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  • Letter
  • Open Access

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

  • 1,
  • 2,
  • 3,
  • 4,
  • 4,
  • 5,
  • 6,
  • 7,
  • 5,
  • 8,
  • 9,
  • 10,
  • 11,
  • 1 and
  • 1Email author
Critical Care201115:448

  • Published:


  • Influenza
  • Pandemic Influenza
  • Influenza Infection
  • Th17 Differentiation
  • Viral Pneumonia

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
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, Avda Ramón y Cajal 3, 47005 Valladolid, Spain
Critical Care Department, Hospital Son Llatzer-SEMICYUC, Ctra. Manacor, km 4, 07198 Palma de Mallorca, Spain
Critical Care Department, Hospital Universitario La Fe- SEMICYUC, Avda Campanar 21, Valencia, 46009, Spain
Critical Care Centre Parc Tauli, Sabadell University Hospital, Sabadell, Spain
Critical Care Department, Hospital Universitario de Valme SEMICYUC, Carretera de Cádiz s/n, 41014 Sevilla, Spain
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
University Health Network, Toronto Medical Discovery Tower, 3rd floor Room 913, 101 College Street, Toronto, ON, M5G 1L7, Canada
Critical Care Department, Hospital Universitario Rio Hortega-SACYL-SEMICYUC and CIBER de Enfermedades Respiratorias (Instituto de Salud Carlos III), C/Dulzaina N° 2, 47012 Valladolid, Spain
Critical Care Department, Hospital Clínico Universitario-SACYL/SEMICYUC, Avda Ramón y Cajal 3, 47005 Valladolid, Spain
Intensive Care Unit and Internal Medicine Service, Hospital Gregorio Marañón, C/Doctor Esquerdo 46, Madrid, 28007, Spain
Critical Care Department, Hospital Virgen del Camino-SEMICYUC, C/de Irunlarrea 4, 31008 Pamplona, Spain


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