Severe Hand, Foot And Mouth Disease Research Articles

Inhibition of ESCRT-independent extracellular vesicles biogenesis suppresses enterovirus 71 replication and pathogenesis in mice

Enterovirus 71 (EV71) causes hand-foot-and-mouth disease (HFMD), neurological complications, and even fatalities in infants. Clinically, the increase of extracellular vesicles (EVs) in EV71 patients' serum was highly associated with the severity of HFMD. EV71 boosts EVs biogenesis in an endosomal sorting complex required for transport (ESCRT)-dependent manner to facilitate viral replication. Yet, the impact of EVs-derived from ESCRT-independent pathway on EV71 replication and pathogenesis is highly concerned. Here, we assessed the effects of EV71-induced EVs from ESCRT-independent pathway on viral replication and pathogenesis by GW4869, a neutral sphingomyelinase inhibitor. Detailly, in EV71-infected mice, blockade of the biogenesis of tissue-derived EVs in the presence of GW4869 restored body weight loss, attenuated clinical scores, and improved survival rates. Furthermore, GW4869 dampens EVs biogenesis to reduce viral load and pathogenesis in multiple tissues of EV71-infected mice. Consistently, GW4869 treatment in a human intestinal epithelial HT29 cells decreased the biogenesis of EVs, in which the progeny EV71 particle was cloaked, leading to the reduction of viral infection and replication. Collectively, GW4869 inhibits EV71-induced EVs in an ESCRT-independent pathway and ultimately suppresses EV71 replication and pathogenesis. Our study provides a novel strategy for the development of therapeutic agents in the treatment for EV71-associated HFMD.

Proteomic and phosphoproteomic analysis of responses to enterovirus A71 infection reveals novel targets for antiviral and viral replication

Hand, foot, and mouth disease (HFMD) is a common infectious disease in infants and children, especially those under five years of age. EV-A71 is a common pathogen that causes HFMD and the primary pathogen leading to severe or fatal HFMD, which is characterized by neurological complications. However, the underlying mechanisms of EV-A71 pathogenesis remain largely unknown. In this report, we used proteomic and phosphorylated proteomic methods to characterize the proteome and phosphoproteome profiles of EV-A71-infected human neuroblastoma SK-N-SH cells. More than 7744 host proteins and 10069 phosphorylation modification sites were successfully quantified. Among them, 974 proteins and 3648 phosphorylation modification sites were regulated significantly during EV-A71 infection. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis revealed that EV-A71 altered cell biological processes, including protein synthesis, RNA splicing and metabolism in SK-N-SH cells. Notably, based on the prediction of upregulated kinases during EV-A71 infection, we identified specific kinase inhibitors approved by the FDA, with ceralasertib, bosutinib, flavin mononucleotide, minocycline, pimasertib and acetylcysteine inhibiting EV-A71 infection. Finally, EV-A71 proteins were found to be phosphorylated during infection, with one site (S184 on 3D polymerase) observed to be crucial for viral replication because a S184A mutation knocked out viral replication. The results improve our understanding of the host response to EV-A71 infection of neuroblastoma cells and provide potential targets for developing anti-EV-A71 strategies.

Abundant Neutrophil-Initiated Acute Myocardial Injury Following Coxsackievirus A6 Infection.

Coxsackievirus A6 (CVA6) is currently considered as a predominant pathogen of hand, foot, and mouth disease (HFMD), and is occasionally linked to myocardial injury. We first established a mouse model of CVA6-induced myocardial injury. Next, we analyzed the immune cell phenotypes CVA6-infected mice hearts by fluorescence-activated cell sorting, and found that CVA6 led to massive neutrophils infiltration, suggesting their potential link with the occurrence of myocardial injury. We further used either αGr-1 or αLy6G antibody to deplete neutrophils, and found that neutrophil-depleted animals showed decreased cardiac enzymes, lower degree of pathology in hearts, and reduced inflammatory cytokine production compared to isotype controls. Finally, we confirmed the involvement of neutrophils in myocardial injury of clinical patients with severe HFMD. Our study suggests that excessive neutrophils contribute to myocardial injury caused by CVA6 infection, which provides new insights into myocardial injury during the development of HFMD severity and the outcome of immune cell-mediated therapies.

