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432 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 24, No. 3, March 2018
Using China’s national surveillance data on hand, foot and
mouth disease (HFMD) for 2008–2015, we described the
epidemiologic and virologic features of recurrent HFMD. A
total of 398,010 patients had HFMD recurrence; 1,767 pa-
tients had 1,814 cases of recurrent laboratory-conrmed
HFMD: 99 reinfections of enterovirus A71 (EV-A71) with
EV-A71, 45 of coxsackievirus A16 (CV-A16) with CV-A16,
364 of other enteroviruses with other enteroviruses, 383 of
Epidemiology of Recurrent
Hand, Foot and Mouth Disease,
China, 2008–2015
Jiao Huang,1 Qiaohong Liao,1 Mong How Ooi, Benjamin J. Cowling, Zhaorui Chang,
Peng Wu, Fengfeng Liu, Yu Li, Li Luo, Shuanbao Yu, Hongjie Yu,2 Sheng Wei2
Author aliations: Huazhong University of Science and
Technology, Wuhan, China (J. Huang, S. Wei); Chinese
Center for Disease Control and Prevention, Beijing, China
(J. Huang, Q. Liao, Z. Chang, F. Liu, Y. Li, L. Luo, S. Yu,
H. Yu); Sarawak General Hospital, Kuching, Malaysia (M.H. Ooi);
Universiti Malaysia Sarawak, Kota Samarahan, Malaysia
(M.H. Ooi); The University of Hong Kong, Hong Kong, China
(B.J. Cowling, P. Wu, Y. Li); Fudan University, Shanghai, China
(H. Yu)
DOI: https://doi.org/10.3201/eid2403.171303
1These rst authors contributed equally to this article.
2These senior authors contributed equally to this article.
Page 1 of 1
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Learning Objectives
Upon completion of this activity, participants will be able to:
• Describe the epidemiologic features of recurrent hand-foot-and-mouth disease (HFMD), using national
surveillance data during 2008 –2015 in mainland China
• Identify the virologic features of recurrent HFMD
• Determine the clinical implications of the epidemiologic and virologic features of recurrent HFMD
CME Editor
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CME Author
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Authors
Disclosures: Jiao Huang, PhD; Qiaohong Liao, MD; Zhaorui Chang, MD; Peng Wu, PhD; Fengfeng Liu, MD; Yu Li, MSc; Li Luo,
MD; Shuanbao Yu, PhD; and Sheng Wei, PhD, have disclosed no relevant financial relationships. Mong How Ooi, MBBS, MRCP,
PhD, has disclosed the following relevant financial relationships: served as a speaker or a member of a speakers bureau for Sanofi
Pasteur. Benjamin J. Cowling, PhD, has disclosed the following relevant financial relationships: received grants for clinical research
from Sanofi Pasteur. Hongjie Yu, MD, PhD, has disclosed the following relevant financial relationships: received grants for clinical
research from: Shenzhen Sanofi Pasteur Biological Products; GlaxoSmithKline (China) Investment Co.; YiChang HEC ChangJiang
Pharmaceutical Co.
SYNOPSIS
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 24, No. 3, March 2018 433
EV-A71 with CV-A16 and CV-A16 with EV-A71, and 923
of EV-A71 or CV-A16 with other enteroviruses and other
enteroviruses with EV-A71 or CV-A16. The probability of
HFMD recurrence was 1.9% at 12 months, 3.3% at 24
months, 3.9% at 36 months, and 4.0% at 38.8 months after
the primary episode. HFMD severity was not associated
with recurrent episodes or time interval between episodes.
Elucidation of the mechanism underlying HFMD recur-
rence with the same enterovirus serotype and conrma-
tion that HFMD recurrence is not associated with disease
severity is needed.
Hand, foot and mouth disease (HFMD) is a common
childhood infectious disease that is mainly caused by
enterovirus A71 (EV-A71), coxsackievirus A16 (CV-A16),
and CV-A6 (1). Most HFMD patients exhibit a benign,
self-limiting illness characterized by skin eruptions on the
hands, feet, or buttocks and ulcers or blisters in the mouth
with or without fever (2). However, some patients develop
neurologic or cardiopulmonary complications or die (3,4).
In the past 2 decades, outbreaks of HFMD have been docu-
mented in countries of the Western Pacic, including Ma-
laysia, Japan, Singapore, Vietnam, and Cambodia (5–9).
In China, HFMD has been prevalent since 2007. During
2008–2015, ≈13 million HFMD cases were reported, in-
cluding 123,261 severe cases and 3,322 deaths in 31 prov-
inces of mainland China.
Three inactivated monovalent EV-A71 vaccines have
been licensed in China. Phase 3 clinical trials proved these
vaccines had high ecacy (90.0%–97.4%) against EV-
A71–associated HFMD (10,11) but did not confer cross-
protection for HFMD caused by non–EV-A71 enterovirus-
es (11). A natural infection with EV-A71 also confers no
or only short-term (<2 months duration) cross-protection
against CV-A16–associated illness (12,13). Because of
this limited cross-protection from infections of dierent
enterovirus serotypes, multiple HFMD episodes can occur
in a single person. Although observational studies indicate
that the antibody response induced by the EV-A71 vac-
cine could last >2 years, reinfection with an enterovirus of
the same serotype is still possible because the immunity
induced by a natural enterovirus infection might not be
lifelong (14). We accessed the national surveillance data
for HFMD diagnosed during 2008–2015 in China, in an
attempt to describe the epidemiologic features of patients
with recurrent HFMD and examine the relationship be-
tween disease severity and HFMD recurrence.
Materials and Methods
Data Sources
As described previously (1), HFMD cases were reported
voluntarily to the Chinese Center for Disease Control and
Prevention (China CDC) during January 1, 2008–May 1,
2008, and starting May 2, 2008, cases were mandatorily
reported online to China CDC within 24 hours after diag-
nosis. We collected information on basic demographics
(name, sex, national identication number, date of birth,
home address, name of either of the patient’s parents, con-
tact telephone number); case classication (probable or
conrmed); disease severity (severe or mild); date of illness
onset, diagnosis, and death (if applicable); and enterovirus
serotype (for conrmed cases). For virologic surveillance,
clinical specimens were collected from a subsample of cas-
es from each province and tested by PCR with primers and
probes for panenterovirus, EV-A71, and CV-A16. We as-
sumed that the enterovirus identied in HFMD patient sam-
ples was the causative enterovirus of the HFMD episode.
