Hand, foot and mouth disease (HFMD) is a common acute infectious disease that is mainly caused by enteroviruses. In China, the major causative pathogens are Enterovirus
71 (EV71), Coxsackievirus
A16 (CA16), and Coxsackievirus
A6 (CA6) [1
]. Transmission can occur through direct contact with nose and throat discharges, saliva, and blister fluid, as well as the stools of infected persons. Children under 10 years old, especially children younger than 5 years old, are the most susceptible population. The symptoms of HFMD are usually mild and self-limiting, but severe complications may occasionally occur, which can lead to fatal neurological, cardiovascular, and respiratory problems [3
Outbreaks of HFMD occur worldwide, but these are more frequent in Asian countries [5
]. In 2007, HFMD became a serious public health issue in China [6
]. Later, in March 2008, a HFMD outbreak occurred in mainland China, resulting in a series of severe and fatal cases across multiple provinces, thereby raising serious health concerns nationwide. In response, the Chinese Ministry of Health designated HFMD as a nationally notifiable disease and placed it under standard management. A total of 13.83 million cases have been officially reported in mainland China from 2008 to December 2015 [7
]. Equally striking, Guangdong, a southern province with a typical subtropical climate, is an ideal breeding ground for enteroviruses and accounted for 12.75% of all reported HFMD cases [8
Until now, no effective chemoprophylaxis is available for HFMD. A vaccine for EV 71 has been recently developed, but has not been widely utilized [9
]. Moreover, there is no multivalent vaccine against EV71, Cox A16, Cox A6, and other enterovirus types [10
]. Public health prevention measures are still the most practical and effective means of reducing transmission [11
]. In this circumstance, prevention focuses on underlying risk factors, and public health intervention continues to play an imperative role. Some studies have focused on certain aspects of HFMD risk factors. Ruan et al.
] mainly focus on behavior factors and concluded that hand-washing had a significant protective effect, while Lin et al.
] indicated that exclusive breast feeding is a protective factor against the infection. Xie et al.
] analyzed the importance of public playgrounds in the transmission of HFMD, and Deng et al.
] explored environmental risk factors of HFMD. However, most of these studies only focus on some expects of potential risk factors of HFMD. Behavior factors including cold food consumption, habits of using pacifier and airing out bedding, and clinical factors like birth conditions were not mentioned in previous studies. Therefore we conducted this study to analyze the HFMD cases in Guangdong, to fully examine the risk factors of HFMD. The study finding may have implications for further research and public health intervention.
HFMD caused by enteroviruses continues to be a threat among Asian children [18
]. As no universal vaccine is available for enteroviruses and there is a lack of effective chemoprophylactic treatment against HFMD, identification and prevention of underlying risk factors is still the key to reduce its transmission. Our findings suggested that hand-washing before meals is related with a significant reduction of HFDM risk. This protective association of hand-washing and HFMD is not surprising. Enteroviruses are transmitted predominantly via the fecal-oral route, and contacts with contaminated saliva, vesicular fluids, and fomites, while contaminated hands play an important role in this process [19
]. In addition, enteroviruses achieve optimum growth at 37 °C and are resistant to acidic pH and detergents. Therefore, it is possible for the viruses to survive in the hands for a relatively long period of time [18
]. These findings are also consistent with those obtained in previous studies conducted by Ruan et al.
] and Xie et al.
], both of which supported the importance of hand-hygiene in preventing HFMD. Moreover, a dose-response effect between hand-washing and a lower risk of HFMD infection was reported [13
]. Hand-washing is also an effective intervention in preventing other infectious diseases. Its protective effects ranged from 34% for impetigo to 53% for diarrhea according to a randomized controlled trial [20
]. Our study further emphasized the importance of hand-washing and reported that it is related with a 70% risk reduction for HFMD.