EV-A71 Infections: Life Cycle and Prevention Strategies

Hand, Foot, and Mouth disease (HFMD) is a highly contagious disease caused by enteroviruses, which is common in Asia-Pacific countries, including China, Hong Kong, Korea, Malaysia, Singapore, Thailand, and Vietnam. Children are more susceptible to infection, especially newborns and children under-5-year-old. HFMD may cause severe symptoms like encephalitis, meningitis, myocarditis, and acute pulmonary edema which can lead to death if no early detection or prompt treating is carried out. Various professional researches indicated the main causes of HFMD were enteroviruses in the Picornaviridae family, particularly Coxsackievirus A16 (CVA16) and Enterovirus 71 (EV71). Both factors cause the same beginning symptoms, but while CVA16’s are mild and can be self-recuperated after 10-14 days, EV71’s are more dangerous and can lead to neurological, cardiovascular, and respiratory complications, causing death or permanent brain damages.
 Preventing EV71 infection is extremely necessary as it not only decreases severe HFMD but also interferes with the virus speciation through homologous recombination to reduce the complexity of epidemic situation in the world. Therefore, synthesizing information about the virus life cycle and prevention strategies against EV71 is crucial and essential to provide an overview about the potential methods for vaccines and medicines development or food supplement manufactures which contributes to preventing EV71 infection.

The comparisons of procalcitonin and age between mild and severe Hand, foot, and mouth disease.

Hand, foot, and mouth disease (HFMD) is an epidemic infectious disease in children, usually associated with fever, mouth lesions, and limb rashes. Although benign and self-limiting, it can be dangerous or even fatal in rare cases. Early identification of severe cases is crucial to ensure optimal care. Procalcitonin (PCT) is an early marker for predicting sepsis. Therefore, in this study, we aimed to investigate the significance of PCT levels, age, lymphocyte subsets, N-terminal pro-brain natriuretic peptide (BNP) in the early diagnosis of severe HFMD. Using strict inclusion and exclusion criteria, we retrospectively enrolled 183 children with HFMD between January 2020 and August 2021 and divided them into mild (76 cases) and severe (107 cases) groups according to their condition. Data on the patients' PCT levels, lymphocyte subsets, and clinical characteristics at admission were evaluated and compared using the Student's t-test and χ2 test. We found that compared with mild disease forms, the severe disease forms were associated with higher blood PCT levels (P=0.001) and lower ages of onset (P<0.001). The percentages of lymphocyte subsets, including suppressor T cells (CD3+CD8+), T lymphocytes (CD3+), T helper cells (CD3+CD4+), natural killer cells (CD16+56+), and B lymphocytes (CD19+), were identical between the two disease forms in patients under 3 years of age. Age and blood PCT levels play a vital role in the early identification of severe HFMD.

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.

Coxsackievirus B: The important agent of hand, foot, and mouth disease.

Hand, foot, and mouth disease (HFMD) is a common pediatric infectious illness caused by enteroviruses (EVs). EV-A serotypes are the main pathogens associated with HFMD. In this study, 213 stool samples from 213 children with severe HFMD in Yunnan, China in 2013, 2015, and 2016 were further analyzed retrospectively for EV-B infection. A total of 70.0% of the specimens tested positive for EV.20 EV serotypes were detected. The predominant serotype was enterovirus A71 (EV-A71, 27.7%), followed by coxsackievirus B4 (CV-B4, 16.4%), CV-A16 (9.9%), CV-B5 (6.6%), and Echovirus 9 (E-9,4.7%). EV-A and EV-B accounted for 45.1% and 41.3%, respectively. Among the positive specimens, 28.6% were CV-Bs. Co-infection was present in 19.3% of these cases. In the study, CV-B5 and the majority of CV-B4 isolates belonged to genotypes VI and C3, respectively. This result indicates that EV-B, especially CV-Bs, might be the important agents associated with HFMD and this knowledge will contribute to the prevention and treatment of the disease.

