Mild Hand, Foot And Mouth Disease Research Articles

Integrated analysis reveals important differences in the gut and oropharyngeal microbiota between children with mild and severe hand, foot, and mouth disease

ABSTRACT Little is known about alternation and difference in gut microbiota between patients with mild and severe hand, foot, and mouth disease (HFMD). We investigated the differences in gut and oropharynx microbiota between mild and severe HFMD in young children and changes in bacterial profiles as the disease progresses from acute to convalescent phase. Forty-two patients with confirmed HFMD were studied, among which 32 had severe HFMD and 10 had mild HFMD. First rectal swabs were collected from all patients at an average of 2 days (acute phase) after the onset of symptoms, and second rectal swabs were collected from 8 severe patients at day 9 (convalescent phase) after the onset. Oropharyngeal swabs were obtained from 10 patients in the acute phase and 6 in the convalescent phase. 16S rRNA sequencing was performed for all 70 samples. Compared with mild HFMD, severe HFMD exhibited significantly decreased diversity and richness of gut microbiota. Gut microbiota bacterial profiles observed in the acute and convalescent phases resembled each other but differed from those in mild cases. Additionally, 50% of patients with severe HFMD in the acute phase harboured a dominant pathobiontic bacterial genus. However, none of the patients with mild HFMD had such bacteria. Similar bacterial compositions in oropharynx microbiota were detected between mild and severe cases. Our findings indicate that severe HFMD exhibits significantly impaired diversity of gut microbiota and frequent gut and oropharyngeal inflammation-inducing bacteria. However, the results should be interpreted with caution as the number of subjects was limited.

Epidemiological and etiological characteristics of mild hand, foot and mouth disease in children under 7 years old, Nanjing, China, 2010–2019

BackgroundMild hand, foot and mouth disease (HFMD) cases make up a relatively high proportion of HFMD while have often been overlooked. This study aimed to investigate the epidemiological and etiological characteristics of mild HFMD in Nanjing.MethodsData on mild HFMD cases, during 2010–2019 in Nanjing, were collected from the China Information System for Disease Control and Prevention. This study mainly focused on mild cases aged < 7 years. Descriptive analysis was used to summarize epidemiological and etiological characteristics of mild cases. Flexible spatial scan statistic was used to detect spatial clusters of mild cases.ResultsA total of 175,339 mild cases aged < 7 years were reported, accounting for 94.4% of all mild cases. There was a higher average annual incidence of mild HFMD in children aged < 7 years (4,428 cases/100,000) compared with children aged ≥ 7 years (14 cases/100,000, P < 0.001), and especially children aged 1-year-old (7,908 cases/100,000). Mild cases showed semi-annual peaks of activity, including a major peak (April to July) and a minor peak (September to November). The average annual incidence was higher in males (5,040 cases/100,000) than females (3,755 cases/100,000). Based on the cumulative reported cases, the most likely cluster was detected, including Yuhuatai District, Jiangning District, Jiangbei new Area, and Pukou District. The annual distribution of enterovirus serotypes showed a significant difference. During 2010–2016, Enterovirus 71 (EV71), Coxsackievirus A16 (Cox A16), and other non-EV71/Cox A16 EVs, accounted for 29.1%, 34.6%, 36.3% of all the enterovirus test positive cases, respectively. Moreover, during 2017–2019, Cox A6, Cox A16, EV71, and other non-EV71/Cox A16/Cox A6 EVs, accounted for 47.3%, 32.5%, 10.7%, 9.5%, respectively.ConclusionsChildren under 7 years old are at higher risk of mild HFMD. Regions with high risk are mainly concentrated in the areas surrounding central urban areas. Cox A16 and Cox A6 became the dominant serotypes and they alternated or were co-epidemic. Our findings could provide valuable information for improving the regional surveillance, prevention and control strategies of HFMD.

Herbal Granules of Heat-Clearing and Detoxifying for Children with Mild Hand, Foot, and Mouth Disease: A Bayesian Network Meta-Analysis.