Furthermore, we found that airing out bedding is associated with an increased risk for HFMD and a dose-response effect was also observed. Airing out bedding under the sun is very common among Chinese residents to lower the humidity and dust mite levels of bedding. It is also recommended by some local Centers for Disease Control and Prevention as an intervention to prevent HFMD [21
]. However, we discovered airing out bedding more than thrice per month significantly increases the risk of HFMD by 4.55 times, compared with a frequency of less than once per month. Therefore, it should be noticed that airing out bedding could be a potential risk factor of HFMD. The association between airing out bedding and risk of HFMD can be explained by the persistent characteristics in the environment of enteroviruses and their transmission patterns [19
]. Although the major infectious source of HFMD was patients, touching virus-carrying bedclothes can also lead to infections. We speculated that airing out bedding may increase the chance of exposing bedding to fomites in the external environment, and fomites may also spread from one to other bedclothes during this process. Therefore, we recommended that bedding should be put in a clean and uncrowded place while airing. Furthermore, washing bedding with disinfectants containing oxidants and drying them thoroughly in a clean environment may be a better option [24
]. Besides, we should not ignore the possibility of potential confounder effects. It is possible that families with low socio-economic status are living in places with poor hygiene. Therefore, when the bedding is put outside, there is a higher chance to get contaminated. In addition, we also noticed that crude OR and adjusted OR of airing out bedding were quite different. We performed a Spearman’s Rank Order Correlation to investigate the correlation between airing out bedding and age. The Spearman’s correlation coefficient is −0.329 and the result is significant (p
value < 0.001). The results showed that the family has younger child tended to airing out their bedding more often.
We also discovered that a recent history of cold food consumption may be related to protective effects, which were seldom mentioned in the previous studies. The cold food in our study refers to cold dish, sushi and ice-cream but not including fruits. This finding is inconsistent with a few current prevention guidelines in China [25
]. Since enteroviruses can survive long in low temperatures and can be inactivated by heat treatment, it may be safer to consume cooked food rather than cold food. However, casual relationship between cold food consumption and HFMD cannot be confirmed by the study results since it is a cross-sectional study. In this correlation, children who are healthier may have better immunity and have lower chances of getting infections from eating cold food, while less healthy children may not be given cold food by caregivers [26
]. For this factor, we suggested that the key is proper food handling, regardless if the food is cold or cooked. On the other hand, it is possible that children have more chance to eat cold food may have higher socio-economic status. History of cold food consumption may be a mediator, while socio-economic status may be the main effect in this correlation.
Our findings have both academic value and practical significance. These results provide epidemiological evidence of the benefits of hand-washing and support the importance of hand-washing to prevent HFMD and other infectious diseases. This study also recognized the potential harm of airing out bedding, which was not mentioned in previous studies. In addition, with an AUC of 0.895, the final logistic model showed a good capacity of separating children with high risk of HFMD infection from the control group. For better conclusion, this study covered a more comprehensive range of possible risk factors, namely, demographic factors, birth and feeding conditions, and living habits of child and his/her caregivers.
A few limitations of this study need to be considered. We selected the control subjects from the hospital information system and kindergartens randomly, instead of performing a matching case-control study, which may have led to a potential selection bias. To solve the problem of age distribution being different among the two groups, we adjusted the age in the analysis to eliminate the possible confounding effects. The study is also suffered from Berkson’s bias. The ORs in our results may be lower than the real value since some of the controls are unhealthy children with other diseases. These children may have poor immunity and high risk to get HFMD. Moreover, only HFMD patients who went to hospital were included as cases, which may not be representative for all HFMD infections. Recall bias should not be a serious problem in our study, as most exposures were determined retrospectively from the recall of caregivers. Interviews for the cases were performed when they went to the doctor, and the questions only covered the occurrences two weeks prior to the interview, which may have reduced the recall bias. Besides, as a cross-sectional study, we don’t have sufficient evidence to establish a causal relationship between risk factors and HFMD infection. Further randomized control trial or cohort study may be needed to provide stronger evidence. Another limitation is that we did not have a more detailed set of information describing the methods of hand-washing. The difference between the protective effects of hand-washing using water only and hand-washing with soap should be further explored. Socio-economic factors were not included as a risk factor, which is closely related with personal and environment hygiene. But we investigate whether being a permanent resident have any effect on HMFD infection, which may reflect the participant’s socio-economic status in some extent.