Hand, foot, and mouth disease in China, 2008–12: an epidemiological study  Weijia Xing, PhD, Qiaohong Liao, MD, Cécile Viboud, PhD, Jing Zhang, MD, Junling Sun, PhD, Joseph T Wu, PhD, Zhaorui Chang, MD, Fengfeng Liu, MD, Vicky J Fang, MPhil, Yingdong Zheng, PhD, Benjamin J Cowling, PhD, Jay K Varma, MD, Prof Jeremy J Farrar, PhD, Prof Gabriel M Leung, MD, Dr Hongjie Yu, PhD  The Lancet Infectious Diseases  Volume 14, Issue 4, Pages 308-318 (April 2014) DOI: 10.1016/S1473-3099(13)70342-6 Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 1 Proportions of enterovirus serotypes in laboratory-confirmed cases of hand, foot, and mouth disease by clinical severity in China, 2008–12 (A) Based on mild cases. (B) Based on severe cases who survived. (C) Based on fatal cases. EV71=enterovirus 71. CV-A16=Coxsackie virus A16. The Lancet Infectious Diseases 2014 14, 308-318DOI: (10.1016/S1473-3099(13)70342-6) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 2 Age distribution and clinical severity of probable and laboratory-confirmed cases of hand, foot, and mouth disease in China, 2008–12 (A) Age distribution of probable and laboratory-confirmed cases. (B) Risk of fatality in cases by age group and serotype of virus. (C) Risk of severe illness in cases by age group and serotype of virus. (D) Risk of fatality in severe cases by age group and serotype of virus. We calculated severity estimates in (B)–(D) by extrapolating the serotype distribution in test-positive cases to untested and test-negative cases. The number of mild cases with serotype X (EV71, CV-A16, or other enteroviruses) was estimated to be number of mild cases test-positive for serotype X divided by number of test-positive mild cases times number of mild cases; severe cases were similarly analysed. Results were only similar if the 2010–12 or 2012 data were used (appendix pp 20, 21). EV71=enterovirus 71. CV-A16=Coxsackie virus A16. The Lancet Infectious Diseases 2014 14, 308-318DOI: (10.1016/S1473-3099(13)70342-6) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 3 Estimates of onset-to-diagnosis, onset-to-death, and diagnosis-to-death distributions of probable and laboratory-confirmed cases of hand, foot, and mouth disease in China, 2008–12 (A) Onset-to-diagnosis distribution by serotype of virus (n=7 200 092). (B) Onset-to-death distribution by serotype of virus (n=2457). (C) Diagnosis-to-death distribution by serotype of virus (n=2457). Some intervals are negative because diagnosis was done after death. EV71=enterovirus 71. CV-A16=Coxsackie virus A16. The Lancet Infectious Diseases 2014 14, 308-318DOI: (10.1016/S1473-3099(13)70342-6) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 4 Heat map of surveillance data for hand, foot, and mouth disease by Chinese province, 2008–12 (A) Time series of weekly probable and laboratory-confirmed cases of HFMD, standardised by the number of annual cases. (B) Seasonal distribution of cases of HFMD, plotted as the median value of proportion of cases in each week of the year from 2008 to 2012. For (A) and (B), the provinces were ordered by latitude from northermost (top) to southernmost (bottom). (C) Number of cases of HFMD by week of illness onset. The insert is a superposition of the number of cases without probable cases of HFMD by week of illness onset. HFMD=hand, foot, and mouth disease. EV71=enterovirus 71. CV-A16=Coxsackie virus A16. The Lancet Infectious Diseases 2014 14, 308-318DOI: (10.1016/S1473-3099(13)70342-6) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 5 Latitudinal gradients in periodicity of hand, foot, and mouth disease (A) Amplitude of the annual periodicity. (B) Amplitude of the semiannual periodicity. (C) Contribution of the semiannual periodicity, measured by the ratio of the amplitude of the semiannual periodicity to the sum of the amplitudes of annual and semiannual periodicities (higher ratio suggests a stronger semiannual periodicity). Symbol size is proportional to the number of cases in each province. Black solid lines represent linear regression fit (regression weighted by mean annual number of cases of hand, foot, and mouth disease). p values are given on the graphs. Colours represent different climatic zones (black=cold-temperate, blue=mid-temperate, green=warm-temperate, red=subtropical, turquoise=tropical). The Lancet Infectious Diseases 2014 14, 308-318DOI: (10.1016/S1473-3099(13)70342-6) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 6 Periodicity and peak timing of hand, foot, and mouth disease epidemics in China (A) Amplitude of the annual cycle from pale red (low) to red (high). (B) Importance of the semiannual periodicity, measured by the ratio of the amplitude of the semiannual cycle to the sum of the amplitudes of annual and semiannual cycles. Pale green shows strongly annual epidemics; dark green shows dominant semiannual activity. (C) Timing of primary annual hand, foot, and mouth disease peak, in weeks from Jan 1. Timing is colour coded from pale blue to dark blue. The Lancet Infectious Diseases 2014 14, 308-318DOI: (10.1016/S1473-3099(13)70342-6) Copyright © 2014 Elsevier Ltd Terms and Conditions

Figure 7 Hand, foot, and mouth disease epidemiological regions and predictors (A) Epidemiological regions based on hierarchical clustering, identified with the Euclidian distance between weekly standardised hand, foot, and mouth disease time series. Provinces are colour-coded by climatic region (black=cold-temperate, blue=mid-temperate, green= warm temperate, red=subtropical, turquoise=tropical). (B) Map of the two epidemiological regions identified in (A). (C) Climate predictors of the two main clusters identified in (A), based on stepwise discriminant analysis. The Lancet Infectious Diseases 2014 14, 308-318DOI: (10.1016/S1473-3099(13)70342-6) Copyright © 2014 Elsevier Ltd Terms and Conditions