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. 2021 Feb 19;100(7):e24855. doi: 10.1097/MD.0000000000024855

Prevalence of recessive infection of pathogens of hand, foot, and mouth disease in healthy people in China

A meta-analysis

Yu-Jie Zhou a, Xiu-De Niu b, Ya-Qing Ding c, Zheng Qian a, Bao-Lin Zhao d,∗
Editor: Babak Abdinia
PMCID: PMC7899851  PMID: 33607859

Abstract

Background:

To analyze the prevalence of latent infection of pathogens of hand, foot, and mouth disease (HFMD) in Chinese healthy population and its influencing factors, so as to provide reference for the prevention and control of HFMD.

Methods:

A systematic literature searching about the incidence of latent infection of HFMD was conducted in Chinese and English databases. The inclusion and exclusion criteria of the retrieved literature were established. The qualified literatures were screened and the data were extracted. The pooled rate and its 95% confidence interval was used to assess the latent infection rate of HFMD pathogens in healthy Chinese population, and subgroup analysis was conducted based on gender and age. All statistical analyses were performed using the STATA version 12.0 software.

Results:

A total of 31 literatures were included in this meta-analysis. The recessive infection rate of HFMD pathogens reported in the literature of Chinese healthy people ranged from 4.59% to 44.12%. The results of meta-analysis showed that the latent infection rate of human enteroviruses (HEVs) in healthy Chinese population was 17.5% (14.9–20.1%), among which, the latent infection rates of EV-A71, CV-A16, and other HEVs were 3.3% (2.2–4.4%), 1.7% (1.0–2.5%), and 15.1% (11.1–17.1%), respectively. The latent infection rates of HEVs in healthy men and women in China were 16.7% (12.9–20.4%) and 14.4% (10.8–18.0%), respectively. The latent infection rates of HEVs in the healthy population aged 0 to 5 years and over 5 years were 24.4% (20.4–28.5%) and 9.4% (6.5–12.2%), respectively. Meta regression showed that the factors affecting the latent infection rate of HEVs in Chinese healthy population included sampling period, sampling area, and study population.

Conclusion:

The latent infection rate of HEVs is high in healthy people in China, but it is mainly caused by other enteroviruses. The latent infection rate of HEVs in male was higher than that of female and was greater in people aged 0 to 5 than that of aged over 5 years. Limited by the quantity and quality of the included studies, more high-quality studies are needed for further verification in the future.

Keywords: foot and mouth disease, hand, human enterovirus, inapparent infection, meta-analysis

1. Introduction

Hand, foot, and mouth disease (HFMD) is a common acute infectious disease in children, mostly under 5 years of age, caused by several human enteroviruses (HEVs). The main clinical manifestations of HFMD are skin herpes of hand and foot and oral mucosal rash. In a few cases, there are sterile meningeal encephalitis, brainstem encephalitis, neurogenic pulmonary edema, and cardiac injury.[1] The pathogens that can cause HFMD clinically includes coxsackievirus type 2, 4, 5, 7, 9, and 10 in coxsackievirus group A, ECHO and enterovirus 71 (EV71) in group B, among which coxsackievirus group A (Cox A16) and EV71 are the most common.[2] Cox A16 was the main pathogen prevalent in the early stage of HFMD, but it did not attract wide attention due to its mild symptoms and small number of patients.[3] In recent years, in the outbreak or epidemic of Cox A16 and EV71 in mainland China and Taiwan, it has been found that coincident or alternating epidemic transmission of Cox A16 and EV71 is easy to cause severe disease or even death, and the infection rate of EV71 is increasing year by year.[4,5]

Humans are the only natural host of enterovirus, the infection sources of HFMD include patients, recessive infection.[6] HFMD virus was mainly transmitted by digestive tract (fecal–oral route) and respiratory tract (droplet, cough, sneeze). Hands, towels, toothbrushes, toys, bowls and chopsticks, milk products, and medical devices contaminated with human feces, herpes fluid, and respiratory secretions can also be spread. Among them, the contaminated hand is the key medium of transmission. Although it is not clear whether water and food are involved in transmission, studies have shown the potential for waterborne transmission of enterovirus if water is not treated effectively.[7] People are generally susceptible to enterovirus, especially infants and children.

HFMD is a public health problem that seriously affects children's health, and the number of cases is increasing year by year. At present, the related researches on HFMD mainly focus on the epidemic characteristics and pathogenesis characteristics of the diagnosed population, risk factors of severe cases, and other related aspects. However, the main transmission group of HFMD is the recessive infected person. Since most people show recessive status after human enteroviruses infection, it is difficult to be detected clinically, so it is difficult to carry out effective isolation measures, which may easily lead to further spread of the epidemic.