Suppression of innate and acquired immunity in severe hand foot and mouth disease caused by EV71 infections in children

Hand, foot, and mouth disease (HFMD) is a common children infectious disease caused by human enteroviruses. Most of the cases have minimal symptoms, however, some patients may develop serious neurological, cardiac complications, or even death. The pathological mechanism leading to severe HFMD is not clearly understood, and the immunological status of the individual patient may play an important role. Transcriptomes of peripheral blood mononuclear cells from EV71-infected patients (n=45) and healthy controls (n=36) were examined. Immune pathways were up-regulated in patients with mild disease symptoms (n=11, M) compared to the healthy controls (n=36, H), demonstrating an effective anti-viral response upon EV71 infection. However, in patients with severe symptoms (n=23, S) as well as severe patients following treatment (n=11, A), their innate and acquired immune pathways were down-regulated, indicating a global immunity suppression. Such immune suppression characteristics could thus provide an opportunity for early EV-71 infection prognosis prediction. Based on our cohort, an SVM model using RNA-seq expression levels of five genes (MCL1, ZBTB37, PLEKHM1P, IFNAR2 and YEATS2) was developed and achieved a high ROC-AUC (91·3%) in predicting severe HFMD. Meanwhile, qPCR fold-changes method was performed based three genes (MCL1, IFNAR2 and YEATS2) on additional cohort. This qPCR method achieved a ROC-AUC of 78.6% in predicting severe HFMD, which the patients could be distinguished in 2-3h. Therefore, our models demonstrate the possibility of HFMD severity prediction based on the selected biomarkers that predict severe HFMD effectively.

Clinical Efficacy of Early Administration of Human Immunoglobulin on Children with Severe Hand-foot-mouth Disease.

The objective of this study was to investigate the clinical effect of early administration of human immunoglobulin in children with severe hand, foot and mouth disease (HFMD) and its influence on serum c-reactive protein (CRP), creatine kinase (CK), and creatine kinase isoenzyme (CK-MB). One hundred and forty children with severe HFMD were randomly divided into Group A (n=70) and Group B (n=70) according to the random number table method. Group A was treated with routine treatment. Group B was treated with routine treatment, and an early intravenous injection of human immunoglobulin. Serum CRP, CK, and CK-MB in Group B were lower than those in Group A after treatment (all p <0.001). The total clinical effective rate of Group B was 92.9%, which was higher than that of Group A (80.0%, p=0.026). Early administration of human immunoglobulin may reduce the levels of serum markers CRP, CK, and CK-MB in children with severe HFMD. Key Words: Human immunoglobulin, Children, HFMD (Hand, foot and mouth disease).

The Need for a Vaccine Against Hand, Foot, and Mouth Disease in Malaysia

Hand, foot, and mouth disease (HFMD) is a contagious viral infection, which commonly affects young children under five years of age (Yu et al., 2019). HFMD is caused by serotypes of the Enterovirus A species, particularly enterovirus 71 (EV71) and coxsackievirus A16 (CVA16), in the genus Enterovirus (Takahashi et al., 2016). Symptoms of HFMD usually include fever, sore throat and maculopapular or vesicular rashes on hands, feet and mouth, which resolve spontaneously. On the other hand, severe HFMD, which is often associated with EV71 infection, can lead to life-threatening cardiopulmonary and neurologic complications (Xu et al., 2015).

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

Pulmonary edema that comes on suddenly is the leading cause of mortality in hand-foot-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.

Hand-Foot-and-Mouth Disease-Associated Enterovirus and the Development of Multivalent HFMD Vaccines

Hand-foot-and-mouth disease (HFMD) is an infectious disease of children caused by more than 20 types of enteroviruses, with most cases recovering spontaneously within approximately one week. Severe HFMD in individual children develops rapidly, leading to death, and is associated with other complications such as viral myocarditis and type I diabetes mellitus. The approval and marketing of three inactivated EV-A71 vaccines in China in 2016 have provided a powerful tool to curb the HFMD epidemic but are limited in cross-protecting against other HFMD-associated enteroviruses. This review focuses on the epidemiological analysis of HFMD-associated enteroviruses since the inactivated EV-A71 vaccine has been marketed, collates the progress in the development of multivalent enteroviruses vaccines in different technical routes reported in recent studies, and discusses issues that need to be investigated for safe and effective HFMD multivalent vaccines.

