| Hand-foot-mouth disease(HFMD)is a common infectious disease caused by a variety of enteroviruses,mainly manifested as hand,foot,buttocks rash and mouth ulcers,with or without fever.China has incorporated HFMD as a nationally notifiable disease since May 2,2018.A total of 157,065 cases of severe HFMD occurred in China from 2008 to 2018,with an average annual rate of 1.05/100,000 severe cases,0.76% of severe cases and 2.34% of fatal cases,HFMD has become a very serious public health problem.At present,the disease burden of severe HFMD is relatively heavy,and the pathogen spectrum of severe HFMD is more and more extensive,but the study on the serotyping and gene characteristics of severe HFMD is relatively lacking,and the disease burden is not clear.The research on the risk factors of critical HFMD is relatively insufficient,lacking of multi-center and large sample verification.The occurrence of the sequelae of the survivors and the cognitive development of the surviving children are not clear.In this study,7,994 cases of severe HFMD reported in Jiangsu Province from2009 to 2015 were systematically analyzed.The epidemiology,disease burden,CNS complications caused by different pathogens,pathogen spectrum and gene characteristics of severe HFMD in Jiangsu Province were analyzed.Results showed that 7224 cases were inpatients,611 were PICU inpatients,and 68 were fatal.The average severe illness rate,mortality rate,severity-fatality rate,severity-PICU admission rate,and severity-hospitalization rate were 14.54,0.12,8506,76,430,and903,700 per 1 million,respectively.The prevalence of severe HFMD in Jiangsu Province is from May to July,and the epidemic cycle is every 2 to 3 years.The advantage time point of vaccination or other intervention measures is proposed.The severe rate of severe HFMD was the highest at the age of 12 to 23 months,and the severe illness rate was the highest in the 12–23 months age group,and the greatest mortality rate was in the 6–11 months age group.In addition,the age group below 6months of age also had higher rates of HFMD disease,PICU and hospitalization.The rates of severe disease and death had regional differences(p<0.05).The longer interval between the time from onset to the first clinic visits,the highe rmortality rate and fatality rate.Through the analysis of the types of CNS complications of severe HFMD caused by infection of different serotypes,it was found that the main types of severe HFMD were aseptic meningitis and encephalitis,accounting for 37.44% and 59.60%,respectively.EV-A71 was the main pathogen of different types of CNS complications.Through the characteristic study of the etiological evolution of severe HFMD,it was found that multiple pathogens coexisted in severe HFMD in Jiangsu Province,including EV-A71,CV-A16/10/6/2/4/9,CV-B1/2/3/4/5,Echovirus(E)E6/7/18 and EV-C96,and EV-A71 was the dominant serotype of severe HFMD.Phylogentic analyses demonstrated that EV-A71 strains belonged to subgenotype C4 a,while CV-A16 strains belonged to sub-genotype B1 a and sub-genotype B1 b of genotype B1,CV-A6 strains were assigned to genogroup F,and CV-A10 strains belonged to genogroup D.which provided a scientific basis for the research and development of multivalent vaccine.On the basis of the aboove study,through the multi-center and whole-course dynamic collection of hospital inpatient information system,3,583 laboratory severe cases confirmed in Suzhou Children’s Hospital,Wuxi People’s Hospital,Nanjing Children’s Hospital and Xuzhou Children’s Hospital from 2009 to 2016 were collected.CNS complication of severe HFMD and be classified into aseptic meningitis,viral encephalitis,encephalomyelitis,acute flaccid paralysis(acuteflaccidparalysis,AFP),brainstem encephalitis,pulmonary edema/pulmonary hemorrhage,and cardiorespiratory failure types,and according to the different extent of its further divided into mild group CNS complications,severe complications of CNS group,severe complications of CNS group,through the cumulative score of Logistic regression model,from the perspective of big data to explore the risk factors of critical HFMD.The results showed that the severity-fatality rate,severity-pediatric intensive care unit(PICU)admission rate,and sequelae rate were 8.09‰(29/3 583),11.75%(421/3 583)and 5.30‰(19/3 583).Of them,39.02%(1 398/3 583)patients suffered from mild CNS involvement,59.22%(2 122 / 3 583)patients suffered from severe CNS involvement,1.76%(63 / 3 583)suffered from critical CNS involvement.The rates of the cases whose age of onset was 6-11 months,the rates of cases with atypical rash,respiratory-related signs and symptoms(shortness of breath,slowed