The investigation of the latent infection rate of enterovirus in healthy people is of great significance for the effective prevention of HFMD transmission among children, which is conducive to the understanding of the current situation of the latent infection group of HFMD. Therefore, meta-analysis was adopted in this study to comprehensively analyze the published literature on the recessive infection rate of HFMD pathogens, and to evaluate its influencing factors, so as to provide scientific basis for the prevention and control of HFMD in the future.

2. Materials and methods

2.1. Literature retrieval

The electronic databases were searched by computer for retrieval articles about the prevalence of latent infection of pathogens of hand, foot, and mouth disease in healthy people in China. The China National Knowledge Infrastructure (CNKI) and Chinese WanFang database were used for retrieval in Chinese, and PubMed was used for literature retrieval in English with the search terms of (“HFMD” OR “hand foot and mouth disease”) and (“recessive” OR “inapparent” OR “silent”). Relevant literatures published from January 1, 1996 to April 30, 2020 were searched in the above databases. Retrospective search was conducted on the references cited by relevant literature after screening to prevent the omission of literature search in the above databases.

2.1.1. Ethical approval

This study is a meta-analysis and does not involve patient and animal experiments so the ethical approval is not necessary.

2.2. Inclusion and exclusion criteria

Inclusion criteria:

  • (1)

    the study type is cross-sectional study;

  • (2)

    the research area is mainland China;

  • (3)

    the sample size and the positive number or positive rate of hand, foot, and mouth enterovirus were available;

  • (4)

    the detection method of enterovirus recessive infection was reverse transcription polymerase chain reaction (RT-PCR);

  • (5)

    there are repeated published data in different literatures, and literatures with large sample size are selected.

Exclusion criteria:

  • (1)

    literature on the analysis of recessive infection rate by antibody detection;

  • (2)

    the latent infection rate of medical personnel and other special groups;

  • (3)

    case reports, literature reviews, meeting abstracts, and other research literature;

  • (4)

    repeated publication.

2.3. Literature screening and data extraction

The retrieved articles were imported into the Note Express 3.2 document management software for sorting and deduplication. The 2 researchers screened the literatures according to the inclusion and exclusion criteria. The literature finally included by the 2 researchers was compared with each other, and the inconsistencies were decided to be included or excluded through group discussion. The 2 researchers extracted information from the included literatures, including the first author, the year of publication, the study province, the positive number of enterovirus, the sample size, the type of specimen, whether the sampling period was in epidemic period, the sampling area, the study population, etc.

2.4. Quality evaluation

The methodological Quality of the included studies was assessed using 11 checklists recommended by the Agency for Healthcare Research and Quality (AHRQ).[8] If a item is answered “no” or “unclear,” the project scores “0”; if the answer is “yes,” then the item gets a score of “1.” The quality evaluation score criteria are as follows: low quality = 0 to 3, medium mass = 4 to 7, high quality = 8 to 11.

2.5. Statistical analysis

The point assessment of the recessive infection rate and the 95% confidence interval of each study were combined for the pooled rates, and the DerSimonian and Laird method (D–L method) of random effect model or the Mantel–Haenszel method (M–H method) of fixed effect model was selected according to the heterogeneity.[9] Cohran's Q test was used for qualitative evaluation of the heterogeneity. If P < .1 for Cohran's Q test, heterogeneity was indicated and random effect model was used for meta-analysis. If P ≥ .1 for Cohran's Q test, the fixed effect model was selected for meta-analysis. The heterogeneity was quantified by I2 test, and those with I2 values of 0% to 25%, 26% to 50%, and 51% to 100% were considered as low, medium, and high heterogeneity, respectively.[9]

Meta-regression analysis was used to explore the sources of heterogeneity. Potential publication bias was assessed by Begg's funnel plot and Egger's linear regression test.[10,11] In sensitivity analysis, a single study was omitted item by item to evaluate whether a certain study had a significant impact on the stability of the results. All statistical analysis was performed using STATA version 12.0 software (STATA Corporation, College Station, TX). A P value less than .05 was considered statistically significant.

