Predicting Severe Enterovirus 71-Infected Hand, Foot, and Mouth Disease: Cytokines and Chemokines

Table 1

The association between cytokines, chemokines, and EV71-infected HFMD.

Cytokines/chemokines (sources)	Countries/regions	Study type	Sample type	Complications/severe cases	OR/ROC	Level/value	Progression	value	Study (year)
TNF-α (Mφ)	China-Zhengzhou	Case-control	Serum	Fatal cases (): BE+NPE+sepsis	4.325	Peak value; Declined	The 2nd day; 3-5 days		Duan et al. (2014) [10]
	China-Shandong	Case-control	Serum	NPE (), CNSF ()	4.593	Elevated	The 3rd day	0.001	Sun et al. (2018) [12]
	China-Zhejiang	Case-control	Serum	Severe (): AFP, convulsions; Critical (): coma, dyspnea, PE	—	Elevated	Hospitalized	<0.01	Zheng et al. (2017) [11]
IFN-γ (Th1)	China-Zhengzhou	Case-control	Serum	Fatal cases (): BE+NPE+sepsis	4.325	Low; High	The 2nd day; 3-5days	0.017; <0.017	Duan et al. (2014) [10]
	China-Shandong	Case-control	Serum	NPE (); CNSF ()	4.593	Elevated; Declined	The 1st day; The 3rd day	<0.01	Sun et al. (2018) [12]
	China-Qingdao	Case-control	Blood	Encephalitis ()	2.04	(A allele); Elevated	—	<0.01	Yang et al. (2012) [15]
	Taiwan	Case-control	Plasma	ANSD (), PE (), BE ()	—	Elevated	—	0.048	Wang et al. (2003) [17]
IL-1β (Mφ)	Malaysian	Case-control	Serum, CSF	AM (), E (), AFP (), CRC ()	—	Elevated	Hospitalized	0.013	Griffiths et al. (2012) [14]
	China-Nanjing	Case-control	Plasma, CSF	Severe (): myoclonus, ataxia; Critical (): coma, RF, CC	2.168	Elevated; Declined	Acute stage; Convalescence	<0.05; <0.05	Ye et al. (2015) [20]
IL-6 (Th2, Mφ)	Taiwan	Case-control	CSF, serum	E (12), PLS (3), AM (7), PE (8)	—	Elevated	The 2nd day	<0.001	Lin et al. (2003) [33]
	China-Zhengzhou	Case-control	Serum	Fatal cases (): BE+NPE+sepsis	4.325	Elevated; Declined	2-3 days; 4-5 days	0.003; <0.001	Duan et al. (2014) [10]
	China-Zhejiang	Case-control	Serum	Severe (): AFP, convulsions; Critical (): coma, dyspnea, PE	—	Elevated; Declined	Hospitalized convalescence	<0.01; <0.01	Zheng et al. (2017) [11]
	China-Guangdong	Case-control	Serum	Stages II (), III (), IV ()	—	Elevated	TP0	<0.01	Chen et al. (2014) [31]
	China-Qingdao	Case-control	CSF, serum	Encephalitis ()	3.31	(G allele); Elevated	—	<0.001	Yuan et al. (2015) [34]
	Korea, Seoul	Case-control	Serum	Aseptic meningitis ()	7.44/	Elevated	—	<0.001	Lee et al. (2018) [35]
IL-8 (Mφ)	China-Shandong	Case-control	Plasma	Severe (): E (36) + CNSF + RF+ dysaemia	1.8	(T allele); Elevated	—	0.012	Xu et al. (2016) [37]
	China-Nanjing	Case-control	Plasma	Severe (): myoclonus, ataxia; Critical (): coma, RF, CC	2.168	Elevated; Declined	Acute stage; Convalescence	<0.05; <0.05	Ye et al. (2015) [20]
	China-Shenzhen	Case-control	Serum	Severe (): CNSF+CRC; Critical (): convulsions+coma +BH+dyspnea		Elevated	—	<0.001	He et al. (2019) [38]
	Beijing	Case-control	Serum	Mild (): CNSF, RF; Severe (): PE (8), GT (16), MI (4), death (4)	—	Peak value; Peak value	The 6th day; The 11th day	<0.001	Han et al. (2014) [22]
	Beijing	Case-control	Serum	BE (); PE (); BE+PE ()	5.833	Peak value; Declined	The 1st day; The 4th day	NS; NS; 0.002	Wang et al. (2014) [39]
IL-4 (Th2)	China-Zhengzhou	Case-control	Serum	Fatal cases (): BE+NPE+sepsis	4.325	Elevated	2-4 days	0.001	Duan et al. (2014) [10]
	China	Case-control	Serum	Viral encephalitis ()	15.721	Elevated	—	<0.001	Zhang et al. (2015) [29]
	Beijing	Case-control	Serum	Mild (): CNSF, RF; Severe (): PE (8), GT (16), MI (4), death (4)	—	Higher; Higher	2-6 days; 7-14 days	<0.001	Han et al. (2014) [22]
IL-10 (Th2, Mφ)	Taiwan	Case-control	Plasma	ANSD (), PE (), BE ()	—	Elevated	—	<0.001	Wang et al. (2003) [17]
	China-Shandong	Case-control	Serum	NPE (); CNSD ()	4.593	Elevated; Declined	The 3rd day; The 5th day	0.001; <0.05	Sun et al. (2018) [12]
	China-Qingdao	Case-control	Plasma	Severe (): vomiting, convulsion; Critical (): coma, CRC, PE, CC	2.998	(C allele); Elevated	—	<0.01	Zhao et al. (2017) [40]
	China-Guangdong	Case-control	Serum	Stages II (), III (), IV ()	—	Elevated	TP0	<0.01	Chen et al. (2014) [31]
	China-Qingdao	Case-control	Blood	Encephalitis ()	1.86	(A allele); Elevated	—	<0.05	Yang et al. (2012) [15]
