# The Risk Factors of Acquiring Severe Hand, Foot, and Mouth Disease: A Meta-Analysis

Authors: Bai Jun Sun; Hui Jie Chen; Ye Chen; Xiang Dong An; Bao Sen Zhou
Journal: Canadian Journal of Infectious Diseases and Medical Microbiology
 (2018)

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## Abstract

Objectives. The incidence of severe hand, foot, and mouth disease (HFMD) is not low, especially in mainland China in almost every year recently. In this study, we conducted a meta-analysis to generate large-scale evidence on the risk factors of severe HFMD to provide suggestions on prevention and controlling. Methods. PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang (Chinese) were searched to identify relevant articles. All analyses were performed using Stata 14.0. Results. We conducted a meta-analysis of 11 separate studies. Fever (odds ratio (OR) 7.396, 95% confidence interval (CI) 3.565–15.342), fever for more than 3 days (OR 5.773, 95% CI 4.199–7.939), vomiting (OR 6.023, 95% CI 2.598–13.963), limb trembling (OR 42.348, 95% CI 11.765–152.437), dyspnea (OR 12.869, 95% CI 1.948–85.017), contact with HFMD children (OR 5.326, 95% CI 1.263–22.466), rashes on the hips (OR 1.650, 95% CI 1.303–2.090), pathologic reflexes (OR 3057.064, 95% CI 494.409–19000), Lethargy (OR 31.791, 95% CI 3.369–300.020), convulsions (OR 23.652, 95% CI 1.973–283.592), and EV71 infection (OR 9.056, 95% CI 4.102–19.996) were significantly related to the risk of severe HFMD. We did not find an association between female sex (OR 0.918, 95% CI 0.738–1.142), scatter-lived children (OR 1.347, 95% CI 0.245–7.397), floating population (OR 0.847, 95% CI 0.202–3.549), rash on the hands (OR 0.740, 95% CI 0.292–1.874), rash on the foot (OR 0.905, 95% CI 0.645–1.272), the level of the clinic visited first (below the country level) (OR 5.276, 95% CI 0.781–35.630), breast feeding (OR 0.523, 95% CI 0.167–1.643), and the risk of severe HFMD. Conclusions. Fever, fever for more than 3 days, vomiting, limb trembling, dyspnea, contact with HFMD children, rashes on the hips, pathologic reflexes, lethargy, convulsions, and EV71 infection are risk factors for severe HFMD.


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## Body

## 1. Introduction

Hand, foot, and mouth disease (HFMD) is a common childhood infection disease with characteristic features of fever, oral ulcers, and vesicular rashes on the hands, feet, and buttocks. It is caused by a group of enteroviruses, commonly coxsackie A16 and enterovirus-71 (EV-71). The mode of transmission of HFMD is mainly via the fecal-oral route, respiratory droplets, contact with blister fluid of an infected individual, or general close contact with infected individuals. Most HFMD cases were mild and limited to fever and vesicular exanthema on patients’ palms, soles, and mouth along with discomfortness at certain levels. However, some severe cases with potentially fatal complications such as brain stem encephalitis (BE) and/or pulmonary edema (PE) show rapid progression that may lead to serious sequelae, even death. In recent years, more and more outbreaks of severe cases have been reported [1, 2]. Previous studies have shown that close monitoring and timely intervention may prevent the development of severity and avert the death of severe HFMD [3–5]. Therefore, it is extremely necessary to identify the risk factors which predict the occurrence of severity. Meta-analysis is a means of increasing the effective sample size under investigation through pooling of data from individual association studies, thus enhancing the statistical power [6]. In order to identify risk factors of acquiring severe HFMD, prevent deterioration, and reduce acute mortality, we conducted this meta-analysis to determine the risk factors for severe HFMD.


## 2. Materials and Methods

### 2.1. Study Selection

A systematic search of the literature was done in the following electronic databases: PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang (Chinese). The following keywords were used: severe hand foot mouth disease (HFMD), risk factors, and case control study. The quality of the included studies was assessed using the Newcastle-Ottawa Scale, and studies achieving six or more points were considered to be of high quality.


### 2.2. Inclusion and Exclusion Criteria

Two investigators searched the electronic databases independently according to the following criteria for inclusion: (1) a case-control study including severe and mild disease patient groups; (2) published up to June 2017; (3) diagnosis of severe HFMD and mild HFMD consistent with the criteria defined by us. Abstracts, reviews, case reports, noncomparative studies, and low-quality studies were excluded. In cases of disagreement, a third investigator acted as an arbitrator, and the disagreements were resolved with the research team by discussion.


### 2.3. Data Extraction and Quality Assessment

The following items were extracted from the included studies: the first author’s name, year of publication, source of publication, type of the study, risk factors, total sample size, number of severe and mild HFMD cases, and diagnostic criteria for severe and mild HFMD.The publication bias was evaluated using Egger’s test [7]. If P>0.05, the publication bias exists; otherwise, the publication bias does not exist.


### 2.4. Definitions

HFMD cases were divided into two groups according to Guidelines on the Diagnosis and Treatment of HFMD [8]. The mild HFMD was defined as papular/vesicular skin rashes on the hand, foot, mouth, or buttock, and the severe HFMD was defined as mild HFMD with the addition of neurological, respiratory, or circulatory complications, or death. Neurological complications included aseptic meningitis, encephalitis, and acute flaccid paralysis [9]. The duration of fever was defined as body temperature ≥37.5°C.