3. Results

3.1. Basic information of the included literature

A total of 243 related literatures including 76 in English and 167 in Chinese were obtained through preliminary retrieval. After screening according to inclusion and exclusion criteria, we finally included 29 articles in this meta-analysis.[12–39] The literature selection process and results are shown in Figure 1. Among the 29 articles, 4 were in English and 24 were in Chinese, covering more than 20 counties and cities in 11 provinces of China, and a total of 11,921 subjects were studied. AHRQ quality score in the included literature was 6 on average, 8 on the highest score, and 5 on the lowest score. The detailed information of the included literature on the incidence of HFMD enterovirus recessive infection is shown in Table 1.

Figure 1.

Figure 1

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Selection of studies on the recessive infection of pathogens of HFMD in healthy people in China.

Table 1.

Basic information of the included literature on the incidence of HFMD enterovirus recessive infection.

Refs. First author Publication time Province HEVs (+) Sample size Latent infection (%) Specimen type Sampling time Sampling area Population AHRQ score
[12] Yang HK 2010 Guangdong 21 180 11.67 Feces Epidemic Rural Children and adults 8
[13] Kang N 2010 Guangxi 17 50 34.00 Feces Epidemic Urban Children 6
[14] Yin FQ 2011 Shandong 111 846 13.12 Feces Epidemic Urban and rural Children 6
[15] Liu CH 2011 Shandong 68 386 17.62 Feces Epidemic Urban and rural Children and adults 5
[16] Deng HL 2011 Shaanxi 13 207 6.28 Anal swab Epidemic Urban and rural Children 7
[17] Jiang WG 2011 Shandong 177 1235 14.33 Feces Epidemic and non-epidemic Urban and rural Children and adults 5
[18] Mo LF 2012 Guangdong 20 310 6.45 Feces Non-epidemic Urban Children and adults 8
[19] Ren Y 2012 Guangdong 13 150 8.67 Feces Epidemic and non-epidemic Urban Children and adults 6
[20] Ceng HR 2012 Guangdong 60 136 44.12 Feces Epidemic Rural Children 5
[21] Liu L 2012 Hebei 44 161 27.33 Feces Epidemic Rural Children 6
[22] Wang DL 2012 Guangdong 78 1305 5.98 Anal swab Epidemic Urban Children 8
[23] He Y 2012 Guangdong 18 392 4.59 Anal swab Epidemic and non-epidemic Urban Children 7
[24] Niu WD 2012 Henan 49 200 24.50 Feces Epidemic Rural Children and adults 6
[25] Yi QH 2013 Jiangsu 67 309 21.68 Anal swab Epidemic Urban and rural Children 6
[26] Chen FY 2013 Hebei 40 180 22.22 Anal swab Epidemic Urban and rural Children 5
[27] Zhang 2013 Shandong 59 254 23.23 Feces Epidemic Rural Children 8
[28] Wu 2013 Guangdong 34 320 10.63 Feces Epidemic and non-epidemic Urban Children 7
[29] Li Y 2013 Henan 71 200 35.50 Feces Epidemic Rural Children and adults 5
[30] Cai MS 2013 Guangdong 40 240 16.67 Feces Epidemic Urban Children and adults 5
[31] Liu FR 2014 Guangdong 28 118 23.73 Anal swab Epidemic and non-epidemic Urban Children 6
[32] Sun BC 2014 Zhejiang 51 395 12.91 Anal swab Epidemic and non-epidemic Urban Children 8
[33] Hou ZY 2015 Henan 26 106 24.53 Anal swab Epidemic and non-epidemic Urban Children 5
[34] Feng X 2015 Jiangxi 18 100 18.00 Anal swab Epidemic Urban and rural Children 5
[35] Zhang L 2015 Shandong 123 1275 9.65 Feces Epidemic and non-epidemic Urban and rural Children 6
[36] Gao W 2016 Hebei 11 130 8.46 Anal swab Epidemic and non-epidemic Urban Children 6
[37] Wang HQ 2016 Chongqing 211 1276 16.54 Anal swab Epidemic and non-epidemic Urban and rural Children 8
[38] Wu 2017 Yunnan 90 667 13.49 Feces Epidemic Rural Children and adults 7
[39] Yuan W 2018 Sichuan 75 193 38.86 Feces Epidemic Urban and rural Children 5
[40] Xie Y 2019 Shaanxi 123 600 20.50 Anal swab Epidemic and non-epidemic Urban and rural Children 5
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3.2. Meta-analysis

A total of 11,921 cases were reported in 29 literatures, among which 1756 cases were positive for enterovirus common nucleic acid. The heterogeneity test showed that there was significant heterogeneity in each analysis group, and the results of the random effect model were selected. Meta-analysis showed that the recessive infection rate of HEVs was 17.5% (14.9–20.1%) in healthy Chinese people, among which the recessive infection rate of EV-A71 was 3.3% (2.2–4.4%), the recessive infection rate of CV-A16 was 1.7% (1.0–2.5%), and the recessive infection rate of other enterovirus was 15.1% (11.1–17.1%), as shown in Figure 2.

