Identification and validation of clinical predictors for the risk of neurological involvement in children with hand, foot, and mouth disease in Sarawak

Abstract

Background: Human enterovirus 71 (HEV71) can cause Hand, foot, and mouth disease (HFMD) with neurological complications, which may rapidly progress to fulminant cardiorespiratory failure, and death. Early recognition of children at risk is the key to reduce acute mortality and morbidity.

Methods: We examined data collected through a prospective clinical study of HFMD conducted between 2000 and 2006 that included 3 distinct outbreaks of HEV71 to identify risk factors associated with neurological involvement in children with HFMD.

Results: Total duration of fever >or= 3 days, peak temperature >or= 38.5 degrees C and history of lethargy were identified as independent risk factors for neurological involvement (evident by CSF pleocytosis) in the analysis of 725 children admitted during the first phase of the study. When they were validated in the second phase of the study, two or more (>or= 2) risk factors were present in 162 (65%) of 250 children with CSF pleocytosis compared with 56 (30%) of 186 children with no CSF pleocytosis (OR 4.27, 95% CI2.79-6.56, p < 0.0001). The usefulness of the three risk factors in identifying children with CSF pleocytosis on hospital admission during the second phase of the study was also tested. Peak temperature >or= 38.5 degrees C and history of lethargy had the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 28%(48/174), 89%(125/140), 76%(48/63) and 50%(125/251), respectively in predicting CSF pleocytosis in children that were seen within the first 2 days of febrile illness. For those presented on the 3rd or later day of febrile illness, the sensitivity, specificity, PPV and NPV of >or= 2 risk factors predictive of CSF pleocytosis were 75%(57/76), 59%(27/46), 75%(57/76) and 59%(27/46), respectively.

Conclusion: Three readily elicited clinical risk factors were identified to help detect children at risk of neurological involvement. These risk factors may serve as a guide to clinicians to decide the need for hospitalization and further investigation, including cerebrospinal fluid examination, and close monitoring for disease progression in children with HFMD.

Figure 1

Case definitions. The flow chart shows the algorithm of the investigation and the classification of the disease severity of children with HFMD used in the study. HFMD: Hand, foot, and mouth disease, CSF: Cerebrospinal fluid, CNS: Central nervous system.

Figure 2

Classification of 730 Children with HFMD. The flow chart shows the distribution and classification of disease severity of 730 children with HFMD in the 2006 outbreak according to the duration of fever and the risk factors that were present when they first presented to the hospital. CSF examination is indicated if the children have features indicative of more serious illness of HFMD (see case definition in main text). Hx lethargy: History of lethargy, Temp ≥ 38.5°C: body temperature ≥ 38.5°C, CSF exam: cerebrospinal fluid examination, HFMD: Hand, foot, and mouth disease, HFMD-CNS: Hand, foot, and mouth disease with central nervous system complication, HFMD-Non-CNS: Severe HFMD without central nervous system involvement, BENC: brainstem encephalitis, ASM: aseptic meningitis. a. Of the 48 children with HFMD-CNS, 40 had BENC, 6 had ASM and 2 had BENC associated with cardiorespiratory failure (1 of whom died). b. Of the 102 children with HFMD-CNS, 74 had BENC, 26 had ASM, 1 had encephalitis and 1 had fatal BENC associated with cardiorespiratory failure. c. Of the 24 children with HFMD-CNS, 13 had BENC, 8 had ASM, 1 each had BENC associated with cardiorespiratory failure, encephalitis, and encephalitis associated with acute flaccid paralysis. d. Of the 17 children with HFMD-CNS, 11 had BENC, 5 had BENC associated with cardiorespiratory failure (4 of whom died) and 1 had ASM. e. Of the 40 children with HFMD-CNS, 22 had BENC, 17 had ASM and 1 had fatal BENC associated with cardiorespiratory failure. f. Of the 19 children with HFMD-CNS, 10 had BENC, 7 had ASM and 1 each had encephalitis with acute flaccid paralysis, and BENC associated with cardiorespiratory failure.