Background Regarding ethical considerations of randomized controlled trials (RCTs) in children, limited evidence for mild hand, foot, and mouth disease (HFMD) is available. Recently, with the increasing but result-conflicting RCTs published around herbal granules of heat-clearing and detoxifying (HGs-HD), a head-to-head comparison is urgently needed to choose a suitable therapy for clinical practice. Materials and Methods This study was conducted according to the preferred reporting items for systematic review and meta-analysis (PRISMA) extension statement for network meta-analysis (NMA). Eight databases (Medline, Embase, and so on) and two trial registry platforms (https://www.clinicaltrials.gov and https://www.chictr.org.cn) were searched from inception to May 26, 2021. The NMA was performed using a random-effect model. The treatment hierarchy was summarized and reported as the surface under the cumulative ranking curve (SUCRA) probability values. The rankings of each HGs-HD at primary outcomes were estimated by the inverse probability weighting (IPW) approach and averaged, which presents the comprehensive improvement effect. Results Forty-five RCTs involving 18 interventions were included that studied 5,652 children with mild HFMD. The best performance probability for improving symptoms were respectively presented in terms of fever (Xiao'er Resuqing granules, XRGs, 94.9%), rash (Xiao'er Jinqiao granules, 83.9%), hospitalization (Xiao'er Chiqiao Qingre granules, XCQGs, 92.7%), vesicles (Jinlianhua granules, 91.0%), appetite (Xiao'er Chiqiao Qingre granules, XCQGs, 86.7%), and ulcers (Kouyanqing granules, KouGs, 88.8%). Furthermore, the top 5 rankings for comprehensive improvement effect were Yanning granules (YNGs, 2.256), XCQGs (2.858), XRGs (3.270), KouGs (7.223), and Houerhuan Xiaoyan granules (HXGs, 7.597). Conclusions This is the first NMA of HGs-HD head-to-head comparisons for children with mild HFMD. Of those, YNGs, XCQGs, XRGs, KouGs, and HXGs could be recommended as potential choices for clinical practice. Of course, the results should be interpreted with caution due to the limited high-quality RCTs.

Neurocognitive deficits and sequelae following severe hand, foot, and mouth disease from 2009 to 2017, in JiangSu Province, China: a long-term follow-up study

BackgroundThe aim of this study was to evaluate the long-term sequelae and cognitive profiles resulting from severe hand, foot, and mouth disease (HFMD) with central nervous system (CNS) involvement. Methods294 HFMD cases were included in a retrospective follow-up study. Physical examinations were conducted. The Chinese Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) was used to assess intelligence. Results58 mild HFMD cases and 99 severe HFMD cases with mild CNS involvement did not present any neurological sequelae. In comparison, the sequelae incidence for severe HFMD with more severe CNS complications was 50.0%. The proportion of full-scale intelligence quotient (FSIQ) impairment was 45.0%. In the 2:6–3:11 age group, severe HFMD with more severe CNS complications and lower maternal education level were risk factors for verbal comprehension disorder. Urban–rural residence and lower paternal education level were risk factors for FSIQ disorder. Furthermore, in the 4:0–6:11 age group, severe HFMD with more severe CNS complication was a risk factor for visual spatial disorder and fluid reasoning disorder. Lower paternal education level was a risk factor for FSIQ disorder. ConclusionEarly assessment and intervention among severe HFMD patients with more severe CNS involvement at a very young age will prove beneficial for their future performance.

Translocating lipopolysaccharide correlates with the severity of enterovirus A71-induced HFMD by promoting pro-inflammation and viral IRES activity

BackgroundThe increase of inflammation-inducing enterobacteria was recently observed in severe hand, foot, and mouth disease (HFMD) caused by Enterovirus A71 (EV-A71). This study aimed to verify the occurrence of bacterial translocation (BT) and further explore the contributory role of BT to severity of EV-A71-mediated HFMD cases.MethodsSerum specimens from 65 mild and 65 severe EV-A71-associated HFMD cases and 65 healthy children were collected. EV-A71 VP1 in serum, inflammatory mediators including C-reactive protein, IL-1β, IL-6, interferon-γ and tumor necrosis factor-α, BT related biomarkers including Claudin-3, intestinal fatty acid binding protein, lipopolysaccharide (LPS), soluble CD14 (sCD14) and endotoxin core antibody were measured by ELISA. Bacterial DNA (BactDNA) fragments were quantified by quantified PCR (qPCR). Rhabdomyosarcoma (RD) or SH-SY5Y cells, infected with LPS-pre-incubated EV-A71 or transfected with plasmid containing viral 2Apro or mRNA containing viral internal ribosomal entry site (IRES), were post-treated with or without LPS in vitro. EV-A71 RNA and viral or cellular proteins were determined by qPCR and western blot, respectively.ResultsCompared to mild HFMD patients, remarkably higher inflammatory mediators as well as BT-related biomarkers except BactDNA were observed in severe HFMD cases (all P < 0.05). In severe HFMD group, circulating concentrations of LPS and sCD14 showed statistical correlations with inflammation indices (all P < 0.05), serum levels of EV-A71 VP1 were found to be positively correlated with serum LPS (r = 0.341, P = 0.005) and serum sCD14 (r = 0.458, P < 0.001). In vitro, EV-A71 attachment and internalization were only slightly promoted by LPS pre-incubation; however, EV-A71 proliferation and viral 2Apro-mediated IRES activity were significantly accelerated by LPS post-treatment.ConclusionsOur results collectively indicate that gut-derived translocating LPS contributes to the severity of EV-A71-induced HFMD by driving inflammatory response and viral proliferation via viral 2Apro-mediated IRES.

