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BRIEF REPORT
From the Emory University School of Medicine, Winship
Cancer Institute, Department of Hematology-Oncology, Bone Marrow and
Stem Cell Transplant Center, and Departments of Pathology and
Infectious Diseases, Emory University, Atlanta, Georgia.
An unusually high incidence of acyclovir- and foscarnet-resistant
herpes simplex virus (HSV) infection was noted after
lymphocyte-depleted blood hematopoietic progenitor cell (HPC)
transplantation from HLA-haploidentical family donors. Fourteen adults
with hematologic malignancies underwent blood HPC transplantation from
haploidentical family donors. Pheresis products were stringently
depleted of T and B cells by immunomagnetic adsorption, and patients
received no immunosuppression after transplantation. HSV
reactivation occurred in all 7 evaluable HSV-1- or HSV-2-seropositive
patients, at a median of 40 days after transplantation. Susceptibility
testing of clinically resistant viral isolates demonstrated acyclovir resistance in all 5 cases tested. Second-line therapy produced only
partial responses, and in vitro evidence of foscarnet resistance developed rapidly in all 3 patients treated with foscarnet. Healing of
lesions coincided with T-cell recovery. The prolonged immunodeficiency associated with stringent lymphocyte depletion of the graft appears to
strongly predispose to emergence of drug-resistant HSV. Furthermore, immune reconstitution is necessary for eradication of infection.
(Blood. 2002;99:1085-1088) The use of prophylactic acyclovir (ACV) has
markedly reduced the incidence of early reactivation of herpes simplex
viruses (HSVs) after allogeneic bone marrow or blood hematopoietic
progenitor cell (HPC) transplantation.1,2 Resistance to
ACV develops rapidly in tissue culture as a result of mutations in
either the viral thymidine kinase or DNA polymerase genes; DNA
polymerase mutants are also typically resistant to
foscarnet.3,4 In early reports, clinical and in vitro
resistance to acyclovir was not common after marrow
transplantation.5-7 Recently, several groups have reported
a substantial frequency of drug-resistant HSV infections after marrow
or blood HPC transplantation.8-11 The latter observations
presumably reflect the increased use of unrelated and HLA-mismatched
donors, and T-cell depletion of the donor graft, which are risk factors
for development of resistant herpesvirus infections.10,11
We report an unusually high incidence of drug-resistant HSV infection
after haploidentical blood stem cell transplantation involving
stringent T- and B-cell depletion of the donor graft.
Patient population and transplantation
HSV reactivation, cultures, and susceptibility testing
Characteristics of the 14 patients treated according to protocol
are shown in Table 1; data are also
presented for patients with and without HSV reactivation. Two patients
(both HSV seropositive) died on posttransplantation days 6 and 8, leaving 12 patients fully evaluable for evidence of HSV reactivation.
All of the 12 patients who survived beyond posttransplantation day 8 achieved granulocyte engraftment (absolute neutrophil count [ANC]
> 500/µL for at least 2 consecutive days), at a median of 11 days
after transplantation (range, 9-27 days). Median values for subsets of
CD4+ T cells, CD8+ T cells, and
CD56+ NK cells at intervals after transplantation are shown
in Table 1.
Table 2 provides clinical and virologic
details of HSV disease among study patients. Evidence of HSV
reactivation was seen in all 7 evaluable HSV-1 or HSV-2 seropositive
patients, versus none of the 5 patients seronegative for HSV. As shown
in Table 1, there were no other significant differences between
patients with and without HSV infection. HSV reactivation occurred at a median of 40 days after transplantation (range, 12-136 days), at which
time the median blood CD4 cell count was 3.5/µL (range, 0-44/µL). Sites of reactivation included oral mucosa (3 patients), esophagus (2 patients), and anogenital area (3 patients); one patient
had lesions at 2 sites (anogenital and esophagus). In 5 patients,
lesions developed while the patient was receiving either intravenous
ACV for primary HSV prophylaxis (2 patients) or ganciclovir for
treatment of CMV reactivation (3 patients). No patient was receiving
immunosuppressive medications at the time of HSV reactivation.
