Epidemiology of hand, foot, and mouth disease and genetic characteristics of Coxsackievirus A10 in Taiyuan City, Shanxi Province from 2016–2020

doi:10.21203/rs.3.rs-1982880/v4

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Epidemiology of hand, foot, and mouth disease and genetic characteristics of Coxsackievirus A10 in Taiyuan City, Shanxi Province from 2016–2020

https://doi.org/10.21203/rs.3.rs-1982880/v4

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In recent years, the prevalence of hand, foot, and mouth disease (HFMD)caused by enteroviruses other than enterovirus A71 (EV-A71) and coxsackievirus A16 (CVA16) has gradually increased. The throat swab specimens of 2701 HFMD cases were tested, the VP1 regions of CVA10 RNA were amplified using RT-PCR, and phylogenetic analysis of CVA10 was performed. Children aged 1–5 years accounted for the majority (81.65%) and boys was more than girls. The positivity rates of EV-A71, CVA16, and other EVs were 15.22% (219/1439), 28.77% (414/1439), and 56.01% (806/1439), respectively. CVA10 is one of the important viruses of other EVs. A total of 52 CVA10 strains were used for phylogenetic analysis based on the VP1 region, 31 were from this study, and 21 were downloaded from GenBank. All CVA10 sequences could be assigned to seven genotypes (A, B, C, D, E, F, and G), and genotype C was further divided into C1 and C2 subtypes, only one belonged to subtype C1 and the remaining 30 belonged toC2 in this study. This study emphasized the importance of strengthening the surveillance of the HFMD in order to understand the mechanisms of pathogen variation and evolution, so as to provide a scientific basis for HFMD prevention, control, and vaccine development.

Hand

foot

and mouth disease

Coxsackievirus A10

RT-PCR

VP1 region

Phylogenetic tree

Hand, foot, and mouth disease (HFMD) is a global, acute febrile exanthematous infectious disease usually caused by human enterovirus (EV) and occurs mainly in young children less than 5 years of age [1]. HFMD is a mild disease but sometimes can cause severe complications that can even lead to death [2, 3]. EV belongs to the genus Enterovirus, family Picornaviridae, order Picornavirales. EV is highly infectious to susceptible populations, and EVs that infect human beings can be divided into four species (A–D) [4]. EV-A consists of 25 viruses such as coxsackievirus A2 (CVA2)-CVA8, CVA10, CVA12, CVA14, CVA16, EV-A71, EV-A76, EV-A89-A92, EV-A114, and EV-A119-A125, that can cause HFMD, acute flaccid paralysis (AFP), herpetic angina, encephalitis meningitis, and other diseases. HFMD is one of the most common diseases caused by the members of EV-A [5, 6]. Although EV-A71 and CVA16 were mainly responsible for causing HFMD [7-9], the recent increased frequency of CVA10-associated HFMD outbreaks worldwide, have changed this view [10, 11]. In fact, the pathogen spectrum of HFMD continues to change, CVA10 even replaced EV-A71 and CVA16 as the dominant pathogen for HFMD in some areas. CVA10-associated HFMD outbreaks have been reported in past decades, in several countries including France, Vietnam, Uruguay [12-14], as well as in Fujian Province, Liaoning Province and Shijiazhuang City in China [15-18]. However, the CVA10 genome is less stable than that of EV-A71, CVA16, and CVA6, with more frequently recombination[19]. HFMD associated with CVA10 is more severe, more likely to cause serious nervous system diseases, such as aseptic meningitis and viral meningitis, especially in younger children, and is the new leading cause of severe HFMD in addition to EV-A71 [10, 19]. Thus, more research on the genetic characteristics and evolution of CVA10 epidemic is required.

The enterovirus coding region is divided into three subregions, P1, P2 and P3. P1 encodes four structural proteins (VP1, VP2, VP3 and VP4), whilst the non-structural proteins are encoded in the P2 (2A, 2B and 2C) and P3 (3A, 3B, 3C and 3D polymerase) regions. VP1, VP2 and VP3 are present on the outside of capsid, whereas VP4 is internal. The VP1 protein of CVA10 can identify and bind to receptors on target cells, which contains many important neutralization epitopes [20, 21]. Phylogenetic analysis based on the nucleotide sequence of the entire VP1 region of CVA10 (894 bp) is widely used to understand its genetic evolutionary characteristics and is a reliable and rigorous method for molecular epidemiological studies [18, 22].

