Serum Inflammatory Cytokine Levels Correlate with Hand-Foot-Mouth Disease Severity: A Nested Serial Case-Control Study

Duan, Guangcai; Yang, Haiyan; Shi, Lubin; Sun, Wumei; Sui, Meili; Zhang, Rongguang; Wang, Xinhong; Wang, Fang; Zhang, Weidong; Xi, Yang; Fan, Qi-Wen

doi:10.1371/journal.pone.0112676

Cited by 41 publications

(44 citation statements)

References 30 publications

(33 reference statements)

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“…TNF-α involves the occurrence and development of many diseases, which can promote the production of various inflammatory factors by T cells to promote the occurrence of inflammatory response. The serum levels of TNF-α in severe EV71-infected patients were significantly higher than those in mild patients [10][11][12] (shown as Table 1), which indicated that TNF-α may be involved in disease severity. High levels of TNF-α were detected in severe patients with complications (including brainstem encephalitis, neurogenic pulmonary edema, and sepsis) at disease onset, and then decreased with disease progression [10].…”

Section: Tnf-αmentioning

confidence: 93%

“…The serum levels of TNF-α in severe EV71-infected patients were significantly higher than those in mild patients [10][11][12] (shown as Table 1), which indicated that TNF-α may be involved in disease severity. High levels of TNF-α were detected in severe patients with complications (including brainstem encephalitis, neurogenic pulmonary edema, and sepsis) at disease onset, and then decreased with disease progression [10]. The critical HFMD group (frequent convulsions, coma, brain hernia, pulmonary rales, or circulatory insufficiency) also had higher levels of TNF-α than the severe group (acute flaccid paralysis or convulsions) and mild group [11].…”

Section: Tnf-αmentioning

confidence: 93%

“…Studies suggested that the enhanced expression of IFN-γ is associated with life-threatening complications in severe EV71infected HFMD cases [12,[14][15][16][17]. However, a study showed that the changes of the serum levels of IFN-γ in severe patients were different, which the levels of IFN-γ were very low in the first day and then increased for the first three days and then decreased [10] (as seen in Table 1). Sun et al [12] divided severe HFMD patients into two groups including central nervous system disease (CNSD) group and neurogenic pulmonary edema (NPE) group.…”

Section: Ifn-γ Is Produced By Activated T Cells Natural Killer Cellsmentioning

confidence: 97%

“…IL-4 is mainly produced by Th2 cells, mast cells, and basophils, which can promote the proliferation and differentiation of B cells, induce IgG1 and IgE production, facilitate Th0 cells to differentiate into Th2 cells, and so on [28]. The dynamic changes of the IL-4 with the progression of HFMD and its severity have been studied [10,22,29]. The levels of IL-4 among the cases were significantly different and increased from the 2nd day to the 4th day (p < 0:001), especially in the fatal cases accompanied with brainstem encephalitis, neurogenic pulmonary edema, and sepsis [10].…”

Section: Il-2 Familymentioning

confidence: 99%

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

Zhang

Huang

et al. 2020

Mediators of Inflammation

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Enterovirus 71 (EV71) is one of the most common intestinal virus that causes hand, foot, and mouth disease (HFMD) in infants and young children (mostly ≤5 years of age). Generally, children with EV71-infected HFMD have mild symptoms that resolve spontaneously within 7-14 days without complications. However, some EV71-infected HFMD cases lead to severe complications such as aseptic meningitis, encephalitis, acute flaccid paralysis, pulmonary edema, cardiorespiratory complication, circulatory disorders, poliomyelitis-like paralysis, myocarditis, meningoencephalitis, neonatal sepsis, and even death. The mechanism of EV71 pathogenesis has been studied extensively, and the regulation of host immune responses is suspected to aggravate EV71induced severe complications. Recently, several cytokines or chemokines such as TNF-α, IFN-γ, IL-1β, IL-18, IL-33, IL-37, IL-4, IL-13, IL-6, IL-12, IL-23, IL-27, IL-35, IL-10, IL-22, IL-17F, IL-8, IP-10, MCP-1, G-CSF, and HMGB1 have been reported to be associated with severe EV71 infection by numerous research teams, including our own. This review is aimed at summarizing the pathophysiology of the cytokines and chemokines with severe EV71 infection.

