Epidemiological characteristics of hand, foot, and mouth disease clusters during 2016-2020 in Beijing, China.

Hand, foot, and mouth disease (HFMD) is an infectious disease that usually occurs in children under 5 years and is caused by a group of enteroviruses. This study aimed to investigate the epidemiological characteristics of HFMD clusters from 2016 to 2020 in Tongzhou, Beijing, and explored the genetic evolution of CV-A6. The HFMD case information came from the Information System of China Center for Disease Control and Prevention (CDC), as well as the clusters information verification and on-site investigation by Tongzhou CDC. ARIMA model was applied to forecast HFMD clusters in 2020. Totally 440 HFMD clusters were reported during 2016-2020. The large peak of the clusters occurred in April-July, followed by a smaller peak in October-November during 2016-2019. However, in 2020, the two peaks disappeared. The main site of HFMD clusters was childcare facilities (65.0%) and mostly occurred in urban areas (46.1%). The detection rate of CV-A6 was the highest (36.1%), and cases with CV-A6 infection had the highest proportion of fever. The phylogenetic analysis based on CV-A6 VP1 gene showed that the predominant strains mainly located in Group F during 2016-2017, while changed into Group A during 2018-2020. HFMD clusters presented seasonality, mainly located in childcare facilities and urban areas, and CV-A6 was the major causative agent. Targeted prevention and control measures should be taken to reduce HFMD clusters.

A review and meta-analysis of the epidemiology and clinical presentation of coxsackievirus A6 causing hand-foot-mouth disease in China and global implications.

Coxsackievirus A6 (CV-A6) has been associated with increasingly occurred sporadic hand-foot-mouth disease (HFMD) cases and outbreak events in many countries. In order to understand epidemiological characteristics of CV-A6, we collected the information describing HFMD caused by CV-A6 to describe the detection rate, severe rate and onychomadesis rate, which is defined as one or more nails defluvium, caused by CV-A6 from 2007 to 2017. The results showed that there was an outbreak of CV-A6 every other year, and overall trend of the epidemic of CA6-associated HFMD was increasing in China. The detection rate of CV-A6 in other countries was 32.0% (95% CI: 25.0%~40.0%) before 2013 and 28.0% (95% CI: 20.0%~36.0%) after 2013, respectively. Although the severe rate of HFMD caused by CV-A6 was low (0.10%, 95% CI: 0.01%~0.20%), CV-A6 can cause a high incidence of onychomadesis (28.0%, 95%CI: 21.9%-34.3%). Thus, it would be worthwhile to research and develop an effective multivalent vaccine for CV-A6 to achieve a more powerful prevention of HMFD.

Immunologic Characterization of Cytokine Responses to Enterovirus 71 and Coxsackievirus A16 Infection in Children.

Viral encephalitis is a serious complication of hand, foot, and mouth disease (HFMD), but characteristics of cytokines response in enterovirus 71 (EV-71) and/or coxsackievirus A16 (CV-A16) associated HFMD with or without viral encephalitis remained unclear.We performed a multigroup retrospective study and compared the serum cytokines concentrations among 16 encephalitis patients infected with EV-71 and CV-A16, 24 encephalitis patients with single EV-71 infection, 34 mild HFMD patients with EV-71 infection, 18 mild HFMD patients with CV-A16 infection, and 39 healthy control subjects.Serum levels of interleukin (IL)-4, IL-5, IL-22, and IL-23 were significantly higher in encephalitis patients than in HFMD-alone patients when adjusting for age and sex; IL-2, tumor necrosis factor (TNF)-α, IL-4, IL-22, and IL-1ß were significantly higher in HFMD-alone patients of EV-71 infection than in CV-A16 infected HFMD patients; cerebrospinal fluid level of IL-6 was lower in the EV-71/CV-A16 associated encephalitis than that in the EV-71 alone associated encephalitis patients.Over or low expression of the cytokines cascade in HFMD patients appears to play an important role in the elicitation of the immune response to EV-71 and CV-A16. These data will be used to define a cytokine profile, which might help to recognize HFMD patients with the high risk of developing encephalitis.

Prevalence and genetic characteristics of Saffold cardiovirus in China from 2009 to 2012.

The epidemiology and clinical features of the Saffold cardiovirus (SAFV) remain ambiguous. The present study was designed to systematically and intensively investigate the epidemiological features of SAFV in pediatric patients in China. Three cohorts of pediatric patients were recruited from 2009 to 2012. Cohort 1 comprised patients with acute respiratory tract infections. Cohort 2 comprised patients with diarrhea. Cohort 3 comprised hand, foot, and mouth disease (HFMD) patients. A total of 115 patients (1.6%) among 6052 (17/1647, 12/2013, and 86/2392 in cohorts 1, 2, and 3, respectively) were SAFV-positive. The samples from 82 SAFV-positive patients were successfully sequenced, and four genotypes were identified: 8 SAFV-1, 41 SAFV-2, 29 SAFV-3, and 4 SAFV-6. A significantly higher detection rate was found in the HFMD patients than in other two cohorts (both P <0.001). A higher frequency of severe clinical outcome and nervous system manifestation were also observed in the SAFV-positive HFMD patients. Additionally, 6 (3.5%) cerebrospinal fluid and 7 (2.2%) serum samples from the HFMD-associated encephalitis patients were SAFV-positive. Based on the VP1 sequences, all four genotypes displayed distinct geographical clustering. SAFV infection might be associated with a wide clinical spectrum and contribute to HFMD.

Circulation of Coxsackievirus A10 and A6 in hand-foot-mouth disease in China, 2009-2011.

Coxsackieviruses A10 (CV-A10) and A6 (CV-A6) have been associated with increasingly occurred sporadic hand-foot-mouth disease (HFMD) cases and outbreak events globally. However, our understanding of epidemiological and genetic characteristics of these new agents remains far from complete. This study was to explore the circulation of CV-A10 and CV-A6 in HFMD and their genetic characteristics in China. A hospital based surveillance was performed in three heavily inflicted regions with HFMD from March 2009 to August 2011. Feces samples were collected from children with clinical diagnosis of HFMD. The detection and genotyping of enteroviruses was performed by real-time PCR and sequencing of 5'UTR/VP1 regions. Phylogenetic analysis and selection pressure were performed based on the VP1 sequences. Logistic regression model was used to identify the effect of predominant enterovirus serotypes in causing severe HFMD. The results showed 92.0% of 1748 feces samples were detected positive for enterovirus, with the most frequently presented serotypes as EV-71 (944, 54.0%) and CV-A16 (451, 25.8%). CV-A10 and CV-A6 were detected as a sole pathogen in 82 (4.7%) and 44 (2.5%) cases, respectively. Infection with CV-A10 and EV-71 were independently associated with high risk of severe HFMD (OR = 2.66, 95% CI: 1.40-5.06; OR = 4.81, 95% CI: 3.07-7.53), when adjusted for age and sex. Phylogenetic analysis revealed that distinct geographic and temporal origins correlated with the gene clusters based on VP1 sequences. An overall ω value of the VP1 was 0.046 for CV-A10 and 0.047 for CV-A6, and no positively selected site was detected in VP1 of both CV-A10 and CV-A6, indicating that purifying selection shaped the evolution of CV-A10 and CV-A6. Our study demonstrates variety of enterovirus genotypes as viral pathogens in causing HFMD in China. CV-A10 and CV-A6 were co-circulating together with EV-71 and CV-A16 in recent years. CV-A10 infection might also be independently associated with severe HFMD.