Spontaneous resolution of hemophagocytic lymphohistiocytosis in a child infected with epstein–Barr virus

Rita Alfattal; Hussain Sadeq; Abdullah Ali

doi:10.4103/joah.joah_109_22

CASE REPORT

Year : 2023 | Volume : 14 | Issue : 1 | Page : 57-61

Spontaneous resolution of hemophagocytic lymphohistiocytosis in a child infected with epstein–Barr virus

Rita Alfattal¹, Hussain Sadeq¹, Abdullah Ali²
¹ Department of Pediatrics, General Pediatrics Unit, Al-Amiri Hospital, Kuwait City, Kuwait
² Department of Hematology and Oncology, Pediatric Hematology/Oncology Unit, National Bank of Kuwait Hospital, Kuwait City, Kuwait

Date of Submission	02-Dec-2022
Date of Decision	04-Jan-2023
Date of Acceptance	05-Jan-2023
Date of Web Publication	17-Feb-2023

Correspondence Address:
Dr. Rita Alfattal
Department of Pediatrics, General Pediatrics Unit, Al-Amiri Hospital, Kuwait City
Kuwait

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/joah.joah_109_22

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a rare and complex disorder that involves numerous hematological and immunological reactions. These reactions, if left untreated, may lead to multiorgan failure and death. Corticosteroids are the mainstay of HLH therapy which may also comprise other chemotherapeutic or immunotherapy agents. The components of the 2004 HLH diagnostic criteria may intersect with several other conditions. In this report, we present the case of a 4-year-old boy who was diagnosed with Epstein–Barr virus-related infectious mononucleosis complicated by clinical and laboratory features consistent with HLH, which self-resolved completely without HLH-directed therapy.

Keywords: Child, Epstein–Barr virus, hemophagocytic lymphohistiocytosis, pediatrics

How to cite this article:
Alfattal R, Sadeq H, Ali A. Spontaneous resolution of hemophagocytic lymphohistiocytosis in a child infected with epstein–Barr virus. J Appl Hematol 2023;14:57-61

How to cite this URL:
Alfattal R, Sadeq H, Ali A. Spontaneous resolution of hemophagocytic lymphohistiocytosis in a child infected with epstein–Barr virus. J Appl Hematol [serial online] 2023 [cited 2023 Mar 20];14:57-61. Available from: https://www.jahjournal.org/text.asp?2023/14/1/57/369841

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder that can either be familial or secondary to infections, malignancies, or autoimmune disorders.^[1],[2] HLH is caused by severe impairment of cluster of differentiation 8+ (CD8+) T lymphocytes and natural killer (NK) cells, leading to hyperactivity of cytotoxic T lymphocytes and certain circulating macrophages.^[3],[4] This results in excessive proinflammatory cytokines and histiocytes infiltrating different tissues and organs, potentially leading to multiple organ failures.^[4],[5] HLH usually requires treatment with steroids, immunosuppressive medications, or stem cell transplantation.^[4],[6] This case report discusses a 4-year-old boy with HLH secondary to Epstein–Barr virus (EBV) infection, whose symptoms fortunately resolved spontaneously.

