Table 5.

Epidemiological studies on the more severe forms of HFMD

Study	Results	Conclusions
Liu et al. Shenzhen, China 2008 [37]	145 HFMD cases 124 mild cases 35 % +EV71 21 severe cases 67 % +EV71 Leukocytes and blood glucose levels of the most serious were significantly elevated. Age was less in severe cases (P < 0.05)	EV71 mainly contributes to severe HFMD High fever, elevated white blood cell count, high blood glucose concentrations and an age less than 4 years should be used to predict severe cases
Ang et al. Singapore 2009 [49]	Annual incidence rate of HFMD rose from 125.5 in 2001 to 435.9 in 2007 per 100,000 habitants	HFMD remains a major public health problem in Singapore. Must maintain a high degree of vigilance, particularly for EV 71
Sarma et al. W. Bengal, India 2009 [51]	38 HFMD cases. Children 1–12 years M:F—21:17. Oral lesions 86.6 %. High incidence of EV71	An alarmingly high prevalence of EV71. No significant differences between boys and girls
Wu et al. Hangzhou, China 2010 [24]	28 HFMD cases Severe cases <2 years 88.89 % Severe patients with EV71—92.86 % Mild patients with EV71—36.51 %	Children under 2 with EV71 are the highest risk group for developing the severe form of the disease
Suzuki et al. Tokyo, Japan 2010 [53]	199 HFMD cases. Severe 96. Mild 103 No differences in sex, age, family history. No significant association between the center of care and disease presentation	There is no clear association between center of care and presentation. More studies are needed in this regard
Zeng et al. Shangai, China 2012 [26]	28,058 HFMD cases Neurological disorders, pulmonary edema and hemorrhage 2.6 % 0.04 % deaths More cases in summer and higher frequency in boys than girls 1–4 years 82.27 % EV71 positive: 99.17 % severe cases in 2009, 86.31 % in 2010, 100 % of patients with neurological affectation, edema, pneumonia and hemorrhage	Dominant EV71 circulation led to the outbreak of HFMD and the occurrence of severe and fatal cases in China EV71 is associated predominantly with severe cases of the disease
Wang et al. Beijing, China 2011 [2]	Children 1–3 years OR >2.3 Serious illness OR >1.4 Death OR >2.4 Children OR = 1.56 boys compared to girls 1 day delay in diagnosis associated with severe disease increase (40 %) and the probability of death (54 %) EV71 association with severe disease OR = 16 and death OR = 40, regarding CVA16	HFMD is transmissible especially among preschoolers. Enterovirus 71 was responsible for the most serious cases and deaths in China. The mixture of asymptomatic infected children in school might have contributed to the spread of infection. Diagnosis is very important to reduce the high mortality rate
Fang et al. Shaoxing, China 2014 [43]	19 studies meta-analysis Duration of fever ≥3 days [odds ratio (OR) 10.09, 95 % confidence interval (CI) 6.22–16.35], body temperature ≥37.5 °C (OR 4.91, 95 % CI 1.26–19.18), lethargy (OR 7.75, 95 % CI 3.78–15.89), hyperglycemia (OR 2.77, 95 % CI 2.06–3.71), vomiting (OR 8.83, 95 % CI 1.05–74.57), increased neutrophil count [weighted mean difference (WMD) 0.61, 95 % CI 0.52–0.70], enterovirus 71 (EV71) infection (OR 5.13, 95 % CI 3.11–8.46), young age (WMD—0.44, 95 % CI 0.69–0.19), and home care (OR 1.65, 95 % CI 1.26–2.17) were significantly related to the risk of severe HFMD A confirmed diagnosis at first visit to hospital significantly decreased the risk of severe HFMD (OR 0.30, 95 % CI 0.09–0.99) not find an association between oral rash (OR 1.07, 95 % CI 0.82–1.39), increased leukocyte count (WMD 0.51, 95 % CI 0.05–1.06), male sex (OR 1.06, 95 % CI 0.91–1.24), or living in a rural area (OR 1.39, 95 % CI 0.95–2.02) and the risk of severe HFMD	Duration of fever ≥3 days, body temperature ≥37.5 °C, lethargy, hyperglycemia, vomiting, increased neutrophil count, EV71 infection, and young age are risk factors for severe HFMD. A confirmed diagnosis at first visit to hospital can significantly decrease the risk of severe HFMD
Chen et al. Shangai, China [25]	The mean serum VA concentration for all patients was 0.73 ± 0.26 mmol/L, and 237 (52.7 %) of them presented low concentrations (≥0.7 mmol/L). Both serum concentrations of VA and IFN-a in the patients with complications were significantly lower than in patients without complications (P < 0.01) The decreased concentrations of IFN-a and EV71-IgM were positively related to lower VA levels (correlation coefficient ¼ 0.58 and 0.41, respectively, P < 0.001)	VA status is associated with the antiviral immunity and pathogenetic condition of HFMD in young children. The children with HFMD mostly presented low VA concentrations and simultaneously had lower serum IFNa levels, decreased immune antibody production and more severe illness

HFMD hand, foot and mouth disease