Intestinal microbiota has important effect on severity of hand foot and mouth disease in children

BackgroundThe incidence of hand foot and mouth disease (HFMD) has increased in recent years, making it a very common childhood illness worldwide. The relationship between different enterovirus genotypes and disease severity is not clearly understood. Given that enteroviruses are transmitted through the gastrointestinal tract, we hypothesized that variation in intestinal microorganisms of the host might play a role in the prognosis of HFMD.MethodsWe carried out a meta-transcriptomic-wide association study of fecal samples obtained from a cohort of children (254 patients, 227 tested positive for enterovirus, including 16 patients co-infectied with 2 kinds of enterovirus) with mild and severe HFMD and healthy controls.ResultsWe found there was no significant difference in the amount of each virus type between the mild and severe cases. Genes of enterovirus 71 (EV71) and coxsackievirus A (CV-A) from the severe and mild cases did not show significant clustering. Clostridium sp. L2-50 and Bacteroides stercoris ATCC 43183 were enriched in the guts of children with severe HFMD and KEGG enrichment was found between mild and severe cases.ConclusionsIntestinal microorganisms appear to interact with enterovirus to determine the progression of HFMD. Genes of Bacteroides and Clostridium may be used as predictive markers for a more efficient prognosis and intervention. The enrichment of intestinal bacteria genes with functions may facilitate the development of severe symptoms for HFMD patients.

IFI27 as a potential indicator for severe Enterovirus 71-infected hand foot and mouth disease

The pathogenesis of Enterovirus 71 (EV71)-induced severe hand foot and mouth disease (HFMD) has not yet been clearly established. Further study into the mechanisms underlying host immune responses to EV71 infection and identifying important predictors will be crucial to antiviral treatment and early recognition of severe HFMD. The present study establishes that T help (Th)1 type, Th2 type, and Th17 type cytokine levels in serum of peripheral blood from patients with severe HFMD is higher than in peripheral blood from healthy subjects. The most significant increase occurred as the IL-6. In order to identify the important molecules in peripheral blood mononuclear cells (PBMCs) from severe HFMD patients, we performed transcriptome sequencing analysis of PBMC from severe HFMD patients and compared them to healthy controls. Interferon α-inducible protein 27 (IFI27) and cluster of differentiation 27 (CD27) were found to be the most significant differentially expressed gene. Finally, IFI27 was proved to be present at higher levels in patients with severe HFMD than in patients with mild HFMD. Our results suggest that IFI27 may be an indicator of the severity of cases EV71-induced HFMD.

Genome-wide association study identifies TPH2 variant as a novel locus for severe CV-A6-associated hand, foot, and mouth disease in Han Chinese

BackgroundLittle is known about the association between genetic susceptibility and the severity of hand, foot, and mouth disease (HFMD) infected with coxsackievirus A6 (CV-A6). MethodsThree hundred and sixty-four CV-A6 HFMD patients were enrolled, including 115 severe and 249 mild patients. A genome-wide association study (GWAS) was performed involving eight DNA pools of 115 severe and 115 mild CV-A6 HFMD patients pair-matched by age and gender. Differences in relative allele signal scores of SNPs in Illumina Human OmniZhongHua-8 BeadChips were compared between the two groups. The tag SNPS for potentially functional SNPs or their high linked SNPs were selected for individual genotyping in all 364 patients and assessed for their associations with severe CV-A6 HFMD using multivariable logistic regression analyses. ResultsThe top 30 significant SNPs obtained from pooled DNA GWAS analysis were checked for biological functions and their high linkage disequilibrium (LD) SNPs. Four tag SNPs (rs1558206, rs6927647, rs9375728 and rs10879355) were selected for further individual genotyping in 364 CV-A6 patients. Only SNP rs10879355 was associated with severe CV-A6 HFMD, with CC genotype having a greater risk of severe illness than TT+TC genotypes (OR=2.48, 95%CI: 1.34, 4.56). SNP rs4290270 is in complete LD with rs10879355 in Chinese Han children. ConclusionsThis is the first report that one potentially functional SNP rs4290270 in the TPH2 gene may be associated with the risk of severe CV-A6 HFMD.

