|Year : 2017 | Volume
| Issue : 5 | Page : 438-444
Infectious mononucleosis due to epstein-barr virus infection in children: A profile from eastern India
Madhumita Nandi1, Avijit Hazra2, Mrinal Kanti Das3, Subham Bhattacharya3, Uttam Kumar Sarkar4
1 Department of Pediatrics, NRS Medical College, Kolkata, West Bengal, India
2 Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India
3 Department of Pediatrics, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India
4 Department of Pediatrics, Dr. B. C. Roy Postgraduate Institute of Pediatric Sciences, Kolkata, West Bengal, India
|Date of Submission||11-Jan-2017|
|Date of Acceptance||16-Mar-2017|
|Date of Web Publication||14-Nov-2017|
6/6, Naren Sarkar Road, Kolkata - 700 008, West Bengal
Source of Support: None, Conflict of Interest: None
Objective: The objective of this study is to delineate the clinical and laboratory profile of infectious mononucleosis due to Epstein-Barr virus (EBV) infection in children admitted to tertiary care teaching hospitals. Materials and Methods: Retrospective observational multicentric analysis of clinical and laboratory features of children between 1 month to 12 years with a diagnosis of infectious mononucleosis due to EBV infection confirmed by positive serology over a 12-month period after seeking approval from the Institutional Ethics Committee. Results: Out of 66 children screened, 53 were included in final analysis. The majority were aged between 5 and 8 years with male: female ratio of 1.2:1. Most presentations were during the monsoon months. The common clinical features were fever (100%), splenomegaly (86.7%), and cervical lymphadenopathy (73.5%) in contrast to the classical triad of fever, sore throat, and generalized lymphadenopathy described in the literature. There were no age differences in clinical findings except for generalized and cervical lymphadenopathy and hepatomegaly which were commoner in 9–12 years age band. Although the incidence of common findings matched with previously published studies, there were some notable differences. While frequencies of upper eyelid edema, epitrochlear lymphadenopathy, and splenomegaly were more, those of rash and sore throat were less. Lymphocytosis and presence of atypical lymphocytes were relatively less common in our series. All children recovered. Conclusions: This multicentric study on profiling childhood infectious mononucleosis, possibly first of its kind from Eastern India, has documented clinical and laboratory features associated with this condition. These data can serve as a reference for future studies.
Keywords: Children, Epstein-Barr virus, India, infectious mononucleosis, lymphadenopathy
|How to cite this article:|
Nandi M, Hazra A, Das MK, Bhattacharya S, Sarkar UK. Infectious mononucleosis due to epstein-barr virus infection in children: A profile from eastern India. Med J DY Patil Univ 2017;10:438-44
|How to cite this URL:|
Nandi M, Hazra A, Das MK, Bhattacharya S, Sarkar UK. Infectious mononucleosis due to epstein-barr virus infection in children: A profile from eastern India. Med J DY Patil Univ [serial online] 2017 [cited 2019 May 19];10:438-44. Available from: http://www.mjdrdypu.org/text.asp?2017/10/5/438/218202
| Introduction|| |
Infectious mononucleosis is an acute self-limiting disease primarily caused by Epstein-Barr virus (EBV), a double-stranded DNA virus that is a member of the γ-herpesvirus family. Although the exact mode of transmission in children is not yet known beyond doubt, it is thought to be transmitted primarily through oral secretions. The clinical syndrome is characterized by prolonged fever, fatigue, sore throat, generalized lymphadenopathy, and hepatosplenomegaly. Hematologically, the disease is characterized by intensive lymphoproliferation with atypical forms. In fact, the name infectious mononucleosis was coined by Sprunt and Evans in 1920 to describe a syndrome that resembled an acute infectious disease accompanied by large atypical lymphocytes (called Downey cell) in peripheral blood. Many synonyms for the disease have been used, including glandular fever, monocytic angina, Pfeiffer's disease, Filatov's disease, and even kissing disease, but these are gradually being discarded. Symptoms generally resolve over a period of few weeks to months. Complications, though unusual, may occur in the acute stage in the form of meningitis, myocarditis, nephritis, pneumonia, hemophagocytosis, thrombocytopenia, and others. Associations of EBV with potential long-term sequelae, such as acute lymphocytic leukemia and malignant lymphoma, have also been reported.,
Barring case reports and small case series,,,, there is a dearth of studies profiling this disease from our country, especially from Eastern India, which is partly attributable to the relatively low incidence. Therefore, we planned a multicentric retrospective analysis of children admitted with a diagnosis of infectious mononucleosis over a period of 1 year, with the objective of profiling clinical presentation, laboratory findings, and complications of the disease in children of this region.
