This retrospective study included 331 deaths due to HFMD, which were reported to the Center for Disease Control (CDC) of Guangxi province from 2010 to 2014. The patients’ medical history was provided by Guangxi CDC. The diagnostic criteria and clinical stages were based on the guidelines of Ministry of Health for HFMD and the "Clinical Management of EV71". Throat and anal swabs were collected for the detection of enterovirus and coxsackie viruses. The clinical stages were classified as: Stage 1 – vesicular lesions on hand, foot and mouth; Stage 2 – neurological involvement; Stage 3 – early stage of cardiopulmonary failure; Stage 4 – cardiopulmonary failure; and Stage 5 – recovery period [4].

The 331 deaths were distributed in all municipal hospitals in Guangxi province. The clinical data were collected through review of hospital records. The data were collected by three people with a standard data extraction form, and disagreements were resolved by discussion. The form included patients’ information such as age, sex, date and time of registry to hospitals, date and time of death, duration from onset to each major complication, duration from each complication to death, clinical features, white blood count (WBC) and blood glucose. Autopsy with the consent of the parents was performed in 15 cases. Based on the duration from onset to death, these cases were classified into slow (equal or more than 4 days) or fast progressors (less than 4 days).

Among 331deaths, 209 were males (M: F=1.71:1). The age ranged from 4 months to 6 years, and 291(87.9%) were aged below 3 years. 3.0%, 27.2%, 28.4% and 41.4% of patients were diagnosed as stage 1, stage 2, stage 3 and stage 4, respectively at the time of registry to the hospitals. The mean (SD) duration from onset of disease to death was 3.7 (2.2) days. The mean (SD) duration from stage 1 to stage 2 was 43.6 (27.2) hours, from stage 2 to stage 3 was 24.6 (16.2) hours, from stage 3 to stage 4 was 3.9 (1.5) hours, and from stage 4 to death was 4 (1.8) hours. The mean (SD) age of fast progressors was 17.4 (9.2) months, and most of them were diagnosed as stage 3 or stage 4 at registry. The neurological and cardiopulmonary symptoms of these cases are summarized in Table I.

TABLE I  Symptoms and Signs Before Death in Hand-Foot-Mouth Disease (N=331)

The mean (SD) age of fast progressors was significantly lower than that of slow progressors [17.4 (9.2) vs 26.2 (12.7) mo; P<0.01].

301 patients (90.9%) were infected by EV71, nine (2.7%) cases were infected by Coxsackie A16 and two (0.6%) cases were infected by both EV 71 and Coxsackie A 16 viruses. Nineteen (5.7%) cases tested negative for both EV 71 and Coxsackie A 16 virus.

Autopsy in all 15 cases showed similar pathological characteristics. The major pathological changes found in the central nervous system (CNS) were: congestion on the surface of cerebrum, obscured cerebral sulcus, brain stem edema, neuronal necrosis, and neuronophagia and colloid deposition in the brain stem. All lung specimens had pink fluid in alveolar space. Alveolar wall was thickened and widened with interstitial fibrosis, hemangiectasis, and congestion. No obvious infiltration by inflammatory cells was seen in heart.

Our findings were consistent with previous reports suggesting that EV71 was more likely to cause neurological impairment, which could lead to severe cases [5-7]. Previous studies showed that patients had increased heart rate and hypertension (stage 3) before cardiopulmonary failure (stage 4). These patients may have bradycardia and hypotension leading to cardiopulmonary failure [8]. There was no evidence of viral myocarditis in children in present series, and staining for EV71 antigen was negative in the myocardium and lungs. A previous study also showed that neurogenic pulmonary edema associated with brainstem parenchymal damage, which may be not due to direct virus damage or myocarditis-induced viral damage [9]. However, another study [10] suggested that the invasion of spinal cord and medulla by EV71 contributed to pulmonary edema and other respiratory complications. Kao, et al. [11] suggested that pulmonary edema may result from a sympathetic over-activation. The major limitation of this data is its retrospective nature. Moreover, the data were limited to a single province of China. Autopsy was performed in less than 5% of cases, thus limiting the generalizability of the findings.

In conclusion, most cases of HFMD had brainstem encephalitis. Close observation on clinical manifestations such as neurological symptoms is critical to assess the severity and prognosis of the disease. Severe HFMD should be diagnosed earlier before stage 3 and receive proper treatment to reduce the mortality.

Contributors: ZYY and XQC: collected the data and wrote the manuscript, and should be considered co-first authors; DS: collected the data and edited the manuscript; DW: contributed to conception and design of study, and revised the manuscript.

Funding: None; Competing interest: None stated.

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