Host adaptive immunity deficiency in severe pandemic influenza.
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.
Bermejo-Martin
Jesus F
JF
Infection & Immunity Unit, Hospital Clínico Universitario-IECSCYL, Avda, Ramón y Cajal 3, 47005 Valladolid, Spain. jfbermejo@saludcastillayleon.es
Martin-Loeches
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Luoling
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Guillermo
G
Pumarola
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T
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Longsi
L
Ramirez
Paula
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Banner
David
D
Ng
Derek Cheuk
DC
Socias
Lorenzo
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Loza
Ana
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Andaluz
David
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Maravi
Enrique
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Gómez-Sánchez
Maria J
MJ
Gordón
Mónica
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Gallegos
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MC
Fernandez
Victoria
V
Aldunate
Sara
S
León
Cristobal
C
Merino
Pedro
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Blanco
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Martin-Sanchez
Fernando
F
Rico
Lucia
L
Varillas
David
D
Iglesias
Veronica
V
Marcos
Maria Ángeles
MÁ
Gandía
Francisco
F
Bobillo
Felipe
F
Nogueira
Begoña
B
Rojo
Silvia
S
Resino
Salvador
S
Castro
Carmen
C
Ortiz de Lejarazu
Raul
R
Kelvin
David
D
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