Taiyuan city, the capital of Shanxi Province, China, is located to the west of Taihang Mountain and the east of the Yellow River, on the Loess Plateau in Northwestern China. CVA10-associated HFMD had been reported in many provinces and regions of China, but only few studies were published from Taiyuan City. In this study, we analyzed the epidemiological characteristics of HFMD and the genetic characteristics of CVA10 in Taiyuan City, Shanxi Province, from 2016–2020. The study emphasized the importance of strengthening the surveillance of HFMD in order to understand the mechanisms of pathogen variation and evolution, so as to provide a scientific basis for HFMD prevention, control, and vaccine development.

Epidemiological information and sample collection. The epidemiological data was retrieved from the China Information System For Disease Control And Prevention and the population data came from the Taiyuan Statistical Yearbook. A total of 2,701 throat swab specimens were sent to the virus microbiology laboratory of Taiyuan Center for Disease Control and Prevention (Taiyuan CDC) for enterovirus nucleic acid testing within 24h from January 1, 2016 to December 31, 2020. Upon receipt of specimens by laboratory, each specimen was assigned a unique laboratory code and entered into the Gastrointestinal Information Database of Taiyuan CDC (Excel).

RNA extraction and EV identification. Viral RNA was extracted from the throat swab specimens using a MagMAX^TM-96 Viral RNA Isolation Kit (Thermo Fisher Scientific, Foster City, CA) according to the manufacturer′s instructions. RNA was eluted in a final volume of 50μL of elution buffer and used immediately or stored at－80℃. All steps of specimen preparation and RNA extraction were done in the biosafety cabinet. RNA was detected using a three-channel real-time RT-PCR kits (Diagnostic Kit for pan-EV, EV-A71, CVA16, Shanghai ZJ Bio-Tech Co., Ltd, Shanghai, China). A 25 μL reaction system consisting of 1 μL enzyme mixture,19 μL reaction solution, and 5 μL viral nucleic acid was prepared. PCR cycling parameters were set up as per the manufacturer’s protocols: 50 °C for 30 min, 95 °C for 10 min, followed by 45 cycles of 95 °C for 10 s, and 55 °C for 40 s in a CFX96 Real-time Thermal Cycler (Bio-Rad, Hercules, CA, USA). A positive result was defined as a cycle threshold (Ct) value ≤ 43, and the positive control was defined as a Ct value ≤ 35. The negative specimens were not under the scope of our study. The specimens positive for other EVs were detected using commercially available real-time RT-PCR kits ( Nucleic Acid Detection Kit for CVA10, BioMax Biotechnology Co., Ltd, Beijing, China). A 20 μL reaction system consisting of 5 μL primer probe mixture, 5 μL RT-PCR reaction solution (containing enzymes), and 10 μL viral nucleic acid was prepared. PCR cycling parameters were set up according to the instructions: 25 °C for 2 min, 53 °C for 10 min, 95 °C for 2 min, followed by 45 cycles of 95 °C for 5 s, and 60 °C for 30 s in a CFX96 Real-time Thermal Cycler (Bio-Rad, Hercules, CA, USA). A positive result was defined as a Ct value ≤ 37, and the positive control was defined as a Ct value ≤ 32. The negative specimens were not under the scope of our study.