Peripheral Blood Brain Microvascular Endothelial Cells As a Novel Marker in the Detection of Blood-Brain Barrier Injury in EV71 Severe Encephalopathy

Enterovirus 71 (EV71), the main causative agent of hand, foot, and mouth disease (HFMD), is also considered a neuroinvasive virus. EV71 causes sporadic epidemics and outbreaks with more than 13 million people worldwide, predominantly occurring in the Asia-Pacific, and elicited more than 3000 deaths, including 2457 deaths in China from 2008 to 2014. However, there are no available noninvasive biomarkers in peripheral blood for neuro-EV71 infection and optimizing therapeutic options. Brain microvascular endothelial cells (BMECs) are a special type of cells that constitute the blood-brain barrier (BBB), which dynamically shed associated with BBB injury. A mouse model of BBB injury induced by microbial and non-microbial agents was performed, using magnetic bead extraction (MBE) to identify circulating endothelial cells (CECs,CD146+/DAPI+), circulating BMECs (cBMECs, CD146+/S100B+/DAPI+) and endothelial progenitor cells (EPCs, CD146+/CD133+/DAPI+), which are identified based on their S100B (brain marker)+/ CD146 (EC marker) +/CD133+ (PC marker) /DAPI (nuclei)+phenotype with significantly higher levels in the experimental group than in the control group. These results indicate that it is feasible to evaluate BBB injury by quantifying BMECs and EPCs with MBE. The whole cell proteins were prepared by us from EV71 infected BMECs, and among the samples infected with EV71, MALDI TOF / TOF mass spectrometry successfully identified 28 proteins, 4 proteins including vimentin (VIM) were significantly up-regulated, 6 proteins were down regulated, and the other 18 proteins were expressed to various degrees at different incubation times. Furthermore, we performed a glioblastoma model with low vimentin expression and found that EV71 may activate the NLRP3 inflammasome via the VIM-ERK-NFκB pathway during EV71 CNS infection, which promotes caspase-1 activation and the inflammatory factor IL-1β release, causing an inflammatory response that ultimately leads to BBB/CNS disorders and neuronal death. The same results for those experiments with neonatal mice of EV71 infection were also observed. The results showed that cBMECs may be used as potential cell-based biomarkers for indexing of BBB injury. Then peripheral blood samples were obtained from the children with severe HFMD infection from a medical center for women and children, and examination showed that the counts of cBMECs were significantly higher in severe HFMD children than in the control children, indicating that the detection of cBMECs may be used for the early diagnosis of severe HFMD. In addition, Mfsd2 antibody specifically on BMECs were attached to magnetic beads and used directly to isolate BMECs from blood, followed by immunofluorescence staining with CD146 antibody, and the two corresponding fluorophores, CD146 and DPAI, appeared microscopically to preliminarily determine BMECs. The use of mfsd2 antibody to isolate BMECs both simplifies experimental procedures and improves detection precision and efficiency. In conclusion, in this study, cBMECs are demonstrated to serve as cellular biomarkers for BBB injury caused by microbial and non-microbial factors. Proteomics combined with mechanistic studies indicate that cBMECs are important indicators of BBB/CNS disorders in severe HFMD. Ultimately, this study successfully established a method to detect EV71 severe encephalopathy in human peripheral blood, which is safer and noninvasive than conventional cerebrospinal fluid puncture and pathological collection methods, causes minimal physical trauma to patients, and is more intuitive and accurate than conventional imaging examination. Therefore, this assay has good clinical application and may provide a new means for noninvasive and visual detection of EV71 severe encephalopathy. However, further cases were also collected to verify the accuracy of peripheral blood BMEC count for diagnosing severe HFMD, while establishing suitable cut-off values for application in early diagnosis. (Acknowledgements: Corresponding author: Hong Cao, gzhcao@smu.edu.cn; The Basic Research Project of Key Laboratory of Guangzhou, China (No.202102100001) and Grant from School of Public Health of Southern Medical University, China, No.GW202222 to H.C.)

Laboratory Indicators for Identifying Hand, Foot, and Mouth Disease Severity: A Systematic Review and Meta-Analysis.

