Abstract
Background
Enterovirus (EV)-related hand, foot, and mouth disease/herpangina (HFMD/HA) has been prevalent in Guangdong Province, China, since 2010.
Methods
Clinical data for EV-related HFMD/HA inpatients admitted to the Department of Paediatrics of Zhujiang Hospital from 2010 to 2013 were retrospectively reviewed. The corresponding EV serotypes were also determined by reverse transcription-polymerase chain reaction or BLAST analysis of the sequenced partial lengths of the viral protein1/5′-untranslated region.
Results
A total of 867 eligible inpatients admitted during 2010–2013 were included in the study. Of these, the serotype of the responsible EV was successfully identified in 824 cases. The incidence of enterovirus 71 (EV71) infection amongst pediatric HFMD/HA inpatients decreased dramatically from 55.5 % in 2010 to 8.1 % in 2013, with a similar decrease recorded for coxsackievirus A16 (CVA16). However, the incidence of non-EV71/CVA16 infection increased from 30.0 % in 2010 to 83.8 % in 2013. We noted that the types of infection caused by different EV serotypes varied: EV71 was responsible for 100 % of the paralysis cases (26/26), 84.6 % of the deaths (11/13), and 84.1 % of cases with severe central nervous system involvement (SCNSI) (74/88); echovirus contributed to 16.4 % of the deaths (2/13) and 4.4 % of the SCNSI cases; and coxsackievirus accounted for only 2.2 % of the SCNSI cases (2/90). The clinical features of HFMD/HA cases varied greatly during the time period examined, with drastic changes in the hospitalization rates (45.1, 63.7, 36.4, and 19.1 % for 2010, 2011, 2012, and 21013, respectively), mortality rates (2.3, 0.9, 2.5, and 0.0 %, respectively), paralysis (5.1, 1.2, 5.4, and 0.0 %, respectively), SCNSI (16.8, 7.1, 12.7, and 2.2 %, respectively), and acute respiratory infection (21.1, 22.0, 45.9, and 59.0 %, respectively).
Conclusions
The incidences of infection caused by different EV serotypes, along with the clinical features of HFMD/HA cases, changed drastically in Guangdong Province, China, from 2010 to 2013, with the biggest changes observed in 2013. The changed constituent ratios of the different EV serotypes might therefore be responsible for the differences in the observed clinical features of HFMD/HA during this period.
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Background
Many enterovirus (EV) serotypes, including EV71, coxsackievirus A (CVA2, 4, 5, 7, 9, 10, 16), and coxsackievirus B (1, 2, 3, 4, 5), have been reported to cause hand, foot and mouth disease/herpangina (HFMD/HA) in humans. Of these, EV71 and CVA16 have traditionally been the two most common serotypes in mainland China [1–2 shows similar changes in the constituent ratios of outpatients infected with EV71, CVA16, and non-EV71/CVA16. Statistially significant differences were observed in the constituent ratios of EV serotypes in outpatients amongst these years (2011 vs 2012 (p = 0.029), others (p < 0.01)), and statistially significant differences also observed in inpatients amongst these years (p < 0.05), except for 2010 vs 2011 (p =0.966).
Constituent ratios of children infected with EV71, CVA16, or non-EV71/CVA16 admitted to Zhujiang Hospital between 2010 and 2013. Non-EV71/CVA16: non-enterovirus 71 and non-coxsackievirus A16; IP: inpatient; OP: outpatient; EV71: enterovirus 71; CVA: coxsackievirus A
Clinical features of HFMD/HA infection changed during the study period
The clinical features of children with HFMD/HA varied greatly over the study period. The hospitalization rate for HFMD/HA cases decreased from 63.7 % in 2010 to 19.1 % in 2013, while the rates of mortality, paralysis, SCNSI, and CNSI fluctuated drastically between 2010 and 2013 (Fig. 3). Additionally, ARI gradually replaced CNSI as the leading complication of HFMD/HA (Fig. 3). The risk of HFMD/HA sharply declined in 2013, with decreasing incidences of CNSI and SCNSI and no occurrences of paralysis or death.