Vitamin D receptor gene methylation in patients with hand, foot, and mouth disease caused by enterovirus 71

To evaluate the epigenetic regulation of the VDR gene in enterovirus 71 (EV71)-associated severe hand, foot, and mouth disease (HFMD), a total of 116 patients with EV71-HFMD, including 58 with mild EV71-HFMD and 58 with severe EV71-HFMD, as well as 60 healthy controls, were enrolled in this study. Quantitative real-time PCR was used to measure the relative levels of VDR mRNA expression, and the methylation status of the VDR promoter was assessed using a MethylTarget™ assay. The DNA methylation levels of the VDR promoter in children with EV71-associated severe HFMD were lower than those in the healthy controls and in children with mild HFMD (P < 0.05). Hypomethylation at CpG site 133 and hypermethylation at the CpG 42 sites and 68 downregulated VDR expression. Moreover, the methylation level of VDR could be used for differential diagnosis of mild and severe EV71-associated HFMD (AUC56, 0.73; AUC68, 0.699; AUC42, 0.694; AUC66, 0.693). VDR expression and promoter methylation were associated with the progression of EV71 infection. Determining the VDR promoter status might help clinicians initiate the appropriate strategy for treatment of EV71-associated HFMD.

Effect of heat-clearing and detoxifying Chinese medicines combined with conventional therapy on mild hand, foot, and mouth disease with fever: An individual patient data meta-analysis.

Background:In China, heat-clearing and detoxifying Chinese medicines combined with conventional therapy are commonly applied to treat the mild hand, foot, and mouth disease (HFMD). However, there is lack of solid evidence on the efficacy and safety of such therapies.Methods:We conducted a pooled analysis with individual patient data from 5 strictly randomized controlled clinical trials to assess the efficacy and safety of this combination therapy for mild HFMD. An intention-to-treat analysis was performed. A 2-stage meta-analysis method was adopted to analyze the pooled effect size.Results:In total, 947 patients were included. Compared with conventional therapy, the combination therapy significantly reduced the progression rate of HFMD from mild to severe (odds ratio [OR] 0.43, 95% confidence interval [CI]: 0.22 to 0.83, P = .01). Meanwhile, the healing time of skin rash and oral ulcer in the combination therapy group was significantly shorter than that of conventional therapy. The overall hazard ratio (HR) of healing time of the skin rash or oral ulcer was 1.22 (95%CI: 1.04 to 1.43; P = .02). However, except Jinlianqingre effervescent tablets, the combination therapy cannot shorten the time to fever resolution (HR 1.12, 95%CI: 0.97 to 1.29, P = .14). Because of the heterogeneity, Jinlianqingre effervescent tablets were analyzed separately and the HRs of the time to fever resolution and the healing time of skin rash or oral ulcer were 3.88 (95%CI: 3.19 to 4.72; P < .0001) and 3.79 (95%CI: 2.81 to 5.11; P < .0001), respectively. There were 30 adverse events reported in total; 2 cases were related to Chinese medicines.Conclusion:In conclusion, the heat-clearing and detoxifying Chinese medicines on top of conventional therapy can effectively reduce the progressive rate of mild HFMD and improve healing of skin and oral mucosal lesions. More studies are needed for the time to fever resolution.

