Pediatric Neurology 138 (2023) 38e44

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Pediatric Neurology
journal homepage: www.elsevier.com/locate/pnu

Research Paper

Epidemiology and Disease Burden of Hospitalized Children With Viral

Central Nervous System Infections in China, 2016 to 2020
Qi Li, MD a, b, #, Ran Wang, MD a, b, #, Hui Xu, MD c, Linlin Zhang, MD a, b, Yiliang Fu, MD a, b,
Jiao Tian, MD a, b, Mengjia Liu, MD a, b, Guoshuang Feng, MD c, Yueping Zeng, MD d,
Xiangpeng Chen, MD a, b, *, Zhengde Xie, MD a, b, *
a
Beijing Key Laboratory of Pediatric Respiratory Infectious Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical
Research Center for Respiratory Diseases, Laboratory of Infection and Virology, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital
Medical University, National Center for Children's Health, Beijing, China
b
Research Unit of Critical Infection in Children, 2019RU016, Chinese Academy of Medical Sciences, Beijing, China
c
Big Data Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
d
Medical Record Management Office, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China

a r t i c l e i n f o a b s t r a c t

Article history: Background: Viral central nervous system (CNS) infections seriously threaten the life and health of
Received 11 September 2022 children, with a high mortality and severe sequelae in China and globally. Surveillance of viral CNS in-
Accepted 22 September 2022 fections in children is important, especially in hospitalized children, to facilitate disease evaluation.
Available online 14 October 2022
Methods: In this study, we collected the data on the discharged Face Sheet of Medical Records from
database from 2016 to 2020 and analyzed the epidemiologic characteristics and disease burden of
Keywords:
hospitalized children (
18 years old) with viral CNS infections in China. We classified the discharge
Viral central nervous system infections
diagnosis of viral CNS infection as viral encephalitis (VE), viral meningitis (VM), viral meningoenceph-
Epidemiology
Hospitalization
alitis (VME), viral encephalomyelitis (VEM), and viral meningomyelitis (VMM).
Children Results: A total of 42,641 cases of viral CNS infections were included in the database, consisting of 39,279
cases with VE (92.47%), 2011 cases with VM (4.73%), 1189 cases with VME (2.80%), 118 cases with VEM
(0.28%), and 44 cases with VMM (0.10%). The number of hospitalized patients with viral CNS infections
accounted for 0.74% (42,641 of 5,790,910) of all hospitalized cases. The onset of viral CNS infections
presented seasonal characteristic, with peaks in June to July and December to January. Seizures are the
most frequent complication of this disorder. Median length of stay and inpatient expenditures for pa-
tients with viral CNS infections were 9 days and 1144.36 USD. Causative viruses were identified in 4.33%
(1848 of 42,641) of patients.
Conclusions: This study will help understand the clinical epidemiology and disease burden of hospital-
ized children with viral CNS infections in China.
© 2022 Elsevier Inc. All rights reserved.

Introduction and meningomyelitis caused by causative pathogens such as bac-

Central nervous system (CNS) infection is an important
cause of death and disability in children and can manifest as
encephalitis, meningitis, meningoencephalitis, encephalomyelitis,
Declarations of interest: None.
* Communications should be addressed to: Drs. Chen and Xie, Big Data Center,
Beijing Children’s Hospital, Capital Medical University, National Center for Chil-
dren’s Health, Beijing, China.
E-mail addresses: chenxp1111@163.com (X. Chen), xiezhendge@bch.com.cn
(Z. Xie).
#
These authors contributed equally.
teria, fungi, and viruses. Recently, viral infections have gradually
become the most common etiology of CNS infections,1 which is
approximately three times as common as CNS infections caused by
bacterial etiologies.2 Viral infections are reported to be responsible
for almost 60% of infectious encephalitis and 36% of meningitis
cases.3-5 It is estimated that 1.5 to 7 patients per 100,000 people are
hospitalized for viral encephalitis (VE) annually, with children
being the highest hospitalization group.6
VE is a class of brain parenchymal lesion that usually leads to
severe neurological sequelae and even death. The pathogenic
spectrum of VE varies from place to place; for example, herpes
simplex virus (HSV) and enterovirus (EV) are the main pathogens of