### 2.5. Meta-Analysis Methods

Stata 14.0 was used for the statistical analysis. The odds ratio (OR) and 95% confidence intervals (CI) were calculated using the fixed effect model or random effect model, and the choice for statistical model was determined by their heterogeneity which were assessed by theX2 and I2 statistics. I2 >50% and X2-statistic (P<0.1) were considered to show significant heterogeneity, and the random effect model was adopted; otherwise, the fixed effect model was used. The OR and 95% CI were used as summary statistics for the comparison of the following risk factors: fever, fever for more than 3 days, vomiting, limb trembling, dyspnea, contact with HFMD children, rashes on the hips, pathologic reflexes, lethargy, convulsions, EV71 infection, female sex, scatter-lived children, floating population, rash on the hands, rash on the foot, the level of the clinic visited first (below the country level), and breast feeding.The pooled estimate of risk was obtained by the Mantel–Haenszel method in the fixed effect model and by the M-H heterogeneity method in the random effect model. AllP values were 2-sided. A P value less than 0.05 was considered to be statistically significant.


## 2.1. Study Selection

A systematic search of the literature was done in the following electronic databases: PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang (Chinese). The following keywords were used: severe hand foot mouth disease (HFMD), risk factors, and case control study. The quality of the included studies was assessed using the Newcastle-Ottawa Scale, and studies achieving six or more points were considered to be of high quality.


## 2.2. Inclusion and Exclusion Criteria

Two investigators searched the electronic databases independently according to the following criteria for inclusion: (1) a case-control study including severe and mild disease patient groups; (2) published up to June 2017; (3) diagnosis of severe HFMD and mild HFMD consistent with the criteria defined by us. Abstracts, reviews, case reports, noncomparative studies, and low-quality studies were excluded. In cases of disagreement, a third investigator acted as an arbitrator, and the disagreements were resolved with the research team by discussion.


## 2.3. Data Extraction and Quality Assessment

The following items were extracted from the included studies: the first author’s name, year of publication, source of publication, type of the study, risk factors, total sample size, number of severe and mild HFMD cases, and diagnostic criteria for severe and mild HFMD.The publication bias was evaluated using Egger’s test [7]. If P>0.05, the publication bias exists; otherwise, the publication bias does not exist.


## 2.4. Definitions

HFMD cases were divided into two groups according to Guidelines on the Diagnosis and Treatment of HFMD [8]. The mild HFMD was defined as papular/vesicular skin rashes on the hand, foot, mouth, or buttock, and the severe HFMD was defined as mild HFMD with the addition of neurological, respiratory, or circulatory complications, or death. Neurological complications included aseptic meningitis, encephalitis, and acute flaccid paralysis [9]. The duration of fever was defined as body temperature ≥37.5°C.


## 2.5. Meta-Analysis Methods

Stata 14.0 was used for the statistical analysis. The odds ratio (OR) and 95% confidence intervals (CI) were calculated using the fixed effect model or random effect model, and the choice for statistical model was determined by their heterogeneity which were assessed by theX2 and I2 statistics. I2 >50% and X2-statistic (P<0.1) were considered to show significant heterogeneity, and the random effect model was adopted; otherwise, the fixed effect model was used. The OR and 95% CI were used as summary statistics for the comparison of the following risk factors: fever, fever for more than 3 days, vomiting, limb trembling, dyspnea, contact with HFMD children, rashes on the hips, pathologic reflexes, lethargy, convulsions, EV71 infection, female sex, scatter-lived children, floating population, rash on the hands, rash on the foot, the level of the clinic visited first (below the country level), and breast feeding.The pooled estimate of risk was obtained by the Mantel–Haenszel method in the fixed effect model and by the M-H heterogeneity method in the random effect model. AllP values were 2-sided. A P value less than 0.05 was considered to be statistically significant.


## 3. Results

### 3.1. Characteristics of Included Studies

The first search strategy generated 109 studies. Only 11 articles [10–20] met the inclusion criteria, and they were all carried out in China. The selection process is shown in Figure 1. All the studies were of high quality according to the Newcastle-Ottawa Scale (NOS). The sample sizes of the included studies ranged from 76 to 761 and amounted to 4082 subjects in total. There were 1640 patients in the severe HFMD group and 2442 patients in the mild HFMD group. The study and patients’ characteristics are summarized in Table 1. The two groups were similar with regard to age and gender.Figure 1
Flow chart showing the selection process for the meta-analysis.Table 1
Characteristics of the included studies and patients into meta-analysis.
Author
Year
Country
Severe HFMD
Mild HFMD
Study quality (score)
Age (months)
Female (%)
Severe HFMD versus mild HFMD
Severe HFMD versus mild HFMD
Wang et al. [10]
2014
China
60
60
∗∗∗∗∗∗
18/17;P=NS
43/36;P=0.457
Yang et al. [11]
2012
China
89
267
∗∗∗∗∗∗
24/25;P=0.345
35/35;P=1.000
Pan et al. [12]
2012
China
105
210
∗∗∗∗∗∗
25/32;P=NS
30/45;P=0.015
Liu et al. [13]
2014
China
249
512
∗∗∗∗∗∗∗
37/37;P=NS
45/45;P>0.05
Zeng et al. [14]
2013
China
139
304
∗∗∗∗∗∗
27/25;P=NS
35/34;P=0.668
Zhang et al. [15]
2017
China
459
246
∗∗∗∗∗∗∗
23/23;P=0.356
35/34;P=0.976
Deng et al. [16]
2016
China
128
88
∗∗∗∗∗∗
NR
37/39;P=0.817
Li et al. [17]
2013
China
116
202
∗∗∗∗∗∗
NR
36/28;P=0.137
Pan et al. [18]
2012
China
229
140
∗∗∗∗∗∗
NR
NR
Luo et al. [19]
2016
China
30
373
∗∗∗∗∗∗
NR
NR
Li [20]
2016
China
36
40
∗∗∗∗∗∗
41/39;P=NS
47/48;P>0.05
NR: not reported; NS: not significant.Now the Newcastle-Ottawa scale is mainly applied in the evaluation of case-control study. The literature was graded in terms of selection, comparability, and outcome, and each aspect consists of a number of assessment items. When the items are up to the requirements, one star can be obtained, of which the comparability can reach a maximum of 2. Six stars (∗∗∗∗∗∗) and more were considered to be of high quality.