| Materials and Methods|| |
The case records of all children admitted to three tertiary care teaching hospitals of Kolkata, with features compatible with a clinical diagnosis of infectious mononucleosis, were screened retrospectively. Records of children admitted over a 1 year period (July 2015–June 2016) were included. Detailed data of children, aged between 1 month and 12 years, in whom the diagnosis of disease was confirmed by serology (IgM antibody against EBV viral capsid antigen [EBV VCA-IgM] positive by enzyme-linked immunosorbent assay testing, indicating recent primary infection) were entered in a structured case report form. The laboratory cutoff value of EBV VCA-IGM was >15 IU/L. Children in whom the serological diagnosis was confirmed but who presented with comorbidities (preexistent or concomitant) were excluded from the study.
In addition to demographic details and clinical findings, information on laboratory workup were extracted. These included complete blood count with peripheral smear to check for atypical lymphocytes. Leukocytosis was defined as total leukocyte count >12,000/μL, lymphocytosis as >50% of white cells lymphocytes, atypical lymphocytosis when >10% lymphocytes atypical. Platelet count <1,00,000/μL was noted as thrombocytopenia. Other laboratory and imaging investigation data included were liver function tests, prothrombin time, urine analysis, urine and blood culture, chest X-ray, and abdominal ultrasonography. Cerebrospinal fluid (CSF) analysis data were only available when central nervous system involvement was suspected. All these data were entered for each case at baseline. The blood count data at 2 weeks and 4 weeks follow-ups were also included. The study was approved by the Institutional Ethics Committee. As it was a retrospective analysis, a waiver of informed consent was granted by the Institutional Ethics Committee.
The data were entered into MS-Excel and then analyzed with Statistica version 8 (StatSoft Inc., 2007, Tulsa, Oklahoma, USA) and MedCalc version 11.6 (Mariakerke, Belgium: MedCalc Software, 2011) statistical software. Key proportions have been expressed with 95% confidence interval (95% CI) values. The analysis of variance test was used to calculate for differences between means of numerical data. Chi-square test was employed for intergroup comparison of categorical variables. P <0.05 was considered statistically significant.
| Results|| |
A total of 66 children were assessed for eligibility based on clinical features at presentation, out of which 53 were included for final analysis as depicted in [Figure 1]. The children were aged between 7 and 144 months (mean ± standard deviation 78.5 ± 6.05 months; 95% CI 68.8–88.2 months). The overall male:female ratio was 1.12:1. Most cases presented during July–September that is the monsoon months, as seen in [Figure 2].
The important age-wise symptoms and signs are delineated in [Table 1]. The most common symptom was fever which was present in all (100%). It was mostly high grade remittent in type and lasted from 7 to 25 days with a median duration of 12 days. A macular or maculopapular, nonpruritic rash was present in 17 (32.1%) children lasting from 2 to 7 days. It was associated with intake of amoxicillin or co-amoxiclav in 5 (9.4%) cases. Cervical lymph nodes were most commonly enlarged followed by epitrochlear lymph nodes. The enlargement was generally accompanied by local tenderness during febrile stage.
|Table 1: Clinical features of children with serologically confirmed infectious mononucleosis|
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Characteristic upper eyelid edema (described as Hoagland sign in literature) was present in 33 (62.3%) children. It mostly appeared within first 5 days of fever and disappeared by 4–5 days before resolution of fever. On age-wise analysis of clinical manifestations, only cervical lymphadenopathy, generalized lymphadenopathy, and hepatomegaly showed statistically significant variation, all being more common in the 9–12 years age group. Cervical lymphadenopathy was present in all children in this age band.
[Table 2] summarizes the age-wise distribution of important laboratory findings. Fourteen (26.4%) children had relative lymphocytosis, but only 9 (17%) had atypical lymphocytosis. Derangements of liver function were seen. Serum alanine transaminase was elevated in 15 cases (28.3%) while alkaline phosphatase was elevated in 8 (15.1%) children. Clinical jaundice (bilirubin >2 mg/dL) was noted in 10 (18.9%) children. CSF analysis was done in 13 cases with clinical suspicion of meningitis out of which 9 (17.0%) showed features of aseptic meningitis, the report being normal in rest four. None of the children had encephalitis, cranial nerve palsies, myocarditis, nephritis, or pneumonia. None had airway obstruction or features of shock.
|Table 2: Laboratory features of children with serologically confirmed infectious mononucleosis|
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Although thrombocytopenia was documented in 22 (41.5%) children, clinically significant bleeding was present in only 2 of them. There was no derangement of prothrombin time in any child. Among the two who had clinical bleeding, a 7-year-old boy had gum bleeding, and another 11-year-old girl had hematuria, ecchymosis, and major gastrointestinal bleeding, causing initial diagnostic confusion with acute leukemia. She had to be resuscitated with 4 units of packed red cells and 12 units of platelet transfusion. Hemophagocytosis developed in 2 children, both of whom could be salvaged by treatment according to standard protocol 2004 of Histiocyte Society Apart from lymphocytosis, which showed a higher prevalence in the preschool children, there were no statistically significant differences between the three age bands in frequencies of individual laboratory findings.
