Bench-to-bedside review: Bacterial pneumonia with influenza - pathogenesis and clinical implications

Seasonal and pandemic influenza are frequently complicated by bacterial infections, causing additional hospitalization and mortality. Secondary bacterial respiratory infection can be subdivided into combined viral/bacterial pneumonia and post-influenza pneumonia, which differ in their pathogenesis. During combined viral/bacterial infection, the virus, the bacterium and the host interact with each other. Post-influenza pneumonia may, at least in part, be due to resolution of inflammation caused by the primary viral infection. These mechanisms restore tissue homeostasis but greatly impair the host response against unrelated bacterial pathogens. In this review we summarize the underlying mechanisms leading to combined viral/bacterial infection or post-influenza pneumonia and highlight important considerations for effective treatment of bacterial pneumonia during and shortly after influenza

Activated protein C ameliorates coagulopathy but does not influence outcome in lethal H1N1 influenza: a controlled laboratory study

Introduction: Influenza accounts for 5 to 10% of community-acquired pneumonias and is a major cause of mortality. Sterile and bacterial lung injuries are associated with procoagulant and inflammatory derangements in the lungs. Activated protein C (APC) is an anticoagulant with anti-inflammatory properties that exert beneficial effects in models of lung injury. We determined the impact of lethal influenza A (H1N1) infection on systemic and pulmonary coagulation and inflammation, and the effect of recombinant mouse (rm-) APC hereon. Methods: Male C57BL/6 mice were intranasally infected with a lethal dose of a mouse adapted influenza A (H1N1) strain. Treatment with rm-APC (125 mu g intraperitoneally every eight hours for a maximum of three days) or vehicle was initiated 24 hours after infection. Mice were euthanized 48 or 96 hours after infection, or observed for up to nine days. Results: Lethal H1N1 influenza resulted in systemic and pulmonary activation of coagulation, as reflected by elevated plasma and lung levels of thrombin-antithrombin complexes and fibrin degradation products. These procoagulant changes were accompanied by inhibition of the fibrinolytic response due to enhanced release of plasminogen activator inhibitor type-1. Rm-APC strongly inhibited coagulation activation in both plasma and lungs, and partially reversed the inhibition of fibrinolysis. Rm-APC temporarily reduced pulmonary viral loads, but did not impact on lung inflammation or survival. Conclusions: Lethal influenza induces procoagulant and antifibrinolytic changes in the lung which can be partially prevented by rm-APC treatmen

Soluble urokinase-type plasminogen activator receptor levels in patients with burn injuries and inhalation trauma requiring mechanical ventilation: an observational cohort study

Soluble urokinase-type plasminogen activator receptor (suPAR) has been proposed as a biologic marker of fibrinolysis and inflammation. The aim of this study was to investigate the diagnostic and prognostic value of systemic and pulmonary levels of suPAR in burn patients with inhalation trauma who need mechanical ventilation. suPAR was measured in plasma and nondirected lung-lavage fluid of mechanically ventilated burn patients with inhalation trauma. The samples were obtained on the day of inhalation trauma and on alternate days thereafter until patients were completely weaned from the mechanical ventilator. Mechanically ventilated patients without burns and without pulmonary disease served as controls. Systemic levels of suPAR in burn patients with inhalation trauma were not different from those in control patients. On admission and follow up, pulmonary levels of suPAR in patients with inhalation trauma were significantly higher compared with controls. Pulmonary levels of suPAR highly correlated with pulmonary levels of interleukin 6, a marker of inflammation, and thrombin-antithrombin complexes, markers of coagulation, but not plasminogen activator activity, a marker of fibrinolysis. Systemic levels of suPAR were predictive of the duration of mechanical ventilation and length of intensive care unit (ICU) stay. Duration of mechanical ventilation and length of ICU stay were significantly longer in burn-injury patients with systemic suPAR levels > 9.5 ng/ml. Pulmonary levels of suPAR are elevated in burn patients with inhalation trauma, and they correlate with pulmonary inflammation and coagulation. Although pulmonary levels of suPAR may have diagnostic value in burn-injury patients, systemic levels of suPAR have prognostic valu

CD14 plays a limited role during influenza A virus infection in vivo

Influenza A is a single stranded (ss)RNA virus that can cause upper respiratory tract infections that in rare cases may progress to pneumonia. Toll-like receptors (TLRs) and CD14 are receptors which recognize viral proteins and nucleic acid of several viruses. CD14 is required for influenza-induced cytokine production during infection of mouse macrophages. In addition, CD14 was shown to bind ssRNA, suggesting an important role for CD14 during infection with influenza. To investigate the role of CD14 during influenza pneumonia we inoculated WT and CD14 KO mice with a non-lethal dose of a mouse adapted strain of influenza A. CD14 KO mice displayed a reduced viral load in the lungs, 2 and 14 days after infection with influenza. Pulmonary cytokine production in CD14 KO mice was reduced at day 2 and elevated at day 8 compared to WT mice. CD14 deficiency did not influence lymphocyte recruitment or lymphocyte activation in lungs and draining lymph nodes 8 days after infection. These data show that CD14 plays a limited role in host defense against infection with influenz

Monocyte chemoattractant protein 1 contributes to an adequate immune response in influenza pneumonia

Monocyte chemoattractant protein 1 (MCP-1) and its receptor CCR2 have been shown to play an import role in leukocyte recruitment to sites of infection and inflammation. To investigate the role of MCP-1 during infection with influenza we inoculated wild-type (WT) and MCP-1 knockout (KO) mice with a non-lethal dose of a mouse adapted strain of influenza A. Influenza infection of WT mice resulted in a profound increase in pulmonary MCP-1 levels. MCP-1 KO mice had enhanced weight loss and did not fully regain their body weight during the 14-day observation period. In addition, MCP-1 KO mice demonstrated elevated viral loads 8 days after infection, which was accompanied by reduced leukocyte recruitment into the infected lungs, primarily caused by a diminished influx of macrophages and granulocytes. Moreover, pulmonary levels of IgA were reduced in MCP-1 KO mice. The pulmonary concentrations of tumor necrosis factor-alpha, interleukin-6, macrophage inflammatory protein 2 and interferon-gamma were higher in MCP-1 KO mice. This study shows that MCP-1 contributes to an adequate protective immune response against influenza infection in mic

Gene expression profiles in murine influenza pneumonia

BACKGROUND: Many in vitro studies have focused on gene expression in influenza-infected leukocytes, lung tissue or cell lines. However, knowledge of in vivo gene expression in these compartments is limited. METHODS: To obtain insight into gene expression profiles during influenza infection, we determined the expression of multiple genes by using a newly developed mouse-specific multiplex ligation-dependent probe amplification assay. RESULTS: The genes involved in inflammation, Toll-like receptor signaling, coagulation, fibrinolysis, cell adhesion, tissue repair and homeostasis were measured in lung tissue, leukocytes in bronchoalveolar lavage fluid and tracheal epithelial cells in mice, before and after intranasal infection with influenza A. Most of the genes investigated were differentially expressed during the course of infection and returned to baseline levels when mice had recovered from the infection. However, expression of several genes remained altered even though mice had completely cleared the virus. CONCLUSION: These data provide the first information on compartmentalized gene expression profiles in the respiratory tract during influenz