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 [1–4].
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).
A beneficial role of IL-17 in lethal influenza has been previously proposed . 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 . 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).
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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