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


RESULTS
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).


CONCLUSIONS
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.


BACKGROUND
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.
Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China (W Xing PhD, Q Liao MD, J Zhang MD, J Sun PhD, Zhaorui Chang MD, F Liu MD, H Yu MD); Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (C Viboud PhD); Division of Epidemiology and Biostatistics, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China (B J Cowling PhD, J T Wu PhD, V J Fang MPhil, Prof G M Leung MD); School of Public Health, Peking University, Health Science Center, Beijing, China (Y Zheng PhD); New York City Department of Health and Mental Hygiene, New York, USA (J K Varma MD); Oxford University Clinical Research Unit - Wellcome Trust Major Overseas Programmes, Vietnam (Prof J J Farrar PhD); ISARIC, Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom (Prof J J Farrar PhD); Department of Medicine, National University of Singapore, Singapore (Prof J J Farrar PhD); The Li Ka Shing Oxford Global Health Programme and Wellcome Trust (Prof J J Farrar PhD).
Weijia
W
Xing
Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China (W Xing PhD, Q Liao MD, J Zhang MD, J Sun PhD, Zhaorui Chang MD, F Liu MD, H Yu MD); Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (C Viboud PhD); Division of Epidemiology and Biostatistics, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China (B J Cowling PhD, J T Wu PhD, V J Fang MPhil, Prof G M Leung MD); School of Public Health, Peking University, Health Science Center, Beijing, China (Y Zheng PhD); New York City Department of Health and Mental Hygiene, New York, USA (J K Varma MD); Oxford University Clinical Research Unit - Wellcome Trust Major Overseas Programmes, Vietnam (Prof J J Farrar PhD); ISARIC, Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom (Prof J J Farrar PhD); Department of Medicine, National University of Singapore, Singapore (Prof J J Farrar PhD); The Li Ka Shing Oxford Global Health Programme and Wellcome Trust (Prof J J Farrar PhD).
Qiaohong
Q
Liao
Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China (W Xing PhD, Q Liao MD, J Zhang MD, J Sun PhD, Zhaorui Chang MD, F Liu MD, H Yu MD); Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (C Viboud PhD); Division of Epidemiology and Biostatistics, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China (B J Cowling PhD, J T Wu PhD, V J Fang MPhil, Prof G M Leung MD); School of Public Health, Peking University, Health Science Center, Beijing, China (Y Zheng PhD); New York City Department of Health and Mental Hygiene, New York, USA (J K Varma MD); Oxford University Clinical Research Unit - Wellcome Trust Major Overseas Programmes, Vietnam (Prof J J Farrar PhD); ISARIC, Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom (Prof J J Farrar PhD); Department of Medicine, National University of Singapore, Singapore (Prof J J Farrar PhD); The Li Ka Shing Oxford Global Health Programme and Wellcome Trust (Prof J J Farrar PhD).
Cécile
C
Viboud
Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China (W Xing PhD, Q Liao MD, J Zhang MD, J Sun PhD, Zhaorui Chang MD, F Liu MD, H Yu MD); Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (C Viboud PhD); Division of Epidemiology and Biostatistics, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China (B J Cowling PhD, J T Wu PhD, V J Fang MPhil, Prof G M Leung MD); School of Public Health, Peking University, Health Science Center, Beijing, China (Y Zheng PhD); New York City Department of Health and Mental Hygiene, New York, USA (J K Varma MD); Oxford University Clinical Research Unit - Wellcome Trust Major Overseas Programmes, Vietnam (Prof J J Farrar PhD); ISARIC, Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom (Prof J J Farrar PhD); Department of Medicine, National University of Singapore, Singapore (Prof J J Farrar PhD); The Li Ka Shing Oxford Global Health Programme and Wellcome Trust (Prof J J Farrar PhD).
Jing
J
Zhang
Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China (W Xing PhD, Q Liao MD, J Zhang MD, J Sun PhD, Zhaorui Chang MD, F Liu MD, H Yu MD); Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (C Viboud PhD); Division of Epidemiology and Biostatistics, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China (B J Cowling PhD, J T Wu PhD, V J Fang MPhil, Prof G M Leung MD); School of Public Health, Peking University, Health Science Center, Beijing, China (Y Zheng PhD); New York City Department of Health and Mental Hygiene, New York, USA (J K Varma MD); Oxford University Clinical Research Unit - Wellcome Trust Major Overseas Programmes, Vietnam (Prof J J Farrar PhD); ISARIC, Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom (Prof J J Farrar PhD); Department of Medicine, National University of Singapore, Singapore (Prof J J Farrar PhD); The Li Ka Shing Oxford Global Health Programme and Wellcome Trust (Prof J J Farrar PhD).
