Background 
Hand-food-mouth disease (HFMD) cases can be fatal. These cases develop rapidly, and it is important to predict the severity of HFMD from mild to fatal and to identify risk factors for mild HFMD. The objective of this study was to correlate the levels of serum inflammatory cytokines with HFMD severity.
Methods 
This study was designed as a nested serial case-control study. The data collected included general information, clinical symptoms and signs, laboratory findings and serum cytokine levels.
Results 
The levels of IL-4, IL-6, IL-10, TNF-α and IFN-γ in patients with severe HFMD were significantly higher than in mild patients during the 2nd to 5th day after disease onset. The levels of IL-4, IL-6, IL-10 and IFN-γ increased from the 2nd day to the 4th day and later decreased. The levels of TNF-α were high on the first two days and subsequently decreased. The changes of IL-10, TNF-α and IFN-γ in the controls were similar for all cases. The levels of IL-4, IL-6 and IL-17 in the controls were not significantly different with the progression of HFMD.
Conclusions 
Our findings indicate that the IL-4, IL-6, IL-10, TNF-α and IFN-γ levels correlate with HFMD severity.

/pdf/serum-inflammatory-cytokine-levels-correlate-with-hand-foot-3qtglvktz9.pdf

Serum inflammatory cytokine levels correlate with hand-foot-mouth disease severity: a nested serial case-control study.

From 2010 to 2012, large outbreaks of EV-A71-related- hand foot and mouth disease (HFMD) occurred annually in China. Some cases had neurological complications and were closely associated with fatal cardiopulmonary collapse, but not all children with central nervous system (CNS) involvement demonstrated a poor prognosis. To identify which patients and which neurological complications are more likely to progress to cardiopulmonary failure, we retrospectively studied 1,125 paediatric inpatients diagnosed with EV-A71-related HFMD in Hunan province, including 1,017 cases with CNS involvement. These patients were divided into cardiopulmonary failure (976 people) group and group without cardiopulmonary failure (149 people). A logistic regression analysis was used to compare the clinical symptoms, laboratory test results, and neurological complications between these two groups. The most significant risk factors included young age, fever duration ≥3 days, coma, limb weakness, drowsiness and ANS involvement. Patients with brainstem encephalitis and more CNS-involved regions were more likely to progress to cardiopulmonary failure. These findings can help front-line clinicians rapidly and accurately determine patient prognosis, thus rationally distributing the limited medical resources and implementing interventions as early as possible.

/pdf/neurological-complications-and-risk-factors-of-2e35lfbkxm.pdf

Neurological complications and risk factors of cardiopulmonary failure of EV-A71-related hand, foot and mouth disease.

An increase in the incidence of hand, foot and mouth disease (HFMD) cases has been observed in the Hunan province of mainland China since 2009 with a particularly higher level of severe cases in 2010–2012. Intestinal viruses of the picornaviridae family are responsible for the human syndrome associated with HFMD with enterovirus 71 (EV71) and Coxsackievirus A16 (Cox A16) being the most common causative strains. HFMD cases associated with EV71 are generally more severe with an increased association of morbidity and mortality. In this study, the etiology surveillance data of HFMD cases in Hunan province from March 2010 to October 2012 were analyzed to determine if there is a statistically relevant linear correlation exists between the detection rate of EV71 in mild cases and the proportion of severe cases among all HFMD patients. As the cases progressed from mild to severe to fatal, the likelihood of EV71 detection increased (25.78%, 52.20% and 84.18%, respectively). For all cases in the timeframe evaluated in this study, the presence of virus was detected in 63.21% of cases; among cases showing positivity for virus, EV71 infection accounted for 50.14%. These results provide evidence to support the observed higher morbidity and mortality associated with this outbreak and emphasizes the importance of early detection in order to implement necessary prevention measures to mitigate disease progression.

Correlation analysis of EV71 detection and case severity in hand, foot, and mouth disease in the Hunan Province of China.