Figure 2.

Figure 2

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Forest plots for the pooled recessive infection of pathogens of HFMD in healthy people in China (a. HEVs, b. EV-A71, c. CV-A16, and d. other HEVs).

3.3. Subgroup analysis

We conducted a subgroup analysis based on gender and age. The results of meta-analysis showed that the rate of HEVs recessive infection was 16.7% (12.9–20.4%) in males and 14.4% (10.8–18.0%) in females. The rate of HEVs recessive infection was 24.4% (20.4–28.5%) at 0 to 5 years old, and 9.4% (6.5–12.2%) at more than 5 years old.

3.4. Meta-regression analysis

In order to further explore the source of heterogeneity, a meta-regression analysis was conducted with the Chinese population HEVs recessive infection rate as the dependent variable and the sample type, sampling period, sampling area, and study population as the covariables. The results showed that the size of the heterogeneity explained by the covariates included in the model was R2 = 34.86%, and the joint test of all covariates in the model was P = .002. The factors affecting the HEVs recessive infection rate in the Chinese population were the sampling period (t = 2.56, P = .016), the sampling area (t = 2.16, P = .039), and the study population (t = 3.03, P = .005), as shown in Table 2.

Table 2.

Meta-regression analysis results of the latent infection rate of HFMD pathogens in healthy Chinese population.

Covariates Coefficient S.E. t value P 95%CI
Sample type
 Feces 0.056 0.053 1.08 .291 −0.051 to 0.164
 Anal swab Reference
Sampling period
 Epidemic 0.094 0.036 2.56 .016 0.019–0.168
 Non-epidemic Reference
Sampling area
 Rural 0.053 0.024 2.16 .039 0.003–0.104
 Urban Reference
Study population
 Children 0.105 0.035 3.03 .005 0.034–0.075
 Adults Reference
Constant 0.167 0.071 2.37 .025 0.023–0.312
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3.5. Sensitivity analysis

Meta re-analysis was conducted by removing single studies one by one to observe the influence of a single study on the results. The sensitivity analysis results showed no significant difference in the associated recessive infection rate, indicating that the meta-analysis results were relatively stable and that a single study would not have a significant impact on the meta-analysis results, as shown in Figure 3.

Figure 3.

Figure 3

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Sensitive analysis for the recessive infection of HEVs in healthy people in China by removing single studies one by one.

3.6. Publication bias analysis

The Begg's funnel plot and Egger's linear regression were used to evaluate publication bias, which showed that there was a significant publication bias, as shown in Table 3 and Figure 4.

Table 3.

Meta-analysis results of the latent infection rate of HFMD pathogens in healthy Chinese population.

Group No. of study Latent infection 95%CI Cohran's Q test for heterogeneity (P value) I2 (%) Model Begg's P value Egger's P value
HEV type
 HEVs 29 0.175 0.149–0.201 <.001 94.6 Random <.001 <.001
 EV71 18 0.033 0.022–0.044 <.001 90.4 Random <.001 <.001
 COA16 12 0.017 0.010–0.025 <.001 85.8 Random .024 .008
 Other HEVs 22 0.151 0.111–0.171 <.001 94.9 Random .010 <.001
Gender
 Male 13 0.167 0.129–0.204 <.001 86.5 Random .009 .001
 Female 13 0.144 0.108–0.180 <.001 86.1 Random .161 <.001
Age
 0–5 yr old 27 0.244 0.204–0.285 <.001 95.7 Random .003 <.001
 >5 yr old 17 0.094 0.065–0.122 <.001 87.3 Random .001 <.001
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Figure 4.

Figure 4

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Begg's funnel plot for the pooled recessive infection of HEVs in healthy people in China.

4. Discussion

The results of the present meta-analysis showed that the recessive infection rate of HEVs was high among healthy people in China, mainly with other enteric viruses. The recessive infection rates of EV-A71 and CV-A16 were also high, at 3.3% (2.2–4.4%) and 1.7% (1.0–2.5%), respectively. Subgroup analysis showed that male HEVs recessive infection rate was slightly higher than female. The recessive infection rate of HEVs was significantly higher in the population aged 0 to 5 than in the population aged more than 5 years old. The gender and age distributions of HEVs recessive infection rate in healthy Chinese population are consistent with the distribution characteristics of HFMD cases in China.[41] It is suggested that the prevention and control measures focus on young children should be taken during the epidemic of HFMD.

