Analytic Epidemiological Studies On Neurological Sequelae Following Pediatric Hand,Foot And Mouth Disease

Background:Hand foot and mouth disease(HFMD)is a common childhood illness and causes substantial disease burden in China.A small proportion of infections lead to the Central nervous system(CNS),fatal cardiopulmonary complications and longterm sequelae,particularly in cases associated with EV-A71,making it a serious threat to children’s health.Previous studies only focused on the EV-A71 infection associated sequelae.In recent years,the proportion of severe and fatal HFMD cases caused by other non-EVA71 enterovirus(e.g.CVA10 and CVA6 etc,)has been increasing.It lacks of studies on sequelae of other enterovirus infection.Previous studies on neurodevelopment outcomes following HFMD were located in Taiwan,China since the 1990 s.It lacks of studies on neurodevelopment outcomes in mainland China.Although the studies reported that lesions in the brainstem or spinal cord may be useful for predicting prognosis by Magnetic resonance imaging(MRI),whether such MRI changes resolve or persist over time,and their relationship with long-term outcome,remain unclear.This thesis aims to identify long-term sequelae in mainland China by clinical severity and enterovirus serotypes,including neurological deficits and neurodevelopment outcomes,along with MRI changes over time,and characterize lung function after mechanical ventilation.In addition,we explore the risk factors for poor outcomes.Understanding sequelae is of great importance to update knowledge in HFMD status in mainland China,improve clinical management in the acute phase of illness and intervention programs after the acute illness,as well as strategies for enterovirus serotype surveillance.Study 1: Long-term sequelae and associated factors following severe HFMD,a retrospective studyMethods: This is a retrospective study(case-control study and case series follow-up).HFMD patients with CNS complications caused by EV-A71 or CVA16 treated in the Henan Children’s Hospital between January 2010 and December 2016 were identified.Children were invited to the hospital for neurologic examination,neurodevelopmental assessments and additional investigations,including MRI and lung function tests,as clinically appropriate.For assessment of cognitive,language,motor and adaptive behavior function,we applied the WPPSI-IV,WISC-IV,MABCII and ABAS-II questionnaire.Meanwhile,clinical data during hospitalization,neurological examination at discharge and MRI result at acute illness were collected.A paired chi-square test was used to compare the rate of neurological abnormalities at discharge and investigation.The delay rates of cognition,motor,language,and adaptive behavior domain,which is defined one standard deviation lower than the normative mean,and were compared with the normative base rate of16% by binomial test.Univariate and multivariate logistic regression models were used to explore the risk factors of each domain.Results: Of the 176 patients surveyed,the median onset age was 1.7 years(IQR:1.3-2.5).The median follow-up period was 4.4 years(range [1.4–8.3]).Children were classified into three groups,including CNS only,autonomic nervous system(ANS)dysregulation,and cardiorespiratory failure(CRF),respectively 24,133,and 19 cases.The rate of neurological abnormalities was 25%(43 of 171)at discharge and 10%(17 of 171)at survey(P<0.05).Muscle weakness was both main deficits at discharge(17%)and survey(3.5%).The rate of neurological abnormalities of CRF group was the highest at discharge and survey,but improved the most(79% vs.32%,P<0.05).The rate of poor outcome at overall was 25%(37 of 149),41%(62 of 153)and35%(52 of 149)in cognitive,motor and language domains,which were higher than the normative sample(P<0.05,P<0.05,P<0.05).The delay rate in adaptive domain was 18%(29 of 157)(P>0.05).The multivariate logistic regression model showed children with age at onset less than 2 years had 2.72 times(95%CI:1.18-6.71)risk of poor cognitive outcome than those with age at onset over 2 years.Children with CRF complications had 4.14 times(95%CI : 1.41-13.89)risk of poor motor outcome than those without CRF complications.Children whose parents had higher education level had better performance in cognitive and language outcome(OR=0.23,95%CI:0.07-0.64;OR=0.36,95%CI: 0.07-0.64).For children with ventilated during hospitalization,41% patients(14 of 34)had an obstructive ventilatory defect,and one patient with scoliosis had mixed ventilatory dysfunction.The rate of ventilatory defect in CRF and ANS group is 55%(6 of 11)and 39%(9 of 23)(P>0.05).Persistent abnormalities on brain MRI were 16%(6 of 37),the CRF group had the highest persistent abnormality rate(P<0.05).No abnormalities were detected on spinal MRI at survey.Thalamic and cortical involvement by MRI in the acute stage were significantly associated with poor motor outcome.Summary: The neurological deficits and MRI lesions of the brain and spinal following CNS complications have significantly recovered.The overall performance in cognitive,motor and language domains are significantly different from the normative population.Children who were ventilated may be associated with obstructive ventilatory dysfunction or mixed ventilatory dysfunction.The age at onset less than 2 years is associated with poor cognitive outcome,and CRF complication is associated with motor outcome.MRI at the acute stage may be useful for predicting motor prognosis.Study 2: Neurological sequelae and associated factors following HFMD,a prospective studyMethods: This is a prospective,hospital-based cohort study.Eligible mild and severe HFMD patients who were hospitalized in Henan Children’s Hospital between February 2017 and February 2019 