Case Report

A previously healthy 4-year-old boy presented initially with a history of fever. The fever had been ongoing for 1 week, with enlarged bilateral cervical lymph nodes and a sore throat, for which he had attended a private medical clinic and was treated with amoxicillin/clavulanic acid (90 mg/kg/day orally) after which he developed a full body generalized maculopapular rash. The patient had no history of weight loss, night sweats, or bone pain. Moreover, there was no family history of HLH or similar presentation. On examination, he was found to be generally well, with good growth parameters and no dysmorphia, pallor, or jaundice. Overall, the systemic examination was normal except for being febrile with a slightly enlarged spleen and generalized maculopapular rash. Laboratory results showed: white blood cell (WBC) = 6 × 109/L (normal range (NR): 5–15 × 109/L), hemoglobin = 118 g/L (NR: 110–140 g/L), platelets = 244 × 109/L (NR: 200–490 × 109/L), monocytes = 2.4 × 109/L (NR: 0.2–1 × 109/L), C-reactive protein (CRP) =1.7 mg/L (NR: 0–8 mg/L), and erythrocyte sedimentation rate (ESR) =19 mm/h (NR: 0–15 mm/h), with normal renal and liver function results. Peripheral blood smear results showed lymphocytosis and reactive lymphocytes with no abnormal cells. Viral antibody serology tests confirmed the presence of reactive immunoglobulin M (IgM) antibodies for EBV. The patient was diagnosed with infectious mononucleosis and discharged home once the rash started to fade away. After doing well for 2 weeks, he developed a high-grade fever again, which continued at home for 1 week with fatigue, decreased appetite, abdominal pain, and generalized body swelling, for which he was admitted to the hospital. On examination, the patient looked tired and pale with mild jaundice and generalized edema. The results of cardiac, respiratory, and neurological examinations were all normal. However, an abdominal examination revealed a distended abdomen with mild tenderness and an enlarged nontender liver and spleen, which measured 3 cm below the costal margin. Laboratory results showed: WBC = 15.8 × 109/L (NR: 5–15 × 109/L), hemoglobin = 85 g/L (NR: 110–140 g/L), platelets = 36 × 109/L (NR: 200–490 × 109/L), absolute neutrophil count (ANC) = 0.7 × 109/L (NR: 1.5–8 × 109/L), lymphocytes = 12.6 × 109/L (NR: 6–9 × 109/L), alanine aminotransferase (ALT) =140 U/L (NR: 3–50 U/L), aspartate transaminase (AST) = 209 U/L (NR: 3–50 U/L), albumin = 26 g/L (NR: 35–52 g/L), total bilirubin = 59.4 μmol/L (NR: 0–3.4 μmol/L), Lactate dehydrogenase (LDH) = 1375 U/L (NR: 110–295), triglycerides = 10 mmol/L (NR: 0.4–1.75 mmol/L), CRP = 22 mg/L (NR: 0–8 mg/L), ESR = 21 mm/h (NR: 0–15 mm/h), ferritin = 5440 ng/mL (NR: 23.9–336.2 ng/mL), fibrinogen = 1.30 g/L (NR: 2.2–4.95 g/L), and D-dimer = 4586 ng/mL (NR: <250 ng/mL). Viral serology blood tests identified nonreactive hepatitis B surface antigen and antihepatitis C virus, with EBV DNA subsequently being detected by polymerase chain reaction analysis. Blood smear analysis exhibited leukocytosis with reactive lymphocytes, severe thrombocytopenia, mild hypochromia, and microcytosis. COVID-19 antibodies were not detected. Lymphocyte phenotyping showed low absolute NK cell levels of 186 cells/μl% (NR: 200–1200 cells/μl%). The clinical and laboratory findings were compared to the HLH-2004 diagnostic criteria, as summarized in [Table 1]. Following this, an abdominal computed tomography scan with contrast revealed an enlarged liver (12 cm), an enlarged spleen (11 cm), moderate ascites, and mild bilateral pleural effusion. Electrocardiogram and echocardiography results were both normal. Based on the symptoms and laboratory findings, a diagnosis of HLH secondary to the EBV infection was considered. The H-score was calculated as 243 (through https://www.mdcalc.com/hscore-reactive-hemophagocytic-syndrome), indicating a >99% probability of hemophagocytic syndrome. A bone marrow biopsy followed by starting steroid therapy was planned for the patient. However, on the 10^th day of hospitalization, the patient started to improve spontaneously without any treatment other than supportive management. Upon discharge, the patient was vitally stable and afebrile, with no fatigue or abdominal pain. Outpatient department follow-up after 3 months showed completely normal clinical and laboratory results, with the latest investigations showing WBC = 5.9 × 109/L (NR: 5–15 × 109/L), hemoglobin = 117 g/L (NR: 110–140 g/L), platelets = 377 × 109/L (NR: 200–490 × 109/L), D-dimer 125 ng/mL (NR: <250 ng/mL), fibrinogen = 2.6 g/L (NR: 2.2–4.95 g/L), triglycerides = 1 mmol/L (NR: 0.4–1.75 mmol/L), ALT = 19 U/L (NR: 3–50 U/L), AST = 28 U/L (NR: 3–50 U/L), albumin = 46 g/L (NR: 35–52 g/L), ferritin = 15 ng/mL (NR: 23.9–336.2 ng/mL), with a normal blood smear. The patient remained asymptomatic with normal laboratory findings at 6 and 12 months. During these follow-up visits, the family was counseled on genetic testing for familial HLH; however, they refused to undergo this test.

