Clinical features , pathological findings and outcome of children admitted to a tertiary care paediatric hospital with Epstein-Barr virus infection

Introduction: Epstein-Barr virus (EBV) infection most commonly manifests as acute infectious mononucleosis but is usually asymptomatic. Objective: To describe the clinical features, pathological findings and outcome of children admitted to a tertiary care paediatric hospital with EBV infection. Method: The study group included children who were admitted with various presentations of EBV such as dengue like illness, prolonged fever, myocarditis, encephalitis and haemophagocytic lymphohistiocytosis (HLH) over the last 3 years. Results: In our study, 16 (45.7%) children had a dengue like illness, 5 (14.3%) had myocarditis, 1 (2.9%) had HLH, 2 (5.7%) had encephalitis and 11 (31.4%) had prolonged fever. Conclusions: Dengue like illness and prolonged fever were the 2 most frequent presentations of EBV infection. DOI: http://dx.doi.org/10.4038/sljch.v46i3.8326 (


Introduction
Epstein-Barr virus (EBV) is a gamma herpesvirus 1 .It commonly manifests as acute infectious mononucleosis affecting adolescents and young adults 1 .In young children EBV is usually asymptomatic or mild 1 .EBV is rarely associated with lymphoproliferative disorders and tumours such as nasopharyngeal carcinoma and Burkitt lymphoma 2 ._________________________________________ 1 Chittaranjan Seva Sadan, India *Correspondence: abu89.cmc@gmail.com(Received on 06 December 2016: Accepted after revision on 20 January 2017) The authors declare that there are no conflicts of interest Personal funding was used for the project.Open Access Article published under the Creative

Objective
To describe the clinical features, pathological findings and outcome of children admitted to a tertiary care paediatric hospital with EBV infection.

Method
The study group included children who were admitted to the Chittaranjan Seva Sadan hospital, a tertiary care paediatric hospital in India, with various presentations of EBV such as dengue like illness, prolonged fever (>7 days), myocarditis, encephalitis and haemophagocytic lymphohistiocytosis over the last 3 years.We suspected EBV infection in the following categories of patients: 1. Patients having fever, rash, anasarca, with or without serositis and bleeding or thrombocytopenia and shock where all investigations including blood culture, dengue and chikungunya serology were found to be negative.

Results
Dengue like illness was diagnosed in 16 patients.The ages ranged from 9 months to 12 years.We excluded dengue fever by sending Dengue Ns1 and Dengue RT-PCR (before 5 days) and Dengue IgM antibody (after 7 days).The clinical and features of the 16 patients are shown in Table 1.The 7 patients whose haemoglobin was below 7g/dl were given packed cell transfusion with 15ml/kg of packed red blood cell (PRBC).The 9 (56%) children who needed no transfusion of PRBC, in the second week of admission showed some rise in the haemoglobin level.Of the 12 (75%) patients with low platelet counts, in 9 cases the platelet counts were elevated spontaneously above 150,000/cu mm in the second week.Platelet transfusions were given if the platelet was below 10,000/cu mm or below 40,000/cu mm with active bleeding.In fact, 3 (18.7%)patients needed platelet transfusions.Of the 04 (25%) patients with leucopenia, 3 had neutrophilic dominance.Pancytopenia (Hb<10g/dl, WBC <4000/cu mm, platelet <150,000/cu mm) was detected in 03 (18.7%) patients.Of the 7 (43.7%)children with raised serum glutamic pyruvic transaminase (SGPT) on admission, only one case had elevation of SGPT in the second week.Echocardiography was normal in all patients.Patients were treated with Ringer lactate solution 4-20 ml/kg depending on packed cell volume (PCV) and vital signs.All recovered without sequel except one who later developed features of encephalitis.
Two patients presented with encephalitis.Both were female, aged 9 years and 12 years respectively.They presented with a history of fever, rash and altered sensorium.The first one had generalized tonic clonic seizures (GTCS) on day 6 and the second one had GTCS on day 10.Both had hepatomegaly but splenomegaly was present in only one patient.One patient had cervical lymphadenopathy.Both had low haemoglobin and low platelet levels but in the second week the haemoglobin and platelet counts were raised.Both patients had normal white blood cell counts.SGPT was persistently increased in both patients.Cerebrospinal fluid (CSF) of the first patient was normal but the second patient had lymphocytic pleocytosis with normal protein and sugar.Magnetic resonance imaging (MRI) showed cerebral oedema in the first child but could not be done in the second child.Electroencephalograms (EEGs) and echocardiograms of both patients were normal.They were managed conservatively and treatment of raised intracranial pressure was given.First patient recovered but second patient expired after the 16 th day of fever.
One male patient, aged 2 year and 3 months, presented with fever and rash on day 5, hepatosplenomegaly and cervical lymphadenopathy.Initially complete blood count was normal and the erythrocyte sedimentation rate (ESR) was raised.In the 2 nd week pancytopenia occurred and ESR decreased along with high serum ferritin and triglyceride levels.The bone marrow showed haemophagocytosis and a diagnosis of HLH was made.Treatment was given with dexamethasone 10mg/m 2 and gradually tapered over 3 months along with etoposide.
Five patients presented with features of myocarditis.The ages ranged from 9 months to 1 year and 8 months.The clinical and laboratory features of the 5 patients are shown in Table 2.In the 2 nd week the Hb and platelet levels normalised without transfusion.Sinus tachycardia was noted in the electrocardiograms (ECGs) in all patients and in 01 (20%) patient ST segment elevation was noted.Cardio-thoracic ratio in X-Ray was increased in all patients.All patients had very low ejection fraction varying from 20% to 40%.Inotrope support, immunoglobulin and other conservative managements were given.Three (60%) of them needed ventilator support.Out of five patients 04 (80%) patients recovered but one died.Three of them were given dopamine and levosimendan.Two were treated with dopamine and milrinone.
Eleven patients between ages of 1 year to 12 years presented with a history of prolonged fever (>7 days).The clinical and laboratory features of the 11 patients are shown in Table 3.One patient had inguinal abscess and one had knee and elbow abscess and these were drained.Of the 9 patients with low Hb at presentation, there was an increase in 8 of them in the 2 nd week.While the platelet counts were initially low in 4 patients, they increased spontaneously in the 2 nd week.Other investigations for fever (blood, urine, throat culture, antinuclear antibody, rheumatoid factor, dengue (NS1, IgM), typhidot IgM, Mantoux test, Gastric lavage for cartridge based nucleic acid amplification test (CBNAAT), human immunodeficiency virus (HIV) serology, echocardiograph, ultrasonogram of abdomen were negative.All patient recovered with conservative management.Maximum duration of fever was twenty-nine days.

