title: Elevated levels of circulating histones indicate disease activity in patients with hand, foot, and mouth disease (HFMD).
abstract: BACKGROUND
  Hand, foot, and mouth disease (HFMD) is a common infectious disease in children, characterized by acute viral infection accompanying acute inflammatory responses. Circulating histones are leading mediators of the inflammatory processes. This study aimed to elucidate whether circulating histones play a contributory role during HFMD.
  
  
  METHODS
  We measured plasma levels of histones, myeloperoxidase (MPO), lactate dehydrogenase (LDH), and cytokines in HFMD patients (n = 126) and compared the results with those of a control group (n = 30).
  
  
  RESULTS
  Circulating histone levels were significantly increased in HFMD patients (3.794 ± 0.156 μg/ml) compared with healthy controls (0.238 ± 0.023 μg/ml, p < 0.0001). In addition, their levels were remarkably higher in severe HFMD (n = 38) than in mild HFMD patients (n = 88) (5.232 ± 0.246 vs 3.293 ± 0.161 μg/ml, p < 0.0001). As for other inflammatory markers, MPO, LDH, IL-1β, IL-6, IL-10, MIP-1, and TNF-ɑ were found to be significantly higher in HFMD patients than in healthy subjects. Of these, LDH, IL-6, and TNF-ɑ levels correlated with disease severity (all p < 0.05). In mild HFMD, circulating histones correlated positively with plasma IL-6 and IL-10, whereas in severe HFMD, histones were associated with elevated IL-6 and TNF-ɑ levels.
  
  
  CONCLUSIONS
  These data demonstrate that circulating histones are excessively released in patients with HFMD, which may indicate disease severity and contribute to systemic inflammation by promoting cytokine production (e.g. IL-6). We suggest that in mild HFMD, circulating histones may originate largely from neutrophil activation, whereas in severe HFMD, dying tissue cells and neutrophil activation may be synergistically involved in the increased levels of histones.
authors.affiliation: From the 1 Department of Integrated TCM and Western Medicine, Beijing Youan Hospital affiliated with Capital Medical University , Beijing.
authors.forename: Xiuhui
authors.initials: X
authors.lastname: Li
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.forename: Junhong
authors.initials: J
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Yuping
authors.initials: Y
authors.lastname: Chen
authors.forename: Aiping
authors.initials: A
authors.lastname: Lv
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Jianbo
authors.initials: J
authors.lastname: Ding
authors.forename: Kristine
authors.initials: K
authors.lastname: Von Maltzan
authors.forename: Tao
authors.initials: T
authors.lastname: Wen
mesh_terms: D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood*; D005260:Female; D006232:Hand, Foot and Mouth Disease / Q000276:immunology* / Q000473:pathology; D006657:Histones / Q000097:blood*; D006801:Humans; D007223:Infant; D007249:Inflammation / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000097:blood*; D008297:Male; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D015415:Biomarkers; D016207:Cytokines; D006657:Histones; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D007770:L-Lactate Dehydrogenase
keywords: circulating histones; cytokine; hand, foot, and mouth disease, (HFMD); inflammation