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Case Report
Case of Chronic Active Epstein-Barr Virus Infection Developed Hemophagocytic Lymphohistiocytosis after COVID-19 Infection
Clin Pediatr Hematol Oncol 2023;30:80-4.
Published online October 31, 2023
© 2023 Korean Society of Pediatric Hematology-Oncology

Sumin Jo, Hye Lim Jung, Sooyeon Lim, Eun Sil Kim, Aram Yang, Ji Hee Kwak, Deok Soo Kim, Jung Yeon Shim and Jae Won Shim

Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
Correspondence to: Hye Lim Jung
Department of Pediatrics, Kangbuk Samsung Hospital, 29 Saemunanro, Jongro-gu, Seoul 03181, Korea
Tel: +82-2-2001-2208
Fax: +82-2-2001-1922
E-mail: hl.jung@samsung.com
ORCID ID: orcid.org/0000-0003-0601-510X
Received August 31, 2023; Accepted October 12, 2023.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
In children, prolonged primary Epstein-Barr virus (EBV) infection or reactivation may lead to the development of T or natural killer cell lymphoproliferative disorders, classified as chronic active EBV infection (CAEBV). CAEBV is a prolonged systemic illness lasting beyond three months, with elevated EBV DNA levels in the serum or affected tissue and a lack of underlying immunodeficiency. Notably, EBV is the most common virus that induces secondary hemophagocytic lymphohistiocytosis (HLH), and Coronavirus disease 2019 (COVID-19) has been reported to trigger HLH. We present the case of a 20-year-old Korean male who was diagnosed with CAEBV and developed HLH after being infected with COVID-19. The patient met 7 out of 8 criteria for HLH. Following treatment with corticosteroids and intravenous immunoglobulin, the patient recovered from HLH without additional chemotherapy. HLH treatment should be tailored to each patient based on clinical presentation and disease severity. Prolonged and regular evaluation for developing HLH or lymphoma is necessary for patients with CAEBV.
Keywords: Epstein-Barr virus infections, Chronic active Epstein-Barr virus infection, Hemophagocytic lymphohistiocytosis, COVID-19
Introduction

Epstein-Barr virus (EBV) is a common virus affecting more than 95% of the world’s population. EBV infects tonsillar B lymphocytes via saliva, replicates to induce viremia, and disseminates to the peripheral blood and reticular lymphoid organs, including the liver and spleen [1]. After approximately six weeks of incubation with polyclonal T lymphocyte activation, the host immune response causes EBV-specific CD8 T lymphocytes and natural killer (NK) cell expansion. In children, the initial EBV infection is typically unnoticed or produces mild symptoms [2]. However, approximately 30-50% of teenagers and young adults who experience primary EBV infection develop infectious mononucleosis (IM), a clinical syndrome characterized by fever, fatigue, pharyngitis, lymphadenopathy, and sometimes hepatitis [1].

Furthermore, EBV is the initial virus related to the progression of malignant diseases, such as Burkitt’s lymphoma, Hodgkin’s lymphoma, and nasopharyngeal carcinoma, and is rarely associated with chronic active EBV infection (CAEBV) and T/NK cell lymphoma [1-3]. Specifi-cally, CAEBV is a prolonged and severe systemic EBV infection, which, per the 2016 World Health Organization classification, is classified as an EBV-positive T- or NK- lymphoproliferative disease [3]. Without proper treatment, severe life-threatening diseases such as hemophagocytic lymphohistiocytosis (HLH), disseminated intravascular coagulation, and lymphoma are more likely to occur in patients with CAEBV [4,5].

HLH is a critical hyperimmune state, resulting in excessive production of serum cytokines and multiorgan failure [6,7], and can be divided into primary HLH, which occurs because of genetic factors, or secondary HLH, when caused by factors such as infections, malignancies, and rheumatic diseases [6-8]. Moreover, EBV is the most common virus responsible for secondary HLH [8].

We report a case of HLH caused by COVID-19 infection in a patient diagnosed with CAEBV, who was successfully treated with corticosteroids and intravenous immunoglobulin (IVIG).

Case Report

In June 2022, a 19-year-old Korean male was admitted to our hospital with a two-month history of recurrent fever, fatigue, widespread lymph node (LN), and spleen enlargement. His EBV-related blood tests revealed an elevated EBV DNA titer of 515,000 copies/mL (reference range: <125 copies/mL). The EBV antibody titer increased, with IgG to the viral capsid antigen (VCA) of EBV >750 U/mL and IgG to EBV nuclear antigen (EBNA) >600 U/m. IgM to VCA and EBNA were negative (Fig. 1). An ultrasound-guided cervical LN core needle biopsy revealed an atypical lymphoid proliferative lesion with positive EBV in situ hybridization (Fig. 2).

