Severe chronic active Epstein-Barr virus (EBV) infection is often characterized by protracted fever, lymphadenopathy, hepatosplenomegaly, pancytopenia, and extremely high titers of EBV-related antibodies [1]. Life-threatening complications, including pulmonary involvement, have been reported [1, 2]. There is no established treatment, and clinical improvement is rare. We describe a patient with EBV-associated pneumonia, in whom -interferon appeared to be effective.

A 27-year-old male patient was referred to us because of high fever, pneumonia, severe pancytopenia (hemoglobin, 5.0 g/dL; leukocyte count, 400/mm³; platelet count, 39 000/mm³), hepatosplenomegaly, and generalized lymphadenopathy. Severe chronic active EBV infection was diagnosed on the basis of very high titers of EBV-related antibodies (viral capsid antigen IgG, 10 240:1; early antigen IgG, 640:1) with a low titer of Epstein-Barr nuclear antigen IgG. Epstein-Barr virus genomes were identified in lymphocytes in the biopsied cervical lymph node by in-situ hybridization. There was no evidence of other virus infections, including human immunodeficiency virus. Immunologic assays showed profound depression of natural killer cell activity (lysis, 2%) as well as of specific cytotoxicity against EBV-transformed autologous B lymphocytes by peripheral mononuclear cells (specific killing, 2.6%). Repeated sputum cultures showed no respiratory pathogen. Activated T cells were dominant in bronchoalveolar lavage fluid cells, but neutrophils were not increased. Transbronchial lung biopsies failed to identify any causative microorganisms and showed only mild infiltration of mononuclear cells in alveolar septa and accumulation of macrophages in alveolar spaces. Intensive virologic investigations including polymerase chain reactions for various viral DNAs were all negative. Antibiotic and antifungal therapies did not produce any improvement. Acyclovir was administered with subsequent improvement of fatigue, fever, and pancytopenia (hemoglobin, 10.0 g/dL; leukocyte count, 2000/mm³; platelet count, 100 000/mm³). However, no improvement of pneumonia and mediastinal lymphadenopathy was seen (Figure 1, top panel). A selected defect of -interferon secretion [3] and the partial effect of -interferon in a patient with the X-linked lymphoproliferative syndrome [4] have been previously reported. So has the inhibition of -interferon synthesis by EBV-encoded Bam HI C fragment rightward reading-frame no. 1 (BCRFI) protein [5]. Thus, we administered recombinant -interferon (Shionogi Pharmaceutical Company, Osaka, Japan), 3 x 10⁶ U/d dissolved in 20 mL saline, by inhalation for 14 days with an ultrasonic nebulizer. Improvement of pneumonia on chest roentgenogram with disappearance of the productive cough was observed (Figure 1, middle panel). This treatment was continued for 8 weeks with further improvement, but the titers of EBV-related antibody and natural killer cell activities were not affected. No deterioration was observed after this treatment (Figure 1, bottom panel). We conclude that -interferon may be useful in treating some patients with chronic active EBV infection.

View larger version (67K): [in this window] [in a new window]   Figure 1. Chest roentgenogram. Left panel. Before administration of recombinant interferon. Middle panel. Fourteen days after the initiation of interferon therapy. Right panel. One month after the end of treatment.