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Host adaptive immunity deficiency in severe pandemic influenza

Jesus F Bermejo-Martin12*, Ignacio Martin-Loeches3, Jordi Rello4, Andres Antón5, Raquel Almansa12, Luoling Xu6, Guillermo Lopez-Campos7, Tomás Pumarola5, Longsi Ran6, Paula Ramirez8, David Banner6, Derek Cheuk Ng6, Lorenzo Socias9, Ana Loza10, David Andaluz11, Enrique Maravi12, Maria J Gómez-Sánchez12, Mónica Gordón8, Maria C Gallegos13, Victoria Fernandez13, Sara Aldunate12, Cristobal León10, Pedro Merino14, Jesús Blanco14, Fernando Martin-Sanchez7, Lucia Rico12, David Varillas12, Veronica Iglesias12, Maria Ángeles Marcos5, Francisco Gandía11, Felipe Bobillo11, Begoña Nogueira2, Silvia Rojo2, Salvador Resino15, Carmen Castro16, Raul Ortiz de Lejarazu12 and David Kelvin17186

Author Affiliations

1 Infection & Immunity Unit, Hospital Clínico Universitario-IECSCYL, Avda. Ramón y Cajal 3, 47005 Valladolid, Spain

2 Microbiology & immunology Service, Hospital Clínico Universitario-SACYL, Avda Ramón y Cajal 3, 47005 Valladolid, Spain

3 Critical Care Department, Joan XXIII University Hospital-SEMICYUC. Mallafre Guasch 4, 43007 Tarragona, Spain

4 Critical Care Department, area General. Hospital Vall d'Hebron. Institut de Recerca, Vall d'Hebron-UAB. CIBERES- SEMICYUC. Paseo Vall d'Hebron, 119-129, 08035, Barcelona, Spain

5 Microbiology Service, Hospital Clínic, IDIBAPS, University of Barcelona, Carrer de Casanova 143, 08036, Barcelona, Spain

6 University Health Network, Medical Discovery Tower, 3rd floor Room 913-916,101 College Street, Toronto, ON M5G 1L7, Canada

7 Medical Bioinformatics Department. Instituto de Salud Carlos III. Ctra. Majadahonda-Pozuelo Km. 2200 Majadahonda, Madrid, Spain

8 Critical Care Department, Hospital Universitario La Fe- SEMICYUC, Valencia, Avda Campanar 21, 46009, Spain

9 Critical Care Department, Hospital Son Llatzer- SEMICYUC, Ctra. Manacor, km 4, 07198 Palma de Mallorca, Spain

10 Critical Care Department, Hospital N Sra de Valme- SEMICYUC, Carretera Madrid-Cadiz (Pol. Ind. La Palmera), KM 548 41014 Sevilla, Spain

11 Critical Care Department, Hospital Clínico Universitario-SACYL/SEMICYUC. Avda. Ramón y Cajal 3, 47005 Valladolid, Spain

12 Critical Care Department, Hospital Virgen del Camino- SEMICYUC, C/DE IRUNLARREA 4, 31008 Pamplona, Spain

13 Microbiology Service, Hospital Son Llatzer, Ctra. Manacor, km 4, 07198 Palma de Mallorca, Spain

14 Critical Care Department, Hospital Universitario Rio Hortega-SACYL- SEMICYUC& CIBER de Enfermedades Respiratorias (Instituto de Salud Carlos III). C/Dulzaina N° 2 47012 Valladolid, Spain

15 Laboratory of Molecular Epidemiology of Infectious Diseases, National Centre of Microbiology, Instituto de Salud Carlos III, Ctra. Majadahonda-Pozuelo Km. 2200 Majadahonda, Madrid, Spain

16 Microbiology Service. Hospital N Sra de Valme, Carretera Madrid-Cadiz (Pol. Ind. La Palmera), KM 548 41014 Sevilla, Spain

17 International Institute of Infection and Immunity, Shantou University, 22 Xinling Road, Shantou, Guangdong Province, 515031, PR China

18 University of Sassari, Viale Pasquale Stanislao Mancini, 5 07100 Sassari SS, Italy

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Critical Care 2010, 14:R167  doi:10.1186/cc9259

Published: 14 September 2010



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.


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.


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.


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.