Background

As a common infectious disease among children, hand-foot-mouth disease (HFMD) has aroused wide attention all over the world [1,2,3,4,5]. HFMD is mainly caused by a group of enterovirus, mainly by enterovirus 71(EV71) and coxsackie virus A16 (Cox A16) [4, 6,7,8], it is characterized by fever, oral ulcers, and skin eruptions on hands, feet, buttocks [9,10,11], and transmission occurs through the direct contact with saliva, feces, vesicular fluid, or respiratory droplets of the infected individual, and indirectly by contaminated articles [12, 13].

Generally, the state of HFMD is mild and self-limited. However, many countries or regions have experienced pandemics of severe or fatal HFMD cases in recent years, especially Asia-Pacific countries [14,15,16,17,18]. For China, HFMD is also a major public health problem, and the study of **ng W, et al. showed that about 500 ~ 900 people in China died because of the severe HFMD every year, mainly in children [1], and the mortality rate among children with severe HFMD is also high worldwide [19,20,21,22]. Severe HFMD poses a great threat to one’s health and life, especially the child, as well as bringing psychological and financial burden burdens for families, therefore, the research and investigation of severe HFMD are important.

Previous studies about HFMD were mainly focused on the features of mild HFMD, therefore, the incidence of HFMD worldwide has been controlled to a certain degree [23,24,25]. However, to our knowledge, relevant researches about the clinical or epidemiological characteristics of severe HFMD patients or fatal cases was few, which may impede the further reduction in case fatality. Since Chongqing is one of the districts in China affected by the outbreaks of severe HFMD [1, 24] and studies have shown the incidence of HFMD in Chongqing was higher than the national incidence, as well as that in many countries or regions [24], the present study aimed to investigate the clinical and epidemiological characteristics of severe HFMD and identify risk factors of severe HFMD in our population by taking Chongqing as an example, which may provide theoretical support for further prevention, diagnosis and treatment of severe HFMD.

Methods

Clinical definition

A clinical case of HFMD was defined as a patient with maculopapular or vesicular rash on hands, feet, mouth, or buttocks, with or without fever, according to the guidelines of the National Health Commission of the People’s Republic of China [26]. Children (aged 0–17 years) were diagnosed with severe HFMD if they developed at least one of the following: cardiopulmonary collapse, pulmonary hemorrhage, pulmonary edema, encephalitis, aseptic meningitis, acute flaccid paralysis, myocarditis, or death [27,28,29,30].

Data collection

On 2 May2008, HFMD became a notifiable disease as a Class C (third level of severity and importance of public health) infectious disease in mainland China. Since then, all HFMD cases diagnosed in hospitals were reported to “National Disease Reporting Information System” (NDRIS) within 24 h after diagnoses, including hospitalized and ambulatory cases, not only referred cases, but also self-presenting cases, according to the requirement of the law of the People’s Republic of China on Prevention and Treatment of Infectious Diseases [23]. Therefore, we analyzed the clinical and epidemiological data of severe HFMD children patients from 1 January 2013 to 31 December 2018 in Chongqing.

Specimen collection and laboratory testing

Appropriate clinical specimens from the severe HFMD cases, including fecal sample, rectal swab, throat swab, vesicular fluid, and/or cerebrospinal fluid, were collected. Specimens were placed in 3 mL of sterile viral transport medium and sent to biosafety level two facilities for RT-PCR test within 48 h of collection, using commercially available pan-enterovirus, EV71, and Cox A16 diagnostic kits, according to standardized protocols disseminated by the National Center for Disease Control and Prevention (CDC) [23].

Statistical analysis

The study site is Chongqing, which is located in southwest of China, lying between latitude 28°10′-32°13′ N and longitude 105°11′-110°11′ E. (Fig. 1). The incidence rates of severe HFMD were computed at district level and colored with different colors in the incidence map using the software ArcGIS10.2 (ESRI, Redlands, CA, USA) to show the spatial distribution of severe HFMD.

Fig. 1
figure 1

The distribution of districts and counties in Chongqing, China and its location. The study site is Chongqing, which is located in southwest of China, lying between latitude 28°10′-32°13′ N and longitude 105°11′-110°11′ E. The maps depicted in Fig. 1 were taken from National Geomatics Center of China. (http://www.ngcc.cn/ngcc/)

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The incidence data of severe HFMD from 2013 to 2018 were used for retrospective spatiotemporal analysis. The size of the maximum spatial cluster was defined as a circle with a radius of 92.87 km. The method is based on the geographic coordinates to establish a two-dimensional window of the cylinder. The base circle of the cylinder represents the geographical range and the height represents the length of time. The position and height of the cylinder are dynamically changing. Log likelihood ratio (LLR) was used as the index to measure the abnormal degree of severe HFMD in the scanning window and the Monte Carlo method was used to test LLR for p values. When P < 0.05, we thought that the statistical index of the scanning window compared with outside the window, the relative risk (relative risk, RR) was statistically significant. Parameters were set as: no geographical region overlap, 20% of population at risk, time length was limited to 1 month, and the number of Monte Carlo replication was 999. The areas with the largest LLR values obtained from the scan are called the most significant, and the remaining statistically significant aggregation areas are called secondary potential clusters.