All children were discharged when their fever subsided and general condition improved with satisfactory oral intake and normal blood counts.
| Discussion|| |
We present here multicentric data on the demographic, clinical, and laboratory profile of children with a confirmed diagnosis of infectious mononucleosis due to EBV infection. Although there are some published case series from abroad and smaller ones from other parts of India, there is really an information gap on this topic in India. Since manifestations of infectious disease may vary with ethnic, socioeconomic, and environmental conditions, this retrospective analysis intended to delineate how similar or dissimilar infectious mononucleosis is in Eastern India compared to other parts of India and abroad.
We confined our analysis to serologically confirmed cases. Various tests have been used to confirm the clinical suspicion of EBV-induced infectious mononucleosis in addition to profiling the lymphoproliferation in peripheral blood smears. The traditional heterophile antibody test (monospot test) is now getting replaced by advanced serological tests to differentiate acute from chronic infection and differential diagnosis of EBV-induced infectious mononucleosis from similar clinical syndrome caused by human cytomegalovirus. The detection of IgM antibody to VCA is the most valuable and specific serologic test for the diagnosis of acute EBV infection and is generally sufficient to confirm the diagnosis.
Infectious mononucleosis is regarded primarily a disease of children and adolescents. [Table 3] compares some of the features of this study with that of studies published previously from India and abroad. The majority of patients in our series were in the age group 5–8 years, whereas Balasubramanian et al. reported maximum incidence in the 1–5 years age group from Southern India. Other series from Turkey, Korea, and Taiwan  have shown similar trends in age-wise incidence. Grotto et al. have reported on a large series of infectious mononucleosis affecting young adults (18–23 years) in Israel. We did not find any large gender difference in the incidence, but Son and Shin  from Korea noted an increasing female preponderance with age. We could delineate a seasonal variation, with most of our cases presenting during the rainy season when it is both hot and humid, followed by the summer months. Grotto et al. from Israel reported peak incidence during summer months, while Cengiz et al. from Turkey did not report any significant variation in the seasonal distribution of cases.
|Table 3: Comparison of clinical features and laboratory manifestations with some previously published studies|
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The classic triad of fever, sore throat, and lymphadenopathy is now considered to have relatively low sensitivity and specificity for EBV infection. Fever was the most common clinical presenting feature in our series, being present in 100%, followed by splenomegaly in 86.7%, and cervical lymphadenopathy in 73.5% cases. Balasubramanian et al. have also reported 100% incidence of fever from Chennai. Fever has been the most common presenting feature from other series also. The duration, pattern, and intensity of fever were broadly similar to other published series. Generalized lymphadenopathy has been described in 60%–80% of patients in published literature;,,,, we could find it in 56.6% of cases. Isolated cervical lymphadenopathy was more common in our series than generalized lymphadenopathy. Epitrochlear lymph nodes were enlarged in 54.7% cases as against 20% in the paper from southern India.
Some important differences with classical presenting features described in textbooks can be noted in our series. Sore throat, regarded as one of the components of the classical triad, was present in only 16.9% children of our cohort. Low incidence is also reported by other authors  although the Turkish study  has reported 72.7% incidence of tonsillopharyngitis on clinical examination. There was a higher incidence of splenomegaly in our series (86.7%), ranking second only to fever in the frequency-wise list of clinical features. Other series have reported incidence varying between 12% and 77%. The incidence of hepatomegaly was 64.1%. Chinese children with chronic active EBV infection were reported to have hepatomegaly in 81.1% cases and splenomegaly in 77.4% cases.
A relatively large proportion (62.2%) of children in our series developed upper eyelid edema (Hoagland sign); this sign has been described as a characteristic feature in literature, the incidence of which has varied from 11% to 42%. A Chinese study has reported it in 11.5% whereas the study from Taiwan reported it in 42% of children. However, many series, including the Chennai study, do not have any information on the incidence of this sign. As it appears in the early part of disease and remains for a few days only, it is prone to be missed unless one is aware and it is specifically looked for.