Junling
J
Sun
Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China (W Xing PhD, Q Liao MD, J Zhang MD, J Sun PhD, Zhaorui Chang MD, F Liu MD, H Yu MD); Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (C Viboud PhD); Division of Epidemiology and Biostatistics, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China (B J Cowling PhD, J T Wu PhD, V J Fang MPhil, Prof G M Leung MD); School of Public Health, Peking University, Health Science Center, Beijing, China (Y Zheng PhD); New York City Department of Health and Mental Hygiene, New York, USA (J K Varma MD); Oxford University Clinical Research Unit - Wellcome Trust Major Overseas Programmes, Vietnam (Prof J J Farrar PhD); ISARIC, Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom (Prof J J Farrar PhD); Department of Medicine, National University of Singapore, Singapore (Prof J J Farrar PhD); The Li Ka Shing Oxford Global Health Programme and Wellcome Trust (Prof J J Farrar PhD).
Joseph T
JT
Wu
Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China (W Xing PhD, Q Liao MD, J Zhang MD, J Sun PhD, Zhaorui Chang MD, F Liu MD, H Yu MD); Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (C Viboud PhD); Division of Epidemiology and Biostatistics, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China (B J Cowling PhD, J T Wu PhD, V J Fang MPhil, Prof G M Leung MD); School of Public Health, Peking University, Health Science Center, Beijing, China (Y Zheng PhD); New York City Department of Health and Mental Hygiene, New York, USA (J K Varma MD); Oxford University Clinical Research Unit - Wellcome Trust Major Overseas Programmes, Vietnam (Prof J J Farrar PhD); ISARIC, Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom (Prof J J Farrar PhD); Department of Medicine, National University of Singapore, Singapore (Prof J J Farrar PhD); The Li Ka Shing Oxford Global Health Programme and Wellcome Trust (Prof J J Farrar PhD).
Zhaorui
Z
Chang
Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China (W Xing PhD, Q Liao MD, J Zhang MD, J Sun PhD, Zhaorui Chang MD, F Liu MD, H Yu MD); Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (C Viboud PhD); Division of Epidemiology and Biostatistics, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China (B J Cowling PhD, J T Wu PhD, V J Fang MPhil, Prof G M Leung MD); School of Public Health, Peking University, Health Science Center, Beijing, China (Y Zheng PhD); New York City Department of Health and Mental Hygiene, New York, USA (J K Varma MD); Oxford University Clinical Research Unit - Wellcome Trust Major Overseas Programmes, Vietnam (Prof J J Farrar PhD); ISARIC, Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom (Prof J J Farrar PhD); Department of Medicine, National University of Singapore, Singapore (Prof J J Farrar PhD); The Li Ka Shing Oxford Global Health Programme and Wellcome Trust (Prof J J Farrar PhD).
Fengfeng
F
Liu
Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China (W Xing PhD, Q Liao MD, J Zhang MD, J Sun PhD, Zhaorui Chang MD, F Liu MD, H Yu MD); Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (C Viboud PhD); Division of Epidemiology and Biostatistics, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China (B J Cowling PhD, J T Wu PhD, V J Fang MPhil, Prof G M Leung MD); School of Public Health, Peking University, Health Science Center, Beijing, China (Y Zheng PhD); New York City Department of Health and Mental Hygiene, New York, USA (J K Varma MD); Oxford University Clinical Research Unit - Wellcome Trust Major Overseas Programmes, Vietnam (Prof J J Farrar PhD); ISARIC, Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom (Prof J J Farrar PhD); Department of Medicine, National University of Singapore, Singapore (Prof J J Farrar PhD); The Li Ka Shing Oxford Global Health Programme and Wellcome Trust (Prof J J Farrar PhD).
Vicky J
VJ
Fang
Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China (W Xing PhD, Q Liao MD, J Zhang MD, J Sun PhD, Zhaorui Chang MD, F Liu MD, H Yu MD); Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (C Viboud PhD); Division of Epidemiology and Biostatistics, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China (B J Cowling PhD, J T Wu PhD, V J Fang MPhil, Prof G M Leung MD); School of Public Health, Peking University, Health Science Center, Beijing, China (Y Zheng PhD); New York City Department of Health and Mental Hygiene, New York, USA (J K Varma MD); Oxford University Clinical Research Unit - Wellcome Trust Major Overseas Programmes, Vietnam (Prof J J Farrar PhD); ISARIC, Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom (Prof J J Farrar PhD); Department of Medicine, National University of Singapore, Singapore (Prof J J Farrar PhD); The Li Ka Shing Oxford Global Health Programme and Wellcome Trust (Prof J J Farrar PhD).
Yingdong
Y
Zheng
Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China (W Xing PhD, Q Liao MD, J Zhang MD, J Sun PhD, Zhaorui Chang MD, F Liu MD, H Yu MD); Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (C Viboud PhD); Division of Epidemiology and Biostatistics, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China (B J Cowling PhD, J T Wu PhD, V J Fang MPhil, Prof G M Leung MD); School of Public Health, Peking University, Health Science Center, Beijing, China (Y Zheng PhD); New York City Department of Health and Mental Hygiene, New York, USA (J K Varma MD); Oxford University Clinical Research Unit - Wellcome Trust Major Overseas Programmes, Vietnam (Prof J J Farrar PhD); ISARIC, Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom (Prof J J Farrar PhD); Department of Medicine, National University of Singapore, Singapore (Prof J J Farrar PhD); The Li Ka Shing Oxford Global Health Programme and Wellcome Trust (Prof J J Farrar PhD).
