Volume 16, Number 1—January 2010
Acute Encephalopathy Associated with Influenza A Infection in Adults
|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)|
*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 (9–11). 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.