https://doi.org/10.1016/j.pediatrneurol.2022.09.003
0887-8994/© 2022 Elsevier Inc. All rights reserved.
Q. Li, R. Wang, H. Xu et al.
VE in the United States and Brazil, respectively.5,7,8 Viral meningitis
(VM) usually tends to be self-limiting with a favorable prognosis
and rare sequelae.9 The main causative agent of VM in various
countries has been revealed as EV.10-12 Viral meningoencephalitis
(VME) is often life-threatening because these patients have symp-
toms of both encephalitis and meningitis. A multicenter prospec-
tive study on VME in Turkey showed that EV, adenovirus (AdV), and
human herpesvirus 6 are the main viruses detected in children with
VME.13 Viral myelitis usually presents as acute flaccid paralysis.14
Although wide-type poliovirus has been declared eradicated by
vaccination in most countries and regions around the world, acute
myelitis caused by non-polioviruses has been reported frequently
in recent years.15
Viral CNS infections have received extensive attention in child-
hood CNS diseases in China. In a nationwide study of acute men-
ingitis or encephalitis in China from 2009 to 2018, at least one virus
was detected in 28% of cases,6 suggesting that the virus has become
the main pathogen of CNS infections in China. Although the path-
ogenic spectrum of acute meningitis or encephalitis in China has
been widely reported, 16,17 few detailed descriptions of the epide-
miology and disease burden [length of stay (LOS) and expense] of
hospitalized children with viral CNS infections are available. Here,
we analyzed and reported the epidemiology and disease burden
using data from 42,641 hospitalized children with a clear diagnosis
of viral CNS infections from a database based on 27 children's
hospitals located in 22 provinces in China between 2016 and 2020.
Since almost all patients with viral CNS infections require hospi-
talization, these data can globally reflect the epidemiologic char-
acteristics and disease burden of viral CNS infections in Chinese
children.
Materials and Methods
Data sources
In 2016, the Futang Research Center of Pediatric Development
(FRCPD), the first nonprofit social service organization engaged in
pediatric development research, was set up. Under the supervision
and management of the Ministry of Civil Affairs, FRCPD has become
the first non-profit social service organization engaging in pediatric
development research in China. As of 2021, a children's medical and
health service network system with 47 provincial-level children's
medical institutions as the core and more than 3000 primary
hospitals participating together has been initially formed.
To strengthen the data sharing connection among the member
hospitals of FRCPD, the center established the Children's Health
Data Science Committee which is the FUTang Updating medical
REcords (FUTURE) database.18 A total of 27 tertiary children's hos-
pitals within FRCPD, of which 21 are located in provincial capitals,
uploaded the discharged Face Sheet of Medical Records (FSMRs) of
hospitalized children. The FUTURE database contains FSMR data
from 2016 to 2020, which is organized, checked, and conducted
quality control with reference by FRCPD staffs.
Study design
This is a cross-sectional study of viral CNS infections, consisting
of VE, VM, VME, viral encephalomyelitis (VEM), and viral menin-
gomyelitis (VMM). The diagnostic criteria of viral CNS infections are
stated in Neurology (in Chinese, People's Health Publishing House)
and Clinical Pathway of Viral Encephalitis (Chinese Medical Associ-
ation, file download address: https://www.cma.org.cn/art/2018/10/
17/art_1542_101.html). The data were obtained from FSMRs
uploaded to the FUTURE database from January 2016 to December
2020, and included patients' demographics, admission and
39
Pediatric Neurology 138 (2023) 38e44
discharge information, primary diagnosis, secondary diagnosis,
LOS, and hospitalization expense. The cohort in this study was
stratified by age group, region, year, and residence. Hospitalized
patients were divided into six age groups (day, d, or year, y): 0 to

28 d, 29 d to
1 y, 1 to
3 y, 4 to
6 y, 7 to
12 y, and 13 to
18 y.
The 27 children's hospitals were grouped into seven regions by
geographic location: Northeast China, North China, East China,
South China, Central China, Northwest China, and Southwest China
(Table S1).19 The patients were divided into rural and urban pop-
ulations according to their place of residence.
Eligibility of participants and admission records
Hospitalized patients, who were admitted, should meet the
primary diagnosis of viral CNS infections. The tenth Revision of
International Statistical Classification of Diseases and Related
Health Problems codes (ICD-10) was used to screen cases. We
screened hospitalized children with viral CNS infections in Table S2.
Statistical analysis
In this study, the basic epidemiologic characteristics of the
research subjects were statistically described. Categorical variables
were described in terms of number (rates or constituent ratios), and
differences between groups were compared by chi-square test.
Continuous variables that did not conform to normal distribution
were described as the median (interquartile range, IQR), and
Kruskal-Wallis test as well as Steel-Dwass test (for multiple com-
parisons) was performed to compare the difference among groups.
All statistics were analyzed by using JMP software version 16.0. To
avoid the type I error, differences with P values <0.01 were
considered statistically significant, considering the large sample in
the present study.
Ethics statement
This study was approved by the Ethics Committee of Beijing
Children's Hospital, Capital Medical University (Approval Number:
[2022]-E-218-R). The informed consent of patients was waived as it
only involved retrospective aggregated data analysis of medical
records. Our data were fully deidentified and anonymous to protect
privacy.
Results
Overall
From January 1, 2016, to December 31, 2020, a total of 42,641
hospitalized children with the diagnosis of viral CNS infections (VE,
VM, VME, VEM, VMM) according to the ICD-10 disease codes were
included in this study. Patients with VE, VM, VME, VEM, and VMM
accounted for 92.12% (39,279 cases), 4.72% (2011 cases), 2.79% (1189
cases), 0.28% (118 cases), and 0.10% (44 cases) of total viral CNS
infections, respectively. Children hospitalized with viral CNS in-
fections accounted for 0.74% (42,641 of 5,790,910) of all hospital-
ized cases, of which patients with VE, VM, VME, VEM, and VMM
accounted for 0.68% (39,279 of 5,790,910), 0.03% (2011 of
5,790,910), 0.02% (1189 of 5,790,910), 0.002% (118 of 5,790,910), and
0.001% (44 of 5,790,910), respectively. The male-to-female ratio of
viral CNS infections was 1.60:1.
In terms of age, viral CNS infections in children aged 7 to 12 y
accounted for 31.58% (13,468 of 42,641), followed by 4 to 6 y
(30.99%, 13,213 of 42,641), 1 to 3 y (30.21%, 12,883 of 42,641), 13 to
18 y (4.45%, 1898 of 42,641), 29 d to 1 y (2.68%, 1443 of 42,641), and