### 3.2. Risk Factors of Severe HFMD

#### 3.2.1. Patient Clinical Manifestations

In 8 studies, fever was strongly related to the risk of severe HFMD (OR 7.396, 95% CI 3.565–15.342). In 3 studies, fever for more than 3 days was significantly associated with severe HFMD (OR 5.773, 95% CI 4.199–7.939). In 3 studies, rashes on the hips or buttocks were significantly associated with severe HFMD (OR 1.650, 95% CI 1.303–2.090). However, we found no significant association between rash on the palm, rash on the soles, and severe HFMD in 3 studies, respectively (OR 0.740, 95% CI 0.292–1.874 and OR 0.905 95% CI 0.645–1.272) (Table2; Figures 2–6).Table 2
Meta-analysis of risk factors for the hand, foot, and mouth disease in 18 separate studies.
Risk factors
Number of studies
Severe HFMD
Mild HFMD
OR (95% CI)
Test of heterogeneity
Yes
No
Yes
No
Model
Chi-square
P value
I
2 (%)
Female
4
202
301
438
611
0.918 (0.738, 1.142)
F
5.94
0.115
49.5
Scatter-lived/sporadic children
4
370
343
515
268
1.347 (0.245, 7.397)
R
108.61
≤0.001
97.2
Floating population/migrant
4
307
485
377
650
0.847 (0.202, 3.549)
R
94.44
≤0.001
96.8
Fever
8
1334
34
1176
371
7.396 (3.565, 15.342)
R
18.6
0.005
67.7
Fever for more than 3 days
3
207
124
99
370
5.773 (4.199, 7.939)
F
4.39
0.111
54.5
Vomiting
6
478
603
132
870
6.023 (2.598, 13.963)
R
59.18
≤0.001
91.6
Limb trembling/shaking
4
588
343
46
630
42.348 (11.765, 152.437)
R
21.76
≤0.001
86.2
Dyspnea/breathlessness
4
210
721
29
647
12.869 (1.948, 85.017)
R
23.81
≤0.001
87.4
Contact with HFMD children
4
215
269
84
832
5.326 (1.263, 22.466)
R
54.58
≤0.001
94.5
Rash on the palm/hands
3
700
75
601
52
0.740 (0.292, 1.874)
R
10.73
0.005
81.4
Rash on the soles/foot
3
680
92
558
93
0.905 (0.645, 1.272)
F
0.2
0.904
0
Rashes on the hips/buttocks
3
533
237
368
285
1.650 (1.303, 2.090)
F
2.16
0.340
7.2
Level of the clinic visited first (below the country level)
3
238
160
114
725
5.276 (0.781, 35.630)
R
65.87
≤0.001
97
Breast feeding
3
613
196
824
129
0.523 (0.167, 1.643)
R
30.46
≤0.001
93.4
Pathologic reflexes
3
267
13
0
330
3057.064 (494.409, 19000)
F
3.09
0.213
35.3
Lethargy/hypersomnia
5
278
344
25
732
31.791 (3.369, 300.020)
R
76.16
≤0.001
94.7
Convulsions/twitch
5
334
676
25
1083
23.652 (1.973, 283.592)
R
104.46
≤0.001
96.2
EV71 infection
7
521
149
586
1012
9.056 (4.102, 19.996)
R
56.03
≤0.001
89.3
OR, odds ratio; CI, confidence interval; HFMD, hand, foot, and mouth disease; EV71, enterovirus 71; R, random effect model; F, fixed effect model.Figure 2
Forest plots showing the results of the meta-analysis regarding fever.Figure 3
Forest plots showing the results of the meta-analysis regarding fever for more than 3 days.Figure 4
Forest plots showing the results of the meta-analysis regarding rash on the hands.Figure 5
Forest plots showing the results of the meta-analysis regarding rash on the foot.Figure 6
Forest plots showing the results of the meta-analysis regarding rashes on the hips.We found that vomiting (OR 6.023, 95% CI 2.598–13.963), limb trembling (OR 42.348, 95% CI 11.765–152.437), dyspnea (OR 12.869, 95% CI 1.948–85.017), pathologic reflexes (OR 3057.064, 95% CI 494.409–19000), lethargy (OR 31.791, 95% CI 3.369–300.020), and convulsions (OR 23.652, 95% CI 1.973–283.592) were significantly associated with severe HFMD (Table2; Figures 7–12).Figure 7
Forest plots showing the results of the meta-analysis regarding vomiting.Figure 8
Forest plots showing the results of the meta-analysis regarding limb trembling.Figure 9
Forest plots showing the results of the meta-analysis regarding dyspnea.Figure 10
Forest plots showing the results of the meta-analysis regarding pathologic reflexes.Figure 11
Forest plots showing the results of the meta-analysis regarding lethargy.Figure 12
Forest plots showing the results of the meta-analysis regarding convulsions.


