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Clinical Observation
April 8, 2002

Epstein-Barr Viral Load Assessment in Immunocompetent Patients With Fulminant Infectious Mononucleosis

Author Affiliations

From the Departments of Internal Medicine (Drs van Laar and Deinum), Pediatrics (Drs Buysse and Hjálmarsson), Virology (Dr Vossen), Pulmonary and Critical Care Medicine (Dr van den Berg), and Hematology (Dr van Lom), University Hospital Rotterdam, Rotterdam, the Netherlands.

Arch Intern Med. 2002;162(7):837-839. doi:10.1001/archinte.162.7.837
Abstract

We describe 2 immunocompetent adolescents with fulminant infectious mononucleosis and virus-associated hemophagocytosis. A new quantitative polymerase chain reaction revealed high serum Epstein-Barr virus DNA levels in these patients. One patient died with an increasing viral load not responding to corticosteroids followed by antiviral and intensified immunomodulatory treatment. The other patient received corticosteroids and acyclovir at diagnosis; her rapid recovery was heralded by a steep decline of viral load. We propose monitoring the clinical course of fulminant infectious mononucleosis in immunocompetent patients by Epstein-Barr virus DNA quantification and prompt corticosteroid and antiviral therapy when viral load is high.

Fulminant infectious mononucleosis (IM) with virus-associated hemophagocytosis (VAHS) is a rare manifestation of Epstein-Barr virus (EBV) disease in immunocompetent patients.1,2 Fever; enlarged liver, spleen, and lymph nodes; pancytopenia; hypertriglyceridemia; and hemophagocytosis are all characteristics of VAHS caused by the activated monophagocytic system in multiple organs.1,3 Treatment with chemotherapeutics, immunomodulators, antiviral drugs, and bone marrow transplantation has been described, but no generally accepted guidelines exist for the management of immunocompetent patients with VAHS complicating IM.2,3

We describe 2 patients in whom we related serum EBV DNA levels with disease severity. Based on our experiences, we propose monitoring the effect of initiated therapy by serial EBV DNA quantification.

REPORT OF CASES
PATIENT 1

A 15-year-old, previously healthy girl developed pancytopenia, disseminated intravascular coagulation, and elevation of liver enzyme and serum amylase levels after a 1-week period of flulike symptoms. On admission, she was febrile with circulatory shock, hepatosplenomegaly, pneumonitis, ascites, and pancytopenia. Initial management included inotropic support in the intensive care unit.

Hypercellular reactive bone marrow on day 1 did not contain monoclonal cells. Low serum counts of natural killer, B, and CD4 cells, with relative excess of CD8 cells (0.42 × 109/L), suggested a viral infection. Serological tests indicated acute primary EBV infection. A quantitative real-time polymerase chain reaction (based on a TaqMan assay4) of peripheral blood and bone marrow supernatant showed high EBV DNA levels (2.2 × 106 and 4.7 × 106 copies/mL, respectively). Because of the severity of the EBV-related pancytopenia, prednisolone (1 mg/kg per day) was administered from day 2. Hypertriglyceridemia was noticed on day 4.

On day 15, ganciclovir (3.5 mg/kg per day) was administered because of clinical deterioration and increasing viral load (Figure 1). Acute respiratory distress syndrome and renal failure ensued. Treatment was intensified with immunoglobulins and rituximab on days 18 and 21, respectively. However, the viral load increased and she died of acute respiratory distress syndrome and multiple organ failure on day 22. Autopsy revealed VAHS in her lungs, liver, spleen, and lymph nodes. The bone marrow was hypoplastic. In situ hybridization showed EBV in lymphocytes and macrophages in lung and lymph node tissue.

Figure 1.
Clinical events and serum Epstein-Barr virus DNA (viral load) detected by real-time polymerase chain reaction in 2 patients with fulminant infectious mononucleosis.

Clinical events and serum Epstein-Barr virus DNA (viral load) detected by real-time polymerase chain reaction in 2 patients with fulminant infectious mononucleosis.

