We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Hypercytokinemia and Hyperactivation of Phospho-p38 Mitogen-Activated Protein Kinase in Severe Human Influenza A Virus Infection.
- Authors
Lee, N.; Wong, C. K.; Chan, P. K. S.; Lun, S. W. M.; Lui, G.; Wong, B.; Hui, D. S. C.; Lam, C. W. K.; Cockram, C. S.; Choi, K. W.; Yeung, A. C. M.; Tang, J. W.; Sung, J. J. Y.
- Abstract
Background. We postulate that hypercytokinemia plays a role in immunopathogenesis of severe human influenza. Methods. We prospectively studied 39 consecutive patients who were hospitalized with severe influenza A virus infection. On laboratory confirmation of the diagnosis, paired acute-phase (obtained at hospital admission) and convalescent-phase (obtained >10 days after hospital admission) plasma samples were collected for assay of 11 cytokines and chemokines (interleukin [IL] 1β; IL-6; IL-10; IL-12p70; tumor necrosis factor α; IL-8; monokine induced by interferon [IFN]-γ; IFN-inducible protein 10; monocyte chemoattractant protein 1; regulated upon activation, normal T cell-expressed and secreted; and IFN-γ) using cytometric bead-array analysis and enzyme-linked immunosorbent assay. Simultaneously, virus concentration in the acute-phase nasopharyngeal aspirate was determined using real-time quantitative reverse-transcriptase polymerase chain reaction. Intracellular signaling molecules regulating lymphocyte activation, phospho-p38 mitogen-activated protein kinase and phospho-extracellular signal-regulated protein kinase in CD4+ and CD8+ T lymphocytes were studied in the acute-phase samples using flow cytometric analysis and were compared with results for samples from healthy control subjects. Results. Statistically significant increases in plasma IL-6 (3.7-fold increase), IL-8 (2.6-fold increase), IFN-induced protein 10 (4.9-fold increase), and monokine induced by IFN-γ (2.3-fold increase) concentrations were detected during acute illness (P < .01 for all, by Wilcoxon signed-rank test); the highest concentrations were observed on symptom days 3 and 4. Corresponding plasma cytokine and chemokine concentrations and nasopharyngeal viral loads showed statistically significant correlations (ρ = 0.41 , 0.49, 0.54, and 0.46, respectively; P ⩽ .01). Phospho-p38 mitogen-activated protein kinase expression in CD4+ lymphocytes was increased, correlating with cytokine concentrations (e.g., for IFN-induced protein 10, ρ; P < .01); phospho-extracellular signal-regulated protein kinase was suppressed. Advanced age and comorbidity were associated with aberrant IL-6, IL-8, and monokine induced by IFN-γ responses (P < .05, by Mann-Whitney U test). An elevated IL-6 concentration was independently associated with prolonged hospitalization (hospitalization for >5 days; P = .02), adjusted for age, comorbidity, and virus load. Conclusions. Hypercytokinemia (of proinflammatory and T helper 1 cytokines) is detected in severe influenza, correlating with clinical illness and virus concentration. Hyperactivation of phospho-p38 mitogen-activated protein kinase (in T helper cells) is possibly involved. Early viral suppression may attenuate these potentially deleterious cytokine responses.
- Subjects
INFLUENZA prevention; INFLUENZA research; VIRUS diseases; DIAGNOSIS; CYTOKINES; CHEMOKINES; PROTEIN kinases; PHOSPHOTRANSFERASES; LYMPHOCYTES
- Publication
Clinical Infectious Diseases, 2007, Vol 45, Issue 6, p723
- ISSN
1058-4838
- Publication type
Article
- DOI
10.1086/520981