The Epstein-Barr virus (EBV) is the most common herpesvirus in humans and the most common causative agent of infectious mononucleosis ¹ . It is also known as the “kissing disease” ² . EBV is an acute infection with a characteristic symptomatic triad of fever, sore throat and lymphadenopathy. Sprunt and Evans in 1920 coined the term infectious mononucleosis to describe an acute infectious disease accompanied by atypical large peripheral blood lymphocytes ² . EBV primary infection has recently risen in some countries ³ and children below 2 years of age are highly susceptible ^{4, 5} . EBV is transmitted primarily via oral secretions and may be transmitted via penetrative sexual intercourse ⁶ . Transmission may occur by the exchange of saliva among children. EBV is not spread by non-intimate contact, environmental sources, or fomites ⁶ . During late adolescence 50–70 percent of teenagers get infected with infectious mononucleosis ² . Though it has a self-limiting course, it may sometimes lead to numerous rare, atypical and threatening manifestations. The clinical manifestations in children with EBV infection involve multiple systems and can cause severe illness, meaning that attention should be paid during diagnosis and treatment. The diagnosis of EBV infection is based on clinical features such as- fever, pharyngitis, lymphadenopathy, hepatomegaly, and splenomegaly along with leukocytosis with a predominance of lymphocytes, >10% atypical lymphocytosis, heterophile antibodies (assessed via monospot test), PCR for EBV DNA and serological testing including antibodies for viral capsid antigens, early antigens, and Epstein-Barr nuclear antigen.

EBV DNA PCR has high specificity and sensitivity for identifying patients with infectious mononucleosis ⁷ .

Out of the total of 253 patients, 151 (60%) were male and 102 (40%) were female. The male to female ratio was 3:2 ( Figure 1).

The number of EBV DNA-positive cases observed increased each year. There were 36 EBV DNA positive cases in 2014 (total admissions, 7202) with a prevalence of 5.00 per 1000 admissions, 43 on 2015 (total admissions, 6163) with a prevalence of 6.98 per 1000, 77 on 2016 (total admissions, 7384) with prevalence of 10.43 per 1000 and 97 on 2017 (total admissions, 7972) with prevalence of 12.17 per 1000 admissions ( Figure 2, Figure 3).

Over the 4 years studied here, the numbers of hospitalized children were highest in the 0 to < 4 years group. Of 253 EBV-positive patients, 189 (74.70%) were in group 0 to less than 4 years, 28 (11.06%) in the group of children aged 4 to <6 years, and 36 (14.23%) in those aged 6 to <15 years. Each year, in the group of children under 4 years the percentage of EBV positive cases were more and rate were in increasing trend ( Figure 4, Figure 5).

We calculated the age-specific prevalence of EBV infection to identify the high-risk group. The number of positive cases was highest in the age group 6 months- <1 year, which decreased as age increased. Prevalence is also high in this age group ( Table 1 and Figure 6, Figure 7).

The incidence of EBV infection is higher in male children in Northern China ¹⁰ and Turkey ¹¹ . In India, the male to female ratio of EBV infection in hospitalized children is 2:1 ^{12, 13} . A Korean study found the overall male-to-female ratio of EBV infection to be 1.53:1 ¹⁴ . Our study had a male to female ratio of 3:2. During adolescence, women acquire before men the first infection by EBV ¹⁵ . In the US EBV antibody titers were significantly higher for females ¹⁶ .

We have found that in children under 4 years, the percentage of EBV-positive cases increased each year. However, in children aged 4–<6 years this decreased, but increased in those aged 6 to <15 years. Out of the 253 EBV positive patients, those aged under 4 years made up the highest proportion (74.7%). This drops to 11.06% in those 4–<6 years, and 14.22% in those 6–<15 years. In the study done on the Northern and Southern part of China, the seroprevalence of EBV infection is more than 50% before age 3 ² . Serological evidence of EBV infection is found in around 84% of Chinese children aged >9 years, with peak incidence observed at age 2–3 years ¹⁷ . However, in a study done by Gao et al., the incidence of EBV-IM peaked in children at age of 4–<6 years in Northern China ¹⁰ . In Taiwan, the seropositive rate of EBV is high in children aged 2 years ⁴ . A Danish study found that EBV infection is common in young children, and children under 3 years of age constitute the largest group of hospitalizations for acute EBV infection ⁵ . In a study conducted in Poland, age of infection occurred in two peaks, i) in children aged 1 to 5 years (62%), and ii) in teenagers (24.6%) ¹⁸ . In most developing countries nearly 70% of patients are seropositive for EBV by the age of 2 years ¹⁹ . However in USA, the seroprevalence increased with age, ranging from 54.1% for 6–8 year-olds to 82.9% for 18–19 year-olds ¹⁶ .

