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      The spatial–temporal distribution and etiological characteristics of hand-foot-and-mouth disease before and after EV‑A71 vaccination in Kunming, China, 2017–2020

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          Abstract

          After vaccination with enterovirus 71 (EV-A71), the prevalence of hand-foot-and-mouth disease (HFMD) remained high, and the spatial–temporal distribution of enteroviruses changed. Therefore, it is essential to define the temporal features, spatial distributions, and epidemiological and etiological characteristics of HFMD in Kunming. Between 2017 and 2020, a total of 36,540 children were diagnosed with HFMD in Kunming, including 32,754 children with enterovirus-positive clinical samples. Demographic, geographical, epidemiological and etiological data of the cases were acquired and analyzed. Other enteroviruses replaced EV-A71, and the incidence of EV-A71 decreased dramatically, whereas coxsackievirus A6 (CV-A6) and coxsackievirus A16 (CV-A16) had substantial outbreaks in 2018 and 2019, respectively. The major and minor peaks all extended for 2–4 months compared to before vaccination with the EV-A71 vaccine. From 2019 to 2020, CV-A6, as the predominant serotype, showed only a single peak. Although a high incidence of HFMD was observed in Guandu, Chenggong and Xishan, the annual incidence of different enterovirus serotypes was different in different regions. In 2017, other enteroviruses were most prevalent in Shilin. In 2018, CV-A16 and CV-A6 were most prevalent in Luquan and Shilin, respectively. In 2019, CV-A16 was most prevalent in Jinning. In 2020, CV-A6 and coxsackievirus A10 (CV-A10) were most prevalent in Luquan and Shilin, respectively. Meanwhile, the epidemic cycle of CV-A6 and CV-A16 was only 1 year, and CV-A10 and other enteroviruses were potential risk pathogens. The spatial and temporal distribution of HFMD varies at different scales, and the incidence of HFMD associated with different pathogens has obvious regional differences and seasonal trends. Therefore, research on multivalent combined vaccines is urgently needed, and proper preventive and protective measures could effectively control the incidence of HFMD-like diseases.

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          Most cited references29

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          Clinical features, diagnosis, and management of enterovirus 71.

          Although poliomyelitis has been mostly eradicated worldwide, large outbreaks of the related enterovirus 71 have been seen in Asia-Pacific countries in the past 10 years. This virus mostly affects children, manifesting as hand, foot, and mouth disease, aseptic meningitis, poliomyelitis-like acute flaccid paralysis, brainstem encephalitis, and other severe systemic disorders, including especially pulmonary oedema and cardiorespiratory collapse. Clinical predictors of severe disease include high temperature and lethargy, and lumbar puncture might reveal pleocytosis. Many diagnostic tests are available, but PCR of throat swabs and vesicle fluid, if available, is among the most efficient. Features of inflammation, particularly in the anterior horns of the spinal cord, the dorsal pons, and the medulla can be clearly seen on MRI. No established antiviral treatment is available. Intravenous immunoglobulin seems to be beneficial in severe disease, perhaps through non-specific anti-inflammatory mechanisms, but has not been tested in any formal trials. Milrinone might be helpful in patients with cardiac dysfunction. Copyright © 2010 Elsevier Ltd. All rights reserved.
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            Efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in China.

            Enterovirus 71 (EV71) is one of the major causative agents of outbreaks of hand, foot, and mouth disease or herpangina worldwide. This phase 3 trial was designed to evaluate the efficacy, safety, and immunogenicity of an EV71 vaccine. We conducted a randomized, double-blind, placebo-controlled, multicenter trial in which 10,007 healthy infants and young children (6 to 35 months of age) were randomly assigned in a 1:1 ratio to receive two intramuscular doses of either EV71 vaccine or placebo, 28 days apart. The surveillance period was 12 months. The primary end point was the occurrence of EV71-associated hand, foot, and mouth disease or herpangina. During the 12-month surveillance period, EV71-associated disease was identified in 0.3% of vaccine recipients (13 of 5041 children) and 2.1% of placebo recipients (106 of 5028 children) in the intention-to-treat cohort. The vaccine efficacy against EV71-associated hand, foot, and mouth disease or herpangina was 94.8% (95% confidence interval [CI], 87.2 to 97.9; P<0.001) in this cohort. Vaccine efficacies against EV71-associated hospitalization (0 cases vs. 24 cases) and hand, foot, and mouth disease with neurologic complications (0 cases vs. 8 cases) were both 100% (95% CI, 83.7 to 100 and 42.6 to 100, respectively). Serious adverse events occurred in 111 of 5044 children in the vaccine group (2.2%) and 131 of 5033 children in the placebo group (2.6%). In the immunogenicity subgroup (1291 children), an anti-EV71 immune response was elicited by the two-dose vaccine series in 98.8% of participants at day 56. An anti-EV71 neutralizing antibody titer of 1:16 was associated with protection against EV71-associated hand, foot, and mouth disease or herpangina. The EV71 vaccine provided protection against EV71-associated hand, foot, and mouth disease or herpangina in infants and young children. (Funded by Sinovac Biotech; ClinicalTrials.gov number, NCT01507857.).
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              Hand, foot, and mouth disease in China, 2008-12: an epidemiological study.