Overall, 32% of children had a rash, mostly generalized, nonpruritic, and maculopapular. It occurred following intake of amoxicillin in 9.4%, the reported incidence in previous publications varying from 11% to 60%. Gao et al. showed increased incidence of rash in children below 6 years. No such variation was discernable in this series.
There was no discernable age-wise variation of clinical findings except for generalized and cervical lymphadenopathy and hepatomegaly, all of which were common in the oldest age group. Other papers have noted some age specific variations. The incidence of rashes and organomegaly were higher in children below 6 years and tonsillopharyngitis higher in infants in the report from northern China. The Korean study  did not find any age specific predilection of signs and symptoms except for a headache which was more common in older children.
Regarding laboratory findings, while the incidence of anemia, leukocytosis, and thrombocytopenia matched with other publications, incidence of relative and atypical lymphocytosis, at 26.4% and 16.9% respectively, were substantially lower in our series than in previous reports. The incidence of thrombocytopenia was 41.5%. Two children had clinical bleeding out of whom one had severe life-threatening bleeding. While the reported incidence of thrombocytopenia varies between 5% and 50%, severe life-threatening bleeding is rare. In the Chinese series, out of 21 children who had thrombocytopenia, one suffered intracranial hemorrhage. The reduced platelet count in infectious mononucleosis is mostly self-limiting and does not need any specific intervention. Its exact cause is unknown; transient bone marrow defect, hypersplenism, or formation of platelet agglutinins have been suggested. The cause of severe thrombocytopenia in our case was probably peripheral destruction of platelets, as the bone marrow study done to exclude leukemia was suggestive of increased turnover. Facilities for measurement of antiplatelet antibodies were not available.
Derangements of liver function were noted in quite a few children. Clinical jaundice, albeit mostly mild, occurred in 18.9% children and asymptomatic elevation of liver enzymes occurred in 28.3% cases. Although clinical jaundice is infrequently reported, rise of liver enzymes is frequent in some other series. The Turkish study  reported elevated alanine aminotransferase and aspartate aminotransferase levels in 61.9% and 90.4% of patients who were investigated for these parameters.
Apart from lymphocytosis which was the most common in preschool children, we could not delineate any age-specific characteristics of laboratory features. The studies from Korea  and China  have shown a higher incidence of elevated liver enzymes in older age groups. The Turkish study  did not report any age-related variation.
Apart from thrombocytopenia, two instances of clinical bleeding and thirteen instances of meningitis, other clinically significant acute complications reported in literature, such as hemolytic anemia, acute interstitial nephritis, encephalitis, cranial nerve palsies, retrobulbar neuritis, mononeuropathies, myocarditis and cardiac conduction abnormalities and upper airway obstruction, were not documented in our series. Two children developed hemophagocytic lymphohistiocytosis (HLH) in the present series. The South Indian study  reported acute complications in 10 of 33 children, HLH and upper airway obstruction occurred in four each and septic shock in two. The Chinese series on EBV infection in children reported a relatively high incidence of complications including HLH (24.5%), interstitial pneumonia (24.5%), and hepatic failure (15.1%).
EBV is a ubiquitous virus that infects over 90% of the world population at some point in life. Although EBV infections are often asymptomatic, some patients present with the clinical syndrome of infectious mononucleosis, mostly within the first two decades of life. Patients usually present with fever and lymph node enlargement and physicians often presume that an antibiotic is required. In fact, there is no specific treatment for the disease and antivirals are probably of little use.
| Conclusion|| |
Our study should help to raise awareness regarding the possibility of this disease even in those who do not meet the typical textbook description of fever, lymphadenopathy and sore throat. Appropriate awareness can also reduce diagnostic confusion with more sinister clinical conditions like acute leukemia which it can closely mimic. Clinical triad of splenomegaly, epitrochlear lymphadenopathy, and Hoagland sign in a child with a prolonged fever (>7 days) may be diagnosed as IM with positive EBV-VCA IgM serology. A high index of suspicion and timely diagnosis will definitely help clinicians to avoid a battery of investigations and misuse of antibiotics in some cases of prolonged fever in children.
This study included only children attending tertiary care hospitals of Kolkata with a compatible clinical diagnosis. It may not be representative of the true spectrum of infectious mononucleosis in the community because only the more severe cases and cases with complications tend to get referred to tertiary care centers. Also, as this is a retrospective study, there was no scope of re-examining the patients to make sure that no relevant features or findings were missed. Moreover, as anti-VCA IgM was done only once at the time of presentation, it may be possible that some children although positive may not have been in the acute phase of infection. Follow-up serology would have overcome this limitation which was could not be done, this being a retrospective study.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]