Abstract

Author summary

Citation: Wang R, Wang X, Zhang L, Feng G, Liu M, Zeng Y, et al. (2022) 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 16(7): e0010562. https://doi.org/10.1371/journal.pntd.0010562

Editor: Marilia Sá Carvalho, Fundacao Oswaldo Cruz, BRAZIL

Received: January 11, 2022; Accepted: June 3, 2022; Published: July 5, 2022

Copyright: © 2022 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript.

Funding: National Natural Science Foundation of China (No. 82002130), Beijing Natural Science Foundation (No. 7222059), and the Open Research Fund Program of the State Key Laboratory of Virology of China (No. 2021IOV002) were awarded to R.W. The CAMS Innovation Fund for Medical Sciences (No. 2019-I2M-5-026) was awarded to ZDX. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Flaviviridae constitutes a large viral family that includes highly relevant human clinical pathogens. The genera Flavivirus, including Japanese encephalitis virus (JEV), dengue virus (DENV), and yellow fever virus (YFV), and the genus Hepacivirus, including hepatitis C virus (HCV), are classified into the same family Flaviviridae. These viruses comprise a group of small enveloped, positive-stranded RNA viruses that represent global public health problems.

JEV is mainly distributed in Asia, the Western Pacific, and Northern Australia through Culex mosquitoes as vectors. Japanese encephalitis (JE) caused by JEV infection is a preventable disease. From the inactivated vaccine, which has been available since the 1950s, to the live attenuated vaccine SA14-14-2, which has already been widely used in China and many Asian countries for many years, the two types of vaccines significantly reduced the incidence of JE. An estimated 67,900 JE cases occur worldwide annually, half of which are located in China [1]. Twenty years ago, approximately 75% of JE patients were children aged 0–14 years, whereas adults were generally considered immune because they had experienced at least one natural infection [2]. The JE fatality rate is 20–30%, and 30–50% of survivors suffer from permanent and irreversible neuropsychiatric sequelae, which have placed a heavy burden on the public health system and society [3]. Therefore, JE has become a public health issue of international concern [4]. According to model estimates, 0.8% to 5.2% of children are naturally infected with JEV each year. However, these findings may be more severe in countries and regions where JEV vaccination is not yet included in the national vaccination program [5]. In China, although a decrease in cases among children has been observed since the Expanded Program on Immunization (EPI) was established in April 2008, sporadic and localized outbreaks are still reported frequently [6]. Correspondingly, children remain an at-risk population [5].

Dengue is one of the most common infectious diseases resulting from mosquito-borne flaviviruses and is also the fastest spreading tropical disease worldwide. DENV is prevalent in southern and central China [7]. There are also some imported cases (indigenous cases that have not been reported in some years) due to the high incidence of dengue in the southern border of China or other tropical and subtropical countries [8, 9]. Dengue has no significant susceptible age, and people of all ages are generally susceptible. Dengvaxia, the only commercial vaccine against dengue, has been licensed in more than 20 endemic countries, but it still faces difficulties given its safety profile and immunogenicity. The WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) is only recommended for people aged 9–45 years old [10]. The vast majority of dengue cases occur in children under the age of 15 years [11], and the clinical spectrum ranges from asymptomatic or mild febrile illness to life-threatening hemorrhagic fever syndrome [12]. Especially in the absence of protective vaccines and targeted treatment, children are at high risk of severe dengue [13].

YFV is the first proven human-pathogenic virus, and it remains a serious public health threat in endemic countries. In contrast to JE and dengue, yellow fever (YF) remains an imported disease in China. On March 12, 2016, the first imported case of YF was confirmed by the Chinese Center for Disease Control and Prevention (CDC). There is no evidence of local transmission of YFV in China to date [14]. Most imported cases originate from Africa and South America, which unmasked the low YF vaccination coverage among Chinese travelers and workers to Africa; however, the effectiveness of the YFV-17D vaccine has been sufficiently confirmed [15]. Descriptions of the disease burden among imported pediatric cases in China are limited.