Meta-regression analysis showed that the factors affecting the HEVs recessive infection rate in Chinese population included sampling period (epidemic and non-epidemic), sampling area (city and rural), and study population (children and adults), which were consistent with the epidemiological characteristics reported in China such as the epidemic period of HFMD, higher incidence in rural areas than in urban areas, and more cases concentrated in children under 5 years old. In the future, health education on HFMD prevention in nurseries and primary schools in rural areas should be strengthened, and good hygiene practices should be promoted, especially during epidemics of HFMD. Kindergartens, primary schools, and other key units should strengthen morning screening to identify cases as soon as possible. If a suspicious case is found, the one should be encouraged to return to the hospital for medical treatment and placed in home isolation. Schools should pay close attention to the physical condition of close contacts of the case, and classes may be suspended if necessary.

There was a large heterogeneity in this meta-analysis, so subgroup analysis and meta-regression analysis were used to explore the source of heterogeneity. Gender and age were selected as the grouping factors in this meta-analysis. Since most of the literature grouped these 2 factors, the analysis of these 2 subgroups could appropriately avoid the influence of other confounding factors. For other factors that may influence heterogeneity, meta-regression analysis was used to include the possible influencing factors into the covariables. However, meta regression analysis requires a certain number of covariables, usually no more than the number of included references/10, otherwise, type I error will increase significantly.[42] In this meta-regression analysis, 34.86% of the heterogeneity was explained. Other sources of heterogeneity may include geographical location, climatic factors, sample size, sampling method, etc. In order to evaluate the robustness of meta-analysis results, sensitivity analysis showed that the removal of a single reference would not have a significant impact on the combined results, indicating that the study results were relatively stable. The analysis of publication bias showed that there was significant publication bias in each comparison group. The publication bias may be caused by the unpublished literature with low recessive infection rate or the unsearched gray literatures.

The results of this meta-analysis need to be interpreted with caution and have some limitations. Firstly, the heterogeneity of the studies included in each research group is relatively large. Although subgroup analysis and meta-regression were used in this meta-analysis to explore the sources of heterogeneity, some heterogeneity could not be explained due to the lack of information in the original literature. Secondly, publication bias may lead to higher analytical results, and literature retrieval and screening may result in missing literature inspection. Finally, in the subgroup analysis, some literatures were not stratified according to the grouping factors, resulting in different numbers of literatures included in each comparison group.

In conclusion, Chinese healthy people have a high rate of HEVs recessive infection. The rate of HEVs recessive infection in males was higher than that in females. The recessive infection rate of HEVs was higher in people aged 0 to 5 than in people aged more than 5 years old. The factors influencing the HEVs recessive infection rate in Chinese population include sampling period, sampling area, and study population. Limited by the quantity and quality of the included studies, more high-quality studies are needed for further verification in the future.

Author contributions

Conceptualization: Yu-Jie Zhou, Bao-Lin Zhao.

Data curation: Yu-Jie Zhou, Xiu-De Niu, Ya-Qing Ding, Zhen Qian.

Formal analysis: Yu-Jie Zhou, Xiu-De Niu.

Methodology: Xiu-De Niu, Ya-Qing Ding, Zhen Qian.

Validation: Xiu-De Niu, Ya-Qing Ding, Zhen Qian.

Writing – original draft: Yu-Jie Zhou.

Writing – review & editing: Yu-Jie Zhou, Bao-Lin Zhao.

Footnotes

Abbreviations: Cox A16 = coxsackievirus group A, EV71 = enterovirus 71, HEVs = human enteroviruses, HFMD = hand, foot, and mouth disease, RT-PCR = reverse transcription polymerase chain reaction.

How to cite this article: Zhou YJ, Niu XD, Ding YQ, Qian Z, Zhao BL. Prevalence of recessive infection of pathogens of hand, foot, and mouth disease in healthy people in China: A meta-analysis. Medicine. 2021;100:7(e24855).

YJZ and XDN contribute equally to this work.

There was no funding support in this study.

The authors have no conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

HEVs = human enteroviruses, HFMD = hand, foot, and mouth disease.

HFMD = hand, foot, and mouth disease.

HEVs = human enteroviruses, HFMD = hand, foot, and mouth disease.

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