Fulminant liver failure due to Epstein-Barr virus in immunodeficiency disorders

Abstract

Background:

The majority of patients with Epstein-Barr virus (EBV)-associated hepatitis have a mild clinical course; most infections resolve spontaneously. However, in rare cases, or in patients with underlying immune deficits, outcomes can be fatal.

Methods:

We used a single-centre case series.

Results:

In this report, we describe two cases of acute EBV hepatitis. The first patient developed fulminant hepatitis with multi-organ failure and severe immune dysregulation; he died despite maximal intensive-care management. Post-mortem, his bone marrow biopsy results revealed an X-linked lymphoproliferative disease. This primary immunodeficiency impairs the body's ability to control EBV infection and is a risk factor for developing an EBV-positive T-cell lymphoma in childhood. The second patient presented with hepatitis, cytopenias, and hepatosplenomegaly in the context of persistent EBV viremia and responded well to treatment (dexamethasone, rituximab, and supportive care). Immunodeficiency testing was negative in this case.

Conclusions:

Prompt multidisciplinary management is recommended in cases of severe EBV-associated liver injury.

Lay Summary

Most people are exposed to the Epstein-Barr virus (EBV) at some point in their life. It often causes mild illness, such as mononucleosis, and normally goes away on its own. However, EBV can lead to serious complications, including liver failure, in some people. In rare cases, such as when a person has an underlying immune system issue, EBV can even result in death.

This report describes the clinical course of two young men who developed liver inflammation (hepatitis) due to EBV, and who had very different outcomes.

The first patient, a 20-year-old man with no known medical issues, developed rapidly worsening liver failure and other organ problems. Despite receiving advanced care in the intensive care unit, including treatments to support his liver and immune system, he unfortunately died. Further testing after his death revealed that he had an undiagnosed genetic condition called X-linked lymphoproliferative disease. This rare condition affects the immune system and can lead to life-threatening reactions to EBV, including cancer-like illnesses and widespread immune activation.

The second patient, a 19-year-old man, also presented with liver inflammation and other flu-like symptoms. He received early treatment, including medications to calm the immune response, and made a full recovery. No underlying immune disorder was found in his case.

These two cases highlight the importance of recognizing when EBV infection might be more than just a mild illness. In rare situations, especially when symptoms are severe or worsening quickly, doctors should consider whether there might be an underlying immune problem. Early, specialized care may improve outcomes and potentially save lives.

Introduction

Epstein-Barr virus (EBV) associated hepatitis most commonly occurs in the context of infectious mononucleosis, with a majority of cases being mild and self-limited (1,2). However, EBV is also associated with the development of lymphoproliferative disorders and hemophagocytic lymphohistiocytosis (HLH). HLH is a hyperinflammatory syndrome that can lead to multi-organ failure and, ultimately, death. It can be primary (familial HLH), linked to genetic defects causing immune dysregulation, or secondary, triggered by malignancy or infection (3).

Therefore, in rare cases of EBV infection, particularly in the setting of immune deficiencies or when complicated by HLH, outcomes can be severe and lead to hepatic failure (4). Early recognition of acute liver injury or liver failure due to EBV infection should prompt consideration of an underlying primary immunodeficiency and lead to a timely referral to a multidisciplinary care team; this approach should be applied in both pediatric and adult patients. We describe two cases of EBV-associated hepatitis with markedly different clinical outcomes.

Case Report 1

Patient 1, a white 20-year-old male with no past medical history, presented initially for fever, nausea, and right upper-quadrant pain. Investigations revealed a positive anti-viral capsid IgM antigen, as well as elevated transaminases and hyperbilirubinemia (Table 1). Over the next 10 days, the jaundice progressed, and the patient was admitted due to coagulopathy. Abdominal imaging (Figure 1) revealed hepatosplenomegaly, multiple abdominal lymph nodes, and ascites. N-acetylcysteine and broad-spectrum antibiotics were initiated as the patient remained febrile, and he was transferred to our specialized centre due to the signs of liver failure progressing.

