Clinical characteristics and short-term outcomes of Japanese encephalitis in pediatric and adult patients: a retrospective study in Northern China

Objective The study aimed to compare the clinical characteristics and short-term outcomes of pediatric and adult Japanese encephalitis (JE) patients in order to find out the differences. Methods From August 2006 to October 2019, 107 patients (62 pediatric patients and 45 adult patients) with JE were enrolled. Clinical characteristics and short-term outcomes were analyzed. The short-term outcome of each patient was defined as a good outcome or poor outcome according to their Glasgow Coma Scale (GCS) scores (GCS > 8 vs. GCS ≤ 8) at discharge. Results As for acute complications, the incidence of pulmonary infection was higher in 25 adults (25/45, 55.6%) than in 19 children (19/62, 30.6%; P = 0.01). Upper gastrointestinal bleeding was more common in patients with pulmonary infection, with 10 of these patients experiencing the symptom (10/44, 22.7%) compared to only one patient without pulmonary infection (1/63, 1.6%; P = 0.001). The proportion of mechanical ventilation and admission to the intensive care unit (ICU) for supportive care was higher in patients with pulmonary infection than in patients without infection (P < 0.001, P = 0.008, respectively). The GCS scores at discharge in patients with pulmonary infection (7, 4–12.75) were lower than in patients without pulmonary infection (14, 10-14; P < 0.001). Although the GCS scores at the admission of children (9.5, 7–13) were similar to that of adults (7, 6–13), the GCS scores at the discharge of adults (7, 3.5–13) were lower than that of children (13, 10.75–14; P < 0.001). Conclusion The short-term outcome of JE was worse in adults. Pulmonary infection was correlated with a high incidence of upper gastrointestinal bleeding, mechanical ventilation, and ICU hospitalization in JE. Pulmonary infection is a prognostic predictor of short-term outcomes in patients with JE. Vaccination for adults should be initiated.

Results: As for acute complications, the incidence of pulmonary infection was higher in adults ( / , . %) than in children ( / , . %; P = . ). Upper gastrointestinal bleeding was more common in patients with pulmonary infection, with of these patients experiencing the symptom ( / , . %) compared to only one patient without pulmonary infection ( / , . %; P = .
). The proportion of mechanical ventilation and admission to the intensive care unit (ICU) for supportive care was higher in patients with pulmonary infection than in patients without infection (P < .
). Although the GCS scores at the admission of children ( . , -) were similar to that of adults ( , -), the GCS scores at the discharge of adults ( , . -) were lower than that of children ( , . -; P < . ).

. Introduction
Japanese encephalitis (JE) is a kind of mosquito-borne viral encephalitis caused by the Japanese encephalitis virus (JEV) (1). JE is one of the most common viral encephalitis in Asia with 70,000 cases and 15,000 deaths every year. Approximately 30-50% of survivors have severe neuropsychiatric sequelae. China accounts for 50% of the reported . /fneur. . JE cases (2). Symptomatic patients occur in about 1 in every 250 patients with subclinical infection. The symptoms are mostly nonspecific prodromes, such as fever, headache, altered sensorium, and seizures (3). There is no specific treatment other than supportive therapy (4). Vaccination is still the most important method to prevent the disease. According to the early reports, children under the age of 15 were mainly affected in endemic areas (5,6). The morbidity of JE in adults increases year by year and gradually exceeds that of JE in children due to the vaccination of JE in children. In 2018, 64% of JE cases were adults in China, while 82% of cases were adults in Northern China (7). It is essential for us to comprehend the differences between adults and children with JE, which may enable us to provide better clinical plans to effectively deal with JE patients. There were few studies that demonstrated the differences in acute complications and short-term outcomes between adults and children in Northern China. To further understand the differences between adults and children, we compared and analyzed the clinical characteristics and short-term outcomes between both groups.
. Patients and methods

. . Patients
The retrospective study consists of 141 diagnosed JE cases of all age groups admitted from August 2006 to October 2019, who were admitted to two medical centers in Northern China, namely Shandong Provincial Hospital and Linyi People's Hospital. Out of the total 141 patients, the data of 107 patients were available ( Figure 1). The patients were grouped into the pediatric group (patients < 15 years old) and the adult group (patients ≥ 15 years old).

. . . Inclusion criteria
Patients who satisfied the clinical diagnosis and laboratory criteria.

. . . . Clinical diagnosis
The clinical diagnosis was based on the presence of clinical criteria of acute encephalitis syndrome (AES) (8,9), which were as follows: a person of any age, at any time of year, with the acute onset of fever that lasted less than 14 days, and a change in mental status and/or new onset of seizures (excluding simple febrile seizures).