were enrolled and followed up to receive neurologic examination and neurodevelopment assessments on 2 weeks,6 months and 18 months after discharge.Bayley-III was used for children under 3 years old.WPPSI-IV,WISC-IV and MABC-II were used for children older than 3 years old.ABAS-II was used for children of all ages.For children with abnormal MRI in the acute phase,brain and/or spinal MRI was performed during follow-up.Throat swabs and stool specimens were collected during hospitalization to identify enterovirus serotypes by combined RT-PCR.The temper changes within two weeks after discharge,the rates of neuropathological deficits at discharge and each follow-up were compared between the mild and severe cases and the different serotypes infection.The mixed effects model was used to analyze the association between the developmental scores and the clinical severity,serotypes,and MRI at the acute phase.Cox proportional hazards regression model was used to evaluate the relationship between EV-A71 infection and MRI abnormalities.In the sensitivity analysis,multivariate normal distribution was used to dealing with the missing data by the reason type for loss follow-up at 6 months and 18 months.The imputation datasets were analyzed to check the association between age and severity and developmental scores.Results: A total of 360,163(45%)and 98(27%)cases completed 2 weeks,6months and 18 months visit respectively after discharge.Among 360 cases,there were216(60%)mild cases and 144(40%)cases with CNS complications.The most common pathogens were EV-A71,CVA6 and CVA16 and the number is 111(31%),78(22%)and 48(14%)respectively.Severe cases and EV-A71 infection were associated with temper changes within two weeks after discharge(P<0.05,P<0.05).The rate of neurological abnormalities among severe cases was 15% at discharge,and decreased to 10%,7%,and 0% at 2weeks,6 months,and 18 months respectively(P<0.05).The rate of neurological abnormalities among EV-A71 infection was 14% at discharge,and decreased to 6%,2%,and 0% at 2 weeks,6 months,and 18 months respectively(P<0.05).The multivariate mixed-effects model of clinical severity associated with developmental scores showed severe cases had a cognitive composite score 4.4 points and a motor composite score 4.5 points lower than mild cases(P<0.05,P<0.05).The second visit had a cognitive composite score 2.9 points and a motor composite score4.2 points lower than the first visit(P<0.05,P<0.05),and the third visit had a fullscale IQ score 2.9 points higher than the first visit(P<0.05).The children with age at onset less than 2 years had a cognitive composite score 2.4 points,a language composite score 3.6 points,a motor composite score 4.2 points,a full-scale IQ score6.3 points,adaptive behavior score 3.0 points lower than children with age at onset over 2 years,which was significantly difference.The multivariate mixed-effects model of serotypes of EV-A71,CVA6 and CVA16 associated with developmental scores showed children with CVA16 infection had a cognitive composite score 3.3 points(P<0.05)and a motor composite score 3.9points higher than those with EV-A71 infection(P<0.05).Children with CVA6 infection had a full-scale IQ score 6.2 points(P<0.05),a language comprehension score 7.2 points(P<0.05),and an adaptive behavior score 8.3 points higher than those with EV-A71 infection(P<0.05).A total of 124 cases had brain MRI at the acute illness,and 56(45%)had abnormal brain MRI.A total of 95 cases had spinal MRI at the acute illness,and 23(24%)had abnormal spinal MRI.The univariate and multivariate mixed-effects model of brain MRI associated with developmental scores showed there was no significant difference.The univariate mixed-effects model showed brainstem was associated with motor function(P<0.05).Sensitivity analysis showed that the significant results of age of onset,clinical severity,serotypes and brainstem were almost consistent with the main analysis,which indicated the results are robust.The Cox proportional hazards regression model showed that EV-A71 infection was not significantly associated with the risk of persistent abnormalities among cases with abnormal brain MRI(P>0.05).EV-A71 infection was significantly associated with the risk of persistent abnormalities among cases with abnormal spinal MRI(HR=0.19,P<0.05).Summary: During the 18 months of follow-up,severe cases and EV-A71 infection cases have recovered in neurological deficits much.Severe cases have poor performance in cognitive and motor composite score.CVA16 infection have well performance in cognitive and motor composite score than EV-A71 infection.CVA6 infection have well performance in full-scale IQ score,language comprehension score,and adaptive score than EV-A71 infection.Children with age at onset less than 2 years have worse performance in cognitive,language and motor composite score,full-scale IQ,and adaptive behavior score.MRI at the acute stage may be useful for predicting motor prognosis.EV-A71 infection is associated with the risk of persistent spinal MRI abnormalities.Conclusions: Children with CNS complications may have abnormalities in neurological deficits,motor,language,cognitive functioning and respiratory function after discharge.The age at onset less than 2 years may be related to the cognitive,language,motor and adaptive behavior functioning.The CNS complications is related to the cognitive and motor functioning.The children with EV-A71 infection had better outcomes than those with CVA16 or CVA6 infection.MRI at the acute stage may be useful for predicting motor prognosis.Long-term follow-up programs for neurodevelopmental and respiratory function may be warranted among HFMD children with CNS complications to improve prognosis by early detection and intervention.