A 34-year-old Caucasian male was in his usual state of good health until July 2020 when he presented with a 1-week history of fever up to 39.3 C, sore throat, headaches, cough, and malaise. Having developed this during the SARS-CoV-2 pandemic, he presented to a COVID-19 testing site where jaundice was noted. He was triaged to the emergency room and then hospitalized. He tested negative for SARS-CoV-2 infection by polymerase chain reaction (PCR). A review of the system was negative for oral ulcers, change in vision, enlarged lymph nodes, chest or abdominal discomfort, dyspnea, nausea, vomiting, diarrhea, genital lesions, dysuria, hematuria, arthralgia, myalgia, neurological change, memory deficit, or rash. He had a cholecystectomy two years ago. He reported no illicit drug use, recent travel, or exposure to sick contacts, tuberculosis, ticks, animals, vaping, herbs, or supplements. He had two young children, both in daycare, and his wife was pregnant. The family medical history was unremarkable; no immunodeficiency, malignancy, autoimmunity, or severe infections. He had used over-the-counter acetaminophen and ibuprofen at the recommended doses. Laboratory tests revealed white blood cell count (WBC) 4.6 k/mm3 (range, 4.5-11 k/mm3) with neutrophils 55.6%, lymphocytes 24.2%, and monocytes 13.8%; hemoglobin (Hgb) 13.6 g/dL (range, 13.5-17.5 g/dL); platelets 155 k/mm3 (range, 150-450 k/mm3); peripheral smear with reactive lymphocytes; alkaline phosphatase 94 IU/L (range, 20-140 IU/L); alanine transaminase (ALT) 219 IU/L (range, 5-55 IU/L); aspartate aminotransaminase (AST) 99 IU/L (range, 5-45 IU/L); total bilirubin 8 mg/dL (range, 0.2-1.5 mg/dL); indirect bilirubin 7.1 mg/dL (range, 0.1-1.4 mg/dL); and normal serum creatinine. Urine analysis showed clear orange urine at pH 6.0 (range, 4.5-7) with specific gravity 1.205 (range, 1.010-1.030), protein 20 mg/dL (negative), ketones 20 mg/dL (negative), urobilinogen >20 (range, 0.1-1.8 mg/dL) and negative values for bilirubin, blood, glucose, nitrite, and leukocyte esterase. Serological testing was negative for hepatitis A virus IgM, hepatitis B virus surface antigen, hepatitis B virus core IgM, hepatitis C virus antibody (Ab), human immunodeficiency virus (HIV) p24 antigen (Ag), HIV-1 and HIV-2 Abs, antinuclear antigen Ab, liver-kidney microsomal Ab, mitochondrial Ab, and antismooth muscle Ab. Ceruloplasmin was normal. Iron level was 219 mcg/dL (range, 35-160 mcg/dL), normal TIBC, elevated iron saturation at 83% (range, 30-50%), and low transferrin at 161 mg/dL (range 200-430 mg/dL). IgG level was normal at 957 mg/dL (range, 650-1600 mg/dL). Blood cultures were negative. Abdominal ultrasound showed moderate hepatomegaly and changes consistent with fatty liver disease. Abdominal MRI showed similar changes plus splenomegaly (16 cm). The patient was discharged home on hospital day 3.
On the following day, he was readmitted because of worsening symptoms and normocytic anemia. The Hgb of 12.5 g/dL on the day of entry steadily decreased to 8.7 g/dL on day 8 of this hospitalization. Other remarkable blood count results included WBC 4.2 k/mm3 (range, 4.5-11 k/mm3), neutrophils 1.9 k/mm3 (range, 1.8-7.7 k/mm3), and platelets 155 k/mm3. Peripheral smear revealed an increase in reactive lymphocytes but a normal lymphocyte count and no schistocytes. Other remarkable laboratory findings included AST 56 IU/L, ALT 120 IU/L, total bilirubin 7.7 mg/dL, indirect bilirubin 6.7 mg/dL, ferritin 1570 ng/mL (range, 24-336 ng/mL), fibrinogen 488 mg/dL (range, 200-450 mg/dL), triglycerides 173 mg/dL (range, <149 mg/dL), LDH 341 IU/L (range, 135-220 IU/L), haptoglobin 1 mg/dL (range, 40-280), absolute reticulocyte count 0.1947 million/mm3 (range, 0.62-1.88 million/mm3), plasma free Hgb 60 mg/L (range, 0-9 mg/dL), no urinary hemosiderin, and negative Coomb's test.