Table 1:

Laboratory data over the course of follow-up

Timeline
Case	Day - 14	Day -3	Day 1	Day 2	Day 3*	Day 4*	Day 5*	Day 6*
Patient 1
Platelet count, 109/L		221	109	41	27	67	76	69
Bilirubin, μmol/L	49	189	227	230	84	90	162	309
ALT, U/L	261	475	3,803	3,340	384	227	269	281
AST, U/L		1,066	8,396	7,863	984	500	533	548
INR	1.15	1.58	3.5	7.5	1.2	1.2	1.2	2.5
Ferritin (23–337 μg/L)		37,298						7100
C-reactive protein (0–10 mg/L)			37	34
Triglycerides (0.49–2.82 mmol/L)			3.4		2.0	1.0
Fibrinogen (2.0–4.5 g/L)			0.7	0.7	<0.3
Patient 2		Day -3	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 30
Platelet count, 109/L		100	235	265	365	375	385	396	256
Bilirubin, μmol/L		294	480	312	203	155	134	112	35
ALT, U/L		313	443	452	504	533	565	476	67
AST, U/L		176	189	153	150	149	138	107	32
INR		1.2	0.9	0.9	0.9	0.9	0.9	0.9	–
Ferritin (23–337 μg/L)		9,768	4206	1,500					317
C-reactive protein (0–10 mg/L)							19		5
Triglycerides (0.49–2.82 mmol/L)		3.8	4.66	4.97
Fibrinogen (2.0–4.5 g/L)		2.2		3.0					2.2

*Ongoing high-volume renal replacement therapy and plasmapheresis for patient 1

The days are numbered based on the timing of referral to our specialized centre

Figure 1: CT scan of case 1 C+ showing hepatomegaly (liver size : 21.7 cm) and splenomegaly (spleen size : 18 cm).

Other findings not readily seen in this image include lymphadenopathies, exclusion of a vascular etiology explaining the liver failure, and exclusion of an infectious process from the GI tract

Within the first 24 hours, in addition to liver failure (the model for end-stage liver disease (MELD) score was 37) the patient developed circulatory dysfunction, acute kidney failure, metabolic acidosis, hyponatremia, and a progression of coagulopathy. High-volume renal replacement therapy was started. Progressive hepatic encephalopathy required endotracheal intubation and plasmapheresis. The patient was evaluated for urgent liver transplantation. His EBV viral load was 5,248,075 copies/mL. There was a high initial index of suspicion for HLH considering his fever, cytopenias, splenomegaly, elevated ferritin levels (37,298 μg/L), and low fibrinogen (<0.3). His HScore was 164, suggesting a 44% risk of having HLH. Treatment with IV dexamethasone 10 mg/m² daily was begun on day 2, and intravenous immunoglobulin therapy was added, given the disproportionate inflammatory response and multi-organ failure. On day 3, the preliminary results of a bone marrow biopsy confirmed the presence of hemophagocytosis, and treatment of suspected EBV-HLH with rituximab was initiated. The bone marrow was described as hypocellular, with an atypical T-lymphoid infiltrate and positive EBV, which is compatible with T-cell lymphoma associated with a systemic EBV infection.

On day 5, due to concerns about increased intracranial pressure (ICP) due to hepatic encephalopathy, ICP monitoring was installed, revealing an increased ICP of 50 mmHg. The following day, unilateral mydriasis and the loss of corneal reflex led to repeat imaging that revealed diffuse cerebral edema and intracerebral hemorrhage.

Following the patient's death, additional analysis on the bone marrow biopsy revealed findings compatible with a systemic EBV-positive T-cell lymphoma of childhood and a hemizygous missense variant NM_002351.5(SH2D1A):c.158C>T (p.Thr53Ile) of the SH2D1A gene. This mutation confirmed the diagnosis of X-linked lymphoproliferative (XLP) disease type 1.

Figure 2: Focus of hemophagocytosis (routine H&E stain).