The purpose of this study is to study laboratory indicators for the identification of hand, foot, and mouth disease (HFMD) severity. We searched PubMed, Embase, and the Web of Science for literature that was published before May 2022. The main results are presented as forest plots. Subgroup analyses, sensitivity analyses, and publication bias were also performed. Our study indicated that white blood cells (WBC) (95%CI: 0.205-0.778), blood glucose (95%CI: 0.505-0.778), lymphocytes (95%CI: 0.072-0.239), creatinine (95%CI: 0.024-0.228), interleukin (IL)-2 (95%CI: 0.192-1.642), IL-6 (95%CI: 0.289-0.776), IL-8 (95%CI: 0.499-0.867), IL-10 (95%CI: 0.226-0.930), interferon-γ (IFN-γ) (95%CI: 0.193-2.584), tumor necrosis factor-α (TNF-α) (95%CI: 1.078-2.715), and creatine kinase MB isoenzyme (CK-MB) (95%CI: 0.571-1.459) were associated with an increased risk of HFMD severity, and the results of the sensitivity analysis of these indicators were stable and free of publication bias. Our results suggest that various deleterious immune and metabolic changes can increase the risk of HFMD severity, which can provide a basis for predicting the prognosis and useful evidence for clinicians to manage patients efficiently.

Enterovirus 71 non-structural protein 3A hijacks vacuolar protein sorting 25 to boost exosome biogenesis to facilitate viral replication.

Human enterovirus 71 (EV71) is one of the major agents of the hand, foot, and mouth disease (HFMD), and occasionally causes severe neurological complications. There is clinical evidence that EV71 infection increases the exosomes in the serum of severe HFMD patients, suggesting a role of exosomes in EV71 pathogenesis. However, the relationship between exosomes and EV71 replication remains elusive. In this study, we initially found that EV71 infection elevated exosome biogenesis in the cultured cells. Among EV71 non-structural proteins, we identified EV71 3A, but not 3B, constitutively promoted exosome secretion. In detail, EV71 3A protein interacted with vacuolar protein sorting 25 (VPS25), while knock-down of VPS25 reduced EV71 3A protein- and EV71-induced exosome production. Further studies revealed VPS25 located on exosomes and its expression correlated to the exosome production. During EV71 infection, knock-down of VPS25 decreased exosome biogenesis to attenuate viral replication. Consistently, GW4869, an exosome inhibitor, exerted an obviously antiviral activity against EV71 replication companied with the decrease of exosome secretion or formation. These findings suggest the binding of EV71 3A and VPS25 benefited exosome biogenesis, thereby boosting viral replication. This study uncovers a novel mechanism underlying EV71-mediated exosomes in the regulation of viral replication, which provides potential anti-viral strategies against the EV71 infection and transmission in HFMD.

Trend of hand, foot, and mouth disease from 2010 to 2021 and estimation of the reduction in enterovirus 71 infection after vaccine use in Zhejiang Province, China.

