Date Published: June 6, 2019
Publisher: Public Library of Science
Author(s): Jing Li, Zeyuan Yang, Zhixuan Wang, Yong Xu, Shuibin Luo, Xuelan Yu, Juan Liu, Yan Zhou, Wenbin Tong, Peibin Zeng, Maël Bessaud.
Hand, foot, and mouth disease (HFMD) is well recognized as one of the major threats to children’s health globally. The increasing complexity of the etiology of HFMD still challenges disease control in China. There is little surveillance of the molecular epidemiological characteristics of the enteroviruses (EVs) that cause HFMD in Neijiang city or the Sichuan Basin area in Southwest China. In this study, demographic and epidemiological information for 14,928 probable HFMD cases was extracted and analyzed to describe the epidemic features of HFMD in Neijiang city from Jan 2010 to Dec 2017. The swab samples of select probable HFMD cases from 2012 to 2017 were tested by reverse transcription (RT) real-time PCR to identify the serotype distribution of EVs, and 110 randomly selected RT-real-time PCR positive samples were then amplified and analyzed for the VP1 or VP4 regions of EVs to further analyze the phylogenetic characteristics of the circulating strains in this area. The eight-year average annual incidence was 49.82 per 100,000 in Neijiang. The incidence rates varied between 19.51 and 70.73 per 100,000, demonstrating peaks of incidence in even-number years (2012, 2014 and 2016). The median age of the probable cases was 27 months and the interquartile range (25th to 75th percentile) of ages for the probable HFMD cases was between 14 and 42 months. The male-to-female ratio of the probable HFMD cases was 1.47:1, and scattered children were the major population classification (81.7%). Two epidemic peaks were observed: one major peak between April and July and the other lesser peak between October and December. Of 6513 probable cases tested with RT-real-time PCR, 4015 (61.6%) were positive for enterovirus with the serotype distribution as follows: EV71+, 30.1% (n = 1210); CV-A16+, 28.7% (n = 1154) and a sole pan-enterovirus+, 41.1% (n = 1651). A total of 91 cases (82.7%, 91/110) were successfully amplified and underwent phylogenetic analysis: all EV71+ cases were C4a serotype (n = 23/30); all CV-A16+ cases were B2b serotype (n = 24/30); of 42 sole pan-enterovirus+ samples, 20 were CV-A6, 14 were CV-A10 and the rest within this group were CV-A4 (n = 4), CV-A8 (n = 2), CV-A9 (n = 1) and CV-B3 (n = 1). Our findings provide important evidence that aids the improvement of strategies for vaccination against HFMD and comprehensive disease control in China.
Hand, foot and mouth disease (HFMD) is known as an infectious disease caused by a group of enteroviruses that have a global distribution. Enteroviruses are members of the genus Enterovirus with more than 100 serotypes and are classified into four species: EV-A, EV-B, EV-C and EV-D . Enterovirus 71 (EV71) and coxsackievirus A16 (CV-A16) from EV-A are the main circulating agents that cause HFMD, and EV71 is dominant in severe cases . HFMD mostly occurs in children under 5 years old, resulting in various clinical symptoms including fever, skin eruptions of hands, feet and buttocks, and mouth vesicles or ulcers . In China, the incidence rate of HFMD is estimated to be 120/100,000 per year with 500–900 reported annual deaths and is frequently ranked third after tuberculosis and hepatitis on the list of notifiable infectious diseases [3, 5]. EV71 and CV-A16 are the most prevalent serotypes, accounting for more than 70% of infections reported from a Chinese national-scale investigation from 2008 to 2012, and coxsackievirus A6 (CV-A6) and coxsackievirus A10 (CV-A10) have emerged with increasing epidemics in recent years [6–8].
A total of 14 928 probable cases of HFMD were reported during 2010–2017 in Neijiang, China, of which 47 (0.31%) were severe cases (Table 1). The annual incidence (calculated from probable cases) increased sharply from 19.51 to 70.73 per 100,000 from 2010 to 2012 and varied between 40 and 65 per 100,000 between 2013 and 2017, with an eight-year average annual incidence of 49.82 per 100,000. Notably, the variations in the incidence rates from 2012 to 2017 demonstrated a regular pattern of sine distribution with peaks at even-number years (2012, 2014 and 2016) (Fig 1). The median age of the probable cases was 27 months (range from 1 month to 192 months). The interquartile range (25th to 75th percentile) of ages for the probable HFMD cases was between 14 and 42 months. There were more male than female cases (1.47:1), and most (81.7%) cases were from scattered children (children who do not attend kindergarten and are usually taken care of by their parents), followed by the children in kindergarten (16.5%). The monthly distribution of the probable HFMD cases displayed two epidemic peaks: the major peak was between April and July and the smaller peak was between October and December (Fig 2).
Based on the data of an eight-year (2010–2017) surveillance of HFMD cases in Neijiang city, our study provided a comprehensive review of the epidemiology and distribution of HFMD serotypes in this area. The estimated incidence of HFMD was 49.82 per 100,000, which was lower than the national average of 120 per 100,000 (2008 to 2012)  and the adjacent Chongqing city (also located on inner land in Southwest China with an incidence rate of 114.8 per 100,000 in 2009–2016) . The incidence rate was similar to that from the Sichuan provincial investigation from 2008 to 2013 (43.65 per 100,000). The incidence rates between 2012 and 2017 represented a temporally changing epidemic in Neijiang, similar to the annual epidemic in Japan, but different from other provinces in China[17, 18], Taiwan, Singapore, and Malaysia, where a recurring epidemic was observed every 3 to 4 years. The seasonal pattern of the HFMD epidemic in Neijiang during the study period showed two main epidemic peaks: one in late spring and early summer and the other in late autumn and winter, which was close to that in the Chongqing region . This seasonal pattern is consistent with the large-scale national analysis from 2008 to 2012. Factors driving the epidemic and seasonal pattern may be related to geographic locations, population density, environmental conditions and even the carriers of the virus, which need to be further evaluated.
In conclusion, our findings depicted the HFMD epidemic status and serotype distributions in the Neijiang region and contributed to the databank of comprehensive HFMD control and prevention in China.