. . . . Laboratory criteria
The laboratory criteria were as follows: (1) detectable JEspecific IgM in the cerebrospinal fluid (CSF) or serum, (2) evidence of seroconversion or a 4-fold increase of IgM or IgG in the convalescence phase by the ELISA method, (3) isolation of virus from blood, CSF fluid or tissue, or (4) detection of JE-virus genome in serum, plasma, blood, CSF, or tissue.

. . . Exclusion criteria
The exclusion criteria were as follows: (1) Patients who were not in the acute phase (patients who had a history of fever that lasted more than 14 days) (8,9). (2) Patients with a lack of medical records.
In total, nine patients in the subacute or chronic phase were excluded. Moreover, 25 patients were also excluded due to the unavailability of medical records (Figure 1).

. . Data collection
A review of medical charts was performed, including details of demographic data, initial clinical features, laboratory data, and imaging findings. In addition, acute complications and treatment were also collected in detail. Short-term outcomes were classified into two types according to the Glasgow Coma Scale (GCS) scores at discharge. Patients with a GCS score >8 at discharge were included in the good outcome (GO) group and those with a GCS score ≤8 or depending on mechanical ventilation were included in the poor outcome (PO) group (10).
The acute complications were also recorded in detail, as shown in Table 1    To further evaluate the influence of acute complications such as pulmonary infection, the patients were divided into two groups according to whether they had a pulmonary infection. The results are shown in Table 2. Dyspnea was more common in 13 patients with pulmonary infection (13/44, 29.5%) than in seven patients without infection (7/63, 11.1%; P = 0.016). Respiratory failure was more common in 13 patients with infection (13/44, 29.5%) than in four patients without infection (4/63, 6.3%; P = 0.001). Upper gastrointestinal bleeding was more common in 10 patients with infection (10/44, 22.7%) than in one patient without infection (1/63, 1.6%; P = 0.001). A total of 26 patients with infection (26/44, 59.1%) required mechanical ventilation, which was more common than in 12 patients without infection (12/63, 19%; P < 0.001). The GCS scores at admission in patients with pulmonary infection