VP1 region amplification and nucleotide sequencing. In total, 31 specimens were detected to amplify the entire VP1 region of CVA10 by using the One Step RT-PCR kits (CVA10 Target region (VP1) Molecular typing Kit, BioMax Biotechnology Co., Ltd, Beijing, China) with specific in-house primer pairs (forward primer with nucleotide position 2172-2192nt, CVA10-VP1-S: GCTCAGTAACACTCAYTTYCG, and reverse primer with nucleotide position 3376-3394nt, CVA10-VP1-A: CTCGAGAACTGTCYTCCCA). The primers yielded a CVA10 amplification product of 1223 bp, spanning the entire VP1 region of CVA10 (894 bp). The reaction system for each tube consisted of 12.5 μL PCR Buffer, 2 μL PCR Enzyme, 0.5 μL RT Enzyme, 3μL Primer Mix, and 7 μL viral nucleic acid up to a final volume of 25 μl. The amplification conditions were as follows: 45 °C for 10 min, 94 °C for 2 min, followed by 45 cycles of 98 °C for 10 s, 55 °C for 15 s, and 68 °C for 20 s in a ABI ProFlex™ 96-Well PCR System (Thermo Fisher Scientific, Foster City, CA). Amplification products were determined using 1% agarose gel electrophoresis image analysis system, and sent to Tsingke (Beijing) Biotechnology Co., Ltd for DNA bi-directional sequencing.

Phylogenetic analyses. Sequences were spliced by Sequencher software (version 5.4.6), and EV-types were verified by enterovirus automated genotyping tool [23]. Phylogenetic trees were constructed based on the VP1 sequences of the CVA10 identified in this study and the sequences downloaded from the GenBank database using the MEGA software (Version 11.0.11) [24]. Phylogenetic analysis using neighbor joining (NJ) method was performed based on the Kimura 2-parameter model, and the reliability was evaluated by 1000 bootstrap replicates. Bootstrap values greater than 80% were considered statistically significant for grouping. Genotype differences were computed by the group mean distance computing method in MEGA software.

Nucleotide Accession Number. All the CVA10-Taiyuan sequences obtained during this study were submitted in GenBank under accession numbers OP244619 - OP244649, which are shown in supplementary Table S1.

Statistical analyses. Data analyses were performed using IBM SPSS Statistics software (Version 26.0). The Pearson's Chi-Square Test was used to analyze the data, and the value of P＜0.05 was considered statistically significant.

Table S1 GenBank accession numbers assigned for all the CVA10-Taiyuan sequences based on entire VP1 region sequenced in this study.

Coxsackievirus A10 (VP1)
Accession Number	Strain	Accession Number	Strain
OP244619	TY2016022-SX-CHN-CVA10	OP244635	TY2019008-SX-CHN-CVA10
OP244620	TY2016033-SX-CHN-CVA10	OP244636	TY2019031-SX-CHN-CVA10
OP244621	TY2016080-SX-CHN-CVA10	OP244637	TY2019032-SX-CHN-CVA10
OP244622	TY2016140-SX-CHN-CVA10	OP244638	TY2019148-SX-CHN-CVA10
OP244623	TY2016143-SX-CHN-CVA10	OP244639	TY2019191-SX-CHN-CVA10
OP244624	TY2016188-SX-CHN-CVA10	OP244640	TY2019243-SX-CHN-CVA10
OP244625	TY2016196-SX-CHN-CVA10	OP244641	TY2019257-SX-CHN-CVA10
OP244626	TY2016198-SX-CHN-CVA10	OP244642	TY2019363-SX-CHN-CVA10
OP244627	TY2016199-SX-CHN-CVA10	OP244643	TY2019393-SX-CHN-CVA10
OP244628	TY2016213-SX-CHN-CVA10	OP244644	TY2019434-SX-CHN-CVA10
OP244629	TY2016216-SX-CHN-CVA10	OP244645	TY2019440-SX-CHN-CVA10
OP244630	TY2016267-SX-CHN-CVA10	OP244646	TY2019462-SX-CHN-CVA10
OP244631	TY2016536-SX-CHN-CVA10	OP244647	TY2019534-SX-CHN-CVA10
OP244632	TY2018007-SX-CHN-CVA10	OP244648	TY2019543-SX-CHN-CVA10
OP244633	TY2018364-SX-CHN-CVA10	OP244649	TY2020207-SX-CHN-CVA10
OP244634	TY2018441-SX-CHN-CVA10

