Journal Article

Hypercytokinemia and Hyperactivation of Phospho-p38 Mitogen-Activated Protein Kinase in Severe Human Influenza A Virus Infection

N. Lee, C. K. Wong, P. K. S. Chan, S. W. M. Lun, G. Lui, B. Wong, D. S. C. Hui, C. W. K. Lam, C. S. Cockram, K. W. Choi, A. C. M. Yeung, J. W. Tang and J. J. Y. Sung

in Clinical Infectious Diseases

Published on behalf of Infectious Diseases Society of America

Volume 45, issue 6, pages 723-731
Published in print September 2007 | ISSN: 1058-4838
Published online September 2007 | e-ISSN: 1537-6591 | DOI: http://dx.doi.org/10.1086/520981
Hypercytokinemia and Hyperactivation of Phospho-p38 Mitogen-Activated Protein Kinase in Severe Human Influenza A Virus Infection

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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 = 0.78; 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.

Journal Article.  5106 words.  Illustrated.

Subjects: Infectious Diseases ; Immunology ; Public Health and Epidemiology ; Microbiology

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