Table 1: Summary of diagnostic criteria of hemophagocytic lymphohistiocytosis-2004 compared to clinical and laboratory findings in our patient

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Discussion

Although most patients diagnosed with EBV infection have an uneventful recovery, it can sometimes lead to life-threatening complications such as HLH.^[7] HLH is often considered a potentially fatal hyperinflammatory syndrome that can lead to multiple organ failures.^[8]

Primary (or familial) HLH, mostly presenting during infancy or childhood, is usually due to mutations at familial HLH loci.^[2] Genetic testing in such cases has an important role in ruling out familial HLH or any genetic mutation that increases the patient's vulnerability to EBV-triggered HLH.^[9] Familial HLH disorders and their affected genes associated with EBV infection are summarized in [Table 2].^{[2],[10],[11]} Secondary HLH, on the other hand, is often seen in adolescents and adults.^[3] Viral infections are common secondary causes of HLH.^[12] One of the most common viruses associated with HLH is EBV.^[12] A nationwide study performed in Japan showed that 53.1% of HLH cases are attributed to infections, and 54% of these infections are EBV-related.^[13] Other viruses associated with HLH include cytomegalovirus, herpes simplex virus, varicella-zoster virus, measles virus, H1N1 influenza virus, and HIV.^[12] SARS-CoV-2 virus has also been reported to cause HLH-like syndromes.^[14],[15] Less commonly, HLH can be triggered by bacterial (e.g., brucella and tuberculosis), parasitic (e.g., leishmaniasis and malaria), and fungal infections.^[16] Other secondary triggers of HLH include malignant disorders such as leukemias, lymphomas, and solid tumors.^[17] Autoimmune diseases can also lead to HLH.^[18] These diseases include systemic juvenile idiopathic arthritis (sJIA), dermatomyositis, systemic sclerosis, antiphospholipid syndrome, Sjögren's syndrome, ankylosing spondylitis, and sarcoidosis.^[18] The diagnosis of HLH can be challenging as the signs and symptoms can be similar to those of HLH-triggering diseases such as lymphoma, leukemia, or sJIA.^[13]

Table 2: Summary of disorders associated with Epstein-Barr virus-triggered familial hemophagocytic lymphohistiocytosis disorders

