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Volume 16, Number 1—January 2010


Acute Encephalopathy Associated with Influenza A Infection in Adults

Nelson LeeComments to Author , Chun Kwok Wong, Paul K.S. Chan, Niklas Lindegardh, Nicholas J. White, Frederick G. Hayden, Edward H.C. Wong, Ka Shing Wong, Clive S. Cockram, Joseph J.Y. Sung, and David S.C. Hui
Author affiliations: The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China (N. Lee, C.K. Wong, P.K.S. Chan, E. Wong, K.S. Wong, C.S. Cockram, J.J.Y. Sung, D.S.C. Hui); Mahidol University, Bangkok, Thailand (N. Lindegardh, N.J. White); University of Oxford, Oxford, UK (N. Lindegardh, N.J. White); University of Virginia School of Medicine, Charlottesville, Virginia, USA (F.G. Hayden)

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Table 2

Cytokine and chemokine concentrations in CSF and plasma samples from 3 patients with acute encephalopathy associated with influenza A infection, Prince of Wales Hospital, Hong Kong*

Cytokine or chemokine Reference range, pg/mL CSF/plasma cytokine concentration, pg/mL (ratio)
Patient 1 Patient 2 Patient 3
IL-6† <3.1 8.0/6.3 (1.3) 11.6/35.1 (0.3) 2.2/5.9 (0.4)
CXCL8/IL-8‡ <5.0 84.0/15.5 (5.4) 74.8/13.8 (5.4) 21.9/6.3 (3.5)
CXCL10/IP-10† 202–1,480 15,374/102,019 (0.2) 5,101/17,594 (0.3) 1,371/1,550 (0.9)
CCL2/MCP-1‡ < 10-57 996/82 (12.1) 1,287/336 (3.8)
CXCL9/MIG 48–482 11,58/14,001 (0.1) 70/333 (0.2) 145/1,019 (0.1)
IFN-γ <15.6 UD/14.4 4.7/10.1 0.4/2.0
IL-12p70 <7.8 1.5/UD 1.3/UD UD/UD
TNF-α <10.0 1.7/1.4 UD/1.2 UD/UD
IL-10 <7.8 2.5/2.2 UD/7.3 UD/1.7
IL-1β <3.9 UD/UD UD/3.7 UD/UD
CCL5/RANTES 4,382–18,783 4/2,507 14/1,609 1.3/814

*CSF, cerebrospinal fluid; –, test not done due to inadequate sample; UD, undetectable (i.e., below the detection limit of the cytokine/chemokine assay). Cytokines: Interleukin (IL)–1β, IL-6, IL-10, IL-12p70, tumor necrosis factor α (TNF-α). Chemokines: CXCL8/IL-8, monokine induced by interferon-γ (IFN- γ) (CXCL9/MIG), IFN-γ–inducible protein-10 (CXCL10/IP-10), monocyte chemoattractant protein–1 (CCL2/MCP-1), and regulated upon activation normal T cell–expressed and secreted (CCL5/RANTES). The plasma reference ranges are established from >100 healthy adults. The assay sensitivities of IL-1β, IL-6, IL-10, IL-12p70, TNF-α, IL8, MIG, IP-10, MCP-1, RANTES, and IFN-γ are 2.5, 3.3, 3.7, 1.9, 7.2, 0.2, 2.5, 2.8, 2.7, 1.0, and 7.1 pg/mL, respectively. Coefficients of variation are all <10%. In an earlier study involving 39 adult influenza patients hospitalized with cardio-respiratory complications (8), the median (interquartile range) plasma concentrations of IL-6, IL-8, IP-10, MCP-1, and MIG were 10.6 (4.2–18.4), 5.4 (2.5–8.7), 7,043.0 (4,025.1–1,2381.1), 76.5 (49.5-97.0), and 992.1 (499.1–1,992.3) pg/mL, respectively. In CSF, in subjects without neurologic disease/infection, these cytokines/chemokines are either undetectable or present at low levels (911). In a pediatrics influenza cohort, CSF cytokine levels were substantially higher in encephalopathy cases when compared to those with febrile seizure; CSF/plasma concentration was <1 (9).
†CSF cytokine concentrations above plasma reference ranges.
‡CSF/plasma cytokine concentration ratio consistently >3 (3.5–12.1), in addition to CSF cytokine concentrations being above the plasma reference ranges. For IFN-γ, IL-12p70, TNF-α, IL-10, IL-1β and RANTES, because of their low/undetectable levels, the CSF/plasma ratios were not calculated. CSF specimens from patients 1 and 2 were collected at the peak of symptoms, and before antiviral treatment (if given); CSF from patient 3 was collected when persistent tremor developed 18 hours after the ninth dose of oseltamivir; the drug was stopped afterward.

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