28 d (0.08%, 36 of 42,641, Table 1).
Q. Li, R. Wang, H. Xu et al. Pediatric Neurology 138 (2023) 38e44

From a regional perspective, the number of viral CNS infections Next, we analyzed the proportion of viral CNS infection hospi-
cases in East China was the largest, accounting for 35.43% (15,109 of talizations to total hospitalizations by region. Patients from
42,641), followed by those in Northwest China (27.36%, 11,666 of Northwest China had the highest proportion of hospitalization
42,641), North China (16.68%, 7112 of 42,641), Central China (1.48%, 11,666 of 786,313), whereas those from Northeast China had
(10.86%, 4631 of 42,641), Southwest China (7.80%, 3325 of 42,641), the lowest proportion (0.07%, 166 of 252,699, Fig 1B). The hospi-
South China (1.48%, 632 of 42,641), and Northeast China (0.39%, 166 talization proportions of patients from North China, East China,
of 42,641, Table 1). Southwest China, Central China, South China, and Northeast China
The annual cases of viral CNS infections from 2016 to 2020 were were 0.85% (7112 of 839,485), 0.79% (15,109 of 1,922,462), 0.74%
10,575, 9865, 9301, 9385, and 3515, respectively (Table 1). (3325 of 447,593), 0.42% (4631/ of 1,114,236), 0.15% (632 of
Hospitalized children with viral CNS infections living in rural 428,122), and 0.07% (166 of 252,699), respectively (Fig 1B).
and urban areas accounted for 43.23% (18,432 cases) and 56.77% In terms of years, the proportion of annual hospitalizations for
(24,209 cases), respectively (Table 1). viral CNS infections dropped year by year, from 1.01% (10,575 of
The median LOS of children hospitalized with viral CNS in- 1,042,679) in 2016 to 0.34% (3515 of 1,030,847) in 2020 (Fig 1C).
fections were 9 d (IQR 6 to 12), and the median hospitalization The proportions of hospitalization of patients with viral CNS
expense was 1144.36 USD (IQR 806.30 to 1663.52). infections in rural and urban areas were 0.91% (18,432 of 2,012,376)
Epidemiologic data for VE, VM, VME, VEM, and VMM were and 0.64% (24,209 of 3,778,534, Fig 1D).
summarized in Table S3. The age group, region, year, and residence distributions of VE
hospitalization rates were similar to those for viral CNS infections
(Figure S1A). For VM and VME, the largest proportion was found in
Age group, regional, year, and residence distribution of children aged 7 to 12 y, in 2018, and in urban area across the cor-
hospitalization rates for viral CNS infections responding groups (Figure S1B,C). The proportions of VM hospi-
talization rates in East China and VME hospitalization rates in
We first analyzed the proportions of hospitalizations due to viral Northwest China were the largest among all regions, respectively
CNS infections to the total number of hospitalizations within each (Figure S1B,C). It is difficult to summarize the exact distribution of
age group. The proportions of children aged 1 to 3 y (1.06%, 12,883 hospitalization rates, due to the limited number of cases in VEM
of 1,220,452), 4 to 6 y (1.19%, 13,213 of 1,112,355), 7 to 12 y (1.29%, and VME (Figure S1D,E).
13,468 of 1,044,134), and 13 to 18 y (1.03%, 1898 of 183,545) were
similar, whereas the proportion of children aged 0 to 28 d was the
lowest (0.005%, 27 of 585,076) and the proportion of children aged Seasonal pattern of hospitalization for viral CNS infections
29 d to 1 y was 0.07% (1143 of 1,645,348, Fig 1A).
The admission time of hospitalization with viral CNS infections
showed certain seasonal characteristics. The hospitalization rate of
TABLE 1
Demographic Information of Hospitalized Children With Viral CNS Infections Be- viral CNS infections started to increase month by month from the
tween January 1, 2016, and December 31, 2020 lowest in March, peaked in June to July, and then continued to
decline from August to November, rebounded in December to
Categories Hospitalization
January, and finally dropped to the lowest in March (Fig 2).
No. patients 42,641 The admission time of patients with VE showed a similar trend
Sex (n, %)
Male 26,227 (61.51)
to viral CNS infections, whereas the seasonal characteristics of VM
Female 16,414 (38.49) and VME hospitalizations did not show a secondary peak in
Age group (n, %) December to January after the main peak (Figure S2A-C). The sea-
0-28 d 36 (0.08) sonality could not be assessed because monthly case numbers for
29 d-1 y 1143 (2.68)
VEM and VMM were rare (Figure S2D,E).
1-3 y 12,883 (30.21)
4-6 y 13,213 (30.99)
7-12 y 13,468 (31.58)
13-18 y 1898 (4.45) Complications
Region (n, %)
Northeast China 166 (0.39)
North China 7112 (16.68)
Among the children with viral CNS infections, 94.80% (40,423 of
East China 15,109 (35.43) 42,641) had no complication, whereas the remaining 5.20% (2218 to
South China 632 (1.48) 42,641) had, with a male-to-female ratio of 1.34:1. Common com-
Central China 4631 (10.86) plications of viral CNS infections include seizures, central respira-
Northwest China 11,666 (27.36)
tory failure, brain herniation, hemiplegia, and cerebellar ataxia.
Southwest China 3325 (7.80)
Year of admission (n, %) Seizures was found in the largest proportion of complications, ac-
2016 10,575 (24.80) counting for 4.57% (1927 of 42,641) of the total, followed by central
2017 9865 (23.14) respiratory failure (0.49%, 207 of 42,641), brain herniation (0.10%,
2018 9301 (21.81) 42 of 42,641), cerebellar ataxia (0.05%, 22 of 42,641), and hemi-
2019 9385 (22.01)
2020 3515 (8.24)
plegia (0.05%, 20 of 42,641, Fig 3). Among all age groups, children
Residence (n, %) with viral CNS infections aged 29 d to 1 y had the largest proportion
Rural 18,432 (43.23) of complications, with a rate of 9.10% (104 to 1143), followed by
Urban 24,209 (56.77) children aged 1 to 3 y (7.82%, 1008 to 12,883), 13 to 18 y (4.79%, 91 of
LOS [d, median (IQR)] 9 (6-12)
1898), 7 to 12 y (3.92%, 528 of 13,468), 4 to 6 y (3.68%, 486 of
Expense [USD, median (IQR)] 1144.36 (806.30-1663.52)
13,213), and 0 to 28 d (2.78%, one of 36). Statistical analysis showed
Abbreviations: that the incidence of complications in hospitalized children with
CNS ¼ Central nervous system
IQR ¼ Interquartile range
CNS infections living in rural areas (5.81%, 1070 of 18,432) was
LOS ¼ Length of stay higher than that in urban area (4.74%, 1148 of 24,209, Z ¼ 4.897,
USD ¼ US dollar P < 0.0001).
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Q. Li, R. Wang, H. Xu et al. Pediatric Neurology 138 (2023) 38e44