Sequence analysis of VP1 and VP4 genes of enterovirus 71 strains isolated from children with severe and mild hand-foot and mouth disease

Objective To analyze and compare VP1 and VP4 genetic characteristics of human enterovirus 71(EV71) isolated from children with severe and mild hand-foot and mouth disease(HFMD). Methods EV71 strains isolated from severe HFMD patients (6 cases) and mild HFMD patients (6 cases) in Taizhou district, Zhejiang province were included during 2016.Total virus RNA was extracted by Viral RNA Mini Extraction Kit, and reverse transcription polymerase chain reaction(RT-PCR) was used to amplify the sequence of the VP1 and VP4 genes of EV71.And then the sequencing results were compared with those of A, B, C genotype reference EV71 strains from GenBank by nucleotide alignment and amino acid alignment analysis. Results There were no statistically significant differences in sex and age between the two groups(χ2=14.51, t=2.82, all P<0.05). The homogeneity between EV71 strains from severe patients and mild patients was 95.8%~99.6% and 99.1%~100.0% for VP1 nucleotide sequences and amino acid sequences, respectively, while 95.0%~99.9% and 99.0%~100.0% for VP4 nucleotide sequences and amino acid sequences, respectively.The twelve EV71 strains isolated from HFMD patients in Taizhou shared the highest identity with EV71-genotype C, especially genotype C4a.In addition, compared with the mild patients, three respective strains from severe HFMD patients showed mutations at the residue 170 in the VP1 protein(V→L), residue 293 in the VP1 protein(A→S) and residue 7 in the VP4 protein(T→A). Conclusion All EV71 strains isolated from severe and mild HFMD patients in Taizhou district share high homology of nucleotide and amino sequence, and all of them belong to subgenogroup C4a.The mutations in the VP1 and VP4 of EV71 might be related to HFMD disease severity. Key words: Hand-foot and mouth disease; Enterovirus 71; Genotype; Disease severity; Mutation

Pathogen Spectrum of Hand, Foot, and Mouth Disease Based on Laboratory Surveillance — China, 2018

Enterovirus 71 (EV-A71) is the main causative pathogen for severe and fatal patients with Hand, Foot, and Mouth Disease (HFMD) in mainland China from 2008 to 2017. Non-EV-A71 and non-CV-A16 (other enterovirus) serotypes were the major causative-serotypes for mild HFMD in years of 2013, 2015, and 2017. In 2018, other enterovirus serotypes replaced EV-A71 for the first time as the major cause of severe HFMD with a proportion of 70.7%. However, at the national level, only a small proportion of the other enterovirus serotypes were further identified as CV-A6 and CV-A10. Further identification of other enterovirus serotypes is highly recommended for provincial CDCs, especially for severe HFMD. Studies contributing to a multivalent vaccine for HFMD should be prioritized.

Value of abnormal HLA-DR expression on CD14+ monocytes in estimating immune function status and clinical prognosis of patients with hand, foot and mouth disease

Objective To investigate the value of abnormal expression of HLA-DR on peripheral blood monocytes in evaluating the immune function status, clinical prognosis and severity of patients with hand, foot and mouth disease (HFMD). Methods From June 2017 to October 2018, 100 cases of mild HFMD, 80 cases of severe HFMD, 32 cases of critical HFMD and 40 healthy children (control group) were recruited in this study. The patients were divided into two groups, lower DR group (DR-L, HLA-DR expression 30%) according to the HLA-DR expression on monocytes. Flow cytometry was used to detect the CD14+ monocytes expressing HLA-DR and the absolute count of lymphocyte subsets. Immunoturbidimetry was used to detect the levels of IgG, IgM and IgA in plasma samples. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the levels of IFN-γ and IL-10 in plasma samples. Pediatric critical illness score (PCIS) and the pediatric risk of mortality Ⅲ (PRISM Ⅲ) were used to estimate the severity of HFMD. Results ① There were significant differences in HLA-DR expression on monocytes among children with mild, severe and critical HFMD (F=47.102, P 0.05). ④ Compared with the DR-N group, the DR-L group showed decreased IFN-γ level and increased IL-10 level in plasma (P<0.05). The ratio of IFN-γ/IL-10 of the DR-L group was lower than that of the DR-N group and control group (P<0.05). HLA-DR expression was negatively correlated with the concentration of IL-10 in plasma (r=-0.704, P<0.05), and positively correlated with the IFN-γ/IL-10 ratio (r=0.773, P<0.05). ⑤ Compared with the DR-N group, the DR-L group showed lower PCIS and higher PRISM Ⅲ. HLA-DR expression was positively correlated with PCIS (r=0.715, P=0.00) and negatively correlated with PRISM Ⅲ (r=-0.610, P=0.00). ⑥ The incidence of pulmonary edema, pulmonary hemorrhage and cardiopulmonary failure and the mortality of HFMD patients in the DR-L group were significantly higher than those in the DR-N group (P<0.05). Conclusions Patients with severe or critical HFMD had cellular immune dysfunction and abnormal HLA-DR expression on CD14+ monocytes. Assessing the expression of HLA-DR on monocytes could be used to evaluate the cellular immunity of patients with severe or critical HFMD. Lower expression of HLA-DR on CD14+ monocytes might be associated with severe HFMD and poor prognosis. Key words: Hand, foot and mouth disease; HLA-DR; Cellular immunity