We included the HFMD surveillance data of 29 prov-
inces of mainland China collected during January 1, 2008–
December 31, 2015. We excluded data from Hunan and
Hubei Provinces from this study because (since 2010 for
Hunan Province and 2012 for Hubei Province) most of the
hospitals in these provinces reported EV-A71 infection on
the basis of EV-A71 IgM antibody detection assays, which
are unreliable tests (15–17).
Case Denitions
We dened a probable HFMD patient as a patient who had
rashes on the hands, feet, mouth, or buttocks and ulcers or
vesicles in the mouth with or without fever. We dened
a laboratory-conrmed patient as a probable patient with
laboratory evidence of infection with EV-A71, CV-A16,
or other enteroviruses. The diagnostic tests used for entero-
virus detection were reverse transcription PCR and real-
time reverse transcription PCR. Patients were classied as
having severe HFMD if they had any complications (i.e.,
aseptic meningitis, brainstem encephalitis, encephalitis,
encephalomyelitis, acute accid paralysis or autonomic
nervous system dysregulation, pulmonary edema, pulmo-
nary hemorrhage, or cardiorespiratory failure). Otherwise,
patients were classied as having mild HFMD.
We identied patients with >2 episodes of HFMD
reported in the national HFMD surveillance system by
matching records using any of the following 3 screen-
ing criteria: 1) having identical identication number and
identical or highly similar patient name; 2) having identi-
cal patient’s parent name, home address, and birth date
and identical or highly similar patient name; and 3) hav-
ing identical contact telephone number, home address,
and birth date and identical or highly similar patient
name (online Technical Appendix, https://wwwnc.cdc.
gov/EID/article/24/3/17-1303-Techapp1.pdf). We con-
sidered patients to have recurrent HFMD if they experi-
enced >2 independent episodes of HFMD. We dened in-
dependent episodes as consecutive episodes separated by
Hand, Foot and Mouth Disease, China
SYNOPSIS
434 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 24, No. 3, March 2018
an interval of >14 days if the previous episode was mild
and >23 days if the previous episode was severe. We had
estimated the time intervals dening 2 independent epi-
sodes by adding the longest duration of HFMD reported
(7 days for mild illness and 16 days for severe illness)
(18–21) plus the longest incubation period reported (7
days) (4,22–26). We classied patients with >2 indepen-
dent episodes of laboratory-conrmed HFMD as having
recurrent laboratory-conrmed HFMD. Otherwise, we
classied patients as having recurrent probable HFMD.
When counting the number of cases of reinfection with
EV-A71, CV-A16, or other enteroviruses (Figure 1;
Table 1), we considered any 2 laboratory-conrmed epi-
sodes as 1 case of reinfection; therefore, we classied
patients with 3 laboratory-conrmed HFMD episodes as
having 3 cases of reinfection (i.e., we grouped episodes
1 and 2, 1 and 3, and 2 and 3 together) and 4 laboratory-
conrmed HFMD episodes as having 6 cases of reinfec-
tion (i.e., we grouped episodes 1 and 2, 1 and 3, 1 and 4,
2 and 3, 2 and 4, and 3 and 4 together).
Data Analysis
We used medians and interquartile ranges (IQRs) to de-
scribe continuous variables and numbers and percentages
to summarize categorical variables. We used logistic re-
gression with the forward stepwise selection approach to
explore the association between HFMD recurrence and se-
vere disease. We denoted the results as odds ratios (ORs)
with 95% CIs. All statistical tests were 2-sided, and we
considered an α of 0.05 statistically signicant.
We dened the probability of HFMD recurrence as the
probability of occurrence of HFMD among children who
previously had HFMD and estimated recurrence using sur-
vival analysis (the Kaplan-Meier method). To calculate the
probability of HFMD recurrence, we took only the event of
interest into account and censored other events at the end
of observation. When estimating the probability of HFMD
recurrence, we enrolled all patients with recurrent HFMD
(whether probable or laboratory-conrmed) in the analysis.
We censored patients with only 1 HFMD episode. When
estimating the probability of reinfection after EV-A71 with
EV-A71, we included only the case-patients with a primary
episode of EV-A71 infection who were later reinfected
with EV-A71. We censored case-patients who had just 1
infection with EV-A71 (i.e., case-patients who were infect-
ed with EV-A71 then infected with CV-A16 or other en-
teroviruses, case-patients who were infected with EV-A71
then had probable HFMD, and case-patients with a single
episode of EV-A71 infection). We used similar analyses to
estimate the probability of reinfection with the same sero-
type for other serotypes of enterovirus.
We also conducted a sensitivity analysis to account for
the uncertainty of the intervals used to dene 2 independent
HFMD episodes; in this analysis, we used 16 days (for pre-
vious mild episodes) and 61 days (for previous severe epi-
sodes) as cuto values, which were derived from another in-
vestigation conducted in China that also investigated HFMD
recurrence (27). We conducted data cleaning and analyses
using R Project version 3.2.5 (http://cran.r-project.org) and
ArcGIS 10.2 (http://www.esri.com/arcgis/about-arcgis).
This study was approved by the ethics review committees of
China CDC (Beijing, China).
Results
During 2008–2015, a total of 12,256,102 HFMD episodes
occurring in 29 provinces of China were reported to the Chi-
na CDC surveillance system. When using >14-day and >23-
day intervals for dening independent infections, 398,010
patients (having 820,355 [7%] episodes) were identied as
having recurrent HFMD, of which 1,767 (0.4%) patients
(having 3,717 episodes) had recurrent laboratory-conrmed
HFMD (Figure 1). The number of patients with recurrent
HFMD was similar when we repeated this analysis using
the 16-day and 61-day cuto values in the sensitivity analy-
sis, indicating that our estimation of HFMD recurrence was
robust (online Technical Appendix Figure). Compared with
patients with only 1 laboratory-conrmed HFMD episode,
patients with recurrent laboratory-conrmed HFMD had
a similar seasonal pattern, presenting semiannual peaks of
activity with a ma-jor peak in the spring and early summer
(April–June) followed by a smaller peak in autumn (Septem-
ber–October) (Figure 2, panels A, B). Similar seasonality
was also observed for patients with a single episode of and
recurrent probable HFMD (Figure 2, panels C, D).
