A 20-year-old college female with no significant past medical history presented to an urgent care center in the context of fever, chills, body aches and ongoing fatigue for 5 days. She had adjunctive symptoms of rhinorrhea but denied sore throat. She was febrile to 38.5  C, with otherwise stable vital signs. She was fully vaccinated against COVID-19 along with a booster. Physical examination at that time had demonstrated mild pharyngeal erythema, but no evidence of oropharyngeal exudates, sinus tenderness, trismus, or cervical adenopathy. COVID-19 and rapid strep testing was negative. Monospot testing, however, was notably positive and she was diagnosed with infectious mononucleosis (IM). She was ultimately prescribed acyclovir and ondansetron, with continued recommendation for conservative management of fever and rhinorrhea.
Two days later, the patient subsequently presented to our hospital facility in the context of ongoing nausea (without emesis), poor oral intake, and upper abdominal discomfort. She endorsed non-compliance with acyclovir but was taking acetaminophen for conservative management, as well as aspirin/paracetamol/caffeine and ibuprofen for migraines. She described her abdominal pain as band-like across the upper abdomen, waxing and waning, without any specific exacerbating or alleviating factors. She denied easy bruisability, but endorsed some neck discomfort, mild adenopathy, and continued intermittent fevers. She was unclear regarding how she contracted IM, noting that her boyfriend lived in another state, but that she shared an apartment with two fellow college students, locally.
On presentation to the emergency room, she was afebrile but mildly tachycardic (102 beats per minute), with otherwise normal vital signs. Physical examination was remarkable for a dry, non-erythematous oropharynx without palatal petechiae, mild right upper quadrant abdominal tenderness, no noted left upper quadrant tenderness, negative Carnett's sign, and no costovertebral angle tenderness. Initial laboratory diagnostics demonstrated mild hypokalemia to 3.4 mmol/L (reference range: 3.5-5.1 mmol/L), elevated aspartate transaminase (AST) at 165 units/L (reference range: 0-33 units/L), elevated alanine transaminase (ALT) at 116 units/L (reference range: 10-49 units/L), elevated total bilirubin at 3.7 mg/dL (reference range: 0.3-1.2 mg/dL), and adjunctive elevation in alkaline phosphatase to 280 units/L (reference range: 46-116 units/L). Complete blood count demonstrated a normal leukocyte count of 4.6 k/uL (reference range: 4.0-10.8 k/uL), hemoglobin at her baseline of 12.6 g/dL (reference range: 11.0-14.5 g/dL), and thrombocytopenia to 67 k/uL (reference range: 145-400 k/uL) with an inappropriately low immature platelet fraction of 5.6 %. Elevated monocytes (15 %; reference range: 3-12 %) were also noted. Testing for COVID-19, influenza, and respiratory syncytial virus was once again negative.
A contrast-enhanced CT scan of the abdomen and pelvis demonstrated hepatomegaly with subtle heterogeneous enhancement and moderate periportal edema and moderate gallbladder wall thickening without evidence of gallstones, inflammatory changes, or biliary ductal dilatation (Fig. 1). There was moderate splenomegaly (measuring 11.5 cm in the greatest width) and the spleen was noted to have a rounded configuration with heterogeneous enhancement with mottled lucency, but no evidence of wedge-shaped infarction. The remainder of the intra-abdominal organs including the pancreas, adrenals, kidneys, reproductive tract organs, and gastrointestinal tract were unremarkable. A small amount of free fluid was noted in the pelvis, likely reactive in nature. Mildly enlarged retroperitoneal lymph nodes, as well as enlarged inguinal lymph nodes were identified, without overt evidence of bulky adenopathy. A subsequent right upper quadrant ultrasound demonstrated gallbladder wall thickening/edema without evidence of biliary ductal dilatation. The surgical service was consulted given the splenic imaging findings with recommendations for continued conservative management given no indication for acute surgical intervention. The patient was admitted to the hospital for further management.
Additional laboratory diagnostic testing revealed elevated ferritin level of 1486.2 ng/mL (reference range: 7.3-270.7 ng/mL) and an elevated triglyceride level of 526 mg/dL (reference range: 0-149 mg/dL), prompting concern for HLH. Further laboratory testing for EBV DNA, soluble interleukin-2 receptor (sCD25) and work-up for fever of unknown origin, hepatitis, and thrombocytopenia was sent. Testing for acute viral hepatitis, cytomegalovirus, HIV, syphilis, B. henselae, B. quintana, E. chaffeensis, C. burnetii, Leptospira, and tuberculosis was negative. The patient's thrombocytopenia and elevated ferritin level gradually decreased with conservative management and her clinical symptoms improved. Ultimately, EBV DNA returned elevated at 113,149 copies/mL (reference range: <= 200 copies/mL), along with elevated EBV IgM at > 160.0 units/mL. Furthermore, sCD25 returned elevated at 5387.5 pg/mL, effectively fulfilling five criteria for HLH (Table 1). Given the patient's overall clinical improvement, resolution of thrombocytopenia and down-trending ferritin level, she was discharged with recommendations to continue conservative management, and planned outpatient follow up with her primary care provider.