Susceptibility testing was conducted on isolates from 5 patients, either because of development of lesions while on ACV or ganciclovir, or failure to respond to initial therapy; all 5 isolates were ACV resistant by in vitro testing. ACV-resistant lesions failed to respond completely to alternative therapy, including higher doses of ACV, foscarnet, or cidofovir. In vitro resistance to foscarnet developed in all 3 patients who were treated with foscarnet. Eventual healing of lesions correlated with immune recovery; one patient has developed recurrent ACV-resistant HSV lesions in association with a drop in the CD4 cell count (Table 2). The 2 patients with anogenital HSV posed local management challenges because ulcers were large (> 6 cm diameter), but no one developed life-threatening HSV disease or secondary complications despite the long duration of active lesions in surviving patients. Interestingly, in this group of patients all episodes of CMV and VZV reactivation responded promptly to ganciclovir or ACV therapy, respectively (data not shown). Acyclovir-resistant HSV infections occur almost exclusively in immunocompromised patients and are most commonly seen in individuals infected with human immunodeficiency virus.14,15 Several lines of evidence highlight the importance of cell-mediated immunity (mediated by T cells and NK cells) in providing protection from HSV reactivation as well as healing of established lesions.16-19 In the patient population described here, significant NK cell recovery occurred early after transplantation, but did not prevent viral reactivation or facilitate clearance. Healing of HSV lesions correlated with recovery of CD4+ and CD8+ T cells, which was delayed. These data are consistent with in vitro and animal studies implicating CD4+ and CD8+ effector T cells as essential for clearance of HSV and healing of lesions.16,18 Our experience illustrates the importance of drug-resistant HSV in alternative donor transplantation, particularly when stringent lymphocyte depletion is used. The HSV prophylaxis regimen used was not adequate for prevention of HSV reactivation in this clinical setting, although using the same antiviral prophylaxis, we have seen ACV-resistant HSV infection in only 2 (3.4%) of 59 patients receiving transplants from matched unrelated donors at our institution since January 1997 (versus 5 [36%] of 14 patients in the current series, P = .002). Administration of higher doses of prophylactic ACV for longer periods before and after transplantation may reduce the incidence of HSV reactivation and development of drug resistance in these patients; however, it may not completely eliminate the problem given that most reactivation episodes in this series occurred during antiviral therapy. Combination or sequential antiviral prophylaxis may be more effective than single-agent therapy, although this remains to be tested. On the basis of these data, we have modified the HSV
prophylaxis for this protocol: HSV-seropositive patients receive ACV 10 mg/kg intravenously every 8 hours from day
We wish to thank staffs of Emory University Hospital Ward 7E, the Emory Clinic Ambulatory Infusion Clinic, and the Emory Bone Marrow and Stem Cell Transplant Center for clinical care of patients. We also thank Vickie Bartlett for transplant coordination, Grier Banks and the staff of the Emory University Hospital Clinical Microbiology Lab for expert technical assistance, and Sylvia Ennis for assistance in preparation of the manuscript. Isolex cell selection devices were generously provided by Nexell Therapeutics (Irvine, CA) and Baxter HCC.
Submitted May 31, 2001; accepted September 26, 2001.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Amelia Langston, The Emory Clinic, 1365 Clifton Rd NE, Suite B6208, Atlanta, GA 30322; e-mail: amelia_langston{at}emory.org.
1. Saral R, Burns WH, Laskin OL, Santos GW, Lietman PS. Acyclovir prophylaxis of herpes-simplex-virus infections. N Engl J Med. 1981;305:63-67[Abstract]. 2. Wade JC, Newton B, Flournoy N, Meyers JD. Oral acyclovir for prevention of herpes simplex virus reactivation after marrow transplantation. Ann Intern Med. 1984;100:823-828.
3.
Schnipper LE, Crumpacker CS.
Resistance of herpes simplex virus to acycloguanosine: role of viral thymidine kinase and DNA polymerase loci.
Proc Natl Acad Sci U S A.