We next focused on analyzing the 1,767 patients with
recurrent laboratory-conrmed HFMD. During the study
period, 90.3% (1,595) of these patients had 2 episodes and
9.7% (172) had >2 episodes: 161 (9.1%) patients had 3 epi-
sodes and 11 (0.6%) patients had 4 episodes. In total, 9%
(154/1,767) of the patients with recurrent laboratory-con-
rmed HFMD still had >1 episode of probable HFMD, and
1,613 patients had only episodes of laboratory-conrmed
HFMD. Of the 157 (8.9%) patients with >1 severe HFMD
episode (183 total severe episodes), 26 patients (20 with 2
episodes, 3 with 3 episodes, and 3 with 4 episodes) experi-
enced 2 severe HFMD episodes. A total of 1,814 cases of
recurrence occurred among the 1,767 patients with recur-
rent HFMD. Only 144 (8%) of these 1,814 cases involved
reinfection with an enterovirus of the same serotype: 99
(5.5%) with EV-A71 and 45 (2.5%) with CV-A16 (Figure
1). Most recurrent HFMD cases were caused by enterovi-
ruses of dierent serotypes. Of the 1,767 patients, 5 (0.3%)
were found to have an interval of <20 days between con-
secutive HFMD episodes: 2 patients who were reinfected
with enteroviruses of dierent serotypes and 3 patients who
were reinfected with enteroviruses of the same serotype.
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 24, No. 3, March 2018 435
Hand, Foot and Mouth Disease, China
Figure 1. Flowchart showing
screening for and analysis of
patients with recurrent HFMD from
the national HFMD surveillance
database, 29 provinces of China,
2008–2015. Percentages do not
equal 100% because of rounding.
*The number of patients (427,953)
with >2 HFMD episodes is higher
than expected (528,513 – 102,540
= 425,973) because of improved
patient matching. In some situations,
the number of patients with >2
episodes did not change; for
example, a patient initially identied
with 3 episodes might have been
determined to have only 2 episodes,
with the third episode being attributed
to a dierent patient. In other
situations, the number of patients
with >2 episodes decreased; for
example, a patient initially identied
as having 3 episodes might have
been determined to be 3 dierent
patients with 3 dierent episodes.
Therefore, the reduced number
of patients (528,513 – 427,953 =
100,560) with >2 HFMD episodes is
smaller than the number of patients
(102,540) excluded manually.
†The number of patients (398,010)
with recurrence of HFMD is higher
than expected (427,953 – 31,029
= 396,924) because some patients
needed to be excluded and included.
In some situations, patients were
completely included or excluded
from the recurrent HFMD patient
population sample; for example,
all 3 episodes of a patient could
have been determined to not be
independent from each other. In
other situations, patients were
included and excluded from the
recurrent HFMD patient population
sample; for example, a patient
with 3 episodes might have had 2
episodes that were not independent
from each other. In these cases, the
patient had 2 episodes included and
1 episode excluded; therefore, the
number of included patients plus
excluded patients (398,010 + 31,029
= 429,039) exceeded the starting
population number (427,953).
CV-A16, coxsackievirus A16;
EV-A71, enterovirus A71; HFMD,
hand, foot and mouth disease; other
EVs, other non–EV-A71 and
non–CV-A16 enteroviruses.
SYNOPSIS
436 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 24, No. 3, March 2018
Demographic Characteristics
The median ages of patients with recurrent laboratory-con-
rmed HFMD were 22.6 (IQR 14.2–34.0) months for the
rst episode and 36.5 (IQR 25.7–48.7) months for the second
episode. Younger children had more episodes of recurrent
laboratory-conrmed HFMD (p<0.001) and recurrent proba-
ble HFMD (p = 0.001) (online Technical Appendix Table 1).
Few patients (1.5%) had their rst episode of HFMD after 5
years of age. Approximately two thirds (68% or 1,208) of the
patients aected were boys, and 41% were residents of rural
areas. The demographic characteristics age, sex, and rural
residence and the frequency of episodes were similar among
patients with recurrent laboratory-conrmed HFMD, regard-
less of the enterovirus serotypes of reinfections (Table 1).
Geographic Distribution
Patients with recurrent laboratory-conrmed HFMD were
observed in all of the 29 provinces of China we examined
except Tibet. The number of recurrent laboratory-conrmed
HFMD cases varied substantially, ranging from 7 cases in
Qinghai Province to 658 cases in Guangdong Province. Half
of the cases with recurrent laboratory-conrmed HFMD
were reported in 3 provinces: Guangdong (658 cases), Yun-
nan (153 cases), and Sichuan (107 cases) (Figure 3).
Table 1. Demographic characteristics of patients with recurrent probable and laboratory-confirmed HFMD in 29 provinces of China,
2008–2015*
Characteristic
Patients
with
recurrent
probable
HFMD,
N = 396,243
Patients with recurrent laboratory-confirmed HFMD, N = 1,814†
Patients
with
recurrent
laboratory-
confirmed
HFMD,
N = 1,767
Reinfection
after EV-
A71 with
EV-A71,
n = 99
Reinfection
after CV-
A16 with
CV-A16,
n = 45
Reinfection
after other
EVs with
other EVs,
n = 364
Reinfection
after EV-A71
with CV-A16
or after CV-
A61 with EV-
A71, n = 383
Reinfection
after EV-A71
with other EVs
or after other
EVs with EV-
A71, n = 469
Reinfection
after CV-A16
with other EVs
or after other
EVs with CV-
A16, n = 454
Age at first episode
Age, mo,
median
(IQR)
20.8
(12.2–31.4)
24.2
(15.6–36.5)
27.1
(20.9–39.4)
18.8
(12.2–31.4)
26.3
(17.7–36.8)
22.6
(14.5–34.4)
22.8
(14.2–32.8)
22.6
(14.2–34.0)
Age group
<6 mo
7,279 (2)
1 (1)
0
10 (3)
1 (0.3)
4 (1)
7 (2)
23 (1)
6–11 mo
80,982 (20)
10 (12)
7 (16)
77 (21)
39 (10)
76 (16)
72 (16)
283 (16)
12–23 mo
155,973
(39)
46 (46)
14 (31)
144 (40)
132 (35)
181 (39)
176 (38)