#### 3.2.2. Patient Demographic Characteristics

We analyzed the association between demographic characteristics of patients and severe HFMD and found that female gender (OR 1.06, 95% CI 0.91–1.24), scatter-lived children (OR 1.06, 95% CI 0.91–1.24), and floating population (OR 1.06, 95% CI 0.91–1.24) were all not related to the risk of severe HFMD (Table2; Figures 13–15).Figure 13
Forest plots showing the results of the meta-analysis regarding female gender.Figure 14
Forest plots showing the results of the meta-analysis regarding scatter-lived children.Figure 15
Forest plots showing the results of the meta-analysis regarding floating population.


#### 3.2.3. EV71 Infection

Seven studies analyzed the association between EV71 infection and severe HFMD, and the results suggest that EV71 infection significantly increased the probability of severe HFMD (OR 9.056, 95% CI 4.102–19.996) (Table2; Figure 16).Figure 16
Forest plots showing the results of the meta-analysis regarding EV71 infection.


#### 3.2.4. Association between Other Factors and Severe HFMD

Seven studies suggest that contacting with HFMD children significantly increased the risk of severe HFMD (OR 5.326, 95% CI 1.263–22.466). We found no association between the level of the clinic visited first (below the country level) (OR 5.276, 95% CI 0.781–35.630), breast feeding (OR 0.523, 95% CI 0.167–1.643), and severe HFMD (Table2; Figures 17–19).Figure 17
Forest plots showing the results of the meta-analysis regarding contact with HFMD children.Figure 18
Forest plots showing the results of the meta-analysis regarding the level of the clinic visited first (below the country level).Figure 19
Forest plots showing the results of the meta-analysis regarding breast feeding.


### 3.3. Evaluation of Publication Bias

Egger’s test analysis of total complications was performed. The results are shown in Table3. Seventeen compared factors had no publication bias; one risk factor did (rashes on the hips).Table 3
Egger’s test of all risk factors.
Risk factors
Number of studies
Egger’s test
Publication bias (yes or no)
Model
t value
P value
Female
4
−0.12
0.916
No
F
Scatter-lived children
4
1.18
0.361
No
R
Floating population
4
0.58
0.620
No
R
Fever
8
−0.74
0.492
No
R
Fever for more than 3 days
3
−0.04
0.976
No
F
Vomiting
6
1.68
0.168
No
R
Limb trembling
4
1.36
0.306
No
R
Dyspnea
4
3.51
0.072
No
R
Contact with HFMD children
4
−0.72
0.548
No
R
Rash on the hands
3
−1.00
0.499
No
R
Rash on the foot
3
1.92
0.306
No
F
Rashes on the hips
3
−84.52
0.008
Yes
F
Level of the clinic visited first (below the country level)
3
−1.10
0.470
No
R
Breast feeding
3
−9.69
0.065
No
R
Pathologic reflexes
3
1.18
0.448
No
F
Lethargy
5
3.09
0.054
No
R
Convulsions
5
0.40
0.718
No
R
EV71 infection
7
1.83
0.126
No
R
R, random effect model; F, fixed effect model.


## 3.1. Characteristics of Included Studies

The first search strategy generated 109 studies. Only 11 articles [10–20] met the inclusion criteria, and they were all carried out in China. The selection process is shown in Figure 1. All the studies were of high quality according to the Newcastle-Ottawa Scale (NOS). The sample sizes of the included studies ranged from 76 to 761 and amounted to 4082 subjects in total. There were 1640 patients in the severe HFMD group and 2442 patients in the mild HFMD group. The study and patients’ characteristics are summarized in Table 1. The two groups were similar with regard to age and gender.Figure 1
Flow chart showing the selection process for the meta-analysis.Table 1
Characteristics of the included studies and patients into meta-analysis.
Author
Year
Country
Severe HFMD
Mild HFMD
Study quality (score)
Age (months)
Female (%)
Severe HFMD versus mild HFMD
Severe HFMD versus mild HFMD
Wang et al. [10]
2014
China
60
60
∗∗∗∗∗∗
18/17;P=NS
43/36;P=0.457
Yang et al. [11]
2012
China
89
267
∗∗∗∗∗∗
24/25;P=0.345
35/35;P=1.000
Pan et al. [12]
2012
China
105
210
∗∗∗∗∗∗
25/32;P=NS
30/45;P=0.015
Liu et al. [13]
2014
China
249
512
∗∗∗∗∗∗∗
37/37;P=NS
45/45;P>0.05
Zeng et al. [14]
2013
China
139
304
∗∗∗∗∗∗
27/25;P=NS
35/34;P=0.668
Zhang et al. [15]
2017
China
459
246
∗∗∗∗∗∗∗
23/23;P=0.356
35/34;P=0.976
Deng et al. [16]
2016
China
128
88
∗∗∗∗∗∗
NR
37/39;P=0.817
Li et al. [17]
2013
China
116
202
∗∗∗∗∗∗
NR
36/28;P=0.137
Pan et al. [18]
2012
China
229
140
∗∗∗∗∗∗
NR
NR
Luo et al. [19]
2016
China
30
373
∗∗∗∗∗∗
NR
NR
Li [20]
2016
China
36
40
∗∗∗∗∗∗
41/39;P=NS
47/48;P>0.05
NR: not reported; NS: not significant.Now the Newcastle-Ottawa scale is mainly applied in the evaluation of case-control study. The literature was graded in terms of selection, comparability, and outcome, and each aspect consists of a number of assessment items. When the items are up to the requirements, one star can be obtained, of which the comparability can reach a maximum of 2. Six stars (∗∗∗∗∗∗) and more were considered to be of high quality.