Figure 1. Clinical course of the pa-tient and laboratory findings (EBV DNA level, EBV [VCA] IgG, EBV [VCA] IgM, and EBV [EBNA] IgG) are shown. EBV, Epstein–Barr virus; LAP, lymphadenopathy; HLH, he-mophagocytic lymphohistiocytosis; VCA, viral capsid antigen; EBNA, EBV nuclear antigen.

Figure 2. Core needle biopsy of a cervical lymph node shows Epstein-Barr virus (EBV)-positive atypical lymphocytes.

He was admitted to our hospital again in November 2022 with a fever persisting for over 2 months, destructive bilateral otitis media with effusion (OME), and left-sided peripheral facial nerve palsy.

Before presenting to our hospital, the patient was admitted and treated for OME and LN enlargement at another hospital. A bone marrow biopsy was conducted, which revealed hemophagocytic features and positive EBV in situ hybridization with normocellular marrow. Despite the patient receiving treatment with broad-spectrum antibiotics and myringotomy with tympanostomy tube insertion, there was no clinical improvement in OME or facial nerve palsy, prompting the decision to transfer the patient to our hospital.

Physical examination at the second admission revealed multiple enlarged cervical LNs and hepatosplenomegaly. Blood tests showed an elevated EBV DNA titer of 214,000 copies/mL (Fig. 1); the VCA IgG and EBNA IgG tests were positive, whereas the VCA IgM and EBNA IgM tests were negative. Initial complete blood count (CBC) and liver pro-file tests showed normal values, and neck computed tomography (CT) and ultrasonography revealed multiple lymphadenopathies at neck levels II-V (Fig. 3). Ear tissue culture confirmed methicillin-resistant Staphylococcus aureus infection, and the biopsy showed positive EBV in situ hybridization. The patient received antibiotics and corticosteroids.

Figure 3. Neck computed tomogra-phy showing (A, B) multiple enlarged cervical lymph nodes (arrows).

On the 14th day of hospitalization, the patient experienced elevated fever, fatigue, muscle aches, and a productive cough. Additionally, he tested positive for COVID-19 PCR testing. The CBC revealed pancytopenia with a WBC of 1,700/mL (absolute neutrophil count: 330/mL), hemoglobin at 7.5 g/dL, and platelets at 18,000/mL. The patient showed elevated alanine aminotransferase levels (367 IU/L), lactate dehydrogenase levels (684 IU/L), C-reactive protein levels (CRP, 4.9 mg/dL with a reference range <0.6 mg/dL), ferritin levels (23,626 ng/mL with a reference range of 30 to 400 ng/mL), soluble interleukin receptor levels (3,599 U/mL with a reference range 158 to 623 U/mL), and decreased NK cell activity (<40 pg/mL with a reference range >500 pg/mL). Moreover, triglyceride, fibrinogen, and creatinine levels were within normal ranges. Blood culture results were negative, and no other viruses, including cytomegalovirus, parvovirus, or respiratory viruses, were detected. Abdominal CT revealed diffuse hepatosplenomegaly with lymphadenopathy, while chest CT showed infiltration in both lung fields and a substantial amount of pleural effusion. The patient satisfied 7 of the 8 diagnostic criteria for HLH (Table 1). However, after receiving Intravenous Immunoglobulin (IVIG) at a dose of 400 mg/kg for 5 days and red blood cell and platelet transfusions, the fever subsided, and the patient’s CBC, liver profile, and CRP level normalized by the 17th day of hospitalization. We decided not to continue chemotherapy per the 2004-HLH protocol. The patient was discharged on the 24th day of hospitalization.

Table 1 . HLH-2004 diagnostic criteria.

