelial cell interleukin (IL)-12 p80, a macrophage chemoattractant, is associated with human respiratory viral infection and mediates post-viral mortality in the mouse. To better understand the role of IL-12 p80-dependent macrophage chemotaxis in mediating viral immunity, we generated a transgenic mouse strain utilizing a promoter to drive IL-12 p40 gene expression in the airway epithelium. This transgenic strain secreted biologically active IL-12 p80 in a lung-specific manner, and demonstrated a selective increase in the number of resident, unactivated airway macrophages at baseline. Following infection with a sublethal dose of mouse parainfluenza virus type 1 (Sendai virus), the transgenic mice demonstrated an earlier peak and decline in the number of airway inflammatory cells. The transgenic mice were resistant to a lethal dose of virus and this viral resistance was dependent on the increased number of airway macrophages at baseline as partial depletion prior to infection abrogated this phenotype. The survival advantage in the transgenic mice was independent of viral load but was associated with a more rapid decline in the number of airway inflammatory cells and concentrations of multiple chemokines including the CC chemokine ligand 2 (CCL2)/JE, CCL3/macrophage inflammatory protein (MIP)-1α, CCL4/MIP-1β, and CCL5/RANTES. Collectively, these results suggest that IL-12 p80-driven increases in the number of resident airway macrophages prime the host for a protective immune response that can confer increased survival following a lethal respiratory viral infection. [ABSTRACT FROM AUTHOR]

Host defense against viruses probably depends on targeted death of infected host cells and then clearance of cellular corpses by macrophages. For this process to be effective, the macrophage must presumably avoid its own virus-induced death. Here we identify one such mechanism. We show that mice lacking the chemokine Ccl5 are immune compromised to the point of delayed viral clearance, excessive airway inflammation and respiratory death after mouse parainfluenza or human influenza virus infection. Virus-inducible levels of Ccl5 are required to prevent apoptosis of virus-infected mouse macrophages in vivo and mouse and human macrophages ex vivo. The protective effect of Ccl5 requires activation of the Ccr5 chemokine receptor and consequent bilateral activation of Gαi-PI3K-AKT and Gαi-MEK-ERK signaling pathways. The antiapoptotic action of chemokine signaling may therefore allow scavengers to finally stop the host cell-to-cell infectious process. [ABSTRACT FROM AUTHOR]

Recent human infections caused by the highly pathogenic avian influenza virus H5N1 strains emphasize an urgent need for assessment of factors that allow viral transmission, replication, and intra-airway spread. Important determinants for virus infection are epithelial cell receptors identified as glycans terminated by an α2,3-linked sialic acid (SA) that preferentially bind avian strains and glycans terminated by an α2,6-linked SA that bind human strains. The mouse is often used as a model for study of influenza viruses, including recent avian strains; however, the selectivity for infection of specific respiratory cell populations is not well described, and any relationship between receptors in the mouse and human lungs is incompletely understood. Here, using in vitro human and mouse airway epithelial cell models and in vivo mouse infection, we found that the α2,3-linked SA receptor was expressed in ciliated airway and type II alveolar epithelial cells and was targeted for cell-specific infection in both species. The α2,6-linked SA receptor was not expressed in the mouse, a factor that may contribute to the inability of some human strains to efficiently infect the mouse lung. In human airway epithelial cells, α2,6-linked SA was expressed and functional in both ciliated and goblet cells, providing expanded cellular tropism. Differences in receptor and cell-specific expression in these species suggest that differentiated human airway epithelial cell cultures may be superior for evaluation of some human strains, while the mouse can provide a model for studying avian strains that preferentially bind only the α2,3-linked SA receptor. [ABSTRACT FROM AUTHOR]