FIGURE 1. The proportions of children hospitalized for viral CNS infection across categories. Various distributions by (A) age, (B) region, (C) year, and (D) residence. The color version
of this figure is available in the online edition.

LOS and hospitalization expense for viral CNS infections
Statistical analysis showed differences in the LOS and hospital-
ization expense of viral CNS infections by age group, region, and
residence. Among hospitalized children in each group, the longest
LOS was found in patients <28 d (P < 0.0001, Table 2) and the
shortest was in the 1 to 3 y age group (P < 0.01, Table 2). Patients in
the <28 d age group had the highest hospitalization expense
(P < 0.0001, Table 2), and the second highest expense was in the 29
d to 1 y age group (P < 0.0001, Table 2). For each region, patients in
North China had the longest LOS, and those in South China had the
shortest (P < 0.001, Table 2). Patients in Northeast China had the
highest hospitalization expense (P < 0.001, Table 2), and the second
highest expense was in North China (P < 0.0001, Table 2). In terms
of residence, the LOS and expense of patients in rural area was
heavier than that in urban area (P < 0.0001, Table 2).
Pathogen spectrum of viral CNS infections
In this study, the viral pathogen could not be identified in the
vast majority of the children, and only 4.40% (1878 of 42,641) of the
patients had identified causative pathogens. The identified viral
pathogens included EV (4.42%, 83 of 42,641), varicella zoster virus
(9.11%, 171 of 42,641), HSV (9.90%, 186 of 42,641), rubella virus
(0.05%, one of 42,641), cytomegalovirus (0.59%, 11 of 42,641),
mumps virus (MuV, 36.00%, 676 of 42,641), measles virus (MeV,
0.27%, five of 42,641), AdV (28.86%, 542 of 42,641), and Japanese
encephalitis virus (JEV, 10.81%, 203 of 42,641, Fig 4).
Deaths from viral CNS infections
A total of 46 children with viral CNS infection who died were
documented in this study, with a mortality rate of 0.11% (46 of
42,641). The causes of death of these deceased were VE (43 cases),
VME (two cases), and VMM (one case) with fatality rates of 0.11%
(43 of 39,279), 0.17% (two of 1189), and 2.27% (one of 44), respec-
tively. The ratio of male-to-female was 1.30:1. In terms of age, the
median age was 4.5 y (IQR 3 to 7) and the proportion of children
aged 1 to 3 y accounted for 36.96% (17 of 46), followed by 4 to 6 y
(30.43%, 14 of 46), 7 to 12 y (26.09%, 12 of 46), 13 to 18 y (4.35%, two
of 46), and 29 d to 1 y (2.17%, one to 46), and no patient was under
28 d. Among the children who died from viral CNS infection, 78.26%
had no documented complications, whereas 21.74% did (Table 3).
Complications of fatal cases included seizures (2.17%, one of 46),
central respiratory failure (6.52%, three of 46), and brain herniation
(13.04%, six of 46). Seven of them were identified as causative vi-
ruses, consisting of AdV (four cases), JEV (two cases), and MeV (one
case, Table 3).