Epidemiology features. A total of 22,044 clinical HFMD cases were reported to the China Information System for Disease Control And Prevention in Taiyuan during 2016–2020. The average annual HFMD incidence rate was 86.45 per 100,000 population (range 20.68–148.49), and the incidence rate increased from 2016 to 2017 and decreased from 2017 to 2020, with the peak in 2017. Among these HFMD cases, 13,152 were males and 8,892 were females, with an average annual male-to-female ratio of 1.48 (range 1.36–1.56). The average annual incidence in males (101.10 per 100,000 population) was higher than in females (71.18 per 100,000 population) and this difference was statistically significant (χ²=660.330, P＜0.01). Of all cases, 81.65% (17,998) were children aged 1–5, and the average annual incidence is higher in boys than in girls. The majority (99.35 %) of them were scattered children (49.33%), kindergarten children (41.74%) and school going students (8.27%) (Table 1). Although HFMD cases occurred throughout the year, two seasonal peaks were observed from June to August and from October to November during 2016–2019, respectively. The annual HFMD cases were lowest (n=1,100) in 2020 due to the impact of COVID-19 pandemic, with the peak in November (Figure 1).

Table 1 Distribution of reported and detected HFMD cases in Taiyuan from 2016 to 2020

Variable	2016	2017	2018	2019	2020
HFMD Reported Cases	4472	7400	4648	4424	1100
Incidence rate/10⁵	92.17	148.49	90.87	84.56	20.68
Gender
Male (Incidence rate/10⁵)	2728(110.15)	4395(172.94)	2723(104.72)	2673(100.44)	633(23.19)
Female (Incidence rate/10⁵)	1744(73.43)	3005(123.04)	1925(76.55)	1751(68.12)	467(18.04)
Gender ratio	1.56	1.46	1.41	1.53	1.36
Residence
Scattered children	2290	3691	2459	1896	539
Kindergarten children	1839	3204	1722	2012	425
School students	316	458	443	489	118
Other	27	47	24	27	18
Age Group (%)
<1	197(4.41%)	572(7.73%)	291(6.26%)	188(4.25%)	65(5.91%)
1-<2	915(20.46%)	1655(22.36%)	1135(24.42%)	786(17.77%)	204(18.55%)
2-<3	810(18.11%)	1060(14.32%)	742(15.96%)	693(15.66%)	162(14.73%)
3-<4	893(19.97%)	1620(21.89%)	760(16.35%)	910(20.57%)	244(22.18%)
4-<5	819(18.31%)	1110(15.00%)	711(15.30%)	623(14.08%)	169(15.36%)
5-<6	346(7.74%)	638(8.62%)	401(8.63%)	515(11.64%)	77(7.00%)
≥6	492(11.00%)	745(10.07%)	608(13.08%)	709(16.03%)	179(16.27%)
Specimens	586	604	616	603	292
EV-positive (%)	420(71.67%)	328(54.30%)	311(50.49%)	227(37.65%)	153(52.40%)
EV-A71(%)^a	123 (29.29%)	69 (21.04%)	22 (7.07%)	3 (1.32%)	2(1.31%)
CVA16 (%)^b	106 (25.24%)	50 (15.24%)	130(41.80%)	112(49.34%)	16(10.46%)
Other EVs (%)^c	191(45.48%)	209(63.72%)	159(51.13%)	112(49.34%)	135(88.24%)
CVA10 (%)^d	13(6.81%)	0(0.00%)	3(1.89%)	14(12.50%)	1(0.74%)

Notes: “a, b, c” was the proportion of EV-A71, CVA16, and other EVs in positive numbers, respectively. “d” was the proportion of CVA10 in other EVs.

Laboratory detection. 2,701 throat swab specimens were collected from the HFMD patients during 2016–2020, among them 1,439 (53.28%) were positive for human enterovirus (EV-positive), with 219 (15.22%) associated with EV-A71, 414 (28.77%) with CVA16, and 806 (56.01%) with other EVs. The proportion of other EVs was significantly higher than that of EV-A71 and CVA16 in Taiyuan during 2016–2020. CVA10 (31 cases) accounted for 2.15% of all confirmed cases (Table 1).