. Discussion
We conducted the study to analyze the differences between children and adults with JE in clinical features and short-term outcomes. We found that convulsion was more common in children than in adults. Moreover, pulmonary infection was more common in adults than in children. Patients with pulmonary infection were more likely to develop other acute complications such as upper gastrointestinal bleeding and respiratory failure. In addition, patients with pulmonary infection required more mechanical ventilation and ICU support and had worse short-term outcomes. In our study, the proportion of immunotherapy was higher in children. The short-term outcome of adults was worse than that of children.
In this study, no significant difference was seen between both groups with JE in sex and endemic season. The proportion of male patients is higher than that of female patients, which is consistent with previous studies (12). JE cases were distributed mainly between July and October, especially in August and September, which was consistent with mosquito transmission season (7). It is necessary to take protective measures such as using bed nets. The initial clinical symptoms were flu-like symptoms including fever, altered consciousness, and headache. At the initial stage of JE, patients lacked typical clinical manifestations (10). The occurrence of convulsion in children was higher than that in adults (P < 0.001).
The result was consistent with other studies (13).
In addition to central nervous system (CNS) abnormality, other systems such as the digestive system and the respiratory system were also involved (14). In another study, a significant correlation between abnormal breathing and upper gastrointestinal bleeding was observed (15). Therefore, our study compared the acute complications between children and adults.
According to our study, the most prominent problems during the course of JE were pulmonary infection and other critical secondary complications which needed intensive care support (16). Septicemia was more common in children than in adults (P = 0.013). Septicemia is a type of bloodstream infection that causes significant morbidity and mortality. Septicemia was more common in children than in adults throughout the world (17). Moreover, respiratory failure, upper gastrointestinal bleeding, electrolyte disorder, and myocardial damage were also noted. Some complications such as upper gastrointestinal bleeding were related to prognosis (15). It is essential for us to note the complications of patients during hospitalization. To further analyze the influence of complications, the patients were divided into two groups according to whether they had a pulmonary infection. Patients with lower GCS scores at admission were attended to develop pulmonary infections. Dyspnea and respiratory failure were more common in patients with pulmonary infections. At the same time, patients with pulmonary infections needed more supportive care such as mechanical ventilation and ICU admission. The short-term outcome of patients with infection was worse than that of patients without infection (18). According to another study, abnormal breathing patterns predicted a poor outcome, which might explain the phenomenon that patients with pulmonary infection had worse outcomes. Thus, patients with JE require timely treatment of neurological symptoms and acute complications.
According to our study, serological results were noted. The elevated level of CSF protein in pediatric and adult patients in the present study conformed to the published article (19). A previous study found that CSF protein levels were related to neurological symptoms. This might suggest that abnormal intrathecal protein synthesis would lead to poor outcomes (10). The level of CSF leukocyte was higher in adults than in children, although the difference was not significant. The result was also consistent with a previous study. Nearly all patients with JE were lymphocyte predominant, which was accorded with other types of viral encephalitis (14). As for the blood examinations, we compared the levels of platelet, albumin, and creatinine. There were significant differences between both groups in platelet and creatinine. The abnormalities of the serum tests coincided with the previous articles (14).
A comparison of image findings was analyzed in the study. As mentioned in another study, the most common lesion areas were thalamic, basal ganglion, and midbrain in both groups with no difference (20). However, it is worth noting that the proportion of hippocampal damage was higher in adults. A study in Gansu Province found that the proportion of adaptive behavior impairments and intellectual disability in adults with JE was higher than that in children although there was no difference between both groups (21). The imaging results of the study may explain the difference. In addition, another study pointed out that the dynorphin system in the hippocampus was related to seizures. Seizures were more common in adults than in pediatric patients (14,22). However, the sample size was small, which needed further support study. Lesions of the temporal lobe were also observed in our study. Combined with epileptic symptoms, it is easy to confuse the diagnosis of herpes simplex encephalitis and JE (23), so it is necessary to detect other pathogens.
JE is a severe neuropsychiatric disorder with high morbidity and mortality, but there is no effective treatment. Vaccination against JE is important. According to another research, antiviral .
/fneur. . therapy combined with immunotherapy can reduce mortality due to severe JE (24). In the study, we compared the clinical course and treatments between both groups. The proportion of immunotherapy in children was higher than that in adults. Moreover, we compared the proportion of ICU admission and median days from symptom onset to ICU admission. The median days from symptom onset to ICU admission in adults were longer than those in children. It seemed that children with JE were more likely to be treated regularly.
Because of the large time span and the retrospective data collection, it was difficult to collect the long-term prognosis of patients after discharge. Some studies pointed out that the GCS score at admission was associated with mortality, and the GCS score at discharge had a certain statistical significance for the long-term prognosis (13,15). Therefore, we took the GCS score at discharge as the endpoint for the short-term outcome and hoped to predict the long-term prognosis.
In the study, the GCS scores at discharge in adults were lower than those in children, and the proportion of poor outcomes (PO) in adults was higher than that in children. In some studies, researchers tried to analyze the related factors of prognosis (13,25,26). As far as our study was concerned, we analyzed the possible reasons. First, mechanical ventilation in adults was more common than in pediatric patients. A study found that mechanical ventilation was associated with mortality. Another study pointed out that the proportion of poor prognosis in JE patients with mechanical ventilation was higher than that in patients without mechanical ventilation (16,27). Second, the time from onset to hospitalization in adults was longer than that in children, and the duration of treatment in adults was shorter than that in children. In a study, the illness for 7 days or more gave the best prediction of outcome (28). Third, children received more standardized immunotherapy and symptomatic supportive treatments than adults. Fourth, the number of participants in this retrospective study was relatively small.
Although this study confirmed that timely immunotherapy and symptomatic support therapy were effective methods for patients with JE, the cost and sequela were still difficult to improve. Vaccination is still an economical and effective method. According to the latest study of 1,570 cases, the rate of vaccination in children reached 31.3%, while the rate of vaccination in adults was only 0.3% (29). However, there was no significant difference in vaccination between pediatric and adult patients with JE in our study. It might be ascribed to the relatively small sample size. Thus, vaccination for adults should be initiated.

. Conclusion
The short-term outcome of adults was worse than that of children. The short-term outcome of patients with pulmonary infection was worse than that of patients without infection, which means pulmonary infection may be related to poor outcomes. Acute complications such as pulmonary infection should be treated timely in children and adults with JE. Adult patients with JE should be admitted to the hospital early. They also need timely immunotherapy and ICU supportive treatment. Furthermore, vaccination for adults should be initiated.

Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

Ethics statement
The studies involving human participants were reviewed and approved by the Ethics Institutional Review Board of Shandong Provincial Hospital. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

Author contributions
Material preparation, data collection, and analysis were performed by FZ, GX, and YL. The first draft of the manuscript was written by FZ. All the authors commented on previous versions of the manuscript. All authors contributed to the conception and design of the study. All the authors read and approved the final manuscript.

Funding
This study was supported by the National Natural Science Foundation of China [Grant Nos. NSFC82072079 and NSFC82001294].