FIGURE 2. Monthly cases and proportions of children hospitalized for viral CNS infections from January 1, 2016, to December 31, 2020. M(n): number of monthly hospitalizations,
Y(n): number of yearly hospitalizations. The blue bars represent the ratio of M(n)/Y(n), and the orange line represents M(n). The color version of this figure is available in the online
edition.

41
Q. Li, R. Wang, H. Xu et al. Pediatric Neurology 138 (2023) 38e44

FIGURE 3. The complications of hospitalized children with viral CNS infections. (A) Proportions of children with viral CNS infections who had complications or not. (B) Proportions
of children with the complications of seizures, central respiratory failure, brain herniation, hemiplegia, and cerebellar ataxia. The color version of this figure is available in the online
edition.

TABLE 2
LOS and Expense of Hospitalized Children With Viral CNS Infections by Age, Region, and Residence

Categories LOS [d, Median (IQR)] c2 P Value Expense [USD, Median (IQR)] c2 P Value

Age group
0-28 d 20 (13-27) 112.56 <0.0001* 3534.17 (2046.47-4848.46) 364.82 <0.0001x
29 d-1 y 9 (7-13) 1301.29 (934.31-2116.58)
1-3 y 8 (6-12) 1179.24 (875.71-1771.74)
4-6 y 9 (7-13) 1119.72 (774.51-1575.16)
7-12 y 9 (6-13) 1113.24 (744.39-1617.66)
13-18 y 9 (6-12) 1184.69 (840.91-1766.14)
Region
Northeast China 10 (7-14) 2540.88 <0.0001y 1609.87 (1243.16-2202.43) 2389.87 <0.0001k
North China 11 (8-15) 1400.91 (1019.25-2064.72)
East China 9 (6-13) 952.7 (593.84-1502.14)
South China 7 (5-9) 1206.73 (818.12-1865.23)
Central China 10 (7-14) 1185.01 (770.64-2166.58)
Northwest China 8 (6-10) 1174.58 (947.77-1556.21)
Southwest China 7 (6-9) 1060.39 (865.58-1421.75)
Residence
Rural 9 (7-13) 61.73 <0.0001z 1184.03 (877.28-1707.69) 249.78 <0.0001¶
Urban 9 (6-12) 1109.61 (743.86-1626.44)