Genetic characteristics of coxsackievirus A16 isolated in Shenzhen from 2016 to 2017

Objective To investigate the genetic characteristics of VP1 genes carried by coxsackievirus A16 strains isolated from cases of hand foot and mouth disease (HFMD) in Shenzhen during 2016 to 2017. Methods Fecal and anal swab specimens were collected from patients with mild HFMD in four sentinel hospitals and the Institute of Pathogen Biology, Shenzhen Center for Disease Control and Prevention, China during 2016 to 2017. All specimens were tested for CVA16 viral RNA using real-time RT-PCR. The VP1 genes of 51 randomly selected CVA16 strains were amplified by RT-PCR and then sequenced using TaKaRa Biomedical Technology (Dalian). Bioinformatics software, including Mega6.02, BioEdit and DNAStar, was used for comparison and analysis of the VP1 genes. Results CVA16 strains in Shenzhen during 2016 to 2017 mainly belonged to B1a and B1b subtypes as well as an emerging subtype B3. The epidemic of B1b subtype was found in both 2016 (28 strains) and 2017 (19 strains), while the B1a subtype (two strains) was only detected in 2017. Two B3 subtype strains were detected in 2017. The strains of B1b subtype were closely related to the strains isolated in Shanghai (JQ314149), Wenzhou (KP289416) and Beijing (KU254598), while the B1a subtype strains were closely related to the strains isolated in Kunming (JQ316639) and Tailand (GQ184139). The B3 subtype strain was an emerging CVA16 epidemic strain in mainland China. Further comparison of the CVA16 epidemic strains in Shenzhen area during 2016 to 2017 with the CVA16 strains causing severe neurological symptoms showed that two amino acid mutations (S14N and M23L) were found in VP1 protein. Conclusions The epidemic strains of CVA16 were B1b subtype in Shenzhen area in 2016. However, B1a, B1b and the emerging B3 subtype strains were prevalent in 2017. Compared with the CVA16 strains causing severe neurological symptoms, the CVA16 strains circulating in Shenzhen during 2016 to 2017 carried two amino acid mutations inVP1 protein. Key words: Coxsackievirus A16; Hand, foot and mouth disease; Phylogenetic analysis

Global cytokine/chemokine profile identifies potential progression prediction indicators in hand-foot-and-mouth disease patients with Enterovirus A71 infections

ObjectiveNew clinical indicators are urgently needed for predicting the progression and complications of hand-foot-and-mouth disease (HFMD) caused by EV-A71 infections. Materials and methodsSerum specimens from 132 EV-A71 HFMD patients and 73 health children were collected during 2012–2014 in Shenzhen, China. The specific cytokines/chemokines were detected with a 274-human cytokine antibody array, followed by a 38-inflammation cytokine array, and further validated by ELISA. ResultsCytokines varied in different severity of EV-A71 HFMD patients. The ROC curve analysis revealed 5 serum cytokines with high sensitivity and specificity in predicting the disease progression. Eotaxin, IL-8 and IP-10 have showed high AUC values (0.90–0.95) for discrimination between the health controls and the patient group. The three cytokines showed high sensitivity (80–91%) and specificity (88–95%). MMP-8 had a high sensitivity and specificity to predict mild HFMD (100%, 100%). IL-1b and leptin discriminated the severe/critical group from the mild group (79% and 69% in sensitivity, 73% and 63% in specificity). ConclusionsEotaxin, IP-10 and IL-8 could be potential indicators for predicting HFMD progression with EV-A71 infection. MMP-8 is a specific indicator for mild infection, while IL-1b and leptin display potential for predicting the severity and criticality.