Case Report 2

Patient 2, a white 19-year-old male, also with no previous medical history, presented following a two-week episode of fatigue and fever with a positive monospot test (positive IgM EBV antibodies and PCR-EBV of 1 737 801 copies/mL). In the following days, new onset jaundice, transaminitis, and cytopenias led to further inpatient evaluation. Due to the progression of the cytopenias and discovery of splenomegaly, empiric dexamethasone therapy was initiated, and a bone marrow aspirate was performed. The MELD score increased to 19, and transfer from a community hospital to our specialized centre was organized to provide further care. Evaluation by immunology and hematology revealed no definite HLH criteria, and the bone marrow aspirate showed reactive lymphocytes without clonality and without hemophagocytosis. Flow cytometry showed absent CD19+ and CD20+ B lymphocytes. Persistent EBV viremia (in the absence of activated T lymphocytes) and hemolytic anemia, accompanied by the presence of cold agglutinins, led to the initiation of rituximab therapy.

Further evaluation with an immunodeficiency panel did not reveal any underlying disease or rare variants. On his first follow-up visit after discharge, the liver test results had improved, and the jaundice was resolving. Three months after the initial episode, the patient's bilirubin was normal, and he showed sustained improvement in his liver tests (see Table 1).

Discussion

This report describes a case of severe immune dysregulation leading to acute liver failure and multi-organ shock, provoked after initial EBV infection. XLP is a rare primary immunodeficiency caused by mutations in the SH2D1A gene. It is one of the X-linked primary immunodeficiency diseases with defective immune response to EBV infection (5). Clinical presentation is often triggered by EBV infection and includes acute presentations, such as HLH and lymphoma. The median age at presentation is in the first decade of life (6). While complications of primary EBV infection are well described as the initial presentation of XLP, the age of presentation in this case serves as a reminder that this clinical syndrome can also occur in young adults (7). In addition, the high risk of EBV-induced lymphoma has to be taken into account to guide therapeutic management. Unfortunately, in case 1, the early onset of acute liver failure and complications due to increased ICP, even with maximal medical management, resulted in an untimely death. Nevertheless, this case serves as a reminder that clinicians should have a high degree of suspicion for immune dysregulation and neoplastic transformation in cases with severe acute liver injury following EBV infection in an adult patient.

Figure 3: Immunohistochemical study showing an atypical T-lymphoid infiltrate occupying approximately 30%–40% of the marrow (anti-CD3).

In contrast, case 2 details (in the absence of an underlying immune deficit) an absence of transformation into a lymphoproliferative disorder and an adequate response to treatment. Evolution to fulminant liver failure and the need for liver transplantation are rare, yet are the previously described consequences of EBV infection (8,9). In this case, although the clinical evolution was favourable, rituximab was deemed necessary after consultation with a multispecialty team, due to the severity of clinical presentation and the presence of hemolytic anemia with cold agglutinins. Indeed, rituximab works by depleting B cells, the main reservoir for EBV, thus reducing the EBV viral load. It also helps improve hemolytic anemia by eliminating the pathogenic B cells that produce cold agglutinins (10,11).

Overall, the presence of jaundice and acute liver injury following EBV infection requires prompt intervention and close monitoring.

Conclusion

In rare cases, initial EBV infection can be associated with severe adverse outcomes in adult patients. Prompt multidisciplinary management is recommended in cases with a rapid progression of liver injury.

Funding Statement

No financial support was received.

Contributions:

Conceptualization, J Hercun, M Bilodeau; Data Curation, DE Coman, J Hercun; Writing – Original Draft, J Hercun, DE Coman; Writing – Review & Editing, D Corsilli, H Chapdeleine, G Cross, M Bilodeau.

Ethics Approval:

N/A

Informed Consent:

Informed consent for the case report publication was obtained from the patients who were alive at the time of submission.

Registry and the Registration No. of the Study/Trial:

N/A

Data Accessibility:

Additional data will be made available on written request to the corresponding author.

Funding:

No financial support was received.

Disclosures:

The authors have no conflicts of interest to disclose.

Peer Review:

This manuscript was peer reviewed.

Animal Studies:

N/A