Abbreviations:
CNS ¼ Central nervous system
IQR ¼ Interquartile range
LOS ¼ Length of stay
USD ¼ US dollar
Kruskal-Wallis test and Steel-Dwass test were performed to compare the difference among groups (P values <0.01 were considered statistically significant).
*
0 to 28 d group versus 29 d to 1 y group: Z ¼ 6.453, P < 0.0001; 0 to 28 d group versus 1 to 3 y group: Z ¼ 6.919, P < 0.0001; 0 to 28 d group versus 4 to 6 y group: Z ¼ 6.789,
P < 0.0001; 0 to 28 d group versus 7 to 12 y group: Z ¼ 6.717, P < 0.0001; 0 to 28 d group versus 13 to 18 y group: Z ¼ 6.563, P < 0.0001; 1 to 3 y group versus 4 to 6 y group: Z ¼ -
8.061, P < 0.0001; 1 to 3 y group versus 7 to 12 y group: Z ¼ -3.833, P ¼ 0.0018; 4 to 6 y group versus 7 to 12 y group: Z ¼ 3.86423, P ¼ 0.0016.
y
Northeast China versus North China: Z ¼ -2.318, P ¼ 0.0204; Northeast China versus East China: Z ¼ 2.864, P ¼ 0.0042; Northeast China versus South China: Z ¼ 7.228,
P < 0.0001; Northeast China versus Northwest China: Z ¼ 5.647, P < 0.0001; Northeast China versus Southwest China: Z ¼ 7.791, P < 0.0001; North China versus East China:
Z ¼ 29.318, P < 0.0001; North China versus South China: Z ¼ 19.622, P < 0.0001; North China versus Central China: Z ¼ 13.263, P < 0.0001; North China versus Northwest China:
Z ¼ 43.461, P < 0.0001; North China versus Southwest China: Z ¼ 40.884, P < 0.0001; East China versus South China: Z ¼ 11.196, P < 0.0001; East China versus Central China:
Z ¼ -7.917, P < 0.0001; East China versus Northwest China: Z ¼ 16.006, P < 0.0001; East China versus Southwest China: Z ¼ 20.723, P < 0.0001; South China versus Central
China: Z ¼ -12.649, P < 0.0001; South China versus Northwest China: Z ¼ -7.370, P < 0.0001, South China versus Southwest China: Z ¼ -3.099, P ¼ 0.0019; Central China versus
Northwest China: Z ¼ 18.930, P < 0.0001; Central China versus Southwest China: Z ¼ 21.715, P < 0.0001; Northwest China versus Southwest China: Z ¼ 13.026, P < 0.0001.
z
Rural versus urban: Z ¼ 7.857, P < 0.0001.
x
0 to 28 d group versus 29 d to 1 y group: Z ¼ 5.791, P < 0.0001; 0 to 28 d group versus 1 to 3 y group: Z ¼ 6.651, P < 0.0001; 0 to 28 d group versus 4 to 6 y group: Z ¼ 7.278,
P < 0.0001; 0 to 28 d group versus 7 to 12 y group: Z ¼ 7.023, P < 0.0001; 0 to 28 d group versus 13 to 18 y group: Z ¼ 6.361, P < 0.0001; 29 d to 1 y group versus 1 to 3 y group:
Z ¼ 5.719, P < 0.0001; 29 d to 1 y group versus 4 to 6 y group: Z ¼ 10.754, P < 0.0001; 29 d to 1 y group versus 7 to 12 y group: Z ¼ 10.431, P < 0.0001; 29 d to 1 y group versus 13
to 18 y group: Z ¼ 4.769, P < 0.0001; 1 to 3 y group versus 4 to 6 y group: Z ¼ 13.010; P < 0.0001; 1 to 3 y group versus 7 to 12 y group: Z ¼ 12.827, P < 0.0001; 4 to 6 y group
versus 13 to 18 y group: Z ¼ -5.590, P < 0.0001.
k
Northeast China versus North China: Z ¼ 3.551, P ¼ 0.0004; Northeast China versus East China: Z ¼ 10.355, P < 0.0001; Northeast China versus South China: Z ¼ 6.036,
P < 0.0001; Northeast China versus Central China: Z ¼ 5.641, P < 0.0001; Northeast China versus Northwest China: Z ¼ 8.143, P < 0.0001; Northeast China versus Southwest
China: Z ¼ 9.478, P < 0.0001; North China versus East China: Z ¼ 43.216, P < 0.0001; North China versus South China: Z ¼ 6.985, P < 0.0001; North China versus Central China:
Z ¼ 12.663, P < 0.0001; North China versus Northwest China: Z ¼ 21.886, P < 0.0001; North China versus Southwest China: Z ¼ 23.032, P < 0.0001; East China versus South
China: Z ¼ -8.001, P < 0.0001; East China versus Central China: Z ¼ -20.105, P < 0.0001; East China versus Northwest China: Z ¼ -31.389, P < 0.0001; East China versus
Southwest China: Z ¼ -15.456, P < 0.0001; South China versus Southwest China: Z ¼ 2.714, P ¼ 0.0066; Central China versus Southwest China: Z ¼ 4.684, P < 0.0001, Northwest
China versus Southwest China: Z ¼ 10.435, P < 0.0001.
¶
Rural versus urban: Z ¼ 15.804, P < 0.0001.

42
Q. Li, R. Wang, H. Xu et al. Pediatric Neurology 138 (2023) 38e44

FIGURE 4. Pathogen detection rate and partial viral pathogen spectrum in hospitalized children with viral CNS infections. (A) Pathogen detection rate and (B) viral pathogen
spectrum in hospitalized children with viral CNS infections. The color version of this figure is available in the online edition.