Phylogenetic analysis of the VP1 region of CVA10. The entire VP1 sequences of 31 CVA10 were amplified and sequenced in our study. The VP1 nucleotide sequences among CVA10 strains shared 92.6% to 100% nucleotide identity, corresponding to a 96.9% to 100% amino acid identity. A similar analysis with the prototype strain Kowalik showed a 75.9% to 77.0% nucleotide identity, corresponding to a 91.2% to 93.6% amino acid identity. The highest nucleotide similarity with the genotype C downloaded from the GenBank was 91.7% to 100% and amino acid similarity of 96.9% to 100%. A total of 52 CVA10 strains were used for phylogenetic analysis for the VP1 region, including the 31 CVA10 strains identified in this study and 21 reference strains of CVA10 downloaded from the GenBank.

A difference of at least 15% in the VP1 region was used to discriminate genotypes [25]. As entire VP1 sequences of CVA10 available in public database were limited, in order to investigate the origin and spread of CVA10 strains in the world, three representative strains of genotype F on partial VP1 were selected to perform the phylogenetic analysis. Seven genotypes (A, B, C, D, E, F, and G) were assigned with the mean group distance 17.5–30.5% and the distribution of these genotypes showed geographic and temporal circumscribed characterization. Genotype A was only composed with the prototype strain Kowalik isolated in the US in 1950. Foreign epidemic strains such as African viruses, European viruses and Indian viruses mainly clustered in genotype D, E, and F. According to continuous HFMD surveillance, genotype B circulating mainly in China has completely disappeared during 2004–2009 [18].

Thirty-one Taiyuan CVA10 strains along with the domestic reference strains obtained on GenBank belonged to C1 (one strain) and C2 subtypes (30 strains) within genotype C. The only CVA10 belonging to subtype C1 was gotten from 2018. Subtype C2 can be further divided into three evolutionary branches (C2a, C2b and C2c) (Figure 2). An apparent evolutionary trend could be observed from 2016–2020. All the CVA10 strains detected in 2016 belonged to C2a. One CVA10 strain detected in 2018 and two CVA10 strains detected in 2019 belonged to C2b, whereas the remaining CVA10 strains detected between 2018 and 2020 belonged to C2c.

The HFMD epidemic have become a serious public health threat and economic burden in the Asia-Pacific region over the past decade [26, 27]. The Health Ministry of China described the disease as a notifiable infectious disease of class C and established a national enhanced surveillance system for HFMD in May 2008 [2]. According to the data recorded by the China Disease Control and Prevention Information System at the end of 2021, the number of HFMD cases in Shanxi Province ranked among the top three in class C notifiable disease. Nonetheless, studies focused mostly on the EV-A71 and CVA16 and information about other EVs was still limited. In December 2015, China’s Food and Drug Administration approved the monovalent EV-A71 vaccine as an efficient and economic measure to control EV-caused diseases[28]. The vaccine performed excellently in the prevention and control of EV-A71 during the past four years and changed the pathogen spectrum of HFMD. The number of HFMD cases caused by other EVs has gradually increased, even replaced EV-A71 and CVA16 as the dominant pathogen for HFMD. CVA10-associated HFMD outbreaks were reported in many provinces of China, gradually becoming one of the most frequent EV genotypes during the epidemic interval of EV-A71 and CVA16 since 2012 [18]. However, there are currently no preventive vaccines and specific therapeutic drugs for CVA10-associated HFMD, only few studies were published from Taiyuan City. Hence, in this study, we conducted a comprehensive analysis of the epidemiological characteristics and molecular evolution characteristics of CVA10 in Taiyuan City from 2016 to 2020.

The results indicated that more infections were found in males than in females. Except for sex differences at the level of host immune status, another explanation could be related to the extra outdoor activities, including more frequent exposure to unclean toys and facilities by boys, which increases the risk of infection compared to girls[29]. Of all HFMD cases in Taiyuan City, children aged 1–5 accounted for the majority (81.65%) of the cases due to low herd immunity and the majority (99.35%) among them were scattered children, kindergarten children and school students. Such high incidence rates suggest that this particular age group should be used as a key population for HFMD control and prevention. Health education programs should be conducted to prevent HFMD transmission not only for children at kindergartens and schools, but also for the community families with young children. There were obvious seasonal features in HFMD epidemic. Although HFMD cases in Taiyuan City were reported throughout the year, two seasonal peaks were observed from June to August and from October to November during 2016–2019, respectively. The main peak might be due to increase in viral transmission because of extremes temperature [30]. The second peak may be due to a shift in climate from warm dry conditions to cold wet conditions, mainly in the southern provinces. However, this phenomenon is relatively rare in Shanxi, a northern province of China. Nevertheless, epidemiological surveillance and prevention efforts should be strengthened before the peak of disease each year.

