Imbalanced pro- and anti-Th17 responses (IL-17/granulocyte colony-stimulating factor) predict fatal outcome in 2009 pandemic influenza

  • Raquel Almansa1,

    Affiliated with

    • Lorenzo Socias2,

      Affiliated with

      • Paula Ramirez3,

        Affiliated with

        • Ignacio Martin-Loeches4,

          Affiliated with

          • Jordi Vallés4,

            Affiliated with

            • Ana Loza5,

              Affiliated with

              • Jordi Rello6,

                Affiliated with

                • David J Kelvin7,

                  Affiliated with

                  • Cristobal León5,

                    Affiliated with

                    • Jesús Blanco8,

                      Affiliated with

                      • David Andaluz9,

                        Affiliated with

                        • Dariela Micheloud10,

                          Affiliated with

                          • Enrique Maraví11,

                            Affiliated with

                            • Raul Ortiz de Lejarazu1 and

                              Affiliated with

                              • Jesus F Bermejo-Martin1Email author

                                Affiliated with

                                Critical Care201115:448

                                DOI: 10.1186/cc10426

                                Published: 20 October 2011

                                Several clinical studies have confirmed an association between persistent hypercytokinemia and severe 2009 pandemic influenza, but none of these have used predictive models to analyze the relationship between the cytokines involved and disease outcome [14].

                                In the present work, we re-analyzed the results from two cohorts of critically ill patients suffering from pandemic influenza infection in 2009 [1, 2]. Thirty-five critically ill patients hospitalized with primary viral pneumonia were included in the analysis.

                                The levels of 27 cytokines in peripheral blood measured during the first 24 hours following admission to the hospital were included in a Cox regression analysis to evaluate their association with mortality at 28 days. This analysis was adjusted by APACHE II score and the presence/absence of mechanical ventilation in order to preclude their potential influence on the results. IL-6, IL-8, IL-7, IL-17, and granulocyte colony-stimulating factor (G-CSF) yielded P-values <0.2 in the univariate analysis. In the multivariate analysis, high IL-17 levels were associated with increased probability of survival, while high levels of G-CSF were associated with increased risk of mortality at 28 days (P < 0.05; Figure 1). Kaplan Meier curves confirmed the association of IL-17 with survival and of G-CSF with occurrence of earlier death (Figure 1). Patients who died had significantly higher levels of G-CSF than those who survived (mean (standard deviation) pg/ml: 6,709.4 (17,979.1) and 2,043.9 (7,362.7), respectively; Mann Whitney U test); in contrast, surviving patients had higher levels of IL-17 than those who died (mean (standard deviation) pg/ml: 7.7 (8.1) and 1.5 (0.3), respectively; Mann Whitney U test).
                                Figure 1

                                Risk of death based upon G-CSF and IL-17 levels. Top panels: Kaplan-Meier curves showing cumulative survival versus survival. Deciles of cytokine concentrations in plasma (pg/ml) were calculated and used to compare survival time in patients with low (solid line) and high cytokine levels (dashed line). The first decile showing significant differences between groups is represented (40th percentile). Groups were compared by the log-rank test (Mantel-Haenzel). Data collection ended at day 28. Bottom panel: Cox regression analysis for mortality adjusted by APACHE II score and the presence/absence of mechanical ventilation. Logarithmic concentrations of the cytokines were used in the regression analysis to satisfy the linearity assumption. CI, confidence interval; G-CSF, granulocyte colony-stimulating factor; HR, hazard ratio.

                                A beneficial role of IL-17 in lethal influenza has been previously proposed [3]. In our experience, 9 out of the 10 patients who died had undetectable levels of IL-17. G-CSF is the principal cytokine controlling neutrophil development and function and could thus mediate excessive recruitment of neutrophils to the lungs, contributing to impairment of the respiratory system. In turn, G-CSF induces overexpression of negative regulators of Th17 differentiation [5]. In fact, G-CSF levels correlated negatively with IL-17 levels in our cohort, supporting a potential inhibitory role of G-CSF on the secretion of IL-17 in these patients (Spearman r coefficient, -0.43; P-value 0.010).

                                In conclusion, IL-17 has been shown to be protective in severe pandemic influenza, while G-CSF is a risk factor for mortality, indicating the existence of imbalanced pro-and anti-Th17 responses during this disease.



                                granulocyte colony-stimulating factor





                                This work has been conducted by an international team pertaining to the Spanish-Canadian Consortium for the Study of Influenza Immunopathogenesis. The authors would like to thank also the nursing teams who kindly collected the samples and Lucia Rico and Veronica Iglesias for their precious laboratory assistance. The study was scientifically sponsored by the Spanish Society for Critical Care Medicine (SEMICYUC). Funding: Ministerio de Ciencia, MICCIN-FIS/JCYL-IECSCYL-SACYL (Spain); Programa de Investigación Comisionada en Gripe, GR09/0021-EMER07/050-PI081236-RD07/0067; National Institutes of Health (NIH), University Health Network and IDR Canada (DJK).

                                Authors’ Affiliations

                                Infection and Immunity Medical Investigation Unit (IMI), Microbiology and Immunology Service Hospital Clínico Universitario-IECSCYL
                                Critical Care Department, Hospital Son Llatzer-SEMICYUC
                                Critical Care Department, Hospital Universitario La Fe- SEMICYUC
                                Critical Care Centre Parc Tauli, Sabadell University Hospital
                                Critical Care Department, Hospital Universitario de Valme SEMICYUC
                                Critical Care Department, area General, Hospital Vall d’Hebron, Institut de Recerca Vall d’ Hebron-UAB, CIBERES-SEMICYUC
                                University Health Network, Toronto Medical Discovery Tower
                                Critical Care Department, Hospital Universitario Rio Hortega-SACYL-SEMICYUC and CIBER de Enfermedades Respiratorias (Instituto de Salud Carlos III)
                                Critical Care Department, Hospital Clínico Universitario-SACYL/SEMICYUC
                                Intensive Care Unit and Internal Medicine Service, Hospital Gregorio Marañón
                                Critical Care Department, Hospital Virgen del Camino-SEMICYUC


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                                © BioMed Central Ltd 2011