The clinical value of aquaporin-4 in children with hand, foot, and mouth disease and the effect of magnesium sulfate on its expression: a prospective randomized clinical trial

  • Lei Zhu
  • Hong Yin
  • Haomiao Sun
  • Tong Qian
  • Junling Zhu
  • Gongjian Qi
  • Yin Wang
  • Boxiang QiEmail author
Original Article


To evaluate the clinical value of aquaporin-4 (AQP-4) in hand, foot, and mouth disease (HFMD) and to evaluate therapeutic efficacy of magnesium sulfate (MgSO4) and its effect on AQP-4 expression. Children with HFMD were divided into a common group, a severe group and a critical group according to Chinese guidelines; children in the critical group were further divided into two subgroups: routine treatment group and MgSO4 group. Outcome measures included systolic blood pressure (SBP), Heart rate (HR), the levels of AQP-4, interleukin-6 (IL-6), norepinephrine (NE), and neuron-specific enolase (NSE). Serum AQP-4, IL-6, NE, and NSE levels varied significantly among the critical, severe, and common groups before and after treatment. There were no significant differences in AQP-4 levels in cerebrospinal fluid (CSF) between the critical and severe groups before and after treatment; however, CSF AQP-4 levels in these two groups were higher than those in the common group before treatment. Serum and CSF AQP-4 levels in convalescence decreased significantly in the critical and severe groups. SBP, HR and serum AQP-4, IL-6, NE, NSE levels, but not CSF AQP-4 levels, were significantly lower in MgSO4 group than in the routine treatment group. AQP-4 in serum, but not in CSF, is a candidate biomarker for evaluating the severity and prognosis of HFMD; MgSO4 can provide protection on children with critical HFMD.


Hand, foot, and mouth disease Aquaporin-4 Magnesium sulfate Cerebral injury 



The authors thank Ke Wang from Xuzhou Medical University, Xuzhou, China, for his assistance in the protocol review and statistical analyses.

Author contributions

Lei Zhu, Hong Yin, and Bixiang Qi conceived the study. Lei Zhu, Hong Yin, Haomiao Sun, and Boxiang Qi participated in the study design. Gongjian Qi and Junling Zhu participated in the statistical design. Tong Qian and Ying Wang conducted the study, including acquisition, detection, analysis, and interpretation of data. Gongjian Qi and Hong Yin completed the statistical analysis and data interpretation. All authors critically reviewed, edited, and approved the manuscript and made the decision to submit for publication. All authors assume responsibility for the accuracy and completeness of the data.


This study was funded by the Jiangsu Provincial Commission of Health and Family Planning (Q201617), and Xuzhou Science and Technology Planning (KC16SL140).

Compliance with ethical standards

The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and Chinese regulatory requirements, and the study was approved by the Hospital Medical Ethics Committee with the informed consent of the parents of the children.

Competing interests

The authors declare that they have no competing interests.

Ethical approval

All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.


