The strong increase of the proinflammatory cytokines elevates the permeability of the blood–brain barrier and triggers the inflammatory cascade to produce more cytokines (over-response), which subsequently progresses into systemic inflammatory response syndrome, resulting in encephalitis, cardiopulmonary failure, and pulmonary edema.[4,17] Here, we found that another proinflammatory cytokine, HMGB1, which abnormally increased along with the progression of EV71-induced HFMD, showed a highly positive correlation with IL-6 and TNF-α in the serum (Fig. 3). Here, HMGB1 is linked to systemic inflammatory response syndrome.