BackgroundZhejiang, ranked in the top three in HFMD (hand, foot, and mouth disease) incidence, is located in the Yangtze River Delta region of southeast China. Since 2016, the EV71 vaccine has been promoted in Zhejiang Province. This study aimed to investigate the trend and seasonal variation characteristics of HFMD from 2010 to 2021 and estimate the reduction in enterovirus 71 infection after vaccine use.MethodsThe data on HFMD cases in Zhejiang Province from January 2010 to December 2021 were obtained from this network system. Individual information on cases and deaths was imported, and surveillance information, including demographic characteristics and temporal distributions, was computed by the system. The Joinpoint regression model was used to describe continuous changes in the incidence trend. The BSTS (Bayesian structural time-series models) model was used to estimate the monthly number of cases from 2017 to 2021 based on the observed monthly incidence during 2010–2016 by accounting for seasonality and long-term trends. The seasonal variation characteristics of HFMD pathogens were detected by wavelet analysis.ResultsFrom 2010 to 2021, the annual incidence rate fluctuated between 98.81 cases per 100,000 in 2020 and 435.63 cases per 100,000 in 2018, and 1711 severe HFMD cases and 106 fatal cases were reported in Zhejiang Province, China. The annual percent change (APC) in EV71 cases was -30.72% (95% CI: -45.10 to -12.50) from 2016 to 2021. The wavelet transform of total incidence and number of cases of the three pathogens all showed significant periodicity on the 1-year scale. The average 2-year scale periodicity was significant for the total incidence, EV71 cases and Cox A16 cases, but the other enterovirus cases showed significant periodicity on the 30-month scale. The 6-month scale periodicity was significant for the total incidence, EV71 case and Cox A16 case but not for the other enteroviruses case. The relative error percentage of the performance of the BSTS model was 0.3%. The estimated number of cases from 2017 to 2021 after the EV-A71 vaccines were used was 9422, and the reduction in the number of cases infected with the EV71 virus was 73.43% compared to 70.80% when the impact of the COVID-19 epidemic in 2020 was excluded.ConclusionsSince 2010, the incidence of EV71 infections has shown an obvious downward trend. All types of viruses showed significant periodicity on the 1-year scale. The periodicity of the biennial peak is mainly related to EV71 and Cox A16 before 2017 and other enteroviruses since 2018. The half-year peak cycle of HFMD was mainly caused by EV71 and Cox A6 infection. The expected incidence will be 2.76 times(include the cases of 2020) and 2.43 times(exclude the cases of 2020) higher than the actual value assuming that the measures of vaccination are not taken. EV71 vaccines are very effective and should be administered in the age window between 5 months and 5 years.

Effect of enterovirus 71 vaccination on the epidemiological characteristics and etiology in hospitalized children with hand-foot-and-mouth disease: A retrospective study from a tertiary children's hospital.

Enterovirus 71 (EV71) vaccine for hand-foot-and-mouth disease (HFMD) prevention has been available for several years. However, as a new vaccine, the impact of EV71 vaccination on the epidemiology and etiology of HFMD is currently unclear. The purpose of this study was to compare and analyze the changes of epidemiological characteristics and etiology of HFMD patients after the introduction of EV71 vaccine. The data of hospitalized children with HFMD from 2014 to 2020 were collected from the case record department of a tertiary children hospital of Anhui Province. The changes of epidemiological characteristics, time distribution, disease severity and enterovirus serotypes in hospitalized children were analyzed. A total of 7373 cases of HFMD were reported during 2014 to 2020, including 634 (8.6%) severe cases. The number of cases reached the peak in 2016 (n = 1783) and decreased gradually after EV71 vaccination. The results of etiological test showed the positive rate was 80.5%, in which EV71 accounted for 1599 (21.7%) and CV-A16 accounted for 1028 (13.9%) respectively. The number of patients showed a bimodal distribution throughout the year, which were April to June and October to November. The age distribution changed significantly following the introduction of EV71 vaccine. The proportion of 1-year-old group of post-vaccination was significantly higher than that of pre-vaccination (61.9% vs 50.8%, P < .001). The proportion of HFMD caused by EV71 and severe cases decreased significantly after the vaccination (P < .001 for both). While the comparison of epidemiological characteristics and enterovirus serotypes between unvaccinated and vaccinated cases during 2017 to 2020 showed no significant difference. The dominant enterovirus serotypes of hospitalized HFMD changed significantly after the introduction of EV71 vaccine. The proportion of severe cases decreased significantly after the vaccination, but EV71 was still a major pathogen in patients with severe HFMD. More age-appropriate children are recommended to get vaccinated to establish stronger herd immunity in the population.

A retrospective analysis on incidence of hand, foot, and mouth disease in Kota Kinabalu, district of Sabah Malaysia

Malaysia is one of the most affected countries by hand, foot, and mouth disease (HFMD) outbreak. Sabah, as a state of Malaysia, has an incidence of 2,200 HFMD cases in 2018. Kota Kinabalu hits the highest records of HFMD cases compared to other districts. Given the marked increase in HFMD cases, HFMD become a public health concern which is associated with a substantial economic and social burden. From the perspective of public health, it is important to study the disease patterns and associated risk factors. This paper describes the incidence of HFMD and potential demographic risk factors in this understudied Kota Kinabalu District. A total of 3,327 HFMD cases from year 2013 to 2018 were obtained from the Kota Kinabalu Health Office. Cases were classified according to year of incidence, patient’s gender, age, and ethnic. Incidence of HFMD and percentage of severe HFMD were calculated for each category. Odd ratio of severe HFMD for each category was assessed with logistic regression model. Chi-square tests were implemented to identify the association between the case characteristics and severe HFMD. This study found that male and Sabah indigenous group are predominant in HFMD incidence. Chi-square test indicated that severe HFMD is significantly associated with patient’s age and ethnicity.&lt;br /&gt;&lt;br /&gt;

Epidemiological characteristics, routine laboratory diagnosis, clinical signs and risk factors for hand, -foot -and -mouth disease: A systematic review and meta-analysis.

