• Jesus F Bermejo-Martin, Ignacio Martin-Loeches, Jordi Rello, Andres Antón, Raquel Almansa, Luoling Xu, Guillermo Lopez-Campos, Tomás Pumarola, Longsi Ran, Paula Ramirez, David Banner, Derek Cheuk Ng, Lorenzo Socias, Ana Loza, David Andaluz, Enrique Maravi, Maria J Gómez-Sánchez, Mónica Gordón, Maria C Gallegos, Victoria Fernandez, Sara Aldunate, Cristobal León, Pedro Merino, Jesús Blanco, Fernando Martin-Sanchez, Lucia Rico, David Varillas, Veronica Iglesias, Maria Ángeles Marcos, Francisco Gandía, Felipe Bobillo, Begoña Nogueira, Silvia Rojo, Salvador Resino, Carmen Castro, Ortiz de LejarazuRaulR, and David Kelvin.
• Infection & Immunity Unit, Hospital Clínico Universitario-IECSCYL, Avda, Ramón y Cajal 3, 47005 Valladolid, Spain. jfbermejo@saludcastillayleon.es
• Crit Care. 2010 Jan 1; 14 (5): R167.

IntroductionPandemic A/H1N1/2009 influenza causes severe lower respiratory complications in rare cases. The association between host immune responses and clinical outcome in severe cases is unknown.MethodsWe utilized gene expression, cytokine profiles and generation of antibody responses following hospitalization in 19 critically ill patients with primary pandemic A/H1N1/2009 influenza pneumonia for identifying host immune responses associated with clinical outcome. Ingenuity pathway analysis 8.5 (IPA) (Ingenuity Systems, Redwood City, CA) was used to select, annotate and visualize genes by function and pathway (gene ontology). IPA analysis identified those canonical pathways differentially expressed (P < 0.05) between comparison groups. Hierarchical clustering of those genes differentially expressed between groups by IPA analysis was performed using BRB-Array Tools v.3.8.1.ResultsThe majority of patients were characterized by the presence of comorbidities and the absence of immunosuppressive conditions. pH1N1 specific antibody production was observed around day 9 from disease onset and defined an early period of innate immune response and a late period of adaptive immune response to the virus. The most severe patients (n = 12) showed persistence of viral secretion. Seven of the most severe patients died. During the late phase, the most severe patient group had impaired expression of a number of genes participating in adaptive immune responses when compared to less severe patients. These genes were involved in antigen presentation, B-cell development, T-helper cell differentiation, CD28, granzyme B signaling, apoptosis and protein ubiquitination. Patients with the poorest outcomes were characterized by proinflammatory hypercytokinemia, along with elevated levels of immunosuppressory cytokines (interleukin (IL)-10 and IL-1ra) in serum.ConclusionsOur findings suggest an impaired development of adaptive immunity in the most severe cases of pandemic influenza, leading to an unremitting cycle of viral replication and innate cytokine-chemokine release. Interruption of this deleterious cycle may improve disease outcome.

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