HLH-2004 diagnostic guidelines (fulfilled 7 of the 8 criteria below)
CriteriaPatient meeting criterion
1. Fever ≥38.5°C+Max 39.6°C
2. Splenomegaly+
3. Cytopenia (affecting ≥2 of 3 lineages in the peripheral blood) Neutrophils ≤5,000/mL Hemoglobin level <9.2g/L Platelet count ≤110,000/mL+Neutrophil 330/mL
Hemoglobin 7.5 g/L
Platelets 18,000/mL
4. Hypertriglyceridemia and/or hypofibrinogenemia
5. Hemophagocytosis in bone marrow or spleen or lymph nodes (no evidence of malignancy)+
6. Low or absent natural killer cell activity+Decreased NK cell activity
7. Ferritin >500 ng/mL+23,626 ng/mL
8. Soluble interleukin-2 receptor >2,400 U/mL+3,599 U/mL

Discussion

We report the case of a patient with CAEBV with severe EBV-related OME, generalized LN enlargement, and subsequent facial nerve palsy. The patient developed secondary HLH triggered by COVID-19 infection and experienced symptoms of chronic IM, including recurrent high fever, fatigue, and generalized lymphadenopathies. EBV DNA and IgG antibodies against the VCA of EBV and EBNA resulted positive for over 3 months. LN and ear tissue biopsies showed atypical lymphoid proliferative lesions with positive EBV in situ hybridization results, confirming the presence of a prolonged active EBV infection. No other underlying immunodeficiency was observed. Therefore, the patient was diagnosed with CAEBV, satisfying all three diagnostic criteria proposed by Okano et al. [9].

EBV-infected patients can exhibit a wide spectrum of clinical courses, ranging from asymptomatic to IM to malignant diseases. Cases of EBV infection presenting with otitis media preceding facial nerve palsy, as in our case, have rarely been reported in pediatric patients [10,11]. Although the underlying mechanism remains uncertain, it has been theorized that EBV, followed by a secondary bacterial infection, might be involved in developing otitis media and mastoiditis, leading to inflam-mation and edema within the tympanic cavity, which in turn causes facial nerve compression resulting in facial palsy [11].

Similar to the treatment administered to the patient, treating facial palsy associated with otitis media involved managing the suppurative process using appropriate antibiotic therapy. Additionally, corticosteroids for inflam-mation control and surgical drainage of pus can be considered based on the patient’s condition. However, the efficacy of using the antiviral agent acyclovir as a treatment option is uncertain [10,11].

The development of CAEBV involves atypical activation and replication of EBV, leading to rapid growth and a clonal increase in infected T- or NK cells [4]. The infection consists of recurrent or persistent IM-like symptoms, high serum anti-EBV antibody levels, and persistently high EBV genomes in affected tissues and peripheral blood cells [3,5]. Notably, without appropriate treatment, the hematologic malignant diseases risk such as HLH and lymphoma increases. HLH is an uncommon, yet potentially fatal disease caused by the hyperactivation of the immune system, where excessive T cell and macrophage activation results in the overproduction of cytokines, causing severe organ damage in the liver, spleen, bone marrow, and central nervous system [6-8]. The HLH-2004 protocol confirms the HLH diagnosis when five or more of eight diagnostic criteria are met based on clinical symptoms, laboratory findings, and histopathological results (Table 1) [7,12]. Among secondary causes, EBV is the most prevalent trigger of HLH, accounting for approximately 40-60% of cases [8]. Additio-nally, COVID-19, known to trigger a cytokine storm, contributes to secondary HLH [13].

In simple EBV infections, symptomatic treatment can be administered; in cases with a risk of severe complications, steroids may be used [1]. However, in the case of CAEBV, there is an increased risk of developing lymphoma or HLH [4,5]. Therefore, treatment should be initiated before these diseases develop. However, no definitive treatment protocol for CAEBV has been established. While various approaches, such as antiviral agents, immuno-modulatory therapies (IVIG and corticosteroids), and chemotherapy based on etoposide, have been attempted, their effectiveness remains uncertain, with allogeneic stem cell transplantation being the only established treatment [3,4].

HLH should be treated according to the 2004-HLH protocol; thus, the initial therapy should include etoposide, dexamethasone, and cyclosporine. Intrathecal therapy with methotrexate and prednisolone is administered in cases involving the central nervous system. After eight weeks of initial therapy, hematopoietic stem cell transplantation and/or continuous therapy are considered depending on disease progression [6,12]. However, documented cases of secondary HLH have shown improvement through treatment with IVIG and steroids without the need for chemotherapy [14,15]. HLH treatment should be individualized based on the patient’s specific clinical symptoms, laboratory findings, and disease severity.

When managing patients with CAEBV, it is important to consider the appropriate timing and treatment methods, as well as the need for regular and ongoing evaluation to determine the potential development of hematologic malignancies.

Conflict of Interest Statement

The authors have no conflict of interest to declare.

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  • Hye Lim Jung