Discussion are few multicenter studies involving children with viral CNS in-
fections in China, and systematic retrospective study on epidemi-
Viral CNS infections are a group of infectious diseases that ology, LOS, and expense are thus lacking. In this study, based on the
seriously threaten people's health and impose heavy burdens on well-established FUTURE database, for the first time, we retro-
families and society. Viral CNS infections are not managed as spectively analyzed the epidemiologic characteristics, LOS, and
notifiable infectious diseases in China, and most of patients are expense of FSMR in hospitalized children with viral CNS infections
children (
18 years old).6,20 Numerous papers reported the etiol- from 2016 to 2020.
ogy of viral CNS infections in children with or without the epide- Overall, during this period, the number of children hospitalized
miologic, LOS and expense data, which is invaluable for a disease due to viral CNS infections was 42,641 and accounted for 0.74% of
that causes a large number of hospitalizations.2,6,17 To date, there all hospitalized children, indicating that CNS infections in children
are a significant hospitalization reason. The male-to-female ratio of
these children is about 1.6:1, which is similar to that reported
TABLE 3 elsewhere.10 The number of cases remained at about 10,000 per
Death Cases of Hospitalized Children With Viral CNS Infections year from 2016 to 2019, whereas it plummeted to 3724 in 2020,
Categories Hospitalization presumably related to the overall decline in hospitalizations due to
the coronavirus disease 2019 pandemic.21 As an anomaly, the
No. patients (n) 46
Sex (n, %) evident rebound in hospitalizations for viral CNS infections in
Male 26 (56.52) January 2020 may be the result of the overall decline in hospitali-
Female 20 (43.48) zations, particularly including respiratory infections, caused by the
Age [y, median (IQR)] 4.5 (3-7)
coronavirus disease 2019 pandemic since this month.
Age group (n, %)
0-28 d 0 (0.00)
The hospitalization rate of children with viral CNS infection in
29 d-1 y 1 (2.17) each age group >1 year is generally higher than that of children
1-3 y 17 (36.96) within 1 y, which is basically consistent with previous studies.22
4-6 y 14 (30.43) Hospitalization rates for viral CNS infection in neonates and in-
7-12 y 12 (26.09)
fants are generally low as reported previously.22 Hospitalization
13-18 y 2 (4.35)
Disease types (n, %) rates for viral CNS infection are found to be lower in northeastern
VE 43 (93.48) China, whereas those in the rest of China are similar, which may be
VM 0 (0.00) due to factors such as climate and environment. The proportion of
VME 2 (4.35)
hospitalizations for rural children is higher than that for urban
VEM 0 (0.00)
VMM 1 (2.17)
children, and the LOS and expense of rural children is heavier than
Complications (n, %) that of urban children, which may be attributed to the poorer
No complication 36 (78.26) economic and health status of rural areas.
Seizures 1 (2.17) According to the admission month of children with viral CNS
Central respiratory failure 3 (6.52)
infections, the case showed a significant seasonal characteristic,
Brain herniation 6 (13.04)
Pathogens (n, %) with a significant peak in June to July and a potential peak in
No identified pathogen 39 (84.78) December to January, which may due to the seasonality of some
AdV 4 (8.70) viruses. Based on the etiology of viral CNS infections in China, the
JEV 2 (4.35)
most common detected virus was EV; the monthly case caused by
MeV 1 (2.17)
EV peaked from June to August,6,16 which is consistent with sea-
Abbreviations: sonality of EV in other countries.23,24 A secondary peak in hospi-
AdV ¼ Adenovirus
talization for viral CNS infection was also observed in winter, which
CNS ¼ Central nervous system
IQR ¼ Interquartile range may be related to the winter epidemic characteristics of some
JEV ¼ Japanese encephalitis virus encephalitis-causing viruses.25,26
MeV ¼ Measles virus The proportion of complications in hospitalized children with
VE ¼ Viral encephalitis
viral CNS infections was low, and a small number of children had
VEM ¼ Viral encephalomyelitis
VM ¼ Viral meningitis
seizures and other symptoms, suggesting that the general condi-
VME ¼ Viral meningoencephalitis tion of the patients is relatively benign. LOS and expenditure
VMM ¼ Viral meningomyelitis generated by hospitalization were associated with disease severity