As one of the important viruses of other EVs, the entire VP1 sequences of 31 CVA10 were amplified and sequenced from 2016-2020. CVA10 strains in this study belonged to C1 and C2 subtypes in genotype C and was also the predominant genotype during 2010–2016 in China [18]. Only one CVA10 isolated in 2018 belonged to subtype C1 and the others to subtype C2. As the spread of subtype C2, it has been divided into 3 branches (C2a, C2b and C2c). Significant branch shift can be observed from 2016 to 2020, C2b and C2c co-circulate in 2018 and which branch will become mainstream requires our continuous surveillance.

This study had some limitations. First, the proportion of laboratory-confirmed HFMD cases was small due to limited sample size. Second, because there are no complete VP1 sequence of genotype F in Genbank, partial VP1 region sequences of genotype F of CVA10 were used for analysis in this study. However, to fully understand the genetic variation and evolution of CVA10, research based on entire VP1 region or even full-length genome is necessary.

The study emphasized the importance of strengthening the surveillance of HFMD pathogen spectrum in order to understand the mechanisms of pathogen variation and evolution, so as to provide a scientific basis for HFMD prevention, control, and vaccine development. The reported HFMD cases associated with CVA10 in this study raise concerns about the role of CVA10 in explaining new HFMD cases and outbreaks and call for enhanced surveillance of HFMD pathogen spectrum and surveillance of enterovirus etiology.

HFMD: hand, foot, and mouth disease; EV-A71: enterovirus A71; CVA16: coxsackievirus A16; CVA10: coxsackievirus A10; RT-PCR: reverse transcription polymerase chain reaction; EV: enterovirus; CVA2: coxsackievirus A2; AFP: acute flaccid paralysis; CDC: Center for Disease Control and Prevention; Ct value: Cycle threshold value; NJ: neighbor joining.

Supplementary Materials

Supplementary Table S1. GenBank accession numbers assigned for all the CVA10-Taiyuan sequences based on entire VP1 region sequenced in this study.

Authors’ contributions

Data curation, Zijun Cao and Huanhuan Lu; Funding acquisition, Jihong Xu; Investigation, Li Gao; Methodology, Jinbo Xiao; Project administration, Jiane Guo; Resources, Ruihong Gao; Software, Lifeng Zhao; Supervision, Yang Xu; Validation, Zhihong Zuo; Visualization, Rui Wang; Writing – original draft, Hongyan Liu; Writing – review & editing, Jitao Wang and Yong Zhang. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported National Key Research and Development Program of China (Project No. 2021YFC2302003), and Natural Science Foundation of Beijing (Project No. L192014).

Institutional Review Board Statement

The study did not involve human participants or human experimentations, the only human materials used were the throat swab specimens collected from HFMD patients for public health purposes. Specimens were analyzed after informed and verbal consent obtained from the parents or guardians of the children. The study was conducted according to the guidelines of the Declaration of Helsinki, and experimental procedures were approved by the the Institutional Review Board and Human Research Ethics Committee of the Taiyuan Center for Disease Control and Prevention.

Informed Consent Statement

Not applicable

Data Availability Statement

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. All the CVA10-Taiyuan sequences obtained during this study were submitted in GenBank under accession numbers OP244619 - OP244649

Acknowledgements:

The authors are grateful to county CDC staffs in Taiyuan City who were responsible for the specimen collection process.

Conflicts of Interest:

The authors declare that they have no conflict of interest.

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No competing interests reported.

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Epidemiology of hand, foot, and mouth disease and genetic characteristics of Coxsackievirus A10 in Taiyuan City, Shanxi Province from 2016–2020

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