BackgroundFor the past few years, only a few monovalent EV71 vaccines have been developed, while other enterovirus vaccines are in short supply. We conducted a quantitative meta-analysis to explore the epidemiological characteristics, routine laboratory diagnosis, clinical signs and risk factors for hand, foot and mouth disease (HFMD).MethodsPubMed, Embase and the Web of Science were searched for eligible reports published before April 16, 2021, with no publication time or language restrictions. The primary outcome was the odds ratio of the epidemiological characteristics, routine laboratory diagnosis, and clinical signs associated with HFMD severity and death.ResultsAfter screening 10522 records, we included 32 articles comprising 781903 cases of hand, foot and mouth disease. Patients with severe illness developed some clinical signs (hypersomnia (OR = 21.97, 95% CI: 4.13 to 116.74), convulsion (OR = 16.18, 95% CI: 5.30 to 49.39), limb shaking (OR = 47.96, 95% CI: 15.17 to 151.67), and breathlessness (OR = 7.48, 95% CI: 1.90 to 29.40)) and had some changes in laboratory parameters (interleukin-6 levels standardized mean difference (SMD) = 1.57, 95%CI: 0.55 to 2.60), an increased neutrophils ratio (SMD = 0.55, 95%CI: 0.17 to 0.93), cluster of differentiation 4 (CD4+) (SMD = -1.38, 95%CI: -2.33 to -0.43) and a reduced lymphocytes ratio (SMD = -0.48, 95%CI: -0.93 to -0.33)) compared with patients with mild illness. The risk factors for death included cyanosis (OR = 5.82, 95% CI: 2.29 to 14.81), a fast heart rate (OR = 3.22, 95% CI: 1.65 to 6.30), vomiting (OR = 2.70, 95% CI: 1.33 to 5.49) and an increased WBC count (SMD = 0.60, 95% CI: 0.27 to 0.93).ConclusionsChina has the highest incidence of HFMD. Our meta-analyses revealed important risk factors that are associated with the severity and mortality of HFMD.

Disease burden in patients with severe hand, foot, and mouth disease in Jiangsu Province: a cross-sectional study

ABSTRACT This study aimed to estimate the disease burden and health-related quality of life (HRQOL) among patients with severe hand, foot, and mouth disease (HFMD) in Jiangsu Province, China. We analyzed the surveillance data of HFMD cases in Jiangsu Province from 2009 to 2020. Moreover, a cross-sectional study was conducted in Nanjing and Suzhou, China, between January 2017 and May 2018. Patients with severe HFMD and their parents were recruited from selected hospitals. Questionnaires and hospital management systems were used to collect data on direct economic burden. The HRQOL of children was assessed using the TNO-AZL Preschool Quality of Life (TAPQOL) scale. A total of 1,348,737 confirmed cases of HFMD were reported to the NNDRS in Jiangsu province during 2009–2020. Of these, 9,622 were severe cases, with 62 (.64%) of these being fatal. From January 2017 to May 2018, data was collected from 362 severe HFMD cases using a structured questionnaire. The median per capita direct economic burden was RMB 16142.88, and was associated with the region and length of hospital stay (P < .05). The direct economic burden for all cases of severe HFMD in Jiangsu province between 2017 and 2018 was approximately RMB 16.64 million. Finally, the median (IQR) of the TAPQOL scale for children with severe HFMD was 69.23 (56.20, 82.27). Severe HFMD infection is a relatively large burden for individuals, and the burden of EV-A71 infection was seen to be even greater for the population. Prevention of severe HFMD should strengthen hygiene habits and targeted measures for EV-A71 vaccination.