The statistical analyses of clinical data were performed between the fatal cases and survivors using the SPSS software version 19.0 (IBM Corporation, Armonk, NY). We used the chi-square test for analyzing categorical data. General characteristics, family characteristics, symptoms, complications were compared in the two groups, and we performed conditional univariable logistic regression to find predictors that were discriminatory for the death because of severe HFMD [19, 31]. The level of statistical significance for all analyses was P < 0.05.

Ethics statement

All the study procedures were reviewed and approved by the Ethics Committee of Chongqing Center for Disease Control and Prevention. All individual identifying information such as name, address, and telephone number, etc. was anonymized and de-identified prior to analysis. Informed consents were obtained from the individuals or their guardian before the information and the specimens were collected.

Results

General characteristics

A total of 459 severe HFMD cases among children were identified during the study period (2013 ~ 2018), including 415 survivors and 44 fatal cases. The mean age of the patients was 2.15 years (range from 1 months to 16 years), and the ratio of male to female was 1.8:1. Table 1 outlines the general characteristics of all cases including gender, age, the hosting classification of children, identification of enterovirus and the onset season.

Table 1 Demographic characteristics of severe HFMD children patients
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Overall, female children (odds ratio (OR) = 1.92, 95% confidence interval (CI) = 1.03–3.59, P < 0.05) and the children aged 1 to 3(OR = 2.71, 95%CI =1.23–5.98, P < 0.01) are easier to die of severe HFMD. Enterovirus 71 infection (OR = 1.97, 95%CI = 1.02–3.83, P < 0.05) and falling ill in winter (OR = 2.88, 95%CI = 1.28–6.49, P < 0.05) are the risk factors for death. The influence of hosting classification on mortality was not statistically significant. (Table 1.)

The poor prognosis (death) may associated with more than one children in the children patient’s home (OR = 2.69, 95%CI =1.17–6.19, P < 0.05), being taken care of by grandparents (OR = 2.40, 95%CI = 1.28–4.49, P < 0.01) and the caregivers’ education not more than 9 years (OR = 5.52, 95%CI = 2.13–14.29, P < 0.01). Besides, the children patients whose neighborhood also suffer from HFMD disease, may have a better chance of survival (OR = 0.14, 95%CI = 0.02–1.01, P < 0.01). (Table 1.)

Symptoms, and signs

Table 2 shows that the children with severe HFMD who having fever more than 3 days (OR = 2.27, 95%CI = 1.14–4.54, P < 0.05) are easier to die. However, the children patients who had rash more than 3 days (OR = 0.50, 95%CI = 0.26–0.96, P < 0.05), or who were found herpes in the oral cavity (OR = 0.43, 95%CI = 0.23–0.80, P < 0.05) or on cheek (OR = 0.22, 95%CI = 0.09–0.58, P < 0.05), had a better prognosis. (Table 2.)

Table 2 The comparison on general symptoms and nervous, respiratory and circulatory complications between survivors and fatal cases
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Clinical complications

The fatal cases had a higher incidence of consciousness disorders (OR = 8.22, 95%CI = 4.22–16.02, P < 0.01), abnormal pupillary light reflex (OR = 5.96, 95%CI = 2.66–13.34, P < 0.01), vomiting (OR = 3.23, 95%CI = 1.72–6.08, P < 0.01), and general weakness (OR = 2.51, 95%CI = 1.22–5.16, P < 0.05), compared with the survivors. Lethargy, convulsion and dysphoria were not significantly associated with a fatal course. (Table 2.)

The fatal cases had a higher incidence of some respiratory and circulatory complications, such as persistent cough (OR = 2.63, 95%CI = 1.07–3.98, P < 0.05), tachypnea (OR = 2.40, 95%CI = 1.28–4.49, P < 0.01), Moist rales (OR = 7.13, 95%CI = 3.61–14.06, P < 0.01), White frothy sputum (OR = 4.05, 95%CI = 1.22–13.50, P < 0.05), pink frothy sputum (OR = 21.77, 95%CI = 9.78–48.44, P < 0.01), lips cyanosis (OR = 12.82, 95%CI = 6.09–29.96, P < 0.01), the whole body cyanosis (OR = 5.80, 95%CI = 2.73–13.30, P < 0.01), increased heart rate (OR = 2.14, 95%CI = 1.14–4.01, P < 0.05), arrhythmia (OR = 6.54, 95%CI = 3.05–14.04, P < 0.01), cold limbs (OR = 5.59, 95%CI = 2.82–11.10, P < 0.01), pale complexion (OR = 5.29, 95%CI = 2.70–10.37, P < 0.01) and weakened pulse (OR = 7.95, 95%CI = 3.72–14.03, P < 0.01). (Table 2.)

