SHORT REPORT Herpes virus infections occur frequently following treatment with fludarabine: results of a prospective natural history study J OHN C. B YRD, 1,5 L ISA H. MC G RAIL , 1 D UANE R. H OSPENTHAL , 2 ROBIN S. H O WA R D, 3 NANCY A. D OW 4 AND L OUIS F. D IEHL 11 Hematology-Oncology Service, and 2 Infectious Disease Service, Walter Reed Army Medical Center and Uniformed Services University, Washington, D.C. and Bethesda, Maryland, 3 Department of Clinical Investigation, and 4 Department of Pathology, Walter Reed Army Medical Center, Washington, D.C., and 5 Divison of Hematologic Malignancies, Johns Hopkins Oncology Center, Baltimore, Maryland, U.S.A. Received 13 January 1999; accepted for publication 3 February 1999 Summary. We performed a prospective infectious natural history study of 21 patients with low-grade lymphoproli- ferative disorders receiving fludarabine as initial (n ¼ 5) or salvage (n ¼ 16) therapy. 12 (57%) of these patients developed herpes zoster (n ¼ 9), herpes simplex I (n ¼ 1) or herpes simplex II (n ¼ 2) infections at a median of 8 (range 1–17) months following initiation of fludarabine, with 75% of these having completed therapy. All patients with herpes zoster developed severe post-herpetic neuralgia. Factors differentiating patients developing these infections included older age and low serum IgG or IgA. Based upon these prospective data, we conclude that herpes virus infections frequently occur following fludarabine treatment, necessitating aggressive patient education and new prophylactic strategies. Keywords: chronic lymphocytic leukaemia, non-Hodgkin’s lymphoma, varicella zoster, herpes simplex, fludarabine. The therapeutic options for patients with neoplastic dis- orders of mature B cells, including chronic lymphocytic leukaemia (CLL) and low-grade non-Hodgkin’s lymphoma (NHL), have been expanded with the introduction of the purine analogues. Based upon completed studies (Grever 1988; Binet et al, 1996; Loporrier et al, 1997), fludarabine is widely utilized both as initial and salvage treatment in CLL. Despite the frequency of infectious morbidity and related mortality in patients with CLL and NHL, prospective data on the natural history of these disorders either before or after the introduction of fludarabine are lacking. Our initial retrospective reports (Byrd et al, 1993, 1995) along with those of others (Wijermans et al, 1993; Bergmann et al, 1993) identified a high frequency of opportunistic infections following treatment with fludarabine as a salvage therapy. Based on these observations, we initiated a prospective natural history study in 1994 to estimate the frequency, associated morbidity, and risk factors for opportunistic infections in patients following treatment with fludarabine. METHODS Consecutive consenting patients with low-grade lymphopro- liferative disorders received fludarabine therapy at the Walter Reed Army Medical Center (WRAMC) between May 1994 and May 1996. Pre-treatment or sequentially obtained laboratory tests as part of this study included CD4, CD8, CD56 and CD20 absolute lymphocyte counts, serum immunoglobulin (IgG, IgA, IgM) levels, herpes simplex virus I IgG, varicella zoster virus IgG, and human immunodeficiency virus ELISA test. From the time of enrolment on this study until death or time of census, all patients received routine treatment and bimonthly follow-up by a physician at the WRAMC. No patients were lost to follow-up during this period. All initial diagnoses of herpes virus infections were made based upon positive culture or direct fluorescence antibody assays in the setting of clinical symptoms suggesting active herpes virus infections. Post-herpetic neuralgia was defined as pain that developed at the site of active localized or disseminated zoster and persisted for 30 d after disease onset. This was a study to describe the natural history of fludarabine-treated patients. Pretreatment and subsequent British Journal of Haematology , 1999, 105, 445–447 445  1999 Blackwell Science Ltd Correspondence: Dr John C. Byrd, Hematology-Oncology Service, Ward 78, Walter Reed Army Medical Center, Washington, D.C. 20307, U.S.A. e-mail: john_c.byrd@wramaa.chcs.amedd.army.mil.