696 (39)
24–59 mo
145,289
(37)
39 (39)
22 (49)
129 (35)
203 (53)
204 (43)
192 (42)
738 (42)
5–9 y
6,526 (2)
2 (2)
2 (4)
4 (1)
8 (2)
4 (1)
7 (2)
26 (2)
10–14 y
158 (0.04)
1 (1)
0
0
0
0
0
1 (0.05)
>15 y
36 (0.01)
0
0
0
0
0
0
0
Age at second episode
Age, mo,
median
(IQR)
36.4
(24.3–48.5)
40.0
(27.4–50.2)
40.7
(25.7–55.8)
34.7
(24.2–45.9)
42.3
(32.5–53.2)
37.1
(26.8–49.4)
36.8
(26.8–49.2)
36.5
(25.7–48.7)
Age group
<6 mo
236 (0.06)
0
0
1 (0.3)
0
0
0
1 (0.05)
6–11 mo
14,239 (4)
2 (2)
0
12 (3)
3 (1)
14 (3)
13 (3)
47 (3)
12–23 mo
83,568 (21)
17 (17)
8 (18)
89 (25)
35 (9)
73 (16)
73 (16)
309 (17)
24–59 mo
257,729
(65)
69 (70)
29 (64)
232 (64)
298 (78)
335 (71)
315 (69)
1,234 (70)
5–9 y
39,786 (10)
10 (10)
7 (16)
29 (8)
47 (12)
45 (10)
52 (12)
170 (10)
10–14 y
640 (0.16)
1 (1)
1 (2)
1 (0.3)
0
2 (0.4)
1 (0.2)
6 (0.33)
>15 y
45 (0.01)
0
0
0
0
0
0
0
Male sex
259,028
(65)
74 (75)
31 (69)
247 (68)
270 (70)
326 (70)
291 (64)
1,208 (68)
Rural residence
186,700
(47)
49 (49)
19 (42)
115 (32)
187 (49)
190 (41)
167 (37)
716 (41)
Frequency of episodes
2
373,745
(95)
91 (92)
41 (91)
303 (83)
356 (93)
404 (86)
400 (88)
1,595 (90)
3
21,023 (5)
7 (7)
4 (9)
54 (15)
22 (6)
59 (13)
49 (11)
161 (9)
>4‡
1,475 (0.4)
1 (1)
0
7 (2)
5 (1)
6 (1)
5 (1)
11 (1)
Death
20 (0.005)
0
0
0
0
0
0
0
*Data are no. (%) patients unless otherwise indicated. CV-A16, coxsackievirus A16; EV-A71, enterovirus A71; HFMD, hand, foot and mouth disease; IQR,
interquartile range; other EVs, other non–EV-A71 and non–CV-A16 enteroviruses.
†For patients with laboratory-confirmed recurrence of 3 or 4 HFMD episodes, any 2 laboratory-confirmed HFMD epis odes were combined to form a case
of recurrence of laboratory-confirmed HFMD. For example, patients with 3 episodes were categorized as having 3 reinfections, with the first and sec ond,
first and third, and second and third infections being grouped together.
‡For patients with recurrence of laboratory-confirmed HFMD, the hi ghest number of episo des was 4. For patient s with recurrence of probable HFMD, the
highest number of episodes was 8.
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 24, No. 3, March 2018 437
Hand, Foot and Mouth Disease, China
Probability of HFMD Recurrence
Patients in this cohort were under observation for a me-
dian of 38.0 (range 0–97.4) months after their rst HFMD
diagnosis (online Technical Appendix Table 2). The recur-
rent episode occurred 0.5–93.4 (median 11.7) months after
the primary HFMD episode in patients with recurrence of
probable HFMD and 0.5–62.1 (median 12.0) months in pa-
tients with recurrence of laboratory-conrmed HFMD. The
probability of HFMD recurrence was 1.9% at 12 months,
3.3% at 24 months, and 3.9% at 36 months; however, re-
currence remained at 4.0% at 38.8 months after the primary
episode of HFMD (Figure 4, panel A). For patients with
primary EV-A71 infections, the probability of reinfection
with CV-A16 (0.11% [95% CI 0.10%–0.13%]) or other
enteroviruses (0.14% [95% CI 0.13%–0.16%]) was high-
er than that of reinfection with EV-A71 (0.05% [95% CI
0.04%–0.07%]; p<0.001) (Figure 4, panel B). For patients
with primary CV-A16 infections, the probability of rein-
fection with EV-A71 (0.18% [95% CI 0.15%–0.20%]) or
other enteroviruses (0.21% [95% CI 0.18%–0.23%]) was
higher than that of reinfection with CV-A16 (0.04% [95%
CI 0.03%–0.05%]; p<0.001) (Figure 4, panel C). These
ndings suggest that risk for reinfection with dierent en-
terovirus serotypes might be higher than that for reinfection
with identical enterovirus serotypes.
Relationship between HFMD Recurrence
and Severe Illness
Unsurprisingly, we found that illness severity was in-
versely associated with age and onset-to-diagnosis interval.
EV-A71 infections (OR 7.2, 95% CI 4.0–13.0) and other
enterovirus infections (OR 2.7, 95% CI 1.5–5.0) were more
severe than CV-A16 infections. Patients who lived in ur-
ban areas also had increased risk for severe illness (OR 1.8,
95% CI 1.3–2.5). After adjusting for these risk factors, re-
current HFMD episodes were not found to be associated
with illness severity, which means the second and third
HFMD episodes did not appear to be more or less severe
Figure 2. Hand, foot and mouth disease (HFMD) episodes in 29 provinces of China, 2008–2015. A) Patients with recurrent laboratory-
conrmed HFMD. B) Patients with single episode of laboratory-conrmed HFMD. C) Patients with recurrent probable HFMD. D) Patients
with single episode of probable HFMD.
SYNOPSIS
438 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 24, No. 3, March 2018
than the rst episode. In addition, the interval between the
2 episodes was not related to disease severity of the latter
episode (OR 0.97, 95% CI 0.95–1.01) (Table 2).
Discussion
During 2008–2015, we found that 398,010 HFMD pa-
tients with >2 episodes (a total of ≈820,000 episodes)
were reported among children in China; 1,767 of these
recurrences were laboratory-conrmed. The patients who
were reinfected with dierent enterovirus serotypes had
similar age, sex, residence, and frequency of episodes.
Recurrence of HFMD mainly occurred 0–38.8 months
after the primary episode, with a recurrence probability
of 4% at 38.8 months. Reinfection with a dierent en-
terovirus serotype was more likely than reinfection with
an identical enterovirus serotype. The severity of HFMD
Figure 3. Geographic distribution of patients with recurrent HFMD (A) and episodes of enterovirus infection (B) in 29 provinces of China,
2008–2015. A) Pie charts correspond to the number of recurrent laboratory-conrmed HFMD cases. B) Pie charts correspond to the
number of laboratory-conrmed HFMD episodes. CV-A16, coxsackievirus A16; EV-A71, enterovirus A71; HFMD, hand, foot and mouth
disease; other EVs, non–EV-A71 and non–CV-A16 enteroviruses.
