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Saprativ Mondal, Debasis Datta, Abhiroop Ghose Department of Gastroenterology, Fortis Hospital, Aanandapur, Kolkata, West Bengal 700107, India.
Corresponding Author:
Dr Saprativ Mondal Email: sapratibha@live.in
Abstract
Background: Jaundice is a common clinical presentation with diverse causes. Although acute Epstein–Barr virus (EBV) infection usually causes mild hepatitis, secondary hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening complication. Jaundice as the presenting feature of EBV-associated HLH in adults is uncommon. Case Report: A 23-year-old man presented with fever, progressive jaundice, dark urine, sore throat, and severe anemia. Investigations revealed hyperbilirubinemia, transaminitis, hemolysis, markedly elevated inflammatory markers, hyperferritinemia, and hypertriglyceridemia. Common infectious and hematological causes were excluded. High-resolution computed tomography showed atypical bilateral pneumonia, and EBV IgM serology was positive. Based on the clinical and laboratory findings, a diagnosis of EBV-associated secondary HLH was made. The patient improved with supportive care, antibiotics, respiratory support, and blood transfusions, and was discharged in stable condition. Conclusion: This case highlights the importance of considering EBV-associated HLH in adults presenting with unexplained jaundice, hemolytic anemia, and systemic inflammation. Early diagnosis and prompt management can lead to favourable outcomes despite this rare presentation.
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Introduction
Jaundice is a frequently encountered clinical finding that may result from a wide range of hepatic, biliary, or hematological disorders. While most patients are diagnosed with common conditions such as acute viral hepatitis, biliary obstruction, or drug-induced liver injury, atypical systemic infections should also be considered, particularly when accompanied by multisystem involvement. Epstein-Barr virus (EBV) infection is a common viral illness that typically presents with fever, sore throat, lymphadenopathy, and fatigue. Although mild hepatic dysfunction is observed in many patients, clinically apparent jaundice is uncommon. On rare occasions, EBV infection can induce an exaggerated immune response leading to secondary hemophagocytic lymphohistiocytosis (HLH), a potentially fatal hyperinflammatory syndrome characterized by excessive immune activation and multiple organ dysfunction. The diagnosis is often difficult because its manifestations overlap with those of severe infections and other inflammatory conditions. We describe a young adult who presented with jaundice as the predominant clinical feature and was subsequently found to have acute EBV infection complicated by severe hemolysis and features suggestive of secondary HLH. This case emphasizes the importance of considering uncommon etiologies in patients with unexplained jaundice and systemic inflammation.
Case Report
A 23-year-old man presented with a 5-day history of progressive jaundice, dark-coloured urine, fever, and throat discomfort associated with hoarseness of voice. On admission, he was conscious, alert, and hemodynamically stable except for tachycardia. Clinical examination revealed marked icterus and severe pallor. Abdominal examination was unremarkable, with no hepatosplenomegaly or abdominal tenderness. Neurological examination was normal, while respiratory examination demonstrated bilateral wheeze. Initial laboratory investigations showed severe anemia with a hemoglobin of 5.6 g/dL (normal: 13.5-17.5 g/dL), hyperbilirubinemia with a total bilirubin of 9.11 mg/dL (normal: 0.3-1.2 mg/dL), and elevated liver enzymes including AST 273 U/L (normal: 10-40 U/L), ALT 110 U/L (normal: 7-56 U/L), GGT 82 U/L (normal: 8-61 U/L), and ALP 98 U/L (normal: 44-147 U/L), suggestive of predominantly hepatocellular injury. He was stabilized with packed red blood cell transfusions. Inflammatory markers were markedly elevated, with a total leukocyte count of 48,130/µL (normal: 4,000-11,000/µL) and C-reactive protein (CRP) of 156 mg/L (normal: <5 mg/L). Blood, urine, and sputum cultures were sterile. An extensive evaluation for infectious causes of acute hepatitis, including hepatitis A virus, hepatitis E virus, dengue, malaria, leptospirosis, and scrub typhus, was negative. Ultrasonography of the abdomen demonstrated a mildly enlarged heterogeneous liver with minimal gallbladder sludge but no evidence of biliary obstruction. Further evaluation of the anemia suggested ongoing hemolysis. Serum lactate dehydrogenase (LDH) was markedly elevated at 1,913 U/L (normal: 140-280 U/L), while serum haptoglobin was profoundly reduced at 0.07 g/L (normal: 0.3-2.0 g/L). Iron studies showed serum iron 256 µg/dL (normal: 60-170 µg/dL), total iron-binding capacity (TIBC) 493 µg/dL (normal: 250-450 µg/dL), and transferrin saturation 54% (normal: 20-50%). Peripheral blood smear demonstrated anisopoikilocytosis with pencil cells. Direct and indirect antiglobulin (Coombs) tests were negative, excluding autoimmune hemolytic anemia. Flow cytometric analysis using FLAER and CD157 demonstrated no deficient monocyte or neutrophil populations, ruling out paroxysmal nocturnal hemoglobinuria. Because of persistent respiratory symptoms, high-resolution computed tomography (HRCT) of the thorax revealed bilateral multifocal ground-glass opacities, nodular consolidations, and tree-in-bud nodules, predominantly involving the right lower lobe, consistent with infective bronchiolitis/pneumonia. Bronchoscopy with bronchoalveolar lavage (BAL) showed no evidence of bacterial, mycobacterial, or fungal infection. BAL bacterial culture, GeneXpert MTB/RIF, mycobacterial (BACTEC) culture, and fungal cultures were all negative. The combination of persistent fever, hyperferritinemia with a serum ferritin of 17,310 ng/mL (normal: 30-400 ng/mL), hypertriglyceridemia of 235 mg/dL (normal: <150 mg/dL), elevated fibrinogen of 742 mg/dL (normal: 200-400 mg/dL), severe systemic inflammation, and laboratory evidence of hemolysis raised the suspicion of secondary hemophagocytic lymphohistiocytosis (HLH). Subsequent serological testing demonstrated elevated Epstein–Barr virus (EBV) IgM antibodies of 45.5 U/mL (reference: negative <20 U/mL; laboratory-dependent cut-off), suggesting acute EBV infection as the likely trigger. The patient required non-invasive ventilatory support followed by high-flow nasal oxygen, which was gradually weaned as his respiratory status improved. He received empirical intravenous meropenem, oral azithromycin, nebulized salbutamol, inhaled budesonide, and supportive care, including packed red blood cell transfusions. Over the course of hospitalization, his respiratory symptoms, inflammatory markers, jaundice, and liver function tests improved steadily. His hoarseness resolved completely, and he was discharged in stable condition with normalization of the leukocyte count and significant improvement in liver function tests.