We found hospitalization for mononucleosis in all age groups. The number of positive cases was higher in the age group >6 months but <1 year, which decreases as age increases. The prevalence is also high on age group 6 month to 1 year. This indicates that the age group 6 months to less than 1 year is a high-risk group. The most common age group for hospitalization with acute EBV infection in Denmark was 1–2 years ⁵ . In Asia and other developing countries most of the children are infected with EBV in early life, mostly before the age of 1 year. ²⁰ . According to Cocuz et al., admissions for infectious mononucleosis were prevalent in young children, with most occurring in the 1–3 years age group (32.31% of the total IM Cases), followed by those 4–<6 years old (27.69% of the total IM Cases), then those 11–16 years old (26.15% of the total IM Cases) and finally those 7–10 years old (13.84% of the total IM Cases) ²¹ .

Several prior studies have reported in the last decade which shows the changes in the epidemiology of EBV infection. A Japanese study showed that the seroprevalence of EBV in 5–7 years old children was higher than 80% before the early 1990s which decreased to 59% in the years 1995 ²⁰ . Similarly in the USA, the study showed that the seroprevalence in 6–19 year olds declined from 72% in 2003–2004 to 65% in 2009–2010 ²² . But, the EBV primary infection is increasing in England and Wales ²³ . Therefore, we aimed to determine the epidemiological condition of EBV infection over the last years in the Pediatrics Department of Renmin Hospital, Shiyan, China. The EBV positivity rate in hospitalized children is increasing every year. Prevalence is also increased each year. In the years 2000 to 2016, the EBV infection rate in France has increased, whereas its seroprevalence has decreased ³ .

Although most EBV infections are self-limiting, sometimes they may lead to rare, atypical and threatening manifestations. Although serious complications during the acute phase of primary EBV infection are rare ¹ , neurological complications, like meningoencephalitis, acute encephalitis, acute cerebellitis, transverse myelitis, and myeloradiculitis, occur more frequently in children under 2 years of age ^{18, 24, 25} . Furthermore, in immunocompromised individuals, there was an association observed between EBV with several tumors following reactivation of the virus from latency ²⁶ .

Since this study was conducted in children admitted to hospital, the results might lack generalization to the entire population, but may indicate trends and bring up questions deserving further prospective study.

Increasing primary infection of EBV in children may be due to many reasons, including that the virus is active among the population around Shiyan, airborne transmission ²⁷ of the virus is higher in this area, multiple caregivers for each infant, bottle feeding, unnecessary kissing, feeding with chewed food to babies, or through hospital acquired EBV infection e.g. from health care personals, doctors or nurses. There are several reports on the intrauterine transmission of EBV, but none has been substantiated by appropriate viral studies ^{28, 29} . Besides, doctors may be more familiar and experienced with the clinical presentation, symptoms, and signs of infectious mononucleosis.

The next steps should be a focus on awareness to parents and caregivers of children, and development of a vaccine against EBV to reduce the burden of EBV infection in future.

The rate of hospital admission of children due to EBV infection is increasing. Children under 4 years of age are highly susceptible to infection and children of age between 6 months and 1 year are the high-risk group for EBV infection. Vaccination against EBV must be considered to reduce the burden of EBV infection in future.

The data referenced by this article are under copyright with the following copyright statement: Copyright: � 2018 Devkota K et al.

Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

Dataset 1. The number of total admissions and admissions of Epstein-Barr virus (EBV)-positive children under 15 years of age for each of the years 2014–2017. This dataset also contains stratifications of EBV-positive individuals by age and sex. DOI: https://doi.org/10.5256/f1000research.15544.d212141 ⁹ .