Hepatitis C (HC), an important infection-induced inflammatory liver disease, is caused by HCV (family Flaviviridae, genus Hepacivirus) transmission through the blood. The disease is extremely insidious and progresses slowly. Eighty percent of infected individuals can progress to chronic hepatitis C (CHC), and some patients may further develop cirrhosis or even liver cancer if timely treatment is not provided. HC is now classified as a category B notifiable infectious disease in China [16]. According to the World Health Organization (WHO) report, approximately 250 million people worldwide are infected with HCV, of which 3.26 million are children (0–18 years old) [17]. The prevalence of HC increases with age. China is a country with a moderate disease burden for HC [18], and the incidence rate of HCV infection related to transfusion or blood products (invasive medical procedures) has been dramatically reduced due to the implementation of mandatory blood transfusion screening of transfusion recipients since 1993 [19]. In addition to transfusion, 4–10% of HCV infections can be acquired via mother-to-fetus transmission, which is also the most common transmission route of acquisition for children [20]. In contrast, transmission through casual contact is infrequent [21]. Most infants can clear HCV spontaneously. HCV infection in patients during childhood is typically asymptomatic and slowly progressing, and serious complications rarely occur [22]. Nevertheless, HCV infection acquired through vertical transmission in children still has the chance to develop into CHC, end-stage liver disease, and even hepatocellular carcinoma in adulthood without efficient treatment. At present, direct-acting antivirals (DAAs) are an effective method to cure HCV infection [23, 24]. The disease burden of HCV infection in adults and at-risk populations has been fully reported, whereas the available data on the pediatric burden of HC are limited.

Children infected with the aforementioned Flaviviridae virus are more likely to be hospitalized than adults. However, hospitalized children’s epidemiological and economic burdens have not been described in detail. The electronic medical system of Chinese hospitals has generated a huge amount of medical data. The massive amounts generated during the patient’s hospitalization are mainly unstructured data; among these, face sheets of discharge medical records (FSMRs) comprise big data with the highest degree of standardization, the easiest feature for data-mining, and the most evidence-based medicine value. This study is based on a national pediatric patient database of China, including multicenter, observational, cross-sectional studies of 27 pediatric hospitals, to ensure geographic representation and reduce bias to truthfully and objectively describe and analyze the most common epidemiological characteristics, clinical phenotype, length of stay (LOS), expense (in US dollar terms, USD) and potential risk factors for hospitalized children infected with any virus within Flaviviridae (JEV, DENV, YFV and HCV) in Chinese pediatric hospitals. The data obtained can provide important support for the evidence-based Chinese pediatric Flaviviridae virus infection and the prevention policy and strategy for the pediatric population and help evaluate the effectiveness of the prevention and treatment of infection with the virus of the family Flaviviridae in the Chinese population.

Methods

Results

Discussion

The data of this study show that JEV is the virus within the family Flaviviridae that poses the greatest threat to children’s health and leads to the heaviest disease burden among the four viruses in mainland China. In 2004, the WHO report described that JE had overtaken dengue fever as the most important arbovirus disease with a global disease burden [26]. The symptoms, disability, and even death caused by JEV infection are more serious than those of any other arthropod-borne virus. Moreover, no specific treatment is currently available.

Regarding the epidemiological characteristics of JE, our research is consistent with mainstream findings.

First, JE mainly occurs in children under 14 years old [27], and the age of the at-risk population presents an increasing tendency [5, 28]. The results of this study showed that children aged 7–15 years accounted for approximately half of the total number of hospitalizations, which might also be related to the waning positive rate of neutralizing antibodies with age. Previous papers noted that even for children who were completely vaccinated with two shots of JE vaccines, only 25% of vaccinees were positive for JEV neutralizing antibodies (nAbs) at 7.5–8.5 years (age 9.5–11.5 years) after vaccination, and the titer was low [28]. The nAbs continued to decline to lower levels in adulthood [29]. Thus, the use of the third booster shot (the fourth to fifth booster shots of inactivated vaccines) before the age of 18 may further increase the titers of nAbs and should be taken into consideration in policy formulation. The illnesses of children aged 1–3 years were more serious than those of older patients. As previously reported, children with immunocompromised systems had severe clinical symptoms and sequelae [30, 31].