Surveillance for severe hand, foot, and mouth disease from 2009 to 2015 in Jiangsu province: epidemiology, etiology, and disease burden

BackgroundSevere hand, foot, and mouth disease (HFMD) is a common childhood illness caused by various enteroviruses. The disease has imposed increased burden on children younger than 5 years old. We aimed to determine the epidemiology, CNS complication, and etiology among severe HFMD patients, in Jiangsu, China.MethodsEpidemiological, clinical, and laboratory data of severe HFMD cases were extracted from 2009 to 2015. The CNS complication, annually severe illness rates, mortality rates, severity-PICU admission rates, severity-hospitalization rates, and so on were analyzed to assess the disease burden of severe HFMD. All analyses were stratified by time, region, population, CNS involvement and serotypes. The VP1 gene from EV-A71, CV-A16, CV-A6, CV-A10 and other enteroviruses isolates was amplified. Phylogenetic analysis was performed using MEGA5.0.ResultsSeven thousand nine hundred ninety-four severe HFMD cases were reported, of them, 7224 cases were inpatients, 611 were PICU inpatients, and 68 were fatal. The average severe illness rate, mortality rate, severity−fatality rate, severity-PICU admission rate, and severity-hospitalization rate were 14.54, 0.12,8506, 76,430, and 903,700 per 1 million, respectively. The severe illness rate was the highest in the 12–23 months age group, and the greatest mortality rate was in the 6–11 months age group. Geographical difference in severe illness rate and mortality were found. Patients infected with EV-A71 were at a higher proportion in different CNS involvement even death. EV-A71, CV-A16 and other enteroviruses accounted for 79.14, 6.49, and 14.47%, respectively. A total of 14 non-EV-A71/ CV-A16 genotypes including CV-A2, CV-A4, CV-A 6, CV-A9, CV-A10, CV-B1, CV-B2, CV-B3, CV-B4, CV-B5, E-6, E-7, E-18, and EV-C96 were identified. Phylogentic analyses demonstrated that EV-A71 strains belonged to subgenotype C4a, while CV-A16 strains belonged to sub-genotype B1a and sub-genotype B1b of genotype B1. CV-A6 strains were assigned to genogroup F, and CV-A10 strains belonged to genogroup D.ConclusionsFuture mitigation policies should take into account the age, region heterogeneities, CNS conditions and serotype of disease. Additional a more rigorous study between the mild and severe HFMD should be warranted to elucidate the difference epidemiology, pathogen spectrum and immunity patterns and to optimize interventions in the following study.

Hospitalization burden of hand, foot and mouth disease in Anhua county of Hunan province, 2013-2016

Objective: To estimate the serotype and age-specific hospitalization burden associated with hand, foot and mouth disease (HFMD) in Anhua county of Hunan province, between October 2013 and September 2016. Methods: We collected hospitalization records of HFMD patients from 6 virological surveillance hospitals, and reimbursement records through new rural cooperative medical system from 23 township health centers to estimate the age-specific hospitalization burden of HFMD in Anhua. Combined with the results of virological surveillance, the serotype-specific hospitalization burden of HFMD in Anhua, was estimated. Results: During the three years, it was estimated that 3 541 clinical diagnosed HFMD cases, including 3 146 laboratory-confirmed HFMD cases, were hospitalized in Anhua, but only one was diaguosed as being severe. The estimated average hospitalization rate was 723/100 000(95%CI: 699/100 000-747/100 000) for clinical diagnosed HFMD and 642/100 000 (95%CI: 620/100 000-665/100 000) for laboratory-confirmed HFMD between October 2013 and September 2016. The cases caused by Cox A16 (208/100 000) and Cox A6 (202/100 000) had higher hospitalization rates compared with the cases caused by EV71 (130/100 000), Cox A10 (38/100 000) and other enterovirus (64/100 000), and the difference was statistically significant (P<0.001). HFMD-associated hospitalization rates peaked in children aged 1 year (3 845/100 000), and then decreased with age. Compared with the hospitalized HFMD caused by EV71 and Cox A16, Cox A6-associated hospitalizations mainly occurred in younger age groups (P<0.001). Conclusion: Our study revealed a substantial hospitalization burden associated with mild HFMD caused by EV71, Cox A16, Cox A6 and Cox A10, especially in young children, in Anhua.