Benjamin J
BJ
Cowling
Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China (W Xing PhD, Q Liao MD, J Zhang MD, J Sun PhD, Zhaorui Chang MD, F Liu MD, H Yu MD); Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (C Viboud PhD); Division of Epidemiology and Biostatistics, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China (B J Cowling PhD, J T Wu PhD, V J Fang MPhil, Prof G M Leung MD); School of Public Health, Peking University, Health Science Center, Beijing, China (Y Zheng PhD); New York City Department of Health and Mental Hygiene, New York, USA (J K Varma MD); Oxford University Clinical Research Unit - Wellcome Trust Major Overseas Programmes, Vietnam (Prof J J Farrar PhD); ISARIC, Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom (Prof J J Farrar PhD); Department of Medicine, National University of Singapore, Singapore (Prof J J Farrar PhD); The Li Ka Shing Oxford Global Health Programme and Wellcome Trust (Prof J J Farrar PhD).
Jay K
JK
Varma
Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China (W Xing PhD, Q Liao MD, J Zhang MD, J Sun PhD, Zhaorui Chang MD, F Liu MD, H Yu MD); Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (C Viboud PhD); Division of Epidemiology and Biostatistics, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China (B J Cowling PhD, J T Wu PhD, V J Fang MPhil, Prof G M Leung MD); School of Public Health, Peking University, Health Science Center, Beijing, China (Y Zheng PhD); New York City Department of Health and Mental Hygiene, New York, USA (J K Varma MD); Oxford University Clinical Research Unit - Wellcome Trust Major Overseas Programmes, Vietnam (Prof J J Farrar PhD); ISARIC, Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom (Prof J J Farrar PhD); Department of Medicine, National University of Singapore, Singapore (Prof J J Farrar PhD); The Li Ka Shing Oxford Global Health Programme and Wellcome Trust (Prof J J Farrar PhD).
Jeremy J
JJ
Farrar
Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China (W Xing PhD, Q Liao MD, J Zhang MD, J Sun PhD, Zhaorui Chang MD, F Liu MD, H Yu MD); Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (C Viboud PhD); Division of Epidemiology and Biostatistics, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China (B J Cowling PhD, J T Wu PhD, V J Fang MPhil, Prof G M Leung MD); School of Public Health, Peking University, Health Science Center, Beijing, China (Y Zheng PhD); New York City Department of Health and Mental Hygiene, New York, USA (J K Varma MD); Oxford University Clinical Research Unit - Wellcome Trust Major Overseas Programmes, Vietnam (Prof J J Farrar PhD); ISARIC, Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom (Prof J J Farrar PhD); Department of Medicine, National University of Singapore, Singapore (Prof J J Farrar PhD); The Li Ka Shing Oxford Global Health Programme and Wellcome Trust (Prof J J Farrar PhD).
Gabriel M
GM
Leung
Division of Infectious Disease, Key Laboratory of Surveillance and Early-warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China (W Xing PhD, Q Liao MD, J Zhang MD, J Sun PhD, Zhaorui Chang MD, F Liu MD, H Yu MD); Fogarty International Center, National Institutes of Health, Bethesda, MD, USA (C Viboud PhD); Division of Epidemiology and Biostatistics, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China (B J Cowling PhD, J T Wu PhD, V J Fang MPhil, Prof G M Leung MD); School of Public Health, Peking University, Health Science Center, Beijing, China (Y Zheng PhD); New York City Department of Health and Mental Hygiene, New York, USA (J K Varma MD); Oxford University Clinical Research Unit - Wellcome Trust Major Overseas Programmes, Vietnam (Prof J J Farrar PhD); ISARIC, Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom (Prof J J Farrar PhD); Department of Medicine, National University of Singapore, Singapore (Prof J J Farrar PhD); The Li Ka Shing Oxford Global Health Programme and Wellcome Trust (Prof J J Farrar PhD).
Hongjie
H
Yu
D000293:Adolescent; D000367:Age Factors; D002648:Child; D002675:Child, Preschool; D002681:China / Q000453:epidemiology; D004770:Enterovirus / Q000145:classification; D029821:Enterovirus A, Human; D005260:Female; D005843:Geography; D006232:Hand, Foot and Mouth Disease / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality / Q000821:virology; D006801:Humans; D015994:Incidence; D007223:Infant; D008297:Male; D011891:Rain; D012621:Seasons; D012703:Serotyping; D012720:Severity of Illness Index; D013997:Time Factors