Evolution of the clinical features of HFMD/HA inpatients admitted to Zhujiang Hospital between 2010 and 2013. SCNSI: severe central nervous system involvement; HFMD/HA: hand, foot, and mouth disease/herpangina; CNSI: central nervous system involvement; ARI: acute respiratory infection; SARI: severe acute respiratory infection; AMI: acute myocardial injury; AHI: acute hepatic injury. Title: the relationship of enterovirus serotype constituent ratios and the clinical features of infected children. We observed the phenomneon of obvious change of clinical features of children infected with enterovirus and a notable change of enterovirus serotype constituent ratios in Guangdong province, China during 2010–2013, which suggested that change of enterovirus serotype constituent ratios might be responsible for the phenomenon of obvious change of clincial features of children infected with enterovirus
The risks of severe complications of HFMD/HA varied depending on EV serotype
Of the 824 cases with an ascertained EV serotype (EV71 (n = 384, 46.6 %), coxsackievirus (n = 423, 51.3 %), and echovirus (n = 17, 2.1 %)), the mortality rates and neurological complications were disproportionately high in infections caused by EV71 and echoviruses, while severe complications were relatively low in cases caused by coxsackievirus. EV71 was responsible for 100 % of the paralysis cases (26/26), 84.6 % of the deaths (11/13), and 82.2 % of the cases of SCNSI (74/90), echovirus was responsible for 16.4 % of the deaths (2/13) and 4.4 % of the cases of SCNSI, while coxsackievirus was responsible for only 2.2 % of the cases of SCNSI (2/90), without causing death or paralysis.
Discussion
This retrospective study demonstrated that the constituent ratios of EV serotypes in Guangdong Province, China, changed significantly between 2010 and 2013. EV71 was the predominant serotype at the beginning of the study period, but was less prevalent by 2013, with the reverse trend observed for CVA6. By 2013, EV71 infections accounted for less than 10 % of cases, whereas non-EV71/CVA16 serotypes caused more than 80 % of infections (Fig. 2). The overwhelming majority of non-EV71/CVA16 infections were caused by CVA6, indicating that CVA6 was the predominant serotype in Guangdong Province in 2013. Two previous studies also confirmed that CVA6 had become the dominant serotype in Guangdong during late 2012 and 2013 [17, 20], with similar reports from other regions of China in 2013 [21, 10–13], whereas the two most common coxsackievirus serotypes, i.e., CVA6 and CVA16, were generally mild with low incidences of SCNSI and death in children [1, 25–27]. Low incidence of diarrhea in HFMD/HA inpatients was observed in each year, which is somehow akin to previous studies [28, 29].
Echovirus was shown to match the capacity of EV71 for causing death and SCNSI (the 17 echovirus infections contributed to 16.4 % of deaths and 4.4 % of the cases of SCNSI), although its relatively low constituent ratio (2.1 %) reduced its influence on the clinical features of HFMD/HA in Guangdong Province over the study period. The two deaths were infected with Echo 2 and Echo 3, respectively; while the four SCNSI cases infected by Echo 2 (2 cases), Echo 3 (1 case) and Echo 1 (1 case) (data not shown). However, a cluster of echovirus infections contributed to the increase in mortality rates and SCNSI in 2012. Therefore, we concluded that the reduced prevalence of EV71 and the increase in coxsackievirus infections were responsible for the changes in clinical features associated with HFMD/HA between 2010 and 2013. In accordance with our results, other countries or regions that experienced a declined threat of HFMD/HA also documented a decrease in EV71 infections and an increase in coxsackievirus infections.