## 3.2. Risk Factors of Severe HFMD

### 3.2.1. Patient Clinical Manifestations

In 8 studies, fever was strongly related to the risk of severe HFMD (OR 7.396, 95% CI 3.565–15.342). In 3 studies, fever for more than 3 days was significantly associated with severe HFMD (OR 5.773, 95% CI 4.199–7.939). In 3 studies, rashes on the hips or buttocks were significantly associated with severe HFMD (OR 1.650, 95% CI 1.303–2.090). However, we found no significant association between rash on the palm, rash on the soles, and severe HFMD in 3 studies, respectively (OR 0.740, 95% CI 0.292–1.874 and OR 0.905 95% CI 0.645–1.272) (Table2; Figures 2–6).Table 2
Meta-analysis of risk factors for the hand, foot, and mouth disease in 18 separate studies.
Risk factors
Number of studies
Severe HFMD
Mild HFMD
OR (95% CI)
Test of heterogeneity
Yes
No
Yes
No
Model
Chi-square
P value
I
2 (%)
Female
4
202
301
438
611
0.918 (0.738, 1.142)
F
5.94
0.115
49.5
Scatter-lived/sporadic children
4
370
343
515
268
1.347 (0.245, 7.397)
R
108.61
≤0.001
97.2
Floating population/migrant
4
307
485
377
650
0.847 (0.202, 3.549)
R
94.44
≤0.001
96.8
Fever
8
1334
34
1176
371
7.396 (3.565, 15.342)
R
18.6
0.005
67.7
Fever for more than 3 days
3
207
124
99
370
5.773 (4.199, 7.939)
F
4.39
0.111
54.5
Vomiting
6
478
603
132
870
6.023 (2.598, 13.963)
R
59.18
≤0.001
91.6
Limb trembling/shaking
4
588
343
46
630
42.348 (11.765, 152.437)
R
21.76
≤0.001
86.2
Dyspnea/breathlessness
4
210
721
29
647
12.869 (1.948, 85.017)
R
23.81
≤0.001
87.4
Contact with HFMD children
4
215
269
84
832
5.326 (1.263, 22.466)
R
54.58
≤0.001
94.5
Rash on the palm/hands
3
700
75
601
52
0.740 (0.292, 1.874)
R
10.73
0.005
81.4
Rash on the soles/foot
3
680
92
558
93
0.905 (0.645, 1.272)
F
0.2
0.904
0
Rashes on the hips/buttocks
3
533
237
368
285
1.650 (1.303, 2.090)
F
2.16
0.340
7.2
Level of the clinic visited first (below the country level)
3
238
160
114
725
5.276 (0.781, 35.630)
R
65.87
≤0.001
97
Breast feeding
3
613
196
824
129
0.523 (0.167, 1.643)
R
30.46
≤0.001
93.4
Pathologic reflexes
3
267
13
0
330
3057.064 (494.409, 19000)
F
3.09
0.213
35.3
Lethargy/hypersomnia
5
278
344
25
732
31.791 (3.369, 300.020)
R
76.16
≤0.001
94.7
Convulsions/twitch
5
334
676
25
1083
23.652 (1.973, 283.592)
R
104.46
≤0.001
96.2
EV71 infection
7
521
149
586
1012
9.056 (4.102, 19.996)
R
56.03
≤0.001
89.3
OR, odds ratio; CI, confidence interval; HFMD, hand, foot, and mouth disease; EV71, enterovirus 71; R, random effect model; F, fixed effect model.Figure 2
Forest plots showing the results of the meta-analysis regarding fever.Figure 3
Forest plots showing the results of the meta-analysis regarding fever for more than 3 days.Figure 4
Forest plots showing the results of the meta-analysis regarding rash on the hands.Figure 5
Forest plots showing the results of the meta-analysis regarding rash on the foot.Figure 6
Forest plots showing the results of the meta-analysis regarding rashes on the hips.We found that vomiting (OR 6.023, 95% CI 2.598–13.963), limb trembling (OR 42.348, 95% CI 11.765–152.437), dyspnea (OR 12.869, 95% CI 1.948–85.017), pathologic reflexes (OR 3057.064, 95% CI 494.409–19000), lethargy (OR 31.791, 95% CI 3.369–300.020), and convulsions (OR 23.652, 95% CI 1.973–283.592) were significantly associated with severe HFMD (Table2; Figures 7–12).Figure 7
Forest plots showing the results of the meta-analysis regarding vomiting.Figure 8
Forest plots showing the results of the meta-analysis regarding limb trembling.Figure 9
Forest plots showing the results of the meta-analysis regarding dyspnea.Figure 10
Forest plots showing the results of the meta-analysis regarding pathologic reflexes.Figure 11
Forest plots showing the results of the meta-analysis regarding lethargy.Figure 12
Forest plots showing the results of the meta-analysis regarding convulsions.


