Clinical and epidemiological study of hand, foot and mouth disease in China

Abstract

Hand, foot and mouth disease (HFMD) is a common infectious disease among children, mainly caused by a variety of human enteroviruses (EVs) of Species A. There have been repeated HFMD epidemics in the Asia-Pacific region since 1990s, posing a significant threat to children’s health. To illustrate the pathogens spectrum of HFMD and characterize the clinical manifestations of HFMD by virus serotype, this research combined both epidemiological and clinical studies in mainland China.

First, my analyses of national surveillance data from 2010 to 2018 in mainland China revealed a consecutive decline in notifiable EV-A71-associated HFMD incidence from 570 per 1 million person-years in 2016 to 247 per 1 million person-years in 2018, whereas the overall notifiable HFMD incidence remained stable around 1700 per 1 million person-years between 2016 and 2018. Meanwhile, other non-EV-A71 EVs accounted for increasingly more cases in both mild and severe HFMD, with CV-A6 becoming a major serotype of causative pathogens for HFMD since 2013.

Furthermore, I conducted a prospective cohort study on HFMD at a tertiary paediatric hospital in Henan Province of central China. I found infections with other non-EV-A71 EVs could also bring a certain risk of developing severe HFMD, with proportion of CNS complications ranging from 4% (15/343) to 17% (10/59) depending on the specific serotype of EVs, but their risks of severe HFMD were still significantly lower than that of EV-A71. I identified several non-neurological symptoms and clinical tests associated with the risk of severe HFMD.

My systematic review on the dynamics of EV-A71 shedding revealed that over 87% of HFMD patients with EV-A71 shed the virus through the respiratory tract in the first seven days since illness onset, while at least 77% of infected patients shed EV-A71 by stool during the first two weeks, and viral shedding could last long beyond two weeks in stool. Moreover, my analysis of the data from the clinical study suggested that viral loads of EVs were associated with the clinical severity of HFMD, and generally tended to decrease after illness onset.

Finally, I performed a test-negative study based on data of the cohort study, and identified the effectiveness of complete EV-A71 vaccination was 85% and the effectiveness of partial vaccination was 63%. I also found the monovalent EV-A71 vaccines conferred no protective effects on other EVs.

In conclusion, CV-A6 has become an emerging major EV for causing HFMD, while EV-A71-related HFMD incidence has considerably declined since 2016 in mainland China. Other EVs of Species A than EV-A71 can also cause severe HFMD in children, but clinical severity of the illness caused by these EVs was still milder compared with EV-A71. The first two weeks after illness onset was a good time for virologic testing of HFMD patients with EV-A71. Viral load of EVs was a factor associated with severe HFMD. EV-A71 vaccines were effective in preventing EV-A71 infections but could not provide cross-protection for other EVs.