Because this study constitutes a retrospective analysis of patients admitted to an officially designated HFMD hospital that treats patients from the provincial capital and referrals from other regions of Guangdong Province, there is an inherent bias in the study results. Additionally, bias might be generated by uneven patient distribution from the different districts, which might affect the degree to which the clinical features and serotype constituent ratios for EV-related HFMD/HA in Guangdong Province between 2010 and 2013 are represented.
Conclusions
Our study demonstrated that EV71 was the predominant serotype in Guangdong Province at the beginning of the study period, but had declined in prevalence by 2013. In comparison, the incidence of CVA6 infections significantly increased over the same period, with CVA6 becoming the dominant serotype in 2013. Additionally, our data suggested that the changed constituent ratios of the EV serotypes might have influenced the clinical features of HFMD/HA infection in Guangdong Province, China, from 2010 to 2013.
Abbreviations
ALT, alanine amino transferase; ARI, acute respiratory infection; CA, coxsackievirus A; CK, creatine kinase; CK-MB, creatine kinase-MB; CNSI, central nervous system involvement; cTnI, cardiac troponin I; EV, enterovirus; HFMD/HA, hand-foot-mouth disease/herpangina; non-EV71/CVA16, non-enterovirus 71 and non-coxsackievirus A16; RT-PCR, reverse transcription-polymerase chain reaction; SCNSI, severe central nervous system involvement; UTR, untranslated region; VP1, viral protein 1
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Acknowledgments
We thank Fu Ning (Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China) for her considerable advice and for revising the manuscript, all the doctors in the Department of Paediatrics at Zhujiang Hospital, China, for providing the inpatient medical records, and **a N (National Institute of Diagnostics and Vaccine Development in Infectious Disease, **amen University, **amen, China) for providing the primers for amplifying the enteroviral 5′-UTR. This work was supported by National Projects of Major Infectious. Disease Control and Prevention of China (grant number 2012ZX10004213), and by the National High Technology Research and Development Programme of China (863 Programme) (grant number 2011AA02A116). The funders played no role in study design, in the collection, analysis, or interpretation of data, in the writing of the manuscript, or in the decision to submit the manuscript for publication.
Funding
The work was supported by National Projects of Major Infectious Disease Control and Prevention of China (grant number 2012ZX10004213), and by the National High Technology Research and Development Programme of China (863 Programme) (grant number 2011AA02A116).
Availability of data and materials
Data and materials are available in Additional files 1 and 2 (sequence of enterovirus-zhou; clinical data of enterovirus).
Authors’ contributions
H-TZ collected data for the clinical investigation, performed the serotype identification analysis, and drafted the original manuscript. Y-HG participated in the serotype identification analysis and carried out the RT-PCR analysis. BW confirmed the clinical features of the cases. M-JC collected the clinical specimens. Y-XP performed the virus isolation. LX participated in collecting and analyzing the data. S-HT jointly confirmed the clinical features of the cases. NY performed the RT-PCR analysis and revised the manuscript. All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Verbal consent of participating the project was obtained from their legal guardian, father or mother, and we guaranteed the privacy of each case was not violated by processing data anonmously. No individual persons data is involved in this manuscript, therefore, consent of patient to participate the project is not necessary.
Ethics approval and consent to participate
The study was approved by the Ethics Committee of Zhujiang Hospital (ratification no.: ZJYY-2013-YXJYZX-001).
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Additional files
Additional file 1:
Sequence data of non-EV71/CVA16 enterovirus isolated from HFMD/HA inpatients admitted to Zhujiang hospital between 2010 to 2013. (XLSX 40 kb)
Additional file 2:
Demographical and clinical information of HFMD/HA patients admitted to Zhujiang hospital between 2010-2013. (XLS 4462 kb)
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Zhou, HT., Guo, YH., Chen, MJ. et al. Changes in enterovirus serotype constituent ratios altered the clinical features of infected children in Guangdong Province, China, from 2010 to 2013. BMC Infect Dis 16, 399 (2016). https://doi.org/10.1186/s12879-016-1690-0
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DOI: https://doi.org/10.1186/s12879-016-1690-0