Computed tomography of the chest, abdomen, and pelvis showed hepatosplenomegaly without lymphadenopathy. To investigate the cause of the liver abnormalities, a percutaneous liver biopsy was performed on day 2 of hospitalization. This showed portal triad inflammation involving lymphocytes, eosinophils, and granulomatous inflammation (Figure 1), as well as rare lobular microgranulomata (Figure 2). Liver sinusoids had excessive numbers of Kupffer cells (Figure 3) and T-lymphocytes (Figure 4). Occasional benign appearing histiocytes/Kupffer cells had findings of hemophagocytosis of red blood cells and probable leukocytes (Figure 5). Immunohistochemical stains for CMV, HSV-1, and HSV-2 Ags were negative. In situ hybridization for EBV EBER RNA was negative. Special stains for acid-fast bacilli and fungi were negative. Additional testing performed on blood for the HLH possibility included a soluble CD25 (IL-2 receptor) level that was elevated at 1200.3 pg/mL (range, 175.3-858.2). Natural killer cell activity was not assessed.
The infectious disease workup revealed CMV IgM and IgG in serum and CMV DNA in plasma at 41 IU/mL (reference value, undetected; quantification range, 35-106 IU/mL). Primary CMV infection was later confirmed by evidence of a low CMV IgG avidity index of 0.18 (cut off >0.7 for past infection). EBV viral capsid antigen (VCA) IgG and IgM were positive, EBV nuclear antigen IgG >8 (EBNA antibody), and plasma EBV DNA was absent. The blood was negative by PCR for HHV8, ehrlichia, anaplasma, and Coxiella burnetii DNA. Also negative in the blood were brucella IgG and IgM, ehrlichia and anaplasma Abs, parvovirus B19 IgM, Rickettsia rickettsii Abs, and tuberculosis interferon gamma release assay. Histoplasma Ag in blood and urine; blastomyces Ag in urine, CSF, and blood were negative. Flow cytometry applied to the blood was negative for blasts and atypical lymphoid proliferation. Bone marrow biopsy performed on day 6 of the hospitalization (blood count Hgb 9.8 g/dL), showed normocellular marrow for age with 1+ polychromasia, normal trilineage hematopoiesis, increased storage iron, and no hemophagocytosis, malignancy, CMV Ag, EBV EBER RNA, or stainable acid-fast bacilli and fungi.
The patient's condition was improving before he was given oral valganciclovir for 5 days and discharged home. He received no corticosteroids, immune globulin, or other immunomodulatory therapy. After discharge from the hospital, he had four face-to-face follow-up visits over 10 months. At 5 weeks after the onset of illness, the patient had returned to his usual activity level and had no symptoms of CMV DNAemia. At four months, the cytopenia had resolved (WBC 4.0 k/mm3, Hgb 14.3 g/dL, and platelets 210 k/mm3), liver transaminases had normalized, and total bilirubin had improved. At 10 months, the labs showed Hgb 14.5 g/dL, total bilirubin 3.7 mg/dL, direct bilirubin 1 mg/dL, ferritin 280 ng/mL, and haptoglobin 49 mg/dL. The persistent elevation in indirect bilirubin levels could be from residual compensated hemolysis or previously unrecognized Gilbert syndrome. The patient elected to not return for further follow-up.