The high levels of the immunomodulatory molecules IL-1ra and IL-10 could represent an attempt to prevent cytokine-driven inflammatory damage or alternatively a virus-induced evasion mechanism [26-29]. The positive correlation observed between IL-10, viral load MG132 and SOFA, and the negative correlations between this cytokine and the expression levels of the genes participating in the antigen presentation pathway, supports the role of this mediator in favoring viral replication. As detailed in Table Table1,1, bacterial superinfections took place not in the early but in the late course of the disease. This supports the role of the impaired adaptive response and the release of immunosuppressory cytokines in the increased incidence of bacterial superinfection observed in severe disease following infection by p2009A(H1N1) [2].

ConclusionsOur findings suggest a state of host adaptive immunity deficiency (HAID) in the patients with severe pandemic influenza, leading to an unremitting cycle of viral replication and innate cytokine-chemokine release (Figure (Figure5).5). This scenario of HAID resembles to the concept of immunoparalysis described for sepsis [30]. Interruption of this deleterious cycle may lead to improved disease outcome.Figure 5Host adaptive immunity deficiency (HAID) model in severe pandemic influenza. The picture shows the unvirtuous circle of the response to the virus.Key messages? The association between host immune responses and clinical outcome in severe pandemic 2009 influenza is poorly known.

The potential for the use of gene signatures to better assess the immunopathology and clinical management of severe viral infections has been widely demonstrated in the past.? Previous studies examining host gene expression profiles in other emerging viruses such as SARS-associated coronavirus, suggest severe disease is characterized by a malfunction of the switch from innate to adaptive immunity in response to the virus. Similar to severe infections caused by H5N1 influenza virus, dysregulated cytokine secretion has been described in severe cases of p2009A(H1N1).? Pandemic H1N1 patients with severe respiratory disease and poor outcomes are characterized by an impaired activation of those genes participating in the development of the antiviral adaptive response and by persistence of the virus in the respiratory tract.

These findings Cilengitide suggest a state of HAID that resembles the concept of immunoparalysis described for sepsis.? HAID coexists with a persistent release of cytokines in those patients with the poorest outcomes.? These results support the idea that HAID would lead to an unremitting cycle of viral replication and innate cytokine-chemokine release. Interruption of this deleterious cycle with antiviral and/or immunomodulatory therapies may lead to improved disease outcome.