Temporal distribution of severe HFMD

Figure 2 shows the temporal (seasonal) distribution of severe HFMD children from the spring of 2013 to the winter of 2018. Epidemic peaks of severe HFMD were commonly seen in the spring or summer, the highest number of cases reported was in the spring of 2015, and the second highest was in the summer of 2017. Fatal cases could be seen in for seasons. (Fig. 2.)

Fig. 2
figure 2

Seasonal distribution of severe HFMD children (survivors and fatal cases). Epidemic peaks of severe HFMD were commonly seen in the spring or summer, the highest number of cases reported was in the spring of 2015, and the second highest was in the summer of 2017. Fatal cases could be seen in for seasons

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Spatial distribution of severe HFMD

From 2013 to 2018, a total of 459 cases of severe HFMD children were discovered in Chongqing, covering 38 regions, with a total population of 2944, 9983 and an incidence rate of 0.3/100,000. Figure 3 shows the annual incidence of severe HFMD from 2013 to 2018. In the study period, the incidence of HFMD in Chongqing was randomly distributed as a whole. According to the analysis of the incidence of HFMD in Chongqing, the first three high incidence counties were Fuling, Kaixian and Wanzhou successively. (Fig. 3.)

Fig. 3
figure 3

Spatial distribution of severe HFMD children (survivors and fatal cases). Overall, the thematic map of the annual incidence indicated that the northeast and middle parts of Chongqing were still the high incidence regions of HFMD, especially some counties such as Kaixian, Fuling, Wuxi, Liang**, **) except 2014 and 2018. In 2014, the highest incidence region was **, ** from January, 2015 to July, 2017. During this period, the expected cases in this area was 30.86, but the actual number was 153, with a relative risk of 6.93, and P < 0.05. Secondly, the clusters centered in Fuling district from March to July in 2015, and four main urban districts (Yuzhong, Nanan, Dadukou and Jiangbei) in July 2018. (Table 3.)

Table 3 The scanning results of Spatial-Temporal Clusters for serve HFMD cases among children in Chongqing, 2013–2018
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In Fig. 4, the most likely cluster was shown in red color on the map, the secondary cluster was in pink color and the 2nd secondary cluster was in orange color. The three clusters in our study were near the Yangtze River basin. (Fig. 4.)

Fig. 4
figure 4

Spatial clusters of severe HFMD in Chongqing, China from 2013 to 2018. The space scan proposed by Kulldorff is integrated in SaTScan TM v9.4 (http://www.satscan.org/) and clusters are depicted on the map using the software ArcGIS10.2 (https://www.arcgis.com/features/index.html, ESRI, Inc., Redlands, CA, USA). Note: The most likely cluster was shown in red color on the map, the secondary cluster was in pink color and the 2nd secondary cluster was in orange color. The blue curve on the map represents the trunk of the Yangtze River. The map depicted in Fig. 4 were taken from National Geomatics Center of China. (http://www.ngcc.cn/ngcc/)

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Discussion

Severe hand-foot-mouth disease progresses rapidly and may develop severe complications which could be life-threatening [32,33,34,35]. Therefore, screening children with severe HFMD for the abnormal vital signs is important in predicting impending deadly complications and allowing the timely initiation of appropriate interventions [31]. This study aims to describe the clinical and epidemiological features of severe hand-foot-and-mouth disease and identify the risk factors of death in severe HFMD children.

Among the five general characteristics in this study, aged 1 ~ 3 years, enterovirus type 71 infections and failing ill in winter, were the risk factors for the death. Similar to previous reports, in this study, most of the children patients of severe HFMD were under 3 years old, which is probably because the immune function of these children are not yet mature [36,37,50, 51]. The results of this study can be the reference of further clinical and public health practice.

Conclusions

In this study, several clinical risk factors and the temporal, spatial and socio-demographic distribution epidemiological characteristics of severe HFMD contribute to the timely diagnosis and intervention of severe HFMD. Public health or medical staff should take specific measures measures for the children according to the clinical and epidemiological characteristics of severe HFMD, the results of the present study can be the reference of further clinical and public health practice or studies.