A Varicella Outbreak in Diffuse Large B-Cell Lymphoma Patients Receiving Rituximab-Containing Chemotherapy
Authors: Okamoto Akinao , Abe Akihiro , Okamoto Masataka , Inaguma Yoko , Masutaka Tokuda , Morishima Satoko , Yanada Masamitsu , Kanie Tadaharu , Yamamoto Yukiya , Mizuta Shuichi , Akatsuka Yoshiki , Yoshikawa Tetsushi , Emi Nobuhiko 
Published: November 2019

Abstract
Background: Varicella, characterized by a vesicular rash, occurs primarily in young children. Although older individuals can also be affected or vaccinated, outbreaks among adults are rare. We experienced sequential four cases of varicella after an index herpes zoster case in hematological wards.
Methods: All varicella cases were confirmed varicella zoster virus (VZV) infection by PCR. We analyzed presence of anti-VZV IgG and IgM antibodies at the first hospital admission (cryopreserved serum) and the onset of VZV infection by enzyme immunoassay. To identify VZV-positive specimens and to differentiate these strains from the Oka vaccine virus, PCR designed to target the initial part of VZV open reading frame (ORF) 62 was performed on PBMCs or vesicular swabs. Furthermore, we investigated the incidence of localized zoster and generalized zoster/ varicella in rituximab administered patients. Between January 2010 and December 2013 (48 months), we collected data including the number ofrituximab administered patients, rituximab administration, localized zoster patients, and generalized zoster/varicella patients.
Findings: All varicella cases occured in diffuse large B-cell lymphoma patients receiving rituximab-containing chemotherapy (Table 1). On the other hand, only three of the 18 non-varicella patients in the same room were receiving rituximab-containing chemotherapy (P= 0.005, Table 2). Furthermore, all varicella patients had anti-VZV IgG antibody at the first hospital admission (Table 1). Sequencing the first part of ORF 62 in these cases showed the identical sequences and could be distinguished from the Oka vaccine virus, Oka parental virus and Dumas strain. During the 48 months, there were 340 patients who received rituximab. The total number of rituximab administrations was 2086. There were 29 patients with localized zoster (8.5%), and 5 patients with generalized zoster/varicella (1.4%). Four of these patients constituted the cluster reported here. The incidence of generalized zoster/ varicella for 2 months in this case was significantly higher than another 46 months (p<0.001).
Conclusions: Even in the presence of neutralizing antibodies to the virus, lymphoma patients treated with rituximab-containing chemotherapy can possibly become re-infected with varicella. These findings suggest that zoster patients should be strictly isolated in hematology and oncology ward, and prophylactic acyclovir should be considered for such patients when exposed to zoster/varicella.
Abstract 5439. Table 1. Patient characteristics Case Age Ward Treatment and onset Disease type Onset WBC (x109/L) Onset Lymphocyte (x109/L ) Onset serum VZV copy (Copies/mL) preserved IgG (EIA) Onset IgM (EIA) Onset IgG (EIA) Duration of ACV (Days) Complication 1 75 A 2ndrelapse #1 R-EPOCH Day30 Zoster 3.6 0.65 ND ND ND ND 8 None 2 50 A Primary #8 R-CyclOBEAP Day1 varicella 1.7 0.02 1.0×106 7.5 <0.80 5 12 None 3 81 B primary #3 R-CHOP Day14 varicella 5.0 0.03 1.7 × 107 5.8 <0.80 <2.0 44* Hepatitis DIC 4 63 A primary #3 R-CyclOBEAP Day8 varicella 11.8 0.35 2.7 × 104 17.8 <0.80 13.5 5 None 5 68 B 2ndrelapse After #4 R-DeVIC +Rx24Gy varicella 2.2 0.29 2.6 × 103 2.8 <0.80 2.4 7 None
R-EPOCH (rituximab, etoposide, prednisolone, vincristine cyclophosphamide and doxorubicin); R-CyclOBEAP (rituximab, cyclophosphamide, vincristine, etoposide, bleomycin, doxorubicin and prednisolone); R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone); R-DeVIC (dexamethasone, etoposide, ifosfamide and carboplatin); Rx, radiotherapy: ND, not done: ACV, acyclovir: DIC, disseminated intravenous coagulation; * treatment dose.
Table 2. Patients and control cohort characteristics. Varicella (N = 4) Without varicella (N = 18) P Age (median/range) 66/50–68 68/37–82 0.966 Male gender 4 18 - History of chemotherapy (%) 4 (100) 8 (44) 0.096 Rituximab administered (%) 4 (100) 3 (17) 0.005 WBC x109/L (median) 3.6 3.3 0.898 Lymphocyte x109/L (median/) 0.16 0.95 0.068 Albumin g/dL (median) 3.6 3.9 0.392 Creatinine mg/dL (median) 0.71 0.72 0.831 AST IU/L (median) 18 22 0.670
These data were at onset or exposure. WBC: white blood cell, AST: aspartate aminotransferase, T-Bil: total bilirubin.

Disclosures
No relevant conflicts of interest to declare.