              Hand, foot, and mouth disease is a common childhood illness caused by enteroviruses. Increasingly, the disease has a substantial burden throughout east and southeast Asia. To better inform vaccine and other interventions, we characterised the epidemiology of hand, foot, and mouth disease in China on the basis of enhanced surveillance. We extracted epidemiological, clinical, and laboratory data from cases of hand, foot, and mouth disease reported to the Chinese Center for Disease Control and Prevention between Jan 1, 2008, and Dec 31, 2012. We then compiled climatic, geographical, and demographic information. All analyses were stratified by age, disease severity, laboratory confirmation status, and enterovirus serotype. The surveillance registry included 7,200,092 probable cases of hand, foot, and mouth disease (annual incidence, 1·2 per 1000 person-years from 2010-12), of which 267,942 (3·7%) were laboratory confirmed and 2457 (0·03%) were fatal. Incidence and mortality were highest in children aged 12-23 months (38·2 cases per 1000 person-years and 1·5 deaths per 100,000 person-years in 2012). Median duration from onset to diagnosis was 1·5 days (IQR 0·5-2·5) and median duration from onset to death was 3·5 days (2·5-4·5). The absolute number of patients with cardiopulmonary or neurological complications was 82,486 (case-severity rate 1·1%), and 2457 of 82486 patients with severe disease died (fatality rate 3·0%); 1617 of 1737 laboratory confirmed deaths (93%) were associated with enterovirus 71. Every year in June, hand, foot, and mouth disease peaked in north China, whereas southern China had semiannual outbreaks in May and September-October. Geographical differences in seasonal patterns were weakly associated with climate and demographic factors (variance explained 8-23% and 3-19%, respectively). This is the largest population-based study up to now of the epidemiology of hand, foot, and mouth disease. Future mitigation policies should take into account the heterogeneities of disease burden identified. Additional epidemiological and serological studies are warranted to elucidate the dynamics and immunity patterns of local hand, foot, and mouth disease and to optimise interventions. China-US Collaborative Program on Emerging and Re-emerging Infectious Diseases, WHO, The Li Ka Shing Oxford Global Health Programme and Wellcome Trust, Harvard Center for Communicable Disease Dynamics, and Health and Medical Research Fund, Government of Hong Kong Special Administrative Region. Copyright © 2014 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                360623155@qq.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                11 October 2022
                11 October 2022
                2022
                : 12
                : 17028
                Affiliations
                [1 ]GRID grid.415549.8, Department of Infectious Diseases, , Kunming Children’s Hospital, The Affiliated Children’s Hospital of Kunming Medical University, Institute of Pediatric Disease Research in Yunnan, ; Kunming, 650228 People’s Republic of China
                [2 ]GRID grid.415549.8, Department of Pathology, , Kunming Children’s Hospital, The Affiliated Children’s Hospital of Kunming Medical University, Institute of Pediatric Disease Research in Yunnan, ; Kunming, 650228 People’s Republic of China
                [3 ]Yunnan Key Laboratory of Children’s Major Disease Research, Kunming, People’s Republic of China
                [4 ]GRID grid.410739.8, ISNI 0000 0001 0723 6903, Department of Stomatology, , The Affiliated Hospital of Yunnan Normal University, ; Kunming, People’s Republic of China
                [5 ]GRID grid.285847.4, ISNI 0000 0000 9588 0960, The First Department of Hepatopancreatobiliary Surgery, Affiliated Calmette Hospital of Kunming Medical University and The First People’s Hospital of Kunming City, , Liver Transplantation Center of Organ Transplantation Institute of Yunnan Province, ; Kunming, People’s Republic of China
                [6 ]Weather Modification Center of Yunnan Province, Kunming, People’s Republic of China
                [7 ]Weifang Center for Disease Control and Prevention, Shandong, People’s Republic of China
                Article
                21312
                10.1038/s41598-022-21312-2
                9552732
                36220850
                f7478876-0d81-4e6f-b05f-8c59dcf18f53
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 31 December 2021
                : 26 September 2022
                Funding
                Funded by: Spring City Plan
                Award ID: 2020-23
                Award Recipient :
                Funded by: Kunming Science and technology planning project
                Award ID: 2019-1-S-25318000001241
                Award Recipient :
                Funded by: Kunming health and Family Planning Commission Project
                Award ID: 2019-SW-33
                Award Recipient :
                Funded by: Yunnan Province’s reserve medical talents project
                Award ID: H-2019002
                Award Recipient :
                Funded by: Kunming Medical University Applied Basic Research Joint Special Project
                Award ID: 202001AY070001-170
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2022

                Uncategorized
                infectious diseases,disease prevention,paediatrics,public health
                Uncategorized
                infectious diseases, disease prevention, paediatrics, public health

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