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Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza

Jesus F Bermejo-Martin12*, Raul Ortiz de Lejarazu12, Tomas Pumarola3, Jordi Rello4, Raquel Almansa12, Paula Ramírez5, Ignacio Martin-Loeches4, David Varillas12, Maria C Gallegos6, Carlos Serón7, Dariela Micheloud8, Jose Manuel Gomez8, Alberto Tenorio-Abreu9, María J Ramos9, M Lourdes Molina10, Samantha Huidobro11, Elia Sanchez12, Mónica Gordón5, Victoria Fernández6, Alberto del Castillo13, Ma Ángeles Marcos3, Beatriz Villanueva14, Carlos Javier López14, Mario Rodríguez-Domínguez15, Juan-Carlos Galan15, Rafael Cantón15, Aurora Lietor16, Silvia Rojo12, Jose M Eiros12, Carmen Hinojosa17, Isabel Gonzalez17, Nuria Torner18, David Banner19, Alberto Leon20, Pablo Cuesta21, Thomas Rowe1922 and David J Kelvin192022

Author Affiliations

1 National Centre of Influenza, Hospital Clínico Universitario de Valladolid, Avda Ramón y Cajal 3, Valladolid, 47005, Spain

2 Unidad de Investigación en Infección e Inmunidad- Microbiology Service,. Hospital Clínico Universitario de Valladolid- IECSCYL, Avda Ramón y Cajal 3, Valladolid, 47005, Spain

3 Virology Laboratory, Hospital Clinic de Barcelona, Carrer de Casanova 143, Barcelona, 08036, Spain

4 Critical Care Department, Joan XXIII University Hospital-CIBERes Enfermedades Respiratorias-IISPV. Mallafre Guasch 4, Tarragona, 43007, Spain

5 Critical Care Department, Hospital Universitario La Fe, Avda Campanar 21, Valencia, 46009, Spain

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

7 Intensive Care Unit, Hospital General San Jorge, Avenida Martínez De Velasco 36, Huesca, 22004ý, Spain

8 Intensive Care Unit & Internal Medicine Service, Hospital Gregorio Marañón, C/Doctor Esquerdo 46, Madrid, 28007, Spain

9 Microbiology Service, Hospital Universitario de Canarias, Carretera Del Rosario 145, Santa Cruz De Tenerifeý, 38009, Spain

10 Microbiology Service, Hospital General de La Palma, Buenavista de Arriba, s/n, Breña Alta, 38713, Spain

11 Intensive Care Unit, Hospital Universitario de Canarias, Carretera Del Rosario 145, Santa Cruz De Tenerifeý, 38009, Spain

12 Intensive Care Unit, Hospital Virgen del Rocío, Avenida Manuel Siurot s/n, Sevilla, 41013, Spain

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

14 Intensive Care Unit Service, Hospital Lozano Blesa, Avenida San Juan Bosco 15, Zaragozaý,50009, Spain

15 Microbiology Service, Hospital Universitario Ramón y Cajal & CIBERESP, Carretera Colmenar Viejo KM 9,100, Madrid, 28049, Spain

16 Intensive Care Unit, Hospital Universitario Ramón y Cajal, Carretera Colmenar Viejo KM 9,100, Madrid, 28049, Spain

17 Infectious Diseases Service, Hospital Clínico Universitario, Avda Ramón y Cajal 3, Valladolid, 47005, Spain

18 Preventive Medicine Service, Hospital Universitario Valle Hebron & CIBERESP, Paseo Vall d'Hebron, 119-129, Barcelona, 08035, Spain

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

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

21 Intensive Care Unit, Hospital de Villarobredo, Avenida Miguel de Cervantes s/n, Villarrobledo, 02600, Spain

22 Department of Immunology, University of Toronto, Medical Discovery Tower, 3rd floor Room 913-916,101 Collegue Street, Toronto, ON M5G 1L7, Canada

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Critical Care 2009, 13:R201  doi:10.1186/cc8208


See related commentary by Fernández de Castro et al., http://ccforum.com/content/14/1/115, related letter by Krstíc, http://ccforum.com/content/14/2/410, related letter by Kawashima et al., http://ccforum.com/content/14/2/411 and related letter by Krystíc, http://ccforum.com/content/14/3/417

Published: 11 December 2009

Abstract

Introduction

Human host immune response following infection with the new variant of A/H1N1 pandemic influenza virus (nvH1N1) is poorly understood. We utilize here systemic cytokine and antibody levels in evaluating differences in early immune response in both mild and severe patients infected with nvH1N1.

Methods

We profiled 29 cytokines and chemokines and evaluated the haemagglutination inhibition activity as quantitative and qualitative measurements of host immune responses in serum obtained during the first five days after symptoms onset, in two cohorts of nvH1N1 infected patients. Severe patients required hospitalization (n = 20), due to respiratory insufficiency (10 of them were admitted to the intensive care unit), while mild patients had exclusively flu-like symptoms (n = 15). A group of healthy donors was included as control (n = 15). Differences in levels of mediators between groups were assessed by using the non parametric U-Mann Whitney test. Association between variables was determined by calculating the Spearman correlation coefficient. Viral load was performed in serum by using real-time PCR targeting the neuraminidase gene.

Results

Increased levels of innate-immunity mediators (IP-10, MCP-1, MIP-1β), and the absence of anti-nvH1N1 antibodies, characterized the early response to nvH1N1 infection in both hospitalized and mild patients. High systemic levels of type-II interferon (IFN-γ) and also of a group of mediators involved in the development of T-helper 17 (IL-8, IL-9, IL-17, IL-6) and T-helper 1 (TNF-α, IL-15, IL-12p70) responses were exclusively found in hospitalized patients. IL-15, IL-12p70, IL-6 constituted a hallmark of critical illness in our study. A significant inverse association was found between IL-6, IL-8 and PaO2 in critical patients.

Conclusions

While infection with the nvH1N1 induces a typical innate response in both mild and severe patients, severe disease with respiratory involvement is characterized by early secretion of Th17 and Th1 cytokines usually associated with cell mediated immunity but also commonly linked to the pathogenesis of autoimmune/inflammatory diseases. The exact role of Th1 and Th17 mediators in the evolution of nvH1N1 mild and severe disease merits further investigation as to the detrimental or beneficial role these cytokines play in severe illness.