Study progress in capsid protein VP1 of enterovirus 71

Human enterovirus 71 (EV71) is one of the major causative agent of hand, foot and mouth disease (HFMD) in infant.Clinical studies find that EV71 infection can cause a variety of clinical manifestations, from mild HFMD to fatal neurogenic pulmonary edema and even death, but the reasons remain unclear.The capsid protein VP1 of EV71 plays a key role in the processes of viral recognizing, binding and entering into the targeted cells and viral particles assembling.VP1 variation is a major determinant to EV71 fitness and immunogenicity.This study reviews the research progress of the structure, functions and associated antiviral vaccines and drugs of VP1, which further provides a theoretical basis for developing new and more effective antiviral vaccine and drugs. Key words: Enterovirus 71; Hand, foot and mouth disease; Capsid protein VP1

Detection and significance of calcitonin gene-related peptide in children with enterovirus 71 infected hand foot and mouth disease

Objective To detect the plasma calcitonin gene-related peptide (CGRP) in children with enterovirus 71(EV71) infected hand foot and mouth disease(HFMD), and explore the relationship between CGRP and the severity of EV71 infected HFMD. Methods Two hundred children with EV71 infected HFMD in Xi′an Children′s Hospital from January 2017 to December 2017 were selected as the research group, and 50 healthy children were selected as control group in the same period.According to the severity of the disease, the research group was divided into the mild group (n=142) and the severe group (n=58). The level of plasma CGRP was detected by ELISA. Results In acute stage, the level of CGRP in children with EV71 infected HFMD was lower than that in control group, and the difference was statistically significant (t=4.235, P<0.001). The level of CGRP in acute stage in severe group[(29.90±5.10)pg/ml] was significantly lower than that of the mild group[(35.51±5.48)pg/ml], and the difference was statistically significant (t=6.615, P=0.001). The level of CGRP in mild group[(35.51±5.48)pg/ml] was slightly lower than that of the control group[(36.63±5.65)pg/ml], but the difference was insignificant (t=1.120, P=0.086). In recovery stage, the level of CGRP in the severe group was obviously higher than that in the acute stage(t=5.924, P=0.003). According to the ROC curve of CGRP in mild and severe EV71 infected HFMD, the critical value of CGRP in mild and severe HFMD was 28.12 pg/ml, and the sensitivity was 80.0% and the specificity was 50.0%. Conclusion The CGRP is associated with the progression of EV71 HFMD, and when CGRP is lower than 28.12 pg/ml, suggesting the possibility of severe HFMD.The decrease of plasma CGRP may be a risk factor for the progression of EV71 infected HFMD. Key words: Hand foot and mouth disease; Enterovirus 71; Calcitonin gene-related peptide

Epidemiological characteristics of Coxsackie virus A16 caused hand foot and mouth disease cases in Guangdong province, 2012-2016

Objective: To analyze the epidemiological characteristics of hand foot and mouth disease (HFMD) cases caused by Coxsackie virus A16 (Cox A16) in Guangdong province from 2012 to 2016. Methods: The data of mild HFMD cases caused by Cox A16 were collected from 8 sentinel hospitals in 8 prefecture-level cities in Guangdong to estimate Cox A16 infection status and its population and time distribution characteristics. Results: (1) The highest estimated incidence of Cox A16 infection was in 2014 (113.0/100 000), followed by 2016 (86.4/100 000) and 2012 (79.1/100 000), while the estimated incidence was lower in 2015 (29.0/100 000) and 2013 (28.8/100 000). (2) Cox A16 was confirmed to be the predominant pathogen causing HFMD outbreaks (54.6%, 89/163). The number of outbreaks in the year with high incidence (28 outbreaks) was 11.2 times higher than that in the year with low incidence (2.5 outbreaks). (3) Across all age groups, the annual estimated incidence of Cox A16 infection decreased with age (trend χ(2)=853 905.63, P<0.01). The incidence was highest in age group 1 year (1 449.2/100 000), followed by that in age group 3 years (1 097.0/100 000), in age group 2 years (1 083.5/100 000), in age group 4 years (687.8/100 000) and in age group 0 year (604.9/100 000). Among the age groups <12 months, the estimated incidence increased with age (trend χ(2)=5 541.77, P<0.01), which was highest in age group 11-months (2 105.1/100 000), followed by that in age groups 10-months (1 448.6/100 000), 9-months (938.3/100 000), 8-months (703.3/100 000) and 6-months (664.6/100 000). (4) The annual incidence peak was during May (143.9/100 000)-June (131.5/100 000). Conclusion: The prevalence of Cox A16 infection differed with year in Guangdong during 2012-2016. When the incidence of Cox A16 infection was high, more outbreaks occurred. The prevalence occurred mainly in nurseries and kindergartens from May to June each year. Children aged 0-4 years were the high risk group for Cox A16 infection, children aged 6-11 months were at high risk for Cox A16 infection.