Second, JEV is prevalent in all regions of China. Currently, only Xinjiang, Tibet, and Qinghai have not included JE vaccination in the provincial EPI. The sentinel hospitals covered by the FUTURE database are spread across seven geographic regions. Hospitalized cases have been reported in east, central, southwest, northwest, and north China, of which east China reported the largest number of hospitalized cases. JE remains a disease with high incidence in rural areas, although sporadic cases have been reported in cities and suburbs [32]. In general, JEV is more likely to spread in environments with poor hygiene, such as rural areas, where mosquitoes and swine are more numerous. Therefore, we described the epidemiology and disease burden of hospitalized children based on the place of residence [33].

Third, most JE patients were asymptomatic or had mild [34]; thus, the hospitalized cases included patients with more severe symptoms. Our data showed that patients with severe symptoms were predominant (68.06%). In addition, we also determined for the first time that the main complications of hospitalized children with JE were pneumonia and respiratory failure, and the causes of death included brain hernia and encephaledema.

Fourth, the economic burden assessed in this study was derived from data-directed medical costs from hospitals’ billing systems, i.e., inpatient costs (including patient out-of-pocket medical costs). In general, the number of hospitalizations, hospitalization rates, and mortality of children with JE have significantly improved, suggesting that the existing prevention and control policies and treatment methods are effective. There are few reports on the burden of JE disease in children, especially research on age restratification. We calculated a median LOS of 15 days and costs of 7,504.79 USD in this study. In a longitudinal comparison, children who were clinically defined as having severe JE have a lower expense. It is hypothesized that the largest number of children with severe symptoms and the longest span of hospitalization expenditure may set the median apart from other categories where the numbers of cases are far less than severe JE. However, the real reason needs to be explored in depth. In addition, in the horizontal comparison of the four viruses within the family Flaviviridae, JEV infection caused the longest hospitalization LOS and the highest economic burden, indicating that the disease burden caused by JE on children remains the greatest among several common infections with viruses within the family Flaviviridae in mainland China. Nevertheless, the data suggest the importance of JE vaccination, routine surveillance, and infection control in rural children.

Since 1978, dengue has become indigenous in China every 4–7 years with a high incidence in people between 20 and 60 years old. The incidence in males and females was similar with mild disease predominantly noted [35]. The dengue epidemic in China is not only indigenous but also imported, which is similar to JE, but there are still more cases of indigenous people than individuals [36, 37]. Imported dengue cases that occur in waves in southeast Asia can also be secondary to indigenous dengue fever in different regions of China [9]. Due to geographical, topographic and climatic characteristics, the majority of dengue cases in China are concentrated along the southwest border of Yunnan and through the Pearl River Delta [38]. In 2019, a dengue outbreak occurred in mainland China, affecting 13 provinces with a total of 15,187 indigenous cases. The number of cases in this epidemic was more than the annual number of cases during 2005–2018 (except for 2014) [39]. The spatial distribution of indigenous cases was not only located in the provinces with occasional reports on the southwest border, such as Yunnan, Guangdong, Fujian, Zhejiang, South China, and the southeast coast [40–42] but also in provinces with previously few reports, such as Hunan, Jiangxi, and Chongqing [39]. Our statistics showed that 78.57% of cases were hospitalized in 2019, and most of these cases were distributed in the southeastern coastal region and south and central China. The spatial and temporal patterns and clinical features are consistent with the epidemiological background.

Markedly, most cases were found from August to October, although the hospitalizations were limited, which corresponds with the temporal feature of the peak period of indigenous incidence (September and October) [41]. However, the low hospitalization rate induced by dengue suggests that the impact of the dengue epidemic on children remains under control in China. Furthermore, we also present the disease burden of hospitalized children with dengue. Nevertheless, given the limited number of cases, it is difficult to discuss the impact of factors, such as age, gender, ethnicity, and residence, on disease burden.

As the first proven human-pathogenic virus, YFV remains a major public health problem, and an upsurge was recently noted. Fortunately, the YFV-17D vaccine still has protective immunity against circulating strains [43]. This article summarizes the relevant information and disease burden of three confirmed YF cases imported from Africa into China, highlighting the potential transmission of YFV through Asia. Nevertheless, YF is an imported disease [44]; hence, the potential and ever-present public health threat to children caused by international exchanges should not be ignored.

