Research
Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza
-
* Corresponding author: Jesus F Bermejo-Martin jfbermejo@saludcastillayleon.es
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
Critical Care 2009, 13:R201 doi:10.1186/cc8208
Published: 11 December 2009Abstract
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.