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The patient presented in this case study was initially diagnosed with infectious mononucleosis triggered by EBV (confirmed by blood IgM antibody testing). However, after 2 weeks, the patient presented with symptoms and laboratory results collectively indicating a diagnosis of HLH. Based on the HLH-2004 protocol, the diagnostic criteria for HLH must include either a molecular/genetic diagnosis of HLH or the presence of five out of eight diagnostic criteria including fever ≥38.5°C, splenomegaly, bi- or pan-cytopenia (hemoglobin ≤9 g/dL; platelets ≤100 × 109/L; ANC ≤1 × 109/L), elevated ferritin level (>3000 ng/mL), low or absent NK cell activity, hypertriglyceridemia (fasting triglycerides ≤3 mmol/L) and/or hypofibrinogenemia (fibrinogen ≤1.50 g/L), elevated interleukin-2 (IL-2) receptor/CD25 (>2400 μL/mL), and bone marrow biopsy showing hemophagocytosis.^[1],[3],[17] The patient fulfilled the diagnostic criteria by presenting with fever, splenomegaly (confirmed by abdominal ultrasound), pancytopenia, high ferritin levels, high triglyceride levels, and low NK cell counts. CD25 level was not done due to the unavailability of the test in Kuwait. Moreover, a bone marrow biopsy was not performed as the patient recovered unexpectedly before undergoing the procedure. H-score is a novel and highly specific diagnostic tool that was developed in 2014, calculating a score (from 0 to 302) based on nine variables: known underlying immunodepression, temperature, organomegaly, cytopenia, ferritin level, triglyceride level, fibrinogen level, AST level, and hemophagocytosis features on bone marrow aspirate.^[19],[20] Fardet et al. reported that an H-score of 169 indicates a diagnosis of HLH with 93% sensitivity and 86% specificity.^[20] In the present case study, the patient had an H-score of 243, corresponding to a HLH diagnosis probability of >99%. Treatment of HLH usually involves the control of pro-inflammatory cytokine overproduction.^{[20],[21],[22],[23]} While secondary HLH requires the underlying cause to be treated, the only curative therapy for primary HLH at present is allogeneic hematopoietic stem cell transplantation.^[8] Based on the HLH-1994 protocol, the treatment of HLH comprises combinations of dexamethasone and a chemotherapeutic agent (etoposide), with the HLH-2004 protocol advising the addition of cyclosporine to the HLH-2004 treatment regimen.^{[21],[22],[23],[24]} However, our patient improved in terms of clinical presentation and laboratory results before starting the HLH treatment protocol. In the present case, the decision was to proceed with a bone marrow biopsy and then start steroid therapy; however, a positive outcome ultimately occurred as the symptoms resolved spontaneously with supportive management only.

There is a paucity of reported pediatric cases of spontaneously resolved EBV-HLH in the medical literature. In a national 5-year survey done in Japan, 98 pediatric EBV-HLH cases were reported with the mean age of onset of EBV-HLH being 3.9 ± 2.8 years.^[25] All of these cases were treated with the HLH-2004-based regimen (60%), corticosteroid therapy (30%), or IVIG (10%).^[25] In our case, the patient's age was comparable to the age group of the reported survey in Japan; however, our patient recovered from EBV-HLHL spontaneously with no intervention. This makes our patient the youngest reported case (at 4 years of age) that has had spontaneously resolved EBV-HLH. Bakhshi and Pautu reported a previously healthy 9-year-old boy with a similar presentation and outcome to our case with gradual clinical improvement after 1 week of hospital stay.^[26] In comparison, our case showed a resolution of symptoms after 10 days. Another case has been reported in Cyprus involving a 9-month-old girl developing HLH after contracting EBV along with Leishmania donovani.^[27] However, this infant showed signs of complete recovery only after receiving two courses of intravenous liposomal amphotericin B.^[27] Similar to our case, Belyea et al. reported two previously healthy pediatric patients aged 19 and 14 years with spontaneous resolution of EBV-related HLH within 2 weeks.^[4] Both patients underwent molecular testing for familial HLH, and the results came back negative for both patients.^[4] In comparison, a big limitation, we faced in our case is the lack of genetic testing for familial HLH since EBV infection can trigger HLH in a susceptible individual. Although the overall outcome seems good for children who have no genetic predisposition to HLH, the decision of whether to start treatment or to consider watchful waiting can be difficult due to the scarcity of data in the literature on this topic.^[4],[28] In addition, the serious side-effect profile of the treatment modalities can make the decision more difficult.^[4]

In conclusion, we believe that the findings in the present case imply the need for further studies to outline the criteria of watchful waiting versus prompt medical therapy for secondary HLH in children without life-threatening conditions.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that patient names and initials will not be published and due efforts will be made to conceal patient identity, but anonymity cannot be guaranteed.

Acknowledgment

The authors would like to gratefully thank the nursing staff from the Pediatrics Department of Amiri Hospital and the parents of the patient.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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