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Section: Tnf-αmentioning

confidence: 93%

Section: Tnf-αmentioning

confidence: 93%

Section: Ifn-γ Is Produced By Activated T Cells Natural Killer Cellsmentioning

confidence: 97%

Section: Il-2 Familymentioning

confidence: 99%

See 2 more Smart Citations

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

Zhang

Huang

et al. 2020

Mediators of Inflammation

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“…As shown in our previous study, the highest levels of some inflammatory cytokines occurred at 3 dpi in HFMD cases. In terms of above results, RAS activation may induce large amounts of pro-inflammatory cytokines [23]. Numerous studies on the pathogenesis of other viral diseases have also shown that pathogens can affect the stability of the RAS [24][25][26][27].…”

Section: Discussionmentioning

confidence: 93%

Involvement of the renin-angiotensin system in the progression of severe hand-foot-and-mouth disease

Zhang¹,

Chen²,

Zhou³

et al. 2018

PLoS ONE

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BackgroundHand-foot-and-mouth disease (HFMD) is generally considered as a mild exanthematous disease to infants and young children worldwide. HFMD cases are usually mild and self-limiting but for few cases leads to complicated severe clinical outcomes, and even death. Previous studies have indicated that serum Ang II levels in patients with H7N9 infection were related to the severity of infection. However, the mechanisms underlying the pathogenesis of severe HFMD remain unclear. This study was undertaken to clarify the role of the renin-angiotensin system (RAS) in the progression of severe HFMD.MethodsIn the present study, 162 children including HFMD patients and healthy controls were recruited. The data was analyzed by time-series fashion. Concentrations of angiotensin II (Ang II) and noradrenaline (NA) in serum of patients were measured with ELISA. We established a mouse model for enterovirus 71 (EV71) infection and determined concentrations of Ang II, NA in tissue lysates at 3, 5 and 7 days post infection (dpi).ResultsThe concentrations of Ang II and NA in serum of the HFMD patients with mild or severe symptoms were significantly higher than that in healthy controls. Additionally, the concentrations of Ang II and NA in serum of severe cases were significantly higher than those mild cases and the increased concentrations of Ang II and NA showed the same time trend during the progression of HFMD in the severe cases. Furthermore, the concentrations of Ang II and NA in target organs of EV71-infected mice including brains, skeletal muscle, and lungs were increased with the progression of EV71 infection in mice. Histopathological alterations were observed in the brains, skeletal muscle and lungs of EV71-infected mice.ConclusionOur study suggested that activation of the RAS is implicated in the pathogenesis of severe HFMD.

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Local immune dysregulation and subsequent inflammatory response contribute to pulmonary edema caused by Enterovirus infection in mice

Sun

Liu

Dai

et al. 2023

Journal of Medical Virology

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Pulmonary edema that comes on suddenly is the leading cause of mortality in handfoot-and-mouth disease (HFMD) patients; however, its pathogenesis is still largely unclear. A range of research suggest immunopathogenesis during the occurrence of pulmonary edema in severe HFMD patients. Herein, to investigate the potential mechanism of immune dysregulation in the development of pulmonary edema upon Enterovirus (EV) infection, we established mouse infection models for Enteroviruses (EVs) including Coxsackievirus (CV) A6, Enterovirus A71 (EVA71), and CVA2 exhibiting a high incidence of pulmonary edema. We found that EVs infection induced an immune system disorder by reducing the numbers of pulmonary and circulatory T cells, B cells, macrophages, and monocytes and increasing the numbers of lung neutrophils, myeloid-derived suppressor cells (MDSCs), and activated T cells. In addition, the concentrations of C−X−C motif chemokine ligand 1 (CXCL-1), tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and interleukin 6 were increased in EV-infected lungs. Moreover, we found that EVs replication in mice lungs lead to apoptosis of lung cells and degradation of tight junction proteins. In conclusion, EVs infection likely triggered a complexed immune defense mechanism and caused dysregulation of innate immune cells (MDSCs, neutrophils, monocytes, and macrophages) and adaptive cellular immunity (B cells, T cells). This dysregulation increased the release of cytokines and other inflammatory factors from activated immune-related cells and caused lung barrier damage and pulmonary edema.

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Serum Inflammatory Cytokine Levels Correlate with Hand-Foot-Mouth Disease Severity: A Nested Serial Case-Control Study

Cited by 41 publications

References 30 publications

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

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

Involvement of the renin-angiotensin system in the progression of severe hand-foot-and-mouth disease

Local immune dysregulation and subsequent inflammatory response contribute to pulmonary edema caused by Enterovirus infection in mice

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