IL-12 (Th1)	China-Hangzhou	Case-control	Plasma	Mild (): typical symptom; Severe cases (): E (17), E+PE (11)	—	Elevated	Within 24 h	<0.01	Shang et al. (2017) [16]
IL-13 (Th2)	Taiwan	Case-control	Plasma	ANSD (), PE (), BE ()	—	Elevated	—	0.048	Wang et al. (2003) [17]
	China-Guangdong	Case-control	Serum	Stages II (), III (), IV ()	—	Elevated	TP0	<0.01	Chen et al. (2014) [31]
	China-Dongying	Case-control	Serum	Severe (): vomiting, AFP, convulsions, etc.	0.969	(G allele); NS	—	>0.05	Zhang et al. (2019) [32]
IL-17F (Th17)	China-Qingdao	Case-control	Blood	Encephalitis ()	0.31	(C allele); Declined	—	0.006	Lv et al. (2013) [41]
	China-Qingdao	Case-control	Blood	Severe (): typical symptom encephalitis ()	1.916	(T allele); Elevated	—	0.001	Li et al. (2018) [42]
IL-18 (Th1)	Beijing	Case-control	Serum	Mild (): CNSF, RF; Severe (): PE (8), GT (16), MI (4), death (4)	—	Peak value; Peak value	The 3th day; The 11th day	<0.001	Han et al. (2014) [22]
IL-22 (Th17, Th22)	China	Case-control	Serum	Viral encephalitis ()	8.28	Elevated	—	0.026	Zhang et al. (2015) [29]
	China-Zhejiang	Case-control	Plasma	Mild (): typical symptom; Severe (): CRC, BH, MI, etc.	—	Elevated	—	<0.01; <0.001	Cui et al. (2017) [43]
IL-23 (DC, Mφ)	China	Case-control	Serum	Viral encephalitis ()	4.564	Elevated	—	0.002	Zhang et al. (2015) [29]
IL-33 (DC, Mφ)	Shenzhen	Case-control	Plasma	Severe (): myoclonus, vomiting; Critical (): acute RF, PE	2.348	Elevated	Hospitalized	<0.01	Zhang et al. (2013) [24]
IL-27 (APC)	China-Guangzhou	Case-control	Serum	Stages II (), III (), IV ()	—	—; Elevated; Declined	TP0; TP1; TP2	—; <0.05; <0.01	Huang et al. (2016) [44]
IL-35 (Treg)	China-Henan	Case-control	Serum	Mild (): typical symptom; Severe (): CNSF, CRC	—	Declined	—	<0.0001	Huang et al. (2017) [45]
IL-37 (APC)	China-Hefei	Case-control	Blood	Patients (): typical symptom	—	Elevated	—	<0.05	Lv et al. (2019) [27]
IP-10 (Mφ)	Shenzhen	Case-control	Plasma	Severe (): myoclonus, vomiting; Critical (): acute RF, PE	2.348	Elevated	Hospitalized	<0.01	Zhang et al. (2013) [24]
	China-Qingdao	Case-control	Blood	Patients (): typical symptom	0.35	(T allele); Declined	—	<0.05	Yang et al. (2013) [46]
MCP-1 (Mφ)	China-Hangzhou	Case-control	Plasma	Mild (): typical symptom; Severe cases (): E (17), E + PE (11)	—	Elevated	Within 24 h	<0.01	Shang et al. (2017) [16]
	Shenzhen	Case-control	Plasma	Acute RF ()	2.348	Elevated	Hospitalized	<0.01	Zhang et al. (2013) [24]
RANTES (NK, CD8^+)	China-Hangzhou	Case-control	Plasma	Mild (): typical symptom; Severe cases (): E (17), E + PE (11)	—	Elevated	Within 24 h	<0.01	Shang et al. (2017) [16]
HMGB1 (Mφ)	China-Zhejiang	Case-control	Serum	Severe (): AFP, convulsions; Critical (): coma, dyspnea, PE	—	Elevated; Declined	Hospitalized recovered	<0.01; <0.01	Zheng et al. (2017) [11]
G-CSF (EC, FB)	Malaysian	Case-control	CSF	AM (), E (), AFP (), CRC ()	—	Elevated	Hospitalized	<0.01	Griffiths et al. (2012) [14]

Mφ: monocytes/macrophages; Th: helper T lymphocytes; DC: dendritic cells; APC: antigen-presenting cells; Treg cells: regulatory T cells; NK: natural killer cell; EC: endothelial cells; FB: fibroblasts; E: encephalitis; AM: aseptic meningitis; AFP: acute flaccid paralysis; NPE: neurogenic pulmonary edema; CNSF: central nervous system failure; CSF: cerebrospinal fluid; PLS: poliomyelitis-like syndrome; BE: brainstem encephalitis; PE: pulmonary edema; CRC: cardiorespiratory complication; RF: respiratory failure; CC: circulatory collapse; BH: brain hernia; GT: gastrointestinal symptoms; MI: myocardial injury; ANSD: autonomic nervous system dysregulation; AUC: area under the curve; IP-10: interferon-induced protein 10; MCP-1: monocyte chemoattractant protein-1; HMGB1: high mobility group protein 1; G-CSF: granulocyte colony-stimulating factor. Stage II means involvement of the nervous system; stage III means early cardiopulmonary failure; and stage IV means cardiopulmonary failure. TP0 means the day of admission; TP1 means the day the disease improved; and TP3 means the day the disease recovered.