### 3.2.2. Patient Demographic Characteristics

We analyzed the association between demographic characteristics of patients and severe HFMD and found that female gender (OR 1.06, 95% CI 0.91–1.24), scatter-lived children (OR 1.06, 95% CI 0.91–1.24), and floating population (OR 1.06, 95% CI 0.91–1.24) were all not related to the risk of severe HFMD (Table2; Figures 13–15).Figure 13
Forest plots showing the results of the meta-analysis regarding female gender.Figure 14
Forest plots showing the results of the meta-analysis regarding scatter-lived children.Figure 15
Forest plots showing the results of the meta-analysis regarding floating population.


### 3.2.3. EV71 Infection

Seven studies analyzed the association between EV71 infection and severe HFMD, and the results suggest that EV71 infection significantly increased the probability of severe HFMD (OR 9.056, 95% CI 4.102–19.996) (Table2; Figure 16).Figure 16
Forest plots showing the results of the meta-analysis regarding EV71 infection.


### 3.2.4. Association between Other Factors and Severe HFMD

Seven studies suggest that contacting with HFMD children significantly increased the risk of severe HFMD (OR 5.326, 95% CI 1.263–22.466). We found no association between the level of the clinic visited first (below the country level) (OR 5.276, 95% CI 0.781–35.630), breast feeding (OR 0.523, 95% CI 0.167–1.643), and severe HFMD (Table2; Figures 17–19).Figure 17
Forest plots showing the results of the meta-analysis regarding contact with HFMD children.Figure 18
Forest plots showing the results of the meta-analysis regarding the level of the clinic visited first (below the country level).Figure 19
Forest plots showing the results of the meta-analysis regarding breast feeding.


## 3.2.1. Patient Clinical Manifestations

In 8 studies, fever was strongly related to the risk of severe HFMD (OR 7.396, 95% CI 3.565–15.342). In 3 studies, fever for more than 3 days was significantly associated with severe HFMD (OR 5.773, 95% CI 4.199–7.939). In 3 studies, rashes on the hips or buttocks were significantly associated with severe HFMD (OR 1.650, 95% CI 1.303–2.090). However, we found no significant association between rash on the palm, rash on the soles, and severe HFMD in 3 studies, respectively (OR 0.740, 95% CI 0.292–1.874 and OR 0.905 95% CI 0.645–1.272) (Table2; Figures 2–6).Table 2
Meta-analysis of risk factors for the hand, foot, and mouth disease in 18 separate studies.
Risk factors
Number of studies
Severe HFMD
Mild HFMD
OR (95% CI)
Test of heterogeneity
Yes
No
Yes
No
Model
Chi-square
P value
I
2 (%)
Female
4
202
301
438
611
0.918 (0.738, 1.142)
F
5.94
0.115
49.5
Scatter-lived/sporadic children
4
370
343
515
268
1.347 (0.245, 7.397)
R
108.61
≤0.001
97.2
Floating population/migrant
4
307
485
377
650
0.847 (0.202, 3.549)
R
94.44
≤0.001
96.8
Fever
8
1334
34
1176
371
7.396 (3.565, 15.342)
R
18.6
0.005
67.7
Fever for more than 3 days
3
207
124
99
370
5.773 (4.199, 7.939)
F
4.39
0.111
54.5
Vomiting
6
478
603
132
870
6.023 (2.598, 13.963)
R
59.18
≤0.001
91.6
Limb trembling/shaking
4
588
343
46
630
42.348 (11.765, 152.437)
R
21.76
≤0.001
86.2
Dyspnea/breathlessness
4
210
721
29
647
12.869 (1.948, 85.017)
R
23.81
≤0.001
87.4
Contact with HFMD children
4
215
269
84
832
5.326 (1.263, 22.466)
R
54.58
≤0.001
94.5
Rash on the palm/hands
3
700
75
601
52
0.740 (0.292, 1.874)
R
10.73
0.005
81.4
Rash on the soles/foot
3
680
92
558
93
0.905 (0.645, 1.272)
F
0.2
0.904
0
Rashes on the hips/buttocks
3
533
237
368
285
1.650 (1.303, 2.090)
F
2.16
0.340
7.2
Level of the clinic visited first (below the country level)
3
238
160
114
725
5.276 (0.781, 35.630)
R
65.87
≤0.001
97
Breast feeding
3
613
196
824
129
0.523 (0.167, 1.643)
R
30.46
≤0.001
93.4
Pathologic reflexes
3
267
13
0
330
3057.064 (494.409, 19000)
F
3.09
0.213
35.3
Lethargy/hypersomnia
5
278
344
25
732
31.791 (3.369, 300.020)
R
76.16
≤0.001
94.7
Convulsions/twitch
5
334
676
25
1083
23.652 (1.973, 283.592)
R
104.46
≤0.001
96.2
EV71 infection
7
521
149
586
1012
9.056 (4.102, 19.996)
R
56.03
≤0.001
89.3
OR, odds ratio; CI, confidence interval; HFMD, hand, foot, and mouth disease; EV71, enterovirus 71; R, random effect model; F, fixed effect model.Figure 2
Forest plots showing the results of the meta-analysis regarding fever.Figure 3
Forest plots showing the results of the meta-analysis regarding fever for more than 3 days.Figure 4
Forest plots showing the results of the meta-analysis regarding rash on the hands.Figure 5
Forest plots showing the results of the meta-analysis regarding rash on the foot.Figure 6
Forest plots showing the results of the meta-analysis regarding rashes on the hips.We found that vomiting (OR 6.023, 95% CI 2.598–13.963), limb trembling (OR 42.348, 95% CI 11.765–152.437), dyspnea (OR 12.869, 95% CI 1.948–85.017), pathologic reflexes (OR 3057.064, 95% CI 494.409–19000), lethargy (OR 31.791, 95% CI 3.369–300.020), and convulsions (OR 23.652, 95% CI 1.973–283.592) were significantly associated with severe HFMD (Table2; Figures 7–12).Figure 7
Forest plots showing the results of the meta-analysis regarding vomiting.Figure 8
Forest plots showing the results of the meta-analysis regarding limb trembling.Figure 9
Forest plots showing the results of the meta-analysis regarding dyspnea.Figure 10
Forest plots showing the results of the meta-analysis regarding pathologic reflexes.Figure 11
Forest plots showing the results of the meta-analysis regarding lethargy.Figure 12
Forest plots showing the results of the meta-analysis regarding convulsions.