Figure 4. Kaplan-Meier analysis of survival from HFMD recurrence after primary HFMD diagnosis, 29 provinces of China, 2008–2015.
A) Probability of HFMD recurrence among all patients who had probable and laboratory-conrmed HFMD. B) Probability of HFMD
recurrence among case-patients whose primary episode was an infection with EV-A71. C) Probability of HFMD recurrence among
case-patients whose primary episode was an infection with CV-A16. CV-A16, coxsackievirus A16; EV-A71, enterovirus A71; other EVs,
non–EV-A71 and non–CV-A16 enteroviruses; HFMD, hand, foot and mouth disease.
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 24, No. 3, March 2018 439
Hand, Foot and Mouth Disease, China
was not associated with recurrent infections or the time
interval between HFMD episodes.
In a report on a phase 3 clinical trial, an EV-A71 neu-
tralizing antibody titer of 1:16 was associated with protec-
tion against EV-A71–associated HFMD (28). In addition,
EV-A71 was observed to confer cross-neutralization activ-
ity against major global EV-A71 genotypes (A, B1, B3–
B5, C1–C5), although the degree of cross-neutralization
varied (29–31). In an EV-A71 vaccine study, participants
were observed for only 2 years, but results suggested that
the vaccine can provide protection against EV-A71–associ-
ated HFMD for >2 years (14). Infection with enteroviruses
seems to confer lifelong immunity to HFMD, given that
adult cases are rare (1). The reasons underlying the cases
of HFMD recurrence caused by reinfections with the same
serotype, which have a 12-month median interval to re-
infection, are not clear. Measles has been deemed to pro-
vide long-lasting protection against reinfection. However,
measles reinfections have occurred in vaccinated and pre-
sumptively immune persons, either because of insucient
primary antigenic stimulation or inadequate duration of an-
tibody response (32). Study results have suggested the in-
volvement of multiple cellular deciencies, including low
memory B-cell count, reduced polyclonal naive and memo-
ry T-cell responses, and suboptimal antigen-presenting cell
responses, in children with low vaccine responses (33,34).
Agammaglobulinemia is another condition of immunode-
ciency associated with recurrent infections (35). In patients
with inuenza, suboptimal immune responses after the pri-
mary infection led to the failure to generate a protective im-
mune response that could have prevented reinfection (36).
Children with immature immunity or immunodeciency
(37) probably are not able to induce sucient immune
responses (or might induce low-level serologic responses
that wane rapidly) after infection with EV-A71 or CV-A16;
thus, these children are likely susceptible to reinfection
with an enterovirus of the same serotype as their primary
episode. Another possibility (though less likely) is that high
neutralizing antibody titers might not protect some persons
from illnesses induced by enteroviruses. Further investiga-
tions are needed to provide a scientic explanation.
Even though the genotypes of EV-A71 and CV-A16
were not available in this study, previous studies have
shown that the predominant EV-A71 and CV-A16 geno-
types circulating in China have been consistent. Phyloge-
netic analysis of viral protein 1 gene sequences revealed
that the EV-A71 genotype circulating in China since 2008
has been C4 (38–42); hence, the monovalent EV-A71 vac-
cines licensed in China were designed to target the C4
genotype. B1 has been reported to be the predominant
genotype of CV-A16 circulating in China (40–43). There-
fore, we reasonably conclude that in our cohort HFMD re-
currences involving reinfections with enteroviruses of the
same serotype were also highly likely reinfections with the
same genotype.
Recurrent laboratory-conrmed HFMD was largely
(at least 72% of cases) attributable to dierent serotypes
of enterovirus; thus, undoubtedly hundreds of thousands
of patients with HFMD recurrence with dierent serotypes
should have occurred, given clinical samples were collect-
ed from only 4.2% of the patients with probable HFMD
episodes for virologic diagnosis. Our results support
Table 2. Risk factors associated with severe illness in cases of recurrent laboratory-confirmed HFMD, China, 2008–2015*
Risk factor
Mild, N = 3,187, no. (%)
Severe, N = 172, no. (%)
Adjusted OR (95% CI)
Age at HFMD onset, mo
>23
2,054 (96.9)
66 (3.1)
Reference
12–23
836 (91.5)
78 (8.5)
2.4 (1.7–3.6)
<12
297 (91.4)
28 (8.6)
2.6 (1.6–4.4)
Sex
F
1,010 (95.5)
48 (4.5)
Reference
M
2,177 (94.6)
124 (5.4)
0.9 (0.6–1.2)
Enterovirus serotype
CV-A16
857 (98.5)
13 (1.5)
Reference
Other EVs
1,452 (96.0)
61 (4.0)
2.7 (1.5–5.0)
EV-A71
878 (90.0)
98 (10.0)
7.2 (4.0–13.0)
Residence
Rural
1,342 (92.8)
104 (7.2)
Reference
Urban
1,845 (96.4)
68 (3.6)
1.8 (1.3–2.5)
Order episode occurred
First
1,523 (93.9)
99 (6.1)
Reference
Second or after
1,664 (95.8)
73 (4.2)
0.8 (0.5–1.2)
Onset-to-diagnosis interval, d
<1
1,443 (96.3)
55 (3.7)
Reference
2–3
896 (94.0)
57 (6.0)
1.6 (1.1–2.4)
>4
848 (93.4)
60 (6.6)
1.8 (1.2–2.7)
Interval between successive episodes
0.97 (0.95–1.01)
*CV-A16, coxsackievirus A16; EV-A71, ent erovirus A71; HFMD, hand, foot and mouth di sease; OR, odds ratio; other EVs, other non –EV-A71 and non–
CV-A16 enteroviruses.
SYNOPSIS
440 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 24, No. 3, March 2018
the notion that limited or no cross-protection against dif-
ferent serotypes of enterovirus occurs after natural infec-
tion, which is consistent with observations from the EV-
A71 vaccine study (12,14) and a modeling study of natural
infections (13). Antibody-dependent enhancement, which
has been commonly seen in dengue, was also observed
in EV-A71 and CV-B3 infections in mouse models; the
severity of the subsequent episode of infection was en-
hanced by a subneutralizing level of antibody after pri-
mary infection (44,45). However, we did not observe
that HFMD recurrence or the interval between successive
episodes had any eect on disease severity in humans.
