The transcription of cytokine genes in peripheral blood leukocytes (PBL) of 23 children (mean age 3.2 years) with influenza (mostly type A) complicated by encephalopathy (11 patients) or febrile convulsions (12 patients) was compared with systemic cytokine responses in 23 (mean age 5.0 years) with influenza but without neurologic complications, in a study at Nagoya University Graduate School of Medicine, Japan. WBCs were significantly higher in patients with encephalopathy than in patients with febrile convulsions or without neurologic complications (P=.02 and P=.002, respectively). A quantitative polymerase chain reaction (PCR) showed that transcription of the interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-a genes was up-regulated more in patients with encephalopathy than in those without (P=.049, P=.049, and P=.098, respectively). Of 3 patients with encephalopathy and extremely high concentrations of IL-10, 2 died. IL-10 and TNF-a transcriptions were also higher in patients with febrile convulsions than in those without neurologic complications (P=.006 and P=.078, respectively). Plasma IL-6 levels were higher with encephalopathy (P=.071, ANOVA) but not with febrile convulsions. Virus load, quantified by a real-time PCR applied to throat swab samples, was similar in patients with or without encephalopathy or febrile convulsions, and was not correlated with transcription of cytokine genes or plasma cytokine concentrations. Influenza-associated encephalopathy and febrile convulsions may be a consequence of systemic immune responses and are independent of the severity of the influenza virus infection. [1]

COMMENT. Influenza may activate peripheral immune cells to cause an increased cytokine response in patients who develop encephalopathy or FC. A cytokine response after FCs is reported previously with various infections other than influenza [2]. Compared to 11 controls with fever but no convulsion, the secretion of IL-6 and IL-10 is greater in those with FCs. Interleukin 1 receptor antagonist (IL-1Ra) allele 1, one of the first cytokines to be discovered, and an endogenous pyrogen, is increased in Taiwanese children with FC and is a useful marker for predicting susceptibility to FC. [3]

Influenza virus A is a frequent cause of febrile convulsions in Japan and China, whereas in the US and Europe, except for one epidemic in the UK [4] with a 50% incidence of FCs, influenza is an uncommon cause. In the Japanese influenza seasons (1999-2002) 12 of 46 (25%) patients recruited for the present study had febrile convulsions. In Hong Kong, influenza A infection accounted for 10 to 21% in 1997 and 1998, and up to 35% to 44% of FC during peak influenza months, while parainfluenza and adenovirus were less frequently (6 to 10%) associated with FC admissions. [5]

Herpesvirus-6 infection is a more frequent cause of FC than influenza in the US, accounting for one third of all first-time febrile seizures in children up to 2 years of age. The risk of FC with HHV-6 infection was 29% (17% had HHV-6 and roseola) compared to only 9% with non-HHV-6 infections (with otitis or fever of undetermined origin) [6]. The risk of FC with HHV-6 is correlated with a high fever, and with low immunoglobulins, IgA and IgM. FCs with HHV-6 may be prolonged and complex and, like those complicating influenza, a possible encephalitis/encephalopathy etiology is suspected in some [7]. With HHV-6 and roseola, the height of the fever is exceptional and is often considered sufficient to explain the FC. In the Japanese study of influenza cases, the number with repeated febrile seizures (complex FC) during a 24-hour period (28%) is higher than that usually expected (<20%), and fever alone seems an unlikely explanation. The authors propose that the pathogenesis of FCs is similar to that of encephalopathy, and encephalopathy with convulsion may be difficult to differentiate from a complex FC (Millichap JG. Febrile Convulsions. Macmillan, 1968). Both simple or complex FC may occur with a viral infection and positive CSF viral isolation. Children with a proven viral infection and FC have no worse prognosis than those without. [8]

Do complex FCs have a different mechanism from the simple FC or do they both result from fever and infection which, in the complex FC, is neurotropic and encephalopathic and associated with a greater cytokine response? Future studies in the etiology of FCs should emphasize the role of viral infection and cytokines and require the expertise of the specialist in infectious disease. It is appropriate that influenza vaccination is now recommended in infants ages 6-35 months as well as older children.