## 3.2.2. Patient Demographic Characteristics

We analyzed the association between demographic characteristics of patients and severe HFMD and found that female gender (OR 1.06, 95% CI 0.91–1.24), scatter-lived children (OR 1.06, 95% CI 0.91–1.24), and floating population (OR 1.06, 95% CI 0.91–1.24) were all not related to the risk of severe HFMD (Table2; Figures 13–15).Figure 13
Forest plots showing the results of the meta-analysis regarding female gender.Figure 14
Forest plots showing the results of the meta-analysis regarding scatter-lived children.Figure 15
Forest plots showing the results of the meta-analysis regarding floating population.


## 3.2.3. EV71 Infection

Seven studies analyzed the association between EV71 infection and severe HFMD, and the results suggest that EV71 infection significantly increased the probability of severe HFMD (OR 9.056, 95% CI 4.102–19.996) (Table2; Figure 16).Figure 16
Forest plots showing the results of the meta-analysis regarding EV71 infection.


## 3.2.4. Association between Other Factors and Severe HFMD

Seven studies suggest that contacting with HFMD children significantly increased the risk of severe HFMD (OR 5.326, 95% CI 1.263–22.466). We found no association between the level of the clinic visited first (below the country level) (OR 5.276, 95% CI 0.781–35.630), breast feeding (OR 0.523, 95% CI 0.167–1.643), and severe HFMD (Table2; Figures 17–19).Figure 17
Forest plots showing the results of the meta-analysis regarding contact with HFMD children.Figure 18
Forest plots showing the results of the meta-analysis regarding the level of the clinic visited first (below the country level).Figure 19
Forest plots showing the results of the meta-analysis regarding breast feeding.


## 3.3. Evaluation of Publication Bias

Egger’s test analysis of total complications was performed. The results are shown in Table3. Seventeen compared factors had no publication bias; one risk factor did (rashes on the hips).Table 3
Egger’s test of all risk factors.
Risk factors
Number of studies
Egger’s test
Publication bias (yes or no)
Model
t value
P value
Female
4
−0.12
0.916
No
F
Scatter-lived children
4
1.18
0.361
No
R
Floating population
4
0.58
0.620
No
R
Fever
8
−0.74
0.492
No
R
Fever for more than 3 days
3
−0.04
0.976
No
F
Vomiting
6
1.68
0.168
No
R
Limb trembling
4
1.36
0.306
No
R
Dyspnea
4
3.51
0.072
No
R
Contact with HFMD children
4
−0.72
0.548
No
R
Rash on the hands
3
−1.00
0.499
No
R
Rash on the foot
3
1.92
0.306
No
F
Rashes on the hips
3
−84.52
0.008
Yes
F
Level of the clinic visited first (below the country level)
3
−1.10
0.470
No
R
Breast feeding
3
−9.69
0.065
No
R
Pathologic reflexes
3
1.18
0.448
No
F
Lethargy
5
3.09
0.054
No
R
Convulsions
5
0.40
0.718
No
R
EV71 infection
7
1.83
0.126
No
R
R, random effect model; F, fixed effect model.