Discussion
EBV infected patients generally present with fever, headache, sore throat, nausea, abdominal pain and myalgia 4 .In our study, 16 (45.7%)had a dengue like illness, 5 (14.3%) had myocarditis, 1 (2.9%) had HLH, 2 (5.7%) had encephalitis and 11 (31.4%) had prolonged fever.Dengue like illness has been reported with other viruses such as chikungunya, but never with EBV.Neurological manifestations are seen in less than 1% of EBV infection 5 .Among these, meningitis and encephalitis constitute the most common types of neurological manifestations.The patients may have varied symptoms like fever, seizure, bizarre behaviour, headache, and metamorphopsia 6 .The presenting signs included altered consciousness, meningeal signs, bulbar signs cerebellar signs and cranial nerve palsy 7 .Two of our cases who presented with encephalitis had altered sensorium with rash, GTCS and altered sensorium.Meningeal signs and cranial nerve palsy were not noted.MRI showed diffuse cerebral oedema in one case who had normal EEG and CSF.The other child whose CSF showed lymphocytic pleocytosis, progressed to deep coma and expired and MRI could not be done.
One of our patients presented with fever, rash and hepatosplenomegaly with normal complete blood count but in the 2 nd week developed pancytopenia, elevated serum ferritin and triglyceride levels and the bone marrow showed haemophagocytosis.He was diagnosed as HLH and treated with dexamethasone and etoposide.In EBV induced HLH, there is a deficiency in producing EBV specific cytotoxic T cells due to infected primary CD8+ cells, suggesting an impaired or absent function of NK cells and cytotoxic T cells 8 .These cytotoxic T cells are needed to regulate EBV infected B cells.Due to poor regulation of B cells there is persistence of EBV infection.Thus, there is a sustained immune response with persistently high pro-inflammatory cytokines levels (such as interferon γ, tumor necrosis factor α, interleukin 6, 8, 10, 16, 18, and macrophage colony stimulating factor) leading to haemophagocytosis and multi organ failure 9,10 .
Significant cardiac involvement in infectious mononucleosis is extremely rare.Tachycardia is the rule.
The most common changes in electrocardiogram (ECG) are abnormalities of the ST segment and as seen in one patient.Myocarditis caused by EBV infection may become fatal in young patients, especially in children.EBV can cause one single episode or repetitive myocarditis resulting either in congestive heart failure 10 or in complete heart block 12 .We had 5 cases of EBV-induced myocarditis with elevated cardiac enzymes, left ventricular hypokinesia with low ejection fraction (EF) (20% to 40%).Four out of five patient recovered but one patient died.Eleven patients presented with a history of prolonged fever (>7days).Whilst hepatomegaly was present in 91% of them, rash was present in only 45%, splenomegaly in 63% and lymphadenopathy in 54%.All patient recovered with conservative management.In EBV infection generalized lymphadenopathy (90%), splenomegaly (10%) hepatomegaly (10%) are seen 4 .In our study, lymphadenopathy was present in 42.8%, splenomegaly in 34.2% and hepatomegaly in 91.4% cases.