Increased levels of cytokines and high-mobility group box 1 are associated with the development of severe pneumonia, but not acute encephalopathy, in 2009 H1N1 influenza-infected children

Background: The 2009 A(H1N1) influenza virus has caused a large outbreak, and resulted in major complications of severe pneumonia and acute encephalopathy in the pediatric population in Japan. Methods: This study examined six patients with acute encephalopathy, 34 patients with severe pneumonia, five patients with both pneumonia and encephalopathy, and 46 patients without severe complications. The concentrations of 27 cytokines were examined in the cerebrospinal fluid of patients with encephalopathy, and the levels of these cytokines, Cytochrome c, high-mobility group box 1 (HMGB1) were measured in the serum of all patients. Results: Patients with severe pneumonia had higher serum concentrations of 16 cytokines, including Th1 cytokines, Th2 cytokines, chemokines, and growth factors, than patients with uncomplicated influenza. The distribution of 27 cytokines in the CSF did not parallel the serum levels in 11 patients with acute encephalopathy. HMGB1 concentrations in the serum were significantly higher in pneumonia patients with or without encephalopathy than in uncomplicated influenza patients, and were significantly associated with the upregulation of 10 cytokines. Conclusions: Elevated levels of Th2 cytokines appear to be unique to influenza caused by 2009 H1N1 influenza virus and HMGB1 could play an important role in the pathogenesis of severe pneumonia. There appear to be different pathologic processes for encephalopathy and pneumonia.