It seems that antibody-dependent enhancement does not
happen in human infections with enterovirus, further im-
plying that no or short-term cross-reactivity develops for
dierent serotypes of enterovirus.
Three monovalent EV-A71 vaccines are administered
in China (46). Our study indicates that children who receive
an EV-A71 vaccine can still develop HFMD after vaccina-
tion, which is a challenge for monovalent EV-A71 vac-
cines. Even though the EV-A71 vaccine protects against
>90% of the EV-A71 infections that occur in children, chil-
dren still face the risk for infection with other enterovirus
serotypes after vaccination. Hence, public health authori-
ties should inform parents and caregivers about the risk for
the development of HFMD after EV-A71 vaccination, and
multivalent vaccines for HFMD (e.g., EV-A71 combined
with other prevalent circulating serotypes CV-A16 and
CV-A6) are needed for the HFMD epidemic.
This study has several limitations. First, the burden of
HFMD recurrence was underestimated because the disease
is substantially underreported in the surveillance system
(16%–36% estimated) (47) and the observation period for
assessing recurrence was insucient, especially among
patients identied in more recent years. Although the re-
currence of HFMD is rarely reported in other countries
(48,49), our study suggests that it is not uncommon. Sec-
ond, because clinical samples were not collected from all
patients during each HFMD episode and tested, we could
not determine the real number of recurrent HFMD cases;
thus, the probabilities of reinfection with an identical en-
terovirus serotype (i.e., EV-A71 and CV-A16) we calculat-
ed might be underestimated. It is not favorable to estimate
the number of patients with reinfections of the same sero-
type because only a small proportion (4.2%) of HFMD epi-
sodes have been tested for enterovirus diagnosis, although
mathematical modeling methods could be used to solve
this problem. This topic requires further exploration. Third,
we were unable to describe the features of patients with
reinfection of non–EV-A71 and non–CV-A16 serotypes.
Fourth, the short interval between consecutive episodes in
some patients suggests the potential for co-infections rather
than reinfections; thus, co-infections might have occurred
and caused a slight overestimation of the recurrence rate
for HFMD. However, patients with short intervals between
consecutive episodes accounted for a small proportion of
the patients with recurrent HFMD, so the eect that co-
infections played is relatively limited.
In conclusion, our 8-year surveillance study indicates a
high burden of HFMD recurrence among children in China
and shows that each episode of recurrent HFMD is more
likely caused by a dierent enterovirus serotype than that
of the primary episode (both for patients with EV-A71 and
CV-A16 primary infections). Further studies in which vi-
rologic diagnosis is performed for all HFMD episodes are
needed to better quantify the probability of HFMD recur-
rence and probability of reinfection by enterovirus sero-
type, including non–EV-A71 and non–CV-A16 serotypes.
Further investigations are also warranted to elucidate the
mechanism underlying HFMD recurrences resulting from
reinfections with enteroviruses of the same serotype; the
protective antibody levels for EV-A71, CV-A16, and other
enterovirus serotypes; and the duration of immunity and
cross-immunity between serotypes. Finally, more work is
needed to study the eect of HFMD recurrence on disease
severity, even though no association was observed in this
patient cohort.
Acknowledgments
We thank sta members at the Bureau of Disease Control and
Prevention, the National Health and Family Planning
Commission of China, and provincial and local departments of
health for providing assistance in coordinating the data
collection. We also thank sta members at the county,
prefecture, and provincial levels of CDCs and hospitals for
data collection.
This study was supported by grants from the National Science
Fund for Distinguished Young Scholars (no. 81525023 to H.Y.),
the National Natural Science Foundation of China (no. 81473031
to. H.Y.), the Li Ka Shing Oxford Global Health Programme
(no. B9RST00-B900.57 to H.Y.), and TOTAL Foundation
(no. 2015-099 to H.Y.). The funders had no role in study design,
data collection and analysis, decision to publish, or preparation
of the manuscript.
About the Author
Ms. Huang is a doctoral candidate at Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China.
Her research interests are focused on the epidemiology of HFMD.
References
1. Xing W, Liao Q, Viboud C, Zhang J, Sun J, Wu JT, et al. Hand,
foot, and mouth disease in China, 2008-12: an epidemiological
study. Lancet Infect Dis. 2014;14:308–18. http://dx.doi.org/
10.1016/S1473-3099(13)70342-6
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 24, No. 3, March 2018 441
Hand, Foot and Mouth Disease, China
2. Tseng FC, Huang HC, Chi CY, Lin TL, Liu CC, Jian JW, et al.;
CDC-Taiwan Virology Reference Laboratories and Sentinel
Physician Network. Epidemiological survey of enterovirus
infections occurring in Taiwan between 2000 and 2005: analysis
of sentinel physician surveillance data. J Med Virol. 2007;79:
1850–60. http://dx.doi.org/10.1002/jmv.21006
3. Huang CC, Liu CC, Chang YC, Chen CY, Wang ST, Yeh TF.
Neurologic complications in children with enterovirus 71
infection. N Engl J Med. 1999;341:936–42. http://dx.doi.org/
10.1056/NEJM199909233411302
4. Ooi MH, Wong SC, Lewthwaite P, Cardosa MJ, Solomon T.
Clinical features, diagnosis, and management of enterovirus 71.
Lancet Neurol. 2010;9:1097–105. http://dx.doi.org/10.1016/
S1474-4422(10)70209-X
5. Chan LG, Parashar UD, Lye MS, Ong FG, Zaki SR, Alexander JP,
et al.; Outbreak Study Group. Deaths of children during an
outbreak of hand, foot, and mouth disease in Sarawak, Malaysia:
clinical and pathological characteristics of the disease. Clin Infect
Dis. 2000;31:678–83. http://dx.doi.org/10.1086/314032
6. Fujimoto T, Chikahira M, Yoshida S, Ebira H, Hasegawa A,
Totsuka A, et al. Outbreak of central nervous system disease
associated with hand, foot, and mouth disease in Japan during the
summer of 2000: detection and molecular epidemiology of
enterovirus 71. Microbiol Immunol. 2002;46:621–7.
http://dx.doi.org/10.1111/j.1348-0421.2002.tb02743.x
7. Ho M, Chen ER, Hsu KH, Twu SJ, Chen KT, Tsai SF, et al.;
Taiwan Enterovirus Epidemic Working Group. An epidemic of
enterovirus 71 infection in Taiwan. N Engl J Med. 1999;341:929–
35. http://dx.doi.org/10.1056/NEJM199909233411301
8. Chan KP, Goh KT, Chong CY, Teo ES, Lau G, Ling AE. Epidemic
hand, foot and mouth disease caused by human enterovirus 71,
Singapore. Emerg Infect Dis. 2003;9:78–85. http://dx.doi.org/
10.3201/eid1301.020112
9. Tu PV, Thao NTT, Perera D, Truong KH, Tien NTK, Thuong TC,
et al. Epidemiologic and virologic investigation of hand, foot,
and mouth disease, southern Vietnam, 2005. Emerg Infect Dis.