PATIENT 2

A 17-year-old immunocompetent female was admitted after a 2-week period of flulike symptoms. She was febrile and jaundiced and had hepatosplenomegaly, lymphadenopathy, elevated liver enzyme levels, slight leukopenia, hypertriglyceridemia, and activated partial thromboplastin time and prothrombin time. Dyspnea developed with massive bilateral pulmonary infiltrates, pancytopenia, increasing lactate dehydrogenase, and low-grade disseminated intravascular coagulation on day 7. On day 8, respiratory failure required mechanical ventilation and she was transferred to our hospital.

Bone marrow cytologic examination showed megaloblastic erythropoiesis and phagocytosis of erythrocytes, erythroblasts, and platelets by macrophagocytes characteristic for VAHS (Figure 2). There were no monoclonal cells in her bone marrow. Serological testing indicated acute IM with high serum and comparable bone marrow supernatant EBV DNA levels (1.7 × 106 and 1.8 × 106% copies/mL, respectively). These levels were log 2 times higher than EBV DNA in cell sediment of the bone marrow. Epstein-Barr virus DNA was also detected in exudative ascites and bronchial lavage fluid (1.2 × 104 and 3.0 × 104 copies/mL, respectively).

Figure 2.
Bone marrow specimen with phagocytosis of platelets, erythroblasts, and erythrocytes by macrophages in patient 2 with fulminant infectious mononucleosis.

Bone marrow specimen with phagocytosis of platelets, erythroblasts, and erythrocytes by macrophages in patient 2 with fulminant infectious mononucleosis.

Prednisolone (1 mg/kg per day) and acyclovir (30 mg/kg per day for 10 days) were given after establishing the diagnosis EBV pneumonitis with VAHS on day 9. Fever, pancytopenia, and pulmonary infiltrates gradually diminished. Serum EBV DNA levels decreased progressively with 1 log per 3 to 5 days. Corticosteroids were tapered and stopped at day 23. Her EBV levels reached the detection limit (±100 copies/mL) on day 22 and remained unmeasurable after 10 months (Figure 1). After 36 days in the hospital with 11 days of respiratory support, the patient was discharged in good condition. One year later, mild asymptomatic bone marrow hemophagocytosis manifested as macrocytosis with folic acid depletion persisted.

COMMENT

Pulmonary involvement in patients with IM and VAHS is rare and associated with high mortality.1,2 Virus-associated hemophagocytosis is often underdiagnosed in patients.1 In the absence of guidelines on diagnosis and management of severe IM in immunocompetent patients, we relied on these 2 cases for measurement of EBV DNA levels in serum by a recently developed, rapid, sensitive, and easily applied polymerase chain reaction technique. In these patients, EBV DNA levels were 2 orders of magnitude higher than those observed in patients with uncomplicated IM (<100 to 4.5 × 104 copies/mL) and were comparable to those in patients with lymphoproliferative disorders (7.4 × 104 to 3.2 × 106 copies/mL).4 There were no signs of lymphoproliferative disease or immunodeficiency in these young female patients clinically, or from their medical and psychosocial history, human immunodeficiency virus serological tests, or immunological tests. Furthermore, they both were well nourished and from normal social backgrounds.

In our opinion, EBV DNA levels over 106 copies/mL mark a complicated course of EBV disease. This is in line with an earlier study in which viral load, measured semiquantitatively, correlated with disease severity.5 It is generally accepted that clinically severe IM warrants corticosteroid therapy. The high EBV DNA levels in our patients prompted us to add antiviral drugs. We are not sure whether these drugs should be administered immediately upon finding an EBV DNA load exceeding 106 copies/mL. Our experience with the presented cases inclines us to advocate early combination therapy of corticosteroids and antiviral agents in patients with fulminant IM with high viral load, especially when VAHS is present. An absence of a response with this regimen might signify a grave prognosis and should probably lead to better care with an active macrophage inhibiting chemotherapeutic agent such as etoposide, or stronger immunomodulatory agents such as immunoglobulins, specific cytotoxic T cells, or anti-CD20 therapy, depending on the finding of VAHS.2,3,6,7 All these considerations imply that the EBV DNA level should become a valuable parameter in the management of patients with fulminant IM.

Accepted for publication September 6, 2001.

Corresponding author and reprints: Jan A. M. van Laar, MD, Department of Oncology, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands (e-mail: vanlaar@inw1.azr.nl).

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