title: Host adaptive immunity deficiency in severe pandemic influenza.
abstract: BACKGROUND
  Pandemic 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Infection & Immunity Unit, Hospital Clínico Universitario-IECSCYL, Avda, Ramón y Cajal 3, 47005 Valladolid, Spain. jfbermejo@saludcastillayleon.es
authors.forename: Jesus F
authors.initials: JF
authors.lastname: Bermejo-Martin
authors.forename: Ignacio
authors.initials: I
authors.lastname: Martin-Loeches
authors.forename: Jordi
authors.initials: J
authors.lastname: Rello
authors.forename: Andres
authors.initials: A
authors.lastname: Antón
authors.forename: Raquel
authors.initials: R
authors.lastname: Almansa
authors.forename: Luoling
authors.initials: L
authors.lastname: Xu
authors.forename: Guillermo
authors.initials: G
authors.lastname: Lopez-Campos
authors.forename: Tomás
authors.initials: T
authors.lastname: Pumarola
authors.forename: Longsi
authors.initials: L
authors.lastname: Ran
authors.forename: Paula
authors.initials: P
authors.lastname: Ramirez
authors.forename: David
authors.initials: D
authors.lastname: Banner
authors.forename: Derek Cheuk
authors.initials: DC
authors.lastname: Ng
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Socias
authors.forename: Ana
authors.initials: A
authors.lastname: Loza
authors.forename: David
authors.initials: D
authors.lastname: Andaluz
authors.forename: Enrique
authors.initials: E
authors.lastname: Maravi
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Gómez-Sánchez
authors.forename: Mónica
authors.initials: M
authors.lastname: Gordón
authors.forename: Maria C
authors.initials: MC
authors.lastname: Gallegos
authors.forename: Victoria
authors.initials: V
authors.lastname: Fernandez
authors.forename: Sara
authors.initials: S
authors.lastname: Aldunate
authors.forename: Cristobal
authors.initials: C
authors.lastname: León
authors.forename: Pedro
authors.initials: P
authors.lastname: Merino
authors.forename: Jesús
authors.initials: J
authors.lastname: Blanco
authors.forename: Fernando
authors.initials: F
authors.lastname: Martin-Sanchez
authors.forename: Lucia
authors.initials: L
authors.lastname: Rico
authors.forename: David
authors.initials: D
authors.lastname: Varillas
authors.forename: Veronica
authors.initials: V
authors.lastname: Iglesias
authors.forename: Maria Ángeles
authors.initials: MÁ
authors.lastname: Marcos
authors.forename: Francisco
authors.initials: F
authors.lastname: Gandía
authors.forename: Felipe
authors.initials: F
authors.lastname: Bobillo
authors.forename: Begoña
authors.initials: B
authors.lastname: Nogueira
authors.forename: Silvia
authors.initials: S
authors.lastname: Rojo
authors.forename: Salvador
authors.initials: S
authors.lastname: Resino
authors.forename: Carmen
authors.initials: C
authors.lastname: Castro
authors.forename: Raul
authors.initials: R
authors.lastname: Ortiz de Lejarazu
authors.forename: David
authors.initials: D
authors.lastname: Kelvin
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics* / Q000276:immunology; D000328:Adult; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology*; D007251:Influenza, Human / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D012720:Severity of Illness Index