2007;13:1733–41. http://dx.doi.org/10.3201/eid1311.070632
10. Li R, Liu L, Mo Z, Wang X, Xia J, Liang Z, et al. An
inactivated enterovirus 71 vaccine in healthy children. N Engl J Med.
2014;370:829–37. http://dx.doi.org/10.1056/NEJMoa1303224
11. Zhu FC, Meng FY, Li JX, Li XL, Mao QY, Tao H, et al.
Ecacy, safety, and immunology of an inactivated alum-adjuvant
enterovirus 71 vaccine in children in China: a multicentre,
randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet. 2013;381:2024–32. http://dx.doi.org/10.1016/
S0140-6736(13)61049-1
12. Huang WC, Huang LM, Kao CL, Lu CY, Shao PL, Cheng AL,
et al. Seroprevalence of enterovirus 71 and no evidence of cross-
protection of enterovirus 71 antibody against the other enteroviruses
in kindergarten children in Taipei city. J Microbiol Immunol Infect.
2012;45:96–101. http://dx.doi.org/10.1016/j.jmii.2011.09.025
13. Takahashi S, Liao Q, Van Boeckel TP, Xing W, Sun J, Hsiao VY,
et al. Hand, foot, and mouth disease in China: modeling epidemic
dynamics of enterovirus serotypes and implications for vaccination.
PLoS Med. 2016;13:e1001958. http://dx.doi.org/10.1371/
journal.pmed.1001958
14. Li JX, Song YF, Wang L, Zhang XF, Hu YS, Hu YM, et al.
Two-year ecacy and immunogenicity of Sinovac enterovirus 71
vaccine against hand, foot and mouth disease in children. Expert
Rev Vaccines. 2016;15:129–37. http://dx.doi.org/10.1586/
14760584.2016.1096782
15. Yu N, Guo M, He SJ, Pan YX, Chen XX, Ding XX, et al.
Evaluation of human enterovirus 71 and coxsackievirus A16
specic immunoglobulin M antibodies for diagnosis of hand-
foot-and-mouth disease. Virol J. 2012;9:12. http://dx.doi.org/
10.1186/1743-422X-9-12
16. Xu F, Yan Q, Wang H, Niu J, Li L, Zhu F, et al. Performance of
detecting IgM antibodies against enterovirus 71 for early
diagnosis. PLoS One. 2010;5:e11388. http://dx.doi.org/10.1371/
journal.pone.0011388
17. Zhang J, Weng Z, Du H, Xu F, He S, He D, et al. Development and
evaluation of rapid point-of-care tests for detection of enterovirus
71 and coxsackievirus A16 specic immunoglublin M antibodies.
J Virol Methods. 2016;231:44–7. http://dx.doi.org/10.1016/
j.jviromet.2016.01.015
18. Wong SS, Yip CC, Lau SK, Yuen KY. Human enterovirus 71
and hand, foot and mouth disease. Epidemiol Infect.
2010;138:1071–89. http://dx.doi.org/10.1017/S0950268809991555
19. Wang Y, Feng Z, Yang Y, Self S, Gao Y, Longini IM, et al.
Hand, foot, and mouth disease in China: patterns of spread and
transmissibility. Epidemiology. 2011;22:781–92. http://dx.doi.org/
10.1097/EDE.0b013e318231d67a
20. Chia MY, Chiang PS, Chung WY, Luo ST, Lee MS. Epidemiology
of enterovirus 71 infections in Taiwan. Pediatr Neonatol.
2014;55:243–9. http://dx.doi.org/10.1016/j.pedneo.2013.07.007
21. Zhou H, Guo SZ, Zhou H, Zhu YF, Zhang LJ, Zhang W. Clinical
characteristics of hand, foot and mouth disease in Harbin and the
prediction of severe cases. Chin Med J (Engl). 2012;125:1261–5.
22. Liao Y, Ouyang R, Wang J, Xu B. A study of spatiotemporal delay
in hand, foot and mouth disease in response to weather variations
based on SVD: a case study in Shandong Province, China.
BMC Public Health. 2015;15:71. http://dx.doi.org/10.1186/
s12889-015-1446-6
23. Onozuka D, Hashizume M. The inuence of temperature and
humidity on the incidence of hand, foot, and mouth disease in
Japan. Sci Total Environ. 2011;410-411:119–25. http://dx.doi.org/
10.1016/j.scitotenv.2011.09.055
24. Hii YL, Rocklöv J, Ng N. Short term eects of weather on
hand, foot and mouth disease. PLoS One. 2011;6:e16796.
http://dx.doi.org/10.1371/journal.pone.0016796
25. Wu H, Wang H, Wang Q, Xin Q, Lin H. The eect of
meteorological factors on adolescent hand, foot, and mouth disease
and associated eect modiers. Glob Health Action. 2014;7:24664.
http://dx.doi.org/10.3402/gha.v7.24664
26. Yi L, Lu J, Kung HF, He ML. The virology and developments
toward control of human enterovirus 71. Crit Rev Microbiol.
2011;37:313–27. http://dx.doi.org/10.3109/1040841X.2011.580723
27. Sun L, Wand J. System review of hand, foot, and mouth disease
recurrence [in Chinese]. Anhui J Prev Med. 2013;19:5.
28. Zhu F, Xu W, Xia J, Liang Z, Liu Y, Zhang X, et al. Ecacy,
safety, and immunogenicity of an enterovirus 71 vaccine in China.