HC is the only viral infectious disease of the genus hepacivirus in this study. HCV infection has become the second-largest type of viral liver disease in China after hepatitis B virus infection [45], posing a huge threat to public health. Children are susceptible to HCV without a gender preference. However, due to transfusion and blood product control, most children with HCV are infected by vertical transmission with a probability of ~5% [46]. Forty percent of pediatric patients who acquire HCV through vertical transmission can clear the virus spontaneously, even in the absence of special treatment until they are 2 years old, and the chance of clearance is greater than that of adults [47]. Studies have noted that the 0–19 y population has the lowest incidence among all age groups [48]; thus, we conducted statistical analysis by further age stratification of the children. The HC hospitalization rate in the 1–3 y group was the highest, reaching 42.11%, followed by the 4–6 y group with a rate of 36.84%. The onset of HC in children is insidious, and the symptoms are generally mild, which causes the number of HCV infections to be seriously underestimated [49]. CHC is also common in pediatric patients, and the possibility of spontaneous recovery from CHC is very low. However, the liver disease of CHC children is usually mild, and there is less evidence suggesting the development of fatal hepatitis and cirrhosis [50].

The results of this study showed that mild chronic HC was the main type of clinical manifestation in hospitalized children (57.89%), and acute anicteric patients accounted for 31.58% of cases. The median LOS of all hospitalized children was 4 days, which is consistent with the clinical characteristics of HCV infection. In addition, 1 out of 19 children with HC had myocardial damage, and HCV involvement in the development of myocarditis has also been reported previously [51]. In terms of geographical distribution, it was noted that the high-prevalence areas of HCV are concentrated in central, south, northwest, and northeast China [52]. We found that the reported hospitalized cases of HCV were also mainly distributed in northwest (47.37%) and central China (36.84%). Currently, there are no safe and effective vaccines or antiviral drugs against HCV available for children [53, 54]. In particular, the most significant hurdle to develop an HCV vaccine is the high mutation rate of the virus, facilitating its ability to escape the host immune response [55].

There are some limitations to this study. 1) Although the FUTURE database contains FSMRs from 27 children’s hospitals distributed in seven geographic regions of China, here we only retrieved and report the cases as a result of infection with any virus within the family Flaviviridae, and the hospital admissions induced by imported or indigenous infection with Zika virus, tick-borne encephalitis virus, and West Nile virus have not been recorded in the FUTURE database in the past five years. Moreover, although there are indigenous and imported JE and dengue cases, we failed to confirm the etiological types of 454 JE cases and 14 dengue cases via FSMRs. 2) Given that most cases of flavivirus infection (especially JEV and DENV) are asymptomatic or exhibit a mild clinical manifestation with an imperceptible onset, most patients are usually treated during an outpatient procedure. Therefore, the number of reported hospitalized cases in this study should theoretically be much lower than the actual number of infected cases. Thus, the data only represent the real-world situation of some hospitalized patients. However, given the rapid development of the FRCPD monitoring system and the FUTURE database, the influence of this bias on future research will be gradually weakened. 3) JE and YF are vaccine-preventable diseases, but FSMRs do not record the vaccination history of hospitalized children. 4) The burden of hospitalization is disproportionately shared across regions of China due to perceived socioeconomic disparity. 5) Data on the long-term follow-up of inpatients were not collected.

Conclusion

In summary, we combed through the FUTURE database, which includes data from 27 children’s hospitals in China, and described the general epidemiological characteristics and burden of hospitalized children infected by any virus within the family Flaviviridae (JEV, DENV, YFV and HCV). This information will help to better understand the spatial and temporal distribution of flavivirus infections and aid in the timely detection and prevention of indigenous transmission and outbreaks. The findings are also conducive to formulating targeted prevention and control strategies and monitoring, optimizing the allocation of prevention and control resources, and implementing effective public health prevention and control measures in China.

Acknowledgments

We are grateful to investigators from members of the Futang Research Center of Pediatric Development (FRCPD).

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