43
Q. Li, R. Wang, H. Xu et al.
in children. Although most of the children did not show compli-
cations, the LOS and expense of hospitalized children with viral CNS
infection varied among age groups. The LOS and expense of
neonatal patients with VE was significantly higher than that of
patients classified into other age groups. In fact, the immunocom-
promised status of neonates is often a plausible explanation for the
poor prognosis caused by viral CNS infections.23,27 In addition,
accumulated exposure to viral natural infection, which triggers
more diverse immune adaptations with age, may also be respon-
sible for better outcomes in older children.
In China, EV, MuV, HSV, and JEV have been reported as the most
common pathogenic profiles of viral CNS infections.6 The patho-
genic spectrum of viral CNS infections in this study is basically the
same as earlier. Some additional cases were diagnosed with AdV as
the pathogen, especially in four deaths. It has been reported that
AdV infection is associated with viral CNS infections in children,28
suggesting that high attention should be paid to AdV infection
and its secondary viral CNS infections in the prevention and control
of CNS infection in China.
The number of deaths in our study is rare, which to a certain
extent reflects the overall benign prognosis of childhood viral CNS
infections and the increasingly improved medical diagnosis and
treatment system in China in recent years. In addition, the symp-
toms of deceased patients suggest that physicians with severe
complications of CNS infections require intensive attention to
reduce the probability of development as death.
Limitations
There are some limitations in this study. (1) Long-term follow-
up data of hospitalized patients are not collected, which will lead to
the lack of information on severe and even fatal cases, and also have
a certain impact on the evaluation of LOS and expenditure; (2) JEV,
MeV, and MuV infections are vaccine-preventable, but FSMR does
not cover records of vaccination history in hospitalized children;
and (3) The low identification rate of pathogens leads to impaired
fine-grained assessment of disease epidemiologic characteristics,
LOS, and expense.
Conclusions
Viral CNS infections constituted 0.74% of all childhood hospi-
talizations in China between 2016 and 2020, with VE as the pre-
dominant clinical phenotype. The annual hospitalization due to
viral CNS infections was basically the same from 2016 to 2019, and
there was no significant difference in the hospitalization rate across
regions. Significant and potential peaks of hospitalization for viral
CNS infections were formed in summer and winter, respectively.
Overall, neonates and infants and those with viral CNS infections
carried a higher burden of disease, although the establishment of
severe clinical manifestations was relatively infrequent among
children in our database. The results of this study can provide
important reference data for the diagnosis, treatment, and pre-
vention of viral CNS infections.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (82172245, 81971922, and 82002130), Beijing
Natural Science Foundation (L192014 and 7222059), and the CAMS
Innovation Fund for Medical Sciences (2019-I2M-5-026). We are
44
Pediatric Neurology 138 (2023) 38e44
grateful to investigators from members of the Futang Research
Center of Pediatric Development (FRCPD).
Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.pediatrneurol.2022.09.003.
References
1. McGill F, Griffiths MJ, Solomon T. Viral meningitis: current issues in diagnosis
and treatment. Curr Opin Infect Dis. 2017;30:248e256.
2. Kakooza-Mwesige A, Tshala-Katumbay D, Juliano SL. Viral infections of the
central nervous system in Africa. Brain Res Bull. 2019;145:2e17.
3. Brouwer MC, van de Beek D. Viral meningitis in the UK: time to speed up.
Lancet Infect Dis. 2018;18:930e931.
4. Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and
a comparison to infectious encephalitis. Ann Neurol. 2018;83:166e177.
5. Venkatesan A, Murphy OC. Viral encephalitis. Neurol Clin. 2018;36:705e724.
6. Wang LP, Yuan Y, Liu YL, et al. Etiological and epidemiological features of acute
meningitis or encephalitis in China: a nationwide active surveillance study.
Lancet Reg Health West Pac. 2022;20, 100361.
7. Tyler KL. Acute viral encephalitis. N Engl J Med. 2018;379:557e566.
8. Messacar K, Fischer M, Dominguez SR, et al. Encephalitis in US children. Infect
Dis Clin North Am. 2018;32:145e162.
9. Lyons JL. Viral meningitis and encephalitis. Continuum (Minneap Minn).
2018;24:1284e1297.
10. Mathew S, Al Khatib HA, Al Ansari K, et al. Epidemiology profile of viral
meningitis infections among patients in Qatar (2015-2018). Front Med (Lau-
sanne). 2021;8:663694.
11. de Oliveira DB, Candiani TM, Franco-Luiz APM, et al. Etiological agents of viral
meningitis in children from a dengue-endemic area, Southeast region of Brazil.
J Neurol Sci. 2017;375:390e394.
12. Geteneh A, Kassa T, Alemu D, et al. Viral etiologies of meningitis in patients
with presumed pyogenic meningitis at university hospitals in Ethiopia. Infect
Drug Resist. 2021;14:1083e1088.
13. Torun SH, Kaba O, Yakut N, et al. Multicenter prospective surveillance study of
viral agents causing meningoencephalitis. Sci Rep. 2021;11:7216.
14. Asundi A, Cervantes-Arslanian AM, Lin NH, et al. Infect myelitis. Semin Neurol.
2019;39:472e481.
15. Murphy OC, Messacar K, Benson L, et al. Acute flaccid myelitis: cause, diagnosis,
and management. Lancet. 2021;397:334e346.
16. Ai J, Xie Z, Liu G, et al. Etiology and prognosis of acute viral encephalitis and
meningitis in Chinese children: a multicentre prospective study. BMC Infect
Dis. 2017;17:494.
17. Shen H, Zhu C, Liu X, et al. The etiology of acute meningitis and encephalitis
syndromes in a sentinel pediatric hospital, Shenzhen, China. BMC Infect Dis.
2019;19:560.
18. Wang X, Zeng Y, Tian J, et al. A brief introduction to the FUTang Updating
medical REcords (FUTURE) database. Pediatr Investig. 2021;5:247e248.
19. Wang R, Wang X, Zhang L, et al. The epidemiology and disease burden of
children hospitalized for viral infections within the family Flaviviridae in
China: a national cross-sectional study. Plos Negl Trop Dis. 2022;16:e0010562.
20. Kadambari S, Okike I, Ribeiro S, et al. Seven-fold increase in viral meningo-
encephalitis reports in England and Wales during 2004-2013. J Infect.
2014;69:326e332.
21. Chen Y, Klein SL, Garibaldi BT, et al. Aging in COVID-19: vulnerability, immu-
nity and intervention. Ageing Res Rev. 2021;65:101205.
22. Toczylowski K, Wieczorek M, Bojkiewicz E, et al. Pediatric enteroviral central
nervous system infections in Bialystok, Poland: epidemiology, viral types, and
drivers of seasonal variation. Viruses. 2020;12.
23. Moltoni G, D'Arco F, Pasquini L, et al. Non-congenital viral infections of the
central nervous system: from the immunocompetent to the immunocompro-
mised child. Pediatr Radiol. 2020;50:1757e1767.
24. Ben Abid F, Abukhattab M, Ghazouani H, et al. Epidemiology and clinical out-
comes of viral central nervous system infections. Int J Infect Dis. 2018;73:
85e90.
25. Su SB, Chang HL, Chen AK. Current status of mumps virus infection: epide-
miology, pathogenesis, and vaccine. Int J Environ Res Public Health. 2020;17:
1686.
26. Lynch JP, Kajon AE. Adenovirus: epidemiology, global spread of novel sero-
types, and advances in treatment and prevention. Semin Respir Crit Care Med.
2016;37:586e602.
27. Shane AL, Sa nchez PJ, Stoll BJ. Neonatal sepsis. Lancet. 2017;390:1770e1780.
28. Schwartz KL, Richardson SE, MacGregor D, et al. Adenovirus-associated central
nervous system disease in children. J Pediatr. 2019;205:130e137.