breathing,dyspnea,etc),neurological-related signs and symptoms [(hand and foot shaking,convulsions,lethargy(sleepiness),etc],circulatory-related system signs and symptoms(faster heart rate,abnormal skin color,arrhythmia,cold limbs),laboratory-related indicators(increased white blood cell count,increased lymphocyte count,increased platelet count,increased C-reactive protein,etc),clinical auxiliary examination [ electroencephalogram(EEG),brain CT,chest X-ray)] were highest in the critical CNS involvement group,and the differences were significant(P < 0.05).Multivariate logistic regression analysis showed that with the increase of proportion of convulsions,slowed breathing,vomiting,meningeal irritation and other 7variables,the severity of CNS complications increased(P<0.05).This study provides an important scientific basis for the early warning,early intervention and scientific clinical management of severe HFMD.Depending on the type of CNS lesion,the prognosis is different.294 children aged between 2 and 6 months to 6 and 11 months were selected at a 10% rate from3583 severe HFMD and 712 mild HFMD.According to the severity,the cohorts of mild case without CNS complications group,severe HFMD with mild CNS complications group,wtih severe CNS complications group,and with more severe CNS complications group were established.Through the nervous system of examination and physical examination,the results showed that the incidence of sequela is closely related to the severity of the CNS complications,58 mild HFMD cases without CNS complications and 99 severe HFMD cases with mild CNS involvement(aseptic meningitis)are fully recovered,and no legacy neurological sequelae,117 cases of severe HFMD with severe CNS(encephalitis)complication,the incidence of sequelae was 2.6%(3/117),20 cases of severe HFMD with more severe CNS involvement(including brain stem encephalitis,acute flaccid paralysis cases,encephalomyelitis and cardiopulmonary failure),the incidence of sequelae was50.0%(10/20).the types of sequelae include seizures,focal weakness,speech disorders,nystagmus,fine motor disorders,and dyspnea.Cognitive function was assessed using the Wechsler Preschool and Primary Scale of Intelligence-IV(WPPSI-IV),and Cox proportional hazard model was used to further screen the influencing factors of cognitive function.The results showed in 2 years and 6 months to 3 years and 11 months age group,Verbal Comprehension Index(VCI),Visual Spatial Index(VSI),Working Memory Index(WMI),and Full Scale IQ(FSIQ)showed a decreasing trend with the increase of the severity of CNS complication of severe HFMD(P<0.05).The scores of patients with critical CNS complication were all below 80.0.The scores of the above indexes were also relatively higher for children whose parents with high educational level(P<0.05).Moreover,the proportion of VCI disorder,VSI disorder,WMI disorder,and FSIQ disorder(score less than 85)increased with the increase of clinical severity,and the proportion of FSIQ disorder in the severe HFMD with critically CNS group was as high as 62.5%.Multivariate analysis showed that severe HFMD with critically CNS complications(RR=20.5,95%CI:2.2-188.3))and low maternal education level(RR=3.3,95%CI:1.4-8.0)were the influencing factors for VCI disorder.Residence in suburban junction(RR=10.2,95%CI: 1.1-95.0)and father’s low education level(RR=3.2,95%CI:1.2-8.8)were risk factors for FSIQ disorder.In the 4 years to 6 years and 11 months age group,with the increase of the severity of CNS complication,VCI,VSI,WMI,fluid reasoning(Fluid Reasoning Index,FRI),processing speed index(Processing speed Index,PSI)aslo showed a trend of gradual decline in the average score(between 90 ～ 100),which was higher than these in the 2:6-3:11 age group.The educational levels of the children’s parents were aslo correlated with the score(P<0.05).With the increase of clinical severity,the proportion of major index disorder(except VAI)and FSIQ disorder increased.The proportion of FSIQ disorder in the critical group was 41.7%,which was lower than that in the 2:6-3:11 age group.The results of multivariate analysis showed that severe HFMD with critical CNS complication was the risk factor for VSI disorder(RR=8.5,95%CI:1.3-54.8)and FRI disorder(RR=11.7,95%CI:1.1-125.9).The father’s education level with junior high school or less was a risk factor for FSIQ disorder(RR=5.2,95%CI:1.5-18.1).Therefore,early identification of the types of CNS complication and sequelae,considering the social environment in which the children live are of great significance for improving the prognosis of the children. |
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