Acute Encephalopathy Associated with Infl uenza A Infection in Adults

I uenza-associated acute encephalopathy has been described in children, and results in a high frequency of neurologic sequelae and death. Altered consciousness, disorientation, and seizures occur within a few days after the onset of fever and respiratory symptoms (1–3). In some patients, symptoms are transient but in others rapid progression to necrotizing encephalitis, deep coma, and death may occur (1–3). Cases in adults are infrequently reported and remain poorly characterized, although the more complex clinical scenarios in adults may have hindered case recognition (1,4–6). The pathogenesis is unclear, but a hyperactivated cytokine response, rather than viral invasion, is believed responsible in most childhood cases (1–5). We describe 3 cases of acute encephalopathy associated with infl uenza A infection in adults. The clinical, virologic, immunologic fi ndings (cytokines in plasma and cerebrospinal fl uid [CSF]), and CSF penetration of oseltamivir for these cases are reported. The Study At Prince of Wales Hospital, Hong Kong (7), from January 2007 through August 2008, infl uenza infection was diagnosed for >460 hospitalized adult patients for whom acute febrile respiratory illnesses had been diagnosed. Nasopharyngeal aspiration and immunofl uorescence assays (IFA) were used for rapid diagnosis of infl uenza A and B infection, confi rmed by virus isolation. Thirteen (2.8%) patients had signs of confusion or altered consciousness, together with fever and respiratory symptoms (mean ± SD age 77.7 ± 8.8 years). We studied 3 patients from whom CSF was obtained for analysis, and who fulfi lled the defi nition of infl uenza-associated acute encephalopathy (altered mental status >24 hours within 5 days of infl uenza onset and without alternative explanation) (1,2,4–6). Nasopharyngeal aspirates were subjected to IFA, virus isolation, and subsequent subtyping (7). CSF specimens were subjected to virus isolation using MDCK cells, and reverse transcription–PCR to detect infl uenza virus RNA by using H1/H3 subtype-specifi c primers. Herpes simplex virus, herpes zoster virus, and enterovirus DNA/RNA was detected using PCRs (online Technical Appendix, available from www.cdc.gov/EID/content/16/1/139-Techapp.pdf). CSF and plasma samples collected on the same day were analyzed simultaneously for the concentrations of 11 cytokines/chemokines by bead-based multiplex fl ow cytometry. Their assay methods and plasma reference ranges (established from >100 healthy persons) have been described (online Technical Appendix) (7). In CSF, in patients without central nervous system (CNS) disease/infection, cytokines/chemokines are either undetectable (e.g., interleukin-6 [IL-6], CXCL8/IL-8, CXCL10/IP-10, CXCL9/MIG) or present at low levels (e.g., CCL2/MCP-1) (8–10). Concentrations of oseltamivir phosphate (OP) and its biologically active metabolite oseltamivir carboxylate (OC) were measured in CSF and plasma taken simultaneously from 1 patient who received concurrent treatment, using tandem mass spectrometry (11). The assay methods have been described (online Technical Appendix). The clinical and virologic fi ndings are summarized in Table 1. All case-patients were elderly (72–86 years of age), but none were known to have neuropsychiatric illness, dementia, or to be taking psychotropic medication. None had received updated infl uenza vaccination (6). Confusion and altered consciousness developed in patients 1 and 2 one to 2 days after the onset of fever and cough. These patients had no meningismus, focal neurologic deficit, hypotension, respiratory distress, or metabolic disturbances. Brain computed tomography (CT) scans showed no acute cerebral lesion. CSF analyses showed no bacterial or viral pathogen or pleocytosis. Oseltamivir was given to patient 2 only when infl uenza A was later confi rmed