Evidence of hand, foot, and mouth disease (HFMD) in neonates is limited. The aim of this study was to evaluate the clinical symptoms, pathogens, possible transmission routes, and prognosis of neonatal HFMD in Shanghai. This was a case-control study based on the HFMD registry surveillance system. All neonates and infected family members were enrolled between 2016 and 2017 in Shanghai. Neonates with HFMD were followed for at least half a year. Detailed questionnaires, medical history, and physical examination were recorded. Routine blood examination, liver and renal function, immunophenotypes of peripheral blood lymphocytes (CD3, CD4, and CD8 T-cells; NK cells), immunoglobulin (Ig) M, IgG, and IgA, and cytokine interleukin (IL-1β, IL-2R, IL-6, IL-8, IL-10, and TNF-α) levels were measured. All rectal swab specimens were collected and genotyped for enterovirus, and phylogenetic analysis based on the VP1 sequences of coxsackievirus A6 (CV-A6) was performed to investigate molecular and evolutionary characteristics. T-test or nonparametric test was used to evaluate the differences. Logistic analysis was applied to calculate the risk of clinical manifestations in the group of HFMD neonates and their paired siblings. There were 16 neonates among the 12,608 diagnosed patients with HFMD, accounting for 0.13%. All neonatal infections were transmitted by other members of the family, mainly the elder siblings, and were caused by CV-A6. CV-A6 was the emerging and predominant causative agent of HFMD in Shanghai. None of the neonates with HFMD experienced fever, onychomadesis, or severe complications. However, two elder sibling patients showed lethargy, and one developed hypoperfusion. In the elder siblings with HFMD, the proportion of white blood cells was generally higher than in neonates with HFMD. The immunologic function of the neonates with HFMD was basically normal. The levels of inflammatory markers were higher in both neonates and elder siblings with HFMD compared to age-matched controls. The clinical symptoms receded about 1 week after onset. None of the neonates had sequelae. In our study, CV-A6 infection in neonates was benign, but had the character of family clustering. Due to the two-child policy in China, elder siblings may be the main route of HFMD transmission.

/pdf/neonatal-hand-foot-and-mouth-disease-due-to-coxsackievirus-4noxgvmksn.pdf

Neonatal hand, foot, and mouth disease due to coxsackievirus A6 in Shanghai.

The identification of indicators for severe HFMD is critical for early prevention and control of the disease. With this goal in mind, 185 severe and 345 mild HFMD cases were assessed. Patient demographics, clinical features, MRI findings, and laboratory test results were collected. Gradient boosting tree (GBT) was then used to determine the relative importance (RI) and interaction effects of the variables. Results indicated that elevated white blood cell (WBC) count > 15 × 109/L (RI: 49.47, p < 0.001) was the top predictor of severe HFMD, followed by spinal cord involvement (RI: 26.62, p < 0.001), spinal nerve roots involvement (RI: 10.34, p < 0.001), hyperglycemia (RI: 3.40, p < 0.001), and brain or spinal meninges involvement (RI: 2.45, p = 0.003). Interactions between elevated WBC count and hyperglycemia (H statistic: 0.231, 95% CI: 0–0.262, p = 0.031), between spinal cord involvement and duration of fever ≥3 days (H statistic: 0.291, 95% CI: 0.035–0.326, p = 0.035), and between brainstem involvement and body temperature (H statistic: 0.313, 95% CI: 0–0.273, p = 0.017) were observed. Therefore, GBT is capable to identify the predictors for severe HFMD and their interaction effects, outperforming conventional regression methods.

/pdf/machine-learning-algorithms-for-risk-prediction-of-severe-23yy6hhkql.pdf

Machine Learning Algorithms for Risk Prediction of Severe Hand-Foot-Mouth Disease in Children

A small fraction of hand–foot–mouth disease (HFMD) progression from the onset of severity to fatality may be remarkably rapid. Early recognition of children at risk of severity is critical to increase treatment effectiveness and reduce acute mortality. A frequency-matched case–control study was conducted between January 2010 and June 2011 in Ningbo to identify risk factors associated with the occurrence of severity in children with HFMD. Data including demographic characteristics, clinical features, and laboratory test results were collected by trained interviewers through retrospective medical record review and/or face-to-face interviews with children’s parents using a standardized questionnaire. Eighty-nine cases with severe HFMD and 267 controls with mild HFMD were recruited in this study. Palm rashes (OR = 0.004, 95%CI = 0.000–0.039, p   10.8 × 109/L (OR = 4.495, 95%CI = 1.311–15.415, p = 0.017), and human enterovirus 71 infection (OR = 39.172, 95%CI = 9.803–156.522, p < 0.001). Clinicians should pay increased attention to children diagnosed as HFMD with the independent risk factors above.

A case–control study of risk factors for severe hand–foot–mouth disease among children in Ningbo, China, 2010–2011

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A case–control study of risk factors for severe hand–foot–mouth disease among children in Ningbo, China, 2010–2011