Keywords
Infectious mononucleosis; Prevalence; EBV DNA; Epstein–Barr virus
Infectious mononucleosis; Prevalence; EBV DNA; Epstein–Barr virus
We have tried to clarify some queries of reviewer and added few points:
See the authors' detailed response to the review by Anna Mania
The Epstein-Barr virus (EBV) is the most common herpesvirus in humans and the most common causative agent of infectious mononucleosis1. 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 lymphocytes2. EBV primary infection has recently risen in some countries3 and children below 2 years of age are highly susceptible4,5. EBV is transmitted primarily via oral secretions and may be transmitted via penetrative sexual intercourse6. Transmission may occur by the exchange of saliva among children. EBV is not spread by non-intimate contact, environmental sources, or fomites6. During late adolescence 50–70 percent of teenagers get infected with infectious mononucleosis2. 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), serum 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 mononucleosis7.
We retrospectively collected 253 EBV infection with serum EBV DNA positive cases from those who were symptomatically suspected as infectious mononucleosis from symptoms such as fever, pharyngitis, cervical lymphadenopathy and other lymph nodes enlargement on hospitalized patients <15 years old at Renmin Hospital, 3rd Affiliated Hospital of Hubei University of Medicine, Shiyan, (Hubei, China) during the 4-year period from January 1, 2014, to December 31, 2017. At birth, neutrophils make up around 61% of total leukocytes and lymphocytes make up around 31%. After birth, the number of neutrophils goes down and the lymphocyte number goes up, with both reaching about 45% around the 1st week of life. This process continues and by the age of 4 years, lymphocytes reaches around 50% and neutrophils reach around 42%. On growing older, the proportion of lymphocytes starts to fall and that of neutrophils start to increases. By the age of 6 years, the proportion of neutrophils reaches up to 51% and that of lymphocytes falls to 42%8. Owing to this age-specific leukocytes differential, we divided patients into three age groups: <4 years, 4–<6 years and 6–<15 Years. We also made further age-specific groupings, as follows: <30 days, 1–<6 months, 6–<12 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, and 14 years to find out the risk group for EBV infection. A diagnosis of EBV infection was achieved using real time PCR at the Pathology Department at Renmin Hospital.
Real-time PCR ABI iiA7 was used for quantitation of serum EBV DNA. The primers used, targeting the EBNA-1 fragment of EBV, were as follows: 5’-GTAGAAGGCCATTTTTCCAC-3’ (forward) and 5’-TTTCTACGTGACTCCTAGCC-3’ (reverse). PCR was conducted using the following thermocycling conditions: 93°C for 2 min, followed by 10 cycles of 93°C for 45 sec and 55°C for 60 sec, and then 30 cycles of 93°C for 30 sec and 55°C for 45 sec.
All data were analyzed using Microsoft Excel 2010. Age-specific prevalence was calculated. Prevalence was calculated as follows:
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 serum 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 China9 and Turkey10. In India, the male to female ratio of EBV infection in hospitalized children is 2:111,12. A Korean study found the overall male-to-female ratio of EBV infection to be 1.53:113. Our study had a male to female ratio of 3:2. During adolescence, women acquire before men the first infection by EBV14. In the US EBV antibody titers were significantly higher for females15.
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 32. Serological evidence of EBV infection is found in around 84% of Chinese children aged >9 years, with peak incidence observed at age 2–3 years16. 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 China10. In Taiwan, the seropositive rate of EBV is high in children aged 2 years4. 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 infection5. 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%)17. In most developing countries nearly 70% of patients are seropositive for EBV by the age of 2 years18. However in USA, the seroprevalence increased with age, ranging from 54.1% for 6–8 year-olds to 82.9% for 18–19 year-olds15.
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 years5. In Asia and other developing countries most of the children are infected with EBV in early life, mostly before the age of 1 year.19. 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)20.
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 199519. Similarly in the USA, the study showed that the seroprevalence in 6–19 year olds declined from 72% in 2003–2004 to 65% in 2009–201021. But, the EBV primary infection is increasing in England and Wales22. 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 decreased3.
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 rare1, neurological complications, like meningoencephalitis, acute encephalitis, acute cerebellitis, transverse myelitis, and myeloradiculitis, occur more frequently in children under 2 years of age17,23,24. Furthermore, in immunocompromised individuals, there was an association observed between EBV with several tumors following reactivation of the virus from latency25.
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 transmission26 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 studies27,28. 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.
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.d21214129.
We wish to thank Dr Li Lian Director of Pathology Department, Renmin Hospital Dr. Liu Zheng Mei, Dr. Ke Wei, Dr. Tian Cai Xia and entire staff of doctors and nurses at the Department of Pediatrics, Renmin Hospital.
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Is the work clearly and accurately presented and does it cite the current literature?
Yes
Is the study design appropriate and is the work technically sound?
Yes
Are sufficient details of methods and analysis provided to allow replication by others?
Partly
If applicable, is the statistical analysis and its interpretation appropriate?
Yes
Are all the source data underlying the results available to ensure full reproducibility?
Yes
Are the conclusions drawn adequately supported by the results?
Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Cardiology, Internal Medicine
Is the work clearly and accurately presented and does it cite the current literature?
Partly
Is the study design appropriate and is the work technically sound?
Partly
Are sufficient details of methods and analysis provided to allow replication by others?
Partly
If applicable, is the statistical analysis and its interpretation appropriate?
Yes
Are all the source data underlying the results available to ensure full reproducibility?
Yes
Are the conclusions drawn adequately supported by the results?
Partly
Competing Interests: No competing interests were disclosed.
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: infectious diseases, pediatrics
Is the work clearly and accurately presented and does it cite the current literature?
Partly
Is the study design appropriate and is the work technically sound?
Partly
Are sufficient details of methods and analysis provided to allow replication by others?
No
If applicable, is the statistical analysis and its interpretation appropriate?
Partly
Are all the source data underlying the results available to ensure full reproducibility?
Yes
Are the conclusions drawn adequately supported by the results?
Partly
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: infectious diseases, pediatrics
Alongside their report, reviewers assign a status to the article:
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