N Engl J Med. 2014;370:818–28. http://dx.doi.org/10.1056/
NEJMoa1304923
29. Mao Q, Cheng T, Zhu F, Li J, Wang Y, Li Y, et al. The cross-
neutralizing activity of enterovirus 71 subgenotype c4 vaccines in
healthy Chinese infants and children. PLoS One. 2013;8:e79599.
http://dx.doi.org/10.1371/journal.pone.0079599
30. Liu L, Mo Z, Liang Z, Zhang Y, Li R, Ong KC, et al. Immunity and
clinical ecacy of an inactivated enterovirus 71 vaccine in healthy
Chinese children: a report of further observations. BMC Med.
2015;13:226. http://dx.doi.org/10.1186/s12916-015-0448-7
31. Chou AH, Liu CC, Chang JY, Jiang R, Hsieh YC, Tsao A, et al.
Formalin-inactivated EV71 vaccine candidate induced cross-
neutralizing antibody against subgenotypes B1, B4, B5 and
C4A in adult volunteers. PLoS One. 2013;8:e79783.
http://dx.doi.org/10.1371/journal.pone.0079783
32. Linnemann CC, Hegg ME, Rotte TC, Phair JP, Schi GM.
Measles IgM response during reinfection of previously vaccinated
children. J Pediatr. 1973;82:798–801. http://dx.doi.org/10.1016/
S0022-3476(73)80069-1
33. Surendran N, Nicolosi T, Kaur R, Morris M, Pichichero M.
Prospective study of the innate cellular immune response in low
SYNOPSIS
442 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 24, No. 3, March 2018
vaccine responder children. Innate Immun. 2017;23:89–96.
http://dx.doi.org/10.1177/1753425916678471
34. Pichichero ME. Challenges in vaccination of neonates, infants
and young children. Vaccine. 2014;32:3886–94. http://dx.doi.org/
10.1016/j.vaccine.2014.05.008
35. Sugimoto M, Takeichi T, Muramatsu H, Kojima D, Osada Y, Kono M,
et al. Recurrent cellulitis caused by Helicobacter cinaedi in a
patient with X-linked agammaglobulinaemia. Acta Derm Venereol.
2017;97:277–8. http://dx.doi.org/10.2340/00015555-2501
36. Trakulsrichai S, Watcharananan SP, Chantratita W. Inuenza
A (H1N1) 2009 reinfection in Thailand. J Infect Public Health.
2012;5:211–4. http://dx.doi.org/10.1016/j.jiph.2011.10.010
37. Koch RM, Kox M, de Jonge MI, van der Hoeven JG, Ferwerda G,
Pickkers P. Patterns in bacterial- and viral-induced
immunosuppression and secondary infections in the ICU. Shock.
2017;47:5–12. http://dx.doi.org/10.1097/SHK.0000000000000731
38. Zhang Y, Wang J, Guo W, Wang H, Zhu S, Wang D, et al.
Emergence and transmission pathways of rapidly evolving
evolutionary branch C4a strains of human enterovirus 71
in the Central Plain of China. PLoS One. 2011;6:e27895.
http://dx.doi.org/10.1371/journal.pone.0027895
39. Li J, Sun Y, Du Y, Yan Y, Huo D, Liu Y, et al. Characterization of
coxsackievirus A6- and enterovirus 71-associated hand foot and
mouth disease in Beijing, China, from 2013 to 2015. Front
Microbiol. 2016;7:391.
40. He SZ, Chen MY, Xu XR, Yan Q, Niu JJ, Wu WH, et al. Epidemics
and aetiology of hand, foot and mouth disease in Xiamen, China,
from 2008 to 2015. Epidemiol Infect. 2017;145:1865–74.
http://dx.doi.org/10.1017/S0950268817000309
41. Huang X, Wei H, Wu S, Du Y, Liu L, Su J, et al. Epidemiological
and etiological characteristics of hand, foot, and mouth disease in
Henan, China, 2008–2013. Sci Rep. 2015;5:8904. http://dx.doi.org/
10.1038/srep08904
42. Xu M, Su L, Cao L, Zhong H, Dong N, Xu J. Enterovirus
genotypes causing hand foot and mouth disease in Shanghai,
China: a molecular epidemiological analysis. BMC Infect Dis.
2013;13:489. http://dx.doi.org/10.1186/1471-2334-13-489
43. Yong W, Qiao M, Shi L, Wang X, Wang Y, Du X, et al. Genetic
characteristics of coxsackievirus A16 associated with hand,
foot, and mouth disease in Nanjing, China. J Infect Dev Ctries.
2016;10:168–75. http://dx.doi.org/10.3855/jidc.6876
44. Han JF, Cao RY, Deng YQ, Tian X, Jiang T, Qin ED, et al.
Antibody dependent enhancement infection of enterovirus 71
in vitro and in vivo. Virol J. 2011;8:106. http://dx.doi.org/
10.1186/1743-422X-8-106
45. Kishimoto C, Kurokawa M, Ochiai H. Antibody-mediated
immune enhancement in coxsackievirus B3 myocarditis.
J Mol Cell Cardiol. 2002;34:1227–38. http://dx.doi.org/10.1006/
jmcc.2002.2087
46. China Food and Drug Administration. Announcement on licensed
drugs approved by China Food and Drug Administration. 2016
[cited 2017 May 20]. http://app2.sfda.gov.cn/datasearchp/
gzcxSearch.do?searchcx=71&optionType=V1&formRender=cx
47. Wu JT, Jit M, Zheng Y, Leung K, Xing W, Yang J, et al. Routine
pediatric enterovirus 71 vaccination in China: a cost-eectiveness
analysis. PLoS Med. 2016;13:e1001975. http://dx.doi.org/10.1371/
journal.pmed.1001975
48. Dias EDM, Dias M. Recurring hand foot mouth disease in a child.
Ann Trop Med Public Health. 2012;5:40-1. http://dx.doi.org/
10.4103/1755-6783.92879
49. Sutton-Hayes S, Weisse ME, Wilson NW, Ogershok PR. A
recurrent presentation of hand, foot, and mouth disease. Clin
Pediatr (Phila). 2006;45:373–6. http://dx.doi.org/10.1177/
000992280604500412
Address for correspondence: Hongjie Yu, School of Public Health,
Key Laboratory of Public Health Safety, Ministry of Education, Fudan
University, Shanghai 200032, China; email: cfetpyhj@vip.sina.com;
Sheng Wei, Department of Epidemiology and Biostatistics, Ministry of
Education, Key Laboratory of Environment and Health, School of Public
Health, Tongji Medical College, Huazhong University of Science and
Technology, Wuhan, Hubei 430030, China; email: ws1998@hotmail.com
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