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Open Access Highly Accessed Research article

Direct association between pharyngeal viral secretion and host cytokine response in severe pandemic influenza

Raquel Almansa1, Andres Anton2, Paula Ramirez3, Ignacio Martin-Loeches4, David Banner5, Tomás Pumarola2, Luoling Xu5, Jesús Blanco6, Longsi Ran5, Guillermo Lopez-Campos7, Fernando Martin-Sanchez8, Lorenzo Socias9, Ana Loza10, David Andaluz11, Enrique Maravi12, Mónica Gordón3, Maria C Gallegos13, Victoria Fernandez13, Cristobal León10, Pedro Merino6, Maria Ángeles Marcos2, Francisco Gandía11, Felipe Bobillo11, Salvador Resino14, Jose Mª Eiros15, Carmen Castro16, Paula Mateo6, Milagros Gonzalez-Rivera17, Jordi Rello18, Raul Ortiz de Lejarazu15, David J Kelvin5 and Jesus F Bermejo-Martin1*

Author Affiliations

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

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

3 Critical Care Dep., Hospital Universitario La Fe- SEMICYUC, Valencia, Avda Campanar 21, 46009, Spain

4 Critical Care Department. Joan XXIII University Hospital, University Rovira i Virgili, IISPV, CIBER, Enfermedades Respiratorias (CIBERes) Tarragona, Spain

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

6 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

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

8 Health & Biomedical Informatics Research, University of Melbourne ABN: 84 002 705 224, CRICOS Provider Number: 00116K, Australia

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

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

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

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

17 Sequencing Unit. Hospital General Universitario Gregorio Marañón, Dr Esquerdo, Madrid 28007, Spain

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

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BMC Infectious Diseases 2011, 11:232  doi:10.1186/1471-2334-11-232

Published: 31 August 2011



Severe disease caused by 2009 pandemic influenza A/H1N1virus is characterized by the presence of hypercytokinemia. The origin of the exacerbated cytokine response is unclear. As observed previously, uncontrolled influenza virus replication could strongly influence cytokine production. The objective of the present study was to evaluate the relationship between host cytokine responses and viral levels in pandemic influenza critically ill patients.


Twenty three patients admitted to the ICU with primary viral pneumonia were included in this study. A quantitative PCR based method targeting the M1 influenza gene was developed to quantify pharyngeal viral load. In addition, by using a multiplex based assay, we systematically evaluated host cytokine responses to the viral infection at admission to the ICU. Correlation studies between cytokine levels and viral load were done by calculating the Spearman correlation coefficient.


Fifteen patients needed of intubation and ventilation, while eight did not need of mechanical ventilation during ICU hospitalization. Viral load in pharyngeal swabs was 300 fold higher in the group of patients with the worst respiratory condition at admission to the ICU. Pharyngeal viral load directly correlated with plasma levels of the pro-inflammatory cytokines IL-6, IL-12p70, IFN-γ, the chemotactic factors MIP-1β, GM-CSF, the angiogenic mediator VEGF and also of the immuno-modulatory cytokine IL-1ra (p < 0.05). Correlation studies demonstrated also the existence of a significant positive association between the levels of these mediators, evidencing that they are simultaneously regulated in response to the virus.


Severe respiratory disease caused by the 2009 pandemic influenza virus is characterized by the existence of a direct association between viral replication and host cytokine response, revealing a potential pathogenic link with the severe disease caused by other influenza subtypes such as H5N1.

cytokines; critical; influenza; patients; virus