  1. 1.
    Xiao X, Gasparrini A, Huang J et al (2017) The exposure-response relationship between temperature and childhood hand, foot and mouth disease: a multicity study from mainland China. Environ Int 100:102–109. CrossRefGoogle Scholar
  2. 2.
    Lu WH, Hsieh KS, Lu PJ et al (2013) Hexamethonium reverses the lethal cardiopulmonary damages in a rat model of brainstem lesions mimicking fatal enterovirus 71 encephalitis. Crit Care Med 41(5):1276–1285. CrossRefGoogle Scholar
  3. 3.
    Ye N, Gong X, Pang LL et al (2015) Cytokine responses and correlations thereof with clinical profiles in children with enterovirus 71 infections. BMC Infect Dis 15:225. CrossRefGoogle Scholar
  4. 4.
    Yan W, Zhao X, Chen H et al (2016) β-Dystroglycan cleavage by matrix metalloproteinase-2/−9 disturbs aquaporin-4 polarization and influences brain edema in acute cerebral ischemia. Neuroscience 326:141–157. CrossRefGoogle Scholar
  5. 5.
    Rodríguez-Llamazares S, Arroyo-Hernández J, Rodríguez-Bautista H et al (2017) Interventions to teach inhaler techniques, risk stratification of asthma exacerbations with sputum eosinophils, and high-dose infusion of magnesium sulfate for severe asthma. Am J Respir Crit Care Med 195(11):1528–1530. CrossRefGoogle Scholar
  6. 6.
    Qui PT, Khanh TH, Trieu HT et al (2016) Intravenous magnesium sulfate for the management of severe hand, foot, and mouth disease with autonomic nervous system dysregulation in Vietnamese children: study protocol for a randomized controlled trial. Trials 17:98. CrossRefGoogle Scholar
  7. 7.
    Li X, Han X, Yang J et al (2017) Magnesium sulfate provides neuroprotection in eclampsia-like seizure model by ameliorating neuroinflammation and brain edema. Mol Neurobiol 54(10):7938–7948. CrossRefGoogle Scholar
  8. 8.
    Ministry of Health of the People’s Republic of China (2010) Chinese guidelines for the diagnosis and treatment of hand, foot and mouth disease. Accessed 20 Dec 2018
  9. 9.
    Clinical Experts Group of the Ministry of Health for Hand,Foot and Mouth Disease (2011) Experts consensus on rescue and treatment of severe cases with enterovirus 71(EV71) infection. Chin J Pediatr 49(9):675–678. Google Scholar
  10. 10.
    Irazuzta JE, Paredes F, Pavlicich V et al (2016) High-dose magnesium sulfate infusion for severe asthma in the emergency department: efficacy study. Pediatr Crit Care Med 17(2):e29–e33. CrossRefGoogle Scholar
  11. 11.
    McGuire JK, Kulkarni MS, Baden HP (2000) Fatal hypermagnesemia in a child treated with megavitamin/megamineral therapy. Pediatrics 105(2):E18CrossRefGoogle Scholar
  12. 12.
    Kramer P, Miera O, Berger F et al (2018) Prognostic value of serum biomarkers of cerebral injury in classifying neurological outcome after paediatric resuscitation. Resuscitation 122:113–120. CrossRefGoogle Scholar
  13. 13.
    Boyle SH, Brummett BH, Kuhn CM et al (2019) The effects of tryptophan enhancement and depletion on plasma catecholamine levels in healthy individuals. Psychosom Med 81(1):34–40. CrossRefGoogle Scholar
  14. 14.
    Sun Y, Yang J, Sun Y et al (2018) Interleukin-6 gene polymorphism and the risk of systemic inflammatory response syndrome caused by wasp sting injury. DNA Cell Biol 37(12):967–972. CrossRefGoogle Scholar
  15. 15.
    Li J, Liu HR, Shan RB (2017) Value of serum S100B protein and neuron-specific enolase levels in predicting the severity of hand, foot and mouth disease. Zhongguo Dang Dai Er Ke Za Zhi 19(2):182–187. Google Scholar
  16. 16.
    Liao YT, Wang SM, Wang JR et al (2015) Norepinephrine and epinephrine enhanced the infectivity of enterovirus 71. PLoS One 10(8):e0135154. CrossRefGoogle Scholar
  17. 17.
    Lee JY, Son M, Kang JH et al (2018) Serum interleukin-6 levels as an indicator of aseptic meningitis among children with enterovirus 71-induced hand, foot and mouth disease. Postgrad Med 130(2):258–263. CrossRefGoogle Scholar
  18. 18.
    Han D, Sun M, He PP et al (2015) Ischemic postconditioning alleviates brain edema after focal cerebral ischemia reperfusion in rats through down-regulation of aquaporin-4. J Mol Neurosci 56(3):722–729. CrossRefGoogle Scholar
  19. 19.
    Xiong LL, Tan Y, Ma HY et al (2016) Administration of SB239063, a potent p38 MAPK inhibitor, alleviates acute lung injury induced by intestinal ischemia reperfusion in rats associated with AQP4 downregulation. Int Immunopharmacol 38:54–60. CrossRefGoogle Scholar
  20. 20.
    Bryant JL, Guda PR, Ray S et al (2018) Renal aquaporin-4 associated pathology in TG-26 mice. Exp Mol Pathol 104(3):239–249. CrossRefGoogle Scholar
  21. 21.
    Wang C, Yan M, Jiang H et al (2018) Mechanism of aquaporin 4 (AQP 4) up-regulation in rat cerebral edema under hypobaric hypoxia and the preventative effect of puerarin. Life Sci 193:270–281. CrossRefGoogle Scholar
  22. 22.
    Shao P, Wu X, Li H et al (2017) Clinical significance of inflammatory cytokine and chemokine expression in hand, foot and mouth disease. Mol Med Rep 15(5):2859–2866. CrossRefGoogle Scholar
  23. 23.
    Li X, Liu H, Yang Y (2010) Magnesium sulfate attenuates brain edema by lowering AQP4 expression and inhibits glia-mediated neuroinflammation in a rodent model of eclampsia. Behav Brain Res.
  24. 24.
    Bjerring PN, Eefsen M, Larsen FS et al (2011) Hypermagnesemia does not prevent intracranial hypertension and aggravates cerebral hyperperfusion in a rat model of acute hyperammonemia. Hepatology 53(6):1986–1994. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Lei Zhu
    • 1
  • Hong Yin
    • 2
  • Haomiao Sun
    • 3
  • Tong Qian
    • 4
  • Junling Zhu
    • 1
  • Gongjian Qi
    • 1
  • Yin Wang
    • 3
  • Boxiang Qi
    • 1
    Email author
  1. 1.Department of Intensive Care UnitXuzhou Children’s Hospital of Xuzhou Medical UniversityXuzhouChina
  2. 2.Department of PharmacyThe Affiliated Hospital of Xuzhou Medical UniversityXuzhouChina
  3. 3.Department of Infectious DiseaseXuzhou Children’s Hospital of Xuzhou Medical UniversityXuzhouChina
  4. 4.Department of Clinical LaboratoryXuzhou Children’s Hospital of Xuzhou Medical UniversityXuzhouChina

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