## 4. Discussion

A recent meta-analysis involving 19 separate studies [21] found that clinical characteristics such as duration of fever more than 3 days, body temperature ≥37.5°C, lethargy, vomiting, and EV71 infection were significantly related to the risk of severe HFMD which is consistent with our findings. Other than these risk factors, we also found rashes on the hips or buttocks, limb trembling, dyspnea, pathologic reflexes, convulsions, and contact with HFMD children significantly increased the risk of severe HFMD. However, we found no significant association between rash on the palm, rash on the soles, female gender, scatter-lived children, floating population, the level of the clinic visited first (below the country level), breast feeding, and severe HFMD.Previous studies on gender have different conclusions: Pan et al. [12] thought that female have a lower risk of attacking severe HFMD than male; however, Wang et al. [10], Yang et al. [11], and Liu et al. [13] do not think that there is a connection, and our analysis found that there is no association between gender and severe HFMD.Both male and female have the same opportunities to develop severe HFMD. Previous studies have also drawn different conclusions regarding scatter-lived children and floating populations: Zhang et al. [15] thought that scatter-lived children reduce the risk of acquiring severe HFMD, but Wang et al. [10], Yang et al. [11], and Pan et al. [12] got the opposite conclusion. Zhang et al. [15] thought that floating children have a lower risk of acquiring severe HFMD; however, Zeng et al. [14] found a higher risk between them. Yang et al. [11] and Pan et al. [12] did not find any association. Our analysis found both scatter-lived children and floating populations is not related to the risk of severe HFMD.Oral ulcers and vesicular rashes on the hands, feet, and hip/buttocks are common signs of HFMD; however, rashes on different parts can lead to different levels of severity of HFMD. Previous studies regarding rashes on the hands and rashes on the hips have different conclusions: Yang et al. [11] thought that rashes on the hands are protective factors of HFMD, and other two studies found no association between them; Zhang et al. [15] thought that rashes on the hips are risk factors of HFMD, and other two studies found no association between them. Our studies confirm previous conclusions about the relationship between rashes on the feet and severe HFMD but found there is no association between rashes on the hands and severe HFMD and also found that rashes on the hips are risk factors. These remind us to pay close attention to those kinds of patients whose rashes on the hips.Most of previous studies included in our meta-analysis found that fever, vomiting, lethargy, convulsions, and contact with HFMD children are risk factors of severe HFMD, and our study confirmed it. Our study also confirmed that severe HFMD is associated with fever for more than 3 days, limb trembling/shaking, dyspnea, pathologic reflexes, and EV71 infection again. Any of these factors increase the possibility of developing severe HFMD. Therefore, early recognition and meticulous management of patients with these risk factors are required [22, 23].EV71 invades the central nervous system causing severe disease ranging from meningitis to fatal encephalitis [24]. In our study, we retrieved 7 studies that analyzed the association between EV71 infection and severe HFMD, and the meta-analysis showed that EV71 infection was significantly associated with the development of severe HFMD. Enterovirus 71 (EV71) is the key pathogen of HFMD, accounting for 70% severe HFMD cases and 90% HFMD-related deaths [25] Therefore, EV71 vaccine development is very important in preventing severe HFMD epidemics. On December 3, 2015, the China Food and Drug Administration (CFDA) approved the first inactivated enterovirus 71 (EV71) whole virus vaccine for preventing severe hand, foot, and mouth disease (HFMD) [26]. In Mainland China, phase III clinical trials showed that all three EV71 vaccines had good safety and protective efficacy in infants. The protection rates against the EV71-caused HFMD were 97.4%, 94.8%, and 90.0%, respectively, following EV71 vaccination [27–29]. HFMD has become a serious public health issue over the past decades in the Asia-Pacific countries [9]. Inactivated EV71 vaccine will be a valuable tool in protecting children’s health in Mainland China and other countries with high HFMD prevalence.In recent years, coxsackievirus A6 (CV-A6) has caused widespread concern around the world and has gradually emerged as a major pathogen of the hand-foot-mouth disease (HFMD) [30]. The infection caused by CV-A6 is more likely to present with atypical clinical symptoms compared with that by EV-A71 (enterovirus 71, EV-A71) and CV-A16 (coxsackievirus A16, CV-A16) [31], and detoxification is a common clinical manifestation of HFMD caused by CV-A6 [32]. In severe cases, neurological symptoms, aseptic meningitis, and encephalitis occur [33]. However, the current researches on Cox A6 are not comprehensive, and there is a lack of a case-control study on the risk factors of CV-A6. Therefore, more research is needed on coxsackie A6.Liu et al. [13] reported that the level of the clinic visited first (below the country level) has a marked impact on severe HFMD development. However, our study did not come to the same conclusion. In addition, Zhang et al. [15] found breast feeding is a protective factor. However, our study did not produce the same results also. There may be less to do with the number of studies being included and the less number of samples. Therefore, further studies are needed to be conducted to confirm the association between the level of the clinic visited first and severe HFMD as well as the association between breast feeding and severe HFMD.


## 5. Conclusions

In conclusion, we found that eleven factors are associated with the severity of HFMD. Previous conclusion regarding the association between fever (body temperature ≥37.5°C), fever more than 3 days, lethargy, vomiting, and EV71 infection and severe HFMD was consistent with our findings. Also, we found rashes on the hips or buttocks, limb trembling/shaking, dyspnea/breathlessness, pathologic reflexes, convulsions/twitch, and contact with HFMD children significantly increased the risk of severe HFMD. But, we found no significant association between rashes on the palm, rashes on the soles, female gender, scatter-lived children, floating population/migrant, the level of the clinic visited first (below the country level), breast feeding, and severe HFMD. Further studies are needed to confirm our findings.



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*Source: 2751457-2018-06-26.xml*