Enterovirus 71, one of the enteroviruses that are responsible for both hand-foot-and-mouth disease and herpangina, can cause neural injury. During periods of endemic spread of hand-foot-andmouth disease caused by enterovirus 71, CNS infections are also frequently diagnosed and may lead to increased complications from neural injury, as well as death. We present the results of our epidemiologic research on the clinical manifestations of children with CNS infections caused by enterovirus 71.
The study group consisted of 42 patients admitted for CNS infection by enterovirus 71 between April 2009 and October 2009 at the Department of Pediatrics of 5 major hospitals affiliated with the Catholic University of Korea. We retrospectively reviewed initial symptoms and laboratory findings on admission, the specimen from which enterovirus 71 was isolated, fever duration, admission period, treatment and progress, and complications. We compared aseptic meningitis patients with encephalitis patients.
Of the 42 patients (23 men, 19 women), hand-foot-and-mouth disease was most prevalent (n=39), followed by herpangina (n=3), upon initial clinical diagnosis. Among the 42 patients, 15 (35.7%) were classified as severe, while 27 (64.3%) were classified as mild. Factors such as age, fever duration, presence of seizure, and use of intravenous immunoglobulin (IVIG) were statistically different between the 2 groups.
Our results indicate that patients with severe infection caused by enterovirus 71 tended to be less than 3 years old, presented with at least 3 days of fever as well as seizure activity, and received IVIG treatment.
Microbiologically, enteroviruses are a genus of RNA viruses of the Picornaviridae family. The genus of enterovirus includes 3 types of poliovirus (PV 1-3), 23 types of coxsackievirus A (CVA 1-22 and 24), 6 types of coxsackievirus B (CVB 1-6), 28 types of echovirus (ECV 1-7, 9, 11-21, 24-27, and 29-33), as well as other types of enterovirus (EV 68-73)
Enterovirus is spreads through the fecal-oral route. Gastrointestinal infection is followed by primary proliferation in the pharynx or lymph nodes of the small intestine, with spread into various organs in the body
Among the patients who visited 5 medical centers of College of the Medicine, the Catholic University of Korea (Seoul St. Mary's Hospital, St. Vincent's Hospital, Incheon St. Mary's Hospital, Bucheon St. Mary's Hospital, and Uijeongbu St. Mary's Hospital) from April 2009 to October 2009, 42 patients who were hospitalized and treated for clinically severe HFMD or herpangina with CNS infection were enrolled in this study. CNS infection was confirmed when the patient showed abnormal findings in the CSF study, or in radiologic studies such as CT or MRI. Clinical specimens, stools, nasopharyngeal swab, and cerebrospinal fluid were collected from the patients and sent to the Division of Enteric and Hepatitis Viruses, Korea Centers of Disease Control and Prevention. EV71 was detected by real time PCR. Medical records including initial symptoms and findings at the time of hospitalization, fever duration, hospitalization duration, treatment and complications were retrospectively analyzed. In addition, 42 subjects were classified into two groups based on the severity at presentation: mild patients group and severe patients group. The mild patient group included the patients who showed pleocytosis in CSF study, who showed normal findings in brain CT or MRI, and who recovered without any complications. The severe patient group included the patients who showed either, pleocytosis, abnormal findings in brain CT or MRI, or severe CNS complications like acute flaccid paralysis, ataxia, tremor, motor weakness and coma. The two groups were compared for initial clinical manifestations, gender, age, febrile period, maximal body temperature, presence of seizure, hospitalization duration, test results and immunoglobulin treatment in order to identify prognostic factors for severe CNS complications. Statistical analysis was conducted by using SPSS, version 12.0. Statistical significance was determined as
Among 42 pediatric patients with CNS infection by EV 71, 23 patients were male and 19 patients were female (gender ratio 1.2:1) with a mean age of 3.55 (
Age distribution of subjects (range: 6 months-12 years old) was 10 patients (24%) for each 1-2 years and 3-4 years old age group, followed by 5 patients (12%) for 4-5 years old age group, 4 patients (9.5%) for 5-6 years old, and 2 patients (4.8%) for 6-7 years old, suggesting decreased disease prevalence with increased age (
Monthly incidence showed 13 patients diagnosed in June, 10 patients in July, and 8 patients in August, showing significantly higher incidence in summer (
Among 42 subjects, HFMD was the first clinical diagnosis for 39 patients (92.9%), while herpangina was diagnosed in 3 patients (7.1%).
Among 42 subjects, 27 patients (64.3%) were classified into the mild patient group, and 15 patients (35.7%) were classified into the severe patients group (
Among the 15 in the severe patient group, decreased consciousness, seizure, and motor weakness were observed in 5, 4, and 3 patients, respectively, as initial clinical symptoms. However, these symptoms were observed in 2, 0, and 0 patients, respectively, out of the 27 patients in the mild group, indicating a significant difference between the two groups with regards to these symptoms (
When laboratory test results were compared, the severe patient group showed an average CRP level of 1.36 mg/dL, peripheral blood white blood cell (WBC) count of 12,760/mm3, and CSF WBC count of 494.64/mm3, while the mild patient group presented with an average CRP level of 4.54 mg/dL, peripheral blood WBC count of 12,409.26/mm3, and CSF WBC count of 251.33/mm3, indicating no statistically significant difference between the two groups (
With regards to treatment, 8 of 27 patients in the mild group (29.6%) received IVIG treatment compared to 13 of 15 patients in the severe group (86.7%), showing statistically significant difference between two groups (
Positive findings were observed in 35 stool specimens (83.3%), 16 nasopharyngeal swab specimens (38.1%), and 3 CSF specimens (7.1%) out of 42 patients (
Enterovirus infection is prevalent worldwide, and the infection usually spreads in the warm season, especially summer and autumn, when CNS infection by enterovirus increases
Most clinical symptoms are asymptomatic or mild, usually with non-specific symptoms such as fever, irritation, agitation, sore throat, headache, myalgia, vomiting, mild abdominal discomfort, and diarrhea
The standard protocol for enterovirus diagnosis is based on virus culture, but it takes several weeks for confirmation of final results with about 50-70% of sensitivity. CSF specimens are usually used for the analysis of concurrent CNS complication cases, but simultaneous analysis with stool and nasopharyngeal swab specimens can increase the sensitivity
The administration of high dose intravenous immunoglobulin (IVIG) is recommended for the treatment of severe enterovirus CNS infection, and prompt IVIG administration based on early diagnosis of severe CNS infection is required for favorable outcomes
Age distribution of the 42 patients with enterovirus 71 CNS infection.
Seasonal distribution of the 42 EV71 patients (May 2009-Oct. 2009).
Initial clinical manifestations of enterovirus 71 infection.
Enterovirus 71 yield from different specimen types.
Demographic and Clinical Data of 42 Enterovirus 71 CNS Infections
Initial Clinical Manifestations of 42 Patients with Enterovirus Type 71 CNS Infections
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Comparison of Mild Patient Group and Severe Patient Group
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Enterovirus 71 Yield from Different Specimen Type