Discussion
The present case illustrates an unusual presentation of acute Epstein-Barr virus (EBV) infection in a young adult, with jaundice and hemolytic anemia as the predominant clinical manifestations. The absence of classical features of infectious mononucleosis and only minimal respiratory symptoms made the diagnosis particularly challenging. The co-existence of marked hyperbilirubinemia, severe anemia, elevated inflammatory markers, and atypical pneumonia prompted further evaluation, ultimately leading to the diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH). HLH is a life-threatening hyperinfla-mmatory syndrome caused by uncontrolled activation of macrophages, cytotoxic T lymphocytes, and natural killer cells, resulting in excessive cytokine release and multiorgan dysfunction [1,2]. Although primary HLH is predominantly a pediatric disorder caused by inherited genetic defects, secondary HLH occurs in older children and adults and is usually triggered by infections, autoimmune diseases, or malignancies [3]. Early recognition is essential because delayed diagnosis is associated with significant morbidity and mortality. The diagnosis of HLH remains challenging because its clinical manifestations overlap with those of severe infections, sepsis, autoimmune disorders, and hematological malignancies. The diagnostic criteria proposed by the Histiocyte Society provide a useful framework; however, many patients do not fulfil all criteria at initial presentation, and hemophagocytosis may be absent on early bone marrow examination. Therefore, HLH should be considered in patients with persistent fever, unexplained cytopenias, hyperferritinemia, and evidence of systemic inflammation, even when the complete diagnostic criteria are not initially met [4]. Among infectious triggers, EBV is the most frequently implicated viral pathogen in secondary HLH. Other reported infectious causes include cytomegalovirus, human immunodeficiency virus, Mycobacterium tuberculosis, Rickettsia species, Leishmania, and Histoplasma species [5]. EBV-associated HLH results from an exaggerated immune response rather than direct viral cytotoxicity and is associated with a more severe clinical course if not recognized promptly. Hepatic involvement is common during acute EBV infection and usually manifests as mild, transient elevation of aminotransferases. Clinically significant jaundice, however, is uncommon in immunocompetent adults. In the present case, jaundice was multifactorial, resulting from both hepatocellular injury and ongoing hemolysis, as evidenced by elevated bilirubin, markedly raised lactate dehydrogenase, reduced serum haptoglobin, and severe anemia. The presence of atypical pneumonia on high-resolution computed tomography further supported an underlying systemic inflammatory process despite relatively mild respiratory symptoms. Current treatment of secondary HLH focuses on suppression of the hyperinflammatory state while simultaneously treating the underlying trigger. Standard treatment protocols include corticosteroids and etoposide, with additional immunomodulatory therapy in selected patients [6]. However, treatment should be individualized according to disease severity and the underlying etiology. In our patient, prompt supportive management and treatment of the associated infection resulted in gradual clinical and biochemical recovery without progression to multiorgan failure. This case highlights the importance of maintaining a high index of suspicion for HLH in adults presenting with unexplained jaundice, hemolytic anemia, and markedly elevated inflammatory markers, particularly when routine investigations fail to identify a definitive cause.
Conclusion
Secondary HLH should be considered in the differential diagnosis of adults presenting with unexplained jaundice accompanied by severe systemic inflammation and hemolytic anemia. Although EBV infection commonly causes mild hepatitis, jaundice as the initial manifestation of EBV-associated HLH is distinctly uncommon. In our patient, the combination of acute hepatitis, hemolysis, markedly elevated ferritin and triglyceride levels, low haptoglobin, and atypical pneumonia led to the diagnosis of EBV-associated secondary HLH. Early recognition of this rare clinical entity, coupled with timely supportive care and appropriate management of the underlying trigger, was associated with a favourable outcome. This case emphasizes the need to consider HLH in patients with unexplained jaundice and hyperinflammatory features, as prompt diagnosis may be lifesaving.
Contributors: SM: manuscript writing, patient management; DD: manuscript editing, patient management; AG: critical inputs into the manuscript. SM will act as a study guarantor. All authors approved the final version of this manuscript and are responsible for all aspects of this study. Funding: None; Competing interests: None stated.
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