Hand, foot, and mouth disease in China, 2008-12: an epidemiological study

Abstract

Background: Hand, foot, and mouth disease is a common childhood illness caused by enteroviruses. Increasingly, the disease has a substantial burden throughout east and southeast Asia. To better inform vaccine and other interventions, we characterised the epidemiology of hand, foot, and mouth disease in China on the basis of enhanced surveillance.

Methods: We extracted epidemiological, clinical, and laboratory data from cases of hand, foot, and mouth disease reported to the Chinese Center for Disease Control and Prevention between Jan 1, 2008, and Dec 31, 2012. We then compiled climatic, geographical, and demographic information. All analyses were stratified by age, disease severity, laboratory confirmation status, and enterovirus serotype.

Findings: The surveillance registry included 7,200,092 probable cases of hand, foot, and mouth disease (annual incidence, 1·2 per 1000 person-years from 2010-12), of which 267,942 (3·7%) were laboratory confirmed and 2457 (0·03%) were fatal. Incidence and mortality were highest in children aged 12-23 months (38·2 cases per 1000 person-years and 1·5 deaths per 100,000 person-years in 2012). Median duration from onset to diagnosis was 1·5 days (IQR 0·5-2·5) and median duration from onset to death was 3·5 days (2·5-4·5). The absolute number of patients with cardiopulmonary or neurological complications was 82,486 (case-severity rate 1·1%), and 2457 of 82486 patients with severe disease died (fatality rate 3·0%); 1617 of 1737 laboratory confirmed deaths (93%) were associated with enterovirus 71. Every year in June, hand, foot, and mouth disease peaked in north China, whereas southern China had semiannual outbreaks in May and September-October. Geographical differences in seasonal patterns were weakly associated with climate and demographic factors (variance explained 8-23% and 3-19%, respectively).

Interpretation: This is the largest population-based study up to now of the epidemiology of hand, foot, and mouth disease. Future mitigation policies should take into account the heterogeneities of disease burden identified. Additional epidemiological and serological studies are warranted to elucidate the dynamics and immunity patterns of local hand, foot, and mouth disease and to optimise interventions.

Funding: China-US Collaborative Program on Emerging and Re-emerging Infectious Diseases, WHO, The Li Ka Shing Oxford Global Health Programme and Wellcome Trust, Harvard Center for Communicable Disease Dynamics, and Health and Medical Research Fund, Government of Hong Kong Special Administrative Region.

Figure 1. Proportions of enterovirus serotypes among laboratory-confirmed HFMD cases by clinical severity, 2008-2012, China

A: based on mild cases. B: based on severe cases who survived, C: based on fatal cases.

Figure 2. Age distribution and clinical severity of probable and laboratory-confirmed (EV-A71, CA-V16 or other enteroviruses) HFMD cases, 2008-2012, China

A: Age distribution of probable and lab-confirmed cases. B: Risk of fatality among cases by age group and viral etiology. C: Risk of severe illness among cases by age group and viral etiology. D: Risk of fatality among severe cases by age group and viral etiology. EV-A71, enterovirus 71; CA-V16, Coxsackievirus A16; mth, months; y, years. Severity estimates in B-D were calculated by extrapolating the serotype distribution among test-positive cases to untested and test-negative cases. That is, the number of mild cases with serotype X ( = EV-A71, CA-V16 or other enteroviruses) was estimated to be (no. of mild cases test-positive for serotype X)/(no. of test-positive mild cases) x (no. of mild cases); severe cases were similarly analyzed. Results were similar if only the 2010-2012 or 2012 data were used (Appendix Figures 4&5).

Figure 3. Estimates of onset-to-diagnosis, onset-to-death, and diagnosis-to-death distributions of probable and laboratory-confirmed (EV-A71, CA-V16 or other enteroviruses) HFMD cases, 2008-2012, China

A: Onset-to-diagnosis distribution by viral etiology (n=7,200,092). B: Onset-to-death distribution by viral etiology (n=2457). C: Diagnosis-to-death distribution by viral etiology (n=2457). Note that some intervals are negative because diagnosis occurred after death.

Figure 4. Heatmap of HFMD surveillance data from 2008 to 2012 by Chinese province

The provinces were ordered by latitude from Northermost (top) to Southernmost (bottom). A: Time series of weekly probable and lab-confirmed HFMD cases, standardized by the number of annual cases. B: Seasonal distribution of HFMD cases, plotted as the median value of proportion of cases in each week of the year from 2008 to 2012. C: Number of HFMD cases by week of illness onset. The insert is a superposition of the number of cases without probable HFMD cases by week of illness onset.

Figure 5. Latitudinal gradients in periodicity and peak timing of HFMD

A: Amplitude of the annual periodicity. B: Annual peak timing. C: Contribution of the semi-annual periodicity, measured by the ratio of the amplitude of the semi-annual periodicity to the sum of the amplitudes of annual and semi-annual periodicities (higher ratio indicates a stronger semi-annual periodicity). Symbol size is proportional to the number of cases in each province. Black solid line represent linear regression fit (regression weighted by mean annual number of HFMD cases). P-values are given on the graphs. Colors represent different climatic zones (black: cold-temperate, blue mid-temperate, green warm-temperate, orange subtropical, red tropical).

Figure 6. Amplitude and timing of primary HFMD epidemics in China

A: Amplitude of the annual cycle from yellow (low) to red (high), as indicated in the legend. B: Importance of the semi-annual periodicity, measured by the ratio of the amplitude of the semi-annual cycle to the sum of the amplitudes of annual and semi-annual cycles. Pale green indicates strongly annual influenza epidemics, while dark green indicates dominant semi-annual activity. C: Timing of primary annual HFMD peak, in weeks from Jan 1st. Timing is color coded from pale blue to dark blue.

Figure 7. HFMD epidemiological regions and predictors

A: Identified epidemiological regions based on hierarchical clustering, using the Euclidian distance between weekly standardized HFMD time series. Provinces are color-coded by climatic region (black: cold-temperate, blue: mid-temperate, green: warm temperate, orange: subtropical, red: tropical). B: Map of the three epidemiological regions identified in panel A. C: Climate predictors of the two main clusters identified in panel A, based on stepwise discriminant analysis.