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Volume 16, Number 1—January 2010
Dispatch

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)

Main Article

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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References
  1. Studahl  M. Influenza virus and CNS manifestations. J Clin Virol. 2003;28:22532. DOIPubMedGoogle Scholar
  2. Morishima  T, Togashi  T, Yokota  S, Okuno  Y, Miyazaki  C, Tashiro  M, ; Collaborative Study Group on Influenza-Associated Encephalopathy in Japan. Encephalitis and encephalopathy associated with an influenza epidemic in Japan. Clin Infect Dis. 2002;35:5127. DOIPubMedGoogle Scholar
  3. Togashi  T, Matsuzono  Y, Narita  M, Morishima  T. Influenza-associated acute encephalopathy in Japanese children in 1994–2002. Virus Res. 2004;103:758. DOIPubMedGoogle Scholar
  4. Kawada  J, Kimura  H, Ito  Y, Hara  S, Iriyama  M, Yoshikawa  T, Systemic cytokine responses in patients with influenza-associated encephalopathy. J Infect Dis. 2003;188:6908. DOIPubMedGoogle Scholar
  5. van Zeijl  JH, Bakkers  J, Wilbrink  B, Melchers  WJ, Mullaart  RA, Galama  JM. Influenza-associated encephalopathy: no evidence for neuroinvasion by influenza virus nor for reactivation of human herpesvirus 6 or 7. Clin Infect Dis. 2005;40:4835. DOIPubMedGoogle Scholar
  6. Steininger  C, Popow-Kraupp  T, Laferl  H, Seiser  A, Gödl  I, Djamshidian  S, Acute encephalopathy associated with influenza A virus infection. Clin Infect Dis. 2003;36:56774. DOIPubMedGoogle Scholar
  7. Lee  N, Wong  CK, Chan  PKS, Lun  SWM, Lui  G, Wong  B, Hypercytokinemia and hyperactivation of phospho-p38 mitogen-activated protein kinase in severe human influenza A infections. Clin Infect Dis. 2007;45:72331. DOIPubMedGoogle Scholar
  8. Ichiyama  T, Morishima  T, Isumi  H, Matsufuji  H, Matsubara  T, Furukawa  S. Analysis of cytokine levels and NF-kappaB activation in peripheral blood mononuclear cells in influenza virus-associated encephalopathy. Cytokine. 2004;27:317. DOIPubMedGoogle Scholar
  9. Lahrtz  F, Piali  L, Spanaus  KS, Seebach  J, Fontana  A. Chemokines and chemotaxis of leukocytes in infectious meningitis. J Neuroimmunol. 1998;85:3343. DOIPubMedGoogle Scholar
  10. Sprenger  H, Rösler  A, Tonn  P, Braune  HJ, Huffmann  G, Gemsa  D. Chemokines in the cerebrospinal fluid of patients with meningitis. Clin Immunol Immunopathol. 1996;80:15561. DOIPubMedGoogle Scholar
  11. Lindegårdh  N, Hanpithakpong  W, Wattanagoon  Y, Singhasivanon  P, White  NJ, Day  NP. Development and validation of a liquid chromatographic-tandem mass spectrometric method for determination of oseltamivir and its metabolite oseltamivir carboxylate in plasma, saliva and urine. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;859:7483. DOIPubMedGoogle Scholar
  12. Semmler  A, Hermann  S, Mormann  F, Weberpals  M, Paxian  SA, Okulla  T, Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism. J Neuroinflammation. 2008;5:38. DOIPubMedGoogle Scholar
  13. Wang  G, Zhang  J, Li  W, Xin  G, Su  Y, Gao  Y, Apoptosis and proinflammatory cytokine responses of primary mouse microglia and astrocytes induced by human H1N1 and avian H5N1 influenza viruses. Cell Mol Immunol. 2008;5:11320. DOIPubMedGoogle Scholar
  14. Yokota  S, Imagawa  T, Miyamae  T, Ito  S, Nakajima  S, Nezu  A, Hypothetical pathophysiology of acute encephalopathy and encephalitis related to influenza virus infection and hypothermia therapy. Pediatr Int. 2000;42:197203. DOIPubMedGoogle Scholar
  15. Jhee  SS, Yen  M, Ereshefsky  L, Leibowitz  M, Schulte  M, Kaeser  B, Low penetration of oseltamivir and its carboxylate into cerebrospinal fluid in healthy Japanese and caucasian volunteers. Antimicrob Agents Chemother. 2008;52:368793. DOIPubMedGoogle Scholar

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