BackgroundWith concerns about the disastrous health and economic consequences caused by the influenza pandemic, comprehensively understanding the global host response to influenza virus infection is urgent. The role of microRNA (miRNA) has recently been highlighted in pathogen-host interactions. However, the precise role of miRNAs in the pathogenesis of influenza virus infection in humans, especially in critically ill patients is still unclear.MethodsWe identified cellular miRNAs involved in the host response to influenza virus infection by performing comprehensive miRNA profiling in peripheral blood mononuclear cells (PBMCs) from critically ill patients with swine-origin influenza pandemic H1N1 (2009) virus infection via miRNA microarray and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assays. Receiver operator characteristic (ROC) curve analysis was conducted and area under the ROC curve (AUC) was calculated to evaluate the diagnostic accuracy of severe H1N1 influenza virus infection. Furthermore, an integrative network of miRNA-mediated host-influenza virus protein interactions was constructed by integrating the predicted and validated miRNA-gene interaction data with influenza virus and host-protein-protein interaction information using Cytoscape software. Moreover, several hub genes in the network were selected and validated by qRT-PCR.ResultsForty-one significantly differentially expressed miRNAs were found by miRNA microarray; nine were selected and validated by qRT-PCR. QRT-PCR assay and ROC curve analyses revealed that miR-31, miR-29a and miR-148a all had significant potential diagnostic value for critically ill patients infected with H1N1 influenza virus, which yielded AUC of 0.9510, 0.8951 and 0.8811, respectively. We subsequently constructed an integrative network of miRNA-mediated host-influenza virus protein interactions, wherein we found that miRNAs are involved in regulating important pathways, such as mitogen-activated protein kinase signaling pathway, epidermal growth factor receptor signaling pathway, and Toll-like receptor signaling pathway, during influenza virus infection. Some of differentially expressed miRNAs via in silico analysis targeted mRNAs of several key genes in these pathways. The mRNA expression level of tumor protein T53 and transforming growth factor beta receptor 1 were found significantly reduced in critically ill patients, whereas the expression of Janus kinase 2, caspase 3 apoptosis-related cysteine peptidase, interleukin 10, and myxovirus resistance 1 were extremely increased in critically ill patients.ConclusionsOur data suggest that the dysregulation of miRNAs in the PBMCs of H1N1 critically ill patients can regulate a number of key genes in the major signaling pathways associated with influenza virus infection. These differentially expressed miRNAs could be potential therapeutic targets or biomarkers for severe influenza virus infection.

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From early May 2009, the novel influenza A (H1N1) pandemic affected mainland China. Of those infected, a small proportion of patients developed acute respiratory distress syndrome (ARDS) so rapidly and severely that conventional ventilation treatment was ineffective. As an alternative treatment, the effect of extracorporeal membrane oxygenation (ECMO) was evaluated. From November 2009 to January 2010, all patients suffering from influenza A (H1N1)-associated ARDS referred to Beijing Anzhen Hospital for treatment with ECMO were enrolled. We describe the characteristics, treatment, and outcomes of these patients at 1- and 3-month follow-up. Nine patients (four females; mean age, 31.2 [21-59] years) from four centers were enrolled. All females had a history of recent pregnancy or had recently given birth. Before ECMO, patients had severe respiratory failure despite advanced mechanical ventilatory support with a mean partial pressure of arterial oxygen/fraction of inspired oxygen of 52.9 ± 5.1 (45.0-63.8) mm Hg, positive end-expiratory pressure of 17.2 ± 4.2 cmH(2) O, and a Murray Lung Score of 3.6 (3.25-3.75). All nine patients were treated with veno-venous ECMO via percutaneous access. The mean duration of ECMO support was 436.6 ± 652.1 h (67.0-2160.0). At the end of 1-year follow-up, five patients (55.7%) were weaned from ECMO. Five patients (55.7%) survived to hospital discharge. Four patients (44.4%) died while undergoing ECMO. The mean length of intensive care unit and hospital stay was 4-204 days (median, 32) and 4-234 days (median, 38), respectively. There was no significant difference between survivors and nonsurvivors in the screened parameters. Use of ECMO for critically ill patients with 2009 influenza A (H1N1)-related ARDS is feasible and effective. However, this treatment is technically demanding. For success, careful selection of patients is crucial.

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