1980;77:2270-2273 4. Gaudreau A, Hill E, Balfour HH, Erice A, Boivin G. Phenotypic and genotypic characterization of acyclovir-resistant herpes simplex viruses from immunocompromised patients. J Infect Dis. 1998;178:297-303[Medline] [Order article via Infotrieve]. 5. Burns WH, Saral R, Santos GW, et al. Isolation and characterization of resistant herpes simplex virus after acyclovir therapy. Lancet. 1982;1:421-423[CrossRef][Medline] [Order article via Infotrieve]. 6. Wade JC, McLaren C, Meyers JD. Frequency and significance of acyclovir-resistant herpes simplex virus isolated from marrow transplant patients receiving multiple courses of treatment with acyclovir. J Infect Dis. 1983;148:1077-1082[Medline] [Order article via Infotrieve]. 7. Wade JC, Day LM, Crowley JJ, Meyers JD. Recurrent infection with herpes simplex virus after marrow transplantation: role of the specific immune response and acyclovir treatment. J Infect Dis. 1984;149:750-756[Medline] [Order article via Infotrieve]. 8. Reusser P, Cordonnier C, Einsele H, et al. European survey of herpesvirus resistance to antiviral drugs in bone marrow transplant recipients. Bone Marrow Transplant. 1996;17:813-817[Medline] [Order article via Infotrieve]. 9. Darville JM, Ley BE, Roome AP, Foot AB. Acyclovir-resistant herpes simplex virus infections in a bone marrow transplant population. Bone Marrow Transplant. 1998;22:587-589[CrossRef][Medline] [Order article via Infotrieve]. 10. Chen Y, Scieux C, Garrait V, et al. Resistant herpes simplex virus type 1 infection: an emerging concern after allogeneic stem cell transplantation. Clin Infect Dis. 2000;31:927-935[Medline] [Order article via Infotrieve]. 11. Chakrabarti S, Pillay D, Ratcliffe D, Cane PA, Collingham KE, Milligan DW. Resistance to antiviral drugs in herpes simplex virus infections among allogeneic stem cell transplant recipients: risk factors and prognostic significance. J Infect Dis. 2000;181:2055-2058[CrossRef][Medline] [Order article via Infotrieve]. 12. Ljungman P, Lore K, Aschan J, et al. Use of a semi-quantitative PCR for cytomegalovirus DNA as a basis for pre-emptive antiviral therapy in allogeneic bone marrow transplant patients. Bone Marrow Transplant. 1996;17:583-587[Medline] [Order article via Infotrieve]. 13. Hodinka RL. Antiviral susceptibility testing using DNA-DNA hybridization. In: Weidbrauk DL,Farkas DH, eds. Molecular Methods for Virus Detection. San Diego: Academic Press; 1995:103-125. 14. Englund JA, Zimmerman ME, Swierkosz EM, Goodman JL, Scholl DR, Balfour HH. Herpes simplex virus resistant to acyclovir. A study in a tertiary care center. Ann Intern Med. 1990;112:416-422. 15. Erlich KS, Mills J, Chatis P, et al. Acyclovir-resistant herpes simplex virus infections in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1989;320:293296. 16. Koelle DM, Posavad CM, Barnum GR, Johnson ML, Frank JM, Corey L. Clearance of HSV-2 from recurrent genital lesions correlates with infiltration of HSV-specific cytotoxic T lymphocytes. J Clin Invest. 1998;101:1500-1508[Medline] [Order article via Infotrieve]. 17. Gosselin J, TomoIu A, Gallo RC, Flamand L. Interleukin-15 as an activator of natural killer cell-mediated antiviral response. Blood. 1999;94:4209-4210.
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Posavad CM, Huang ML, Barcy S, Koelle DM, Corey L.
Long term persistence of herpes simplex virus-specific CD8+ CTL in persons with frequently recurring genital herpes.
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2000;165:1146-1152 19. Ghiasi H, Cai S, Perng GC, Nesburn AB, Wechsler SL. The role of natural killer cells in protection of mice against death and corneal scarring following ocular HSV-1 infection. Antiviral Res. 2000;45:33-45[CrossRef][Medline] [Order article via Infotrieve].
© 2002 by The American Society of Hematology.
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  M. S. Hossain, J. D. Roback, F. Wang, and E. K. Waller Host and Donor Immune Responses Contribute to Antiviral Effects of Amotosalen-Treated Donor Lymphocytes following Early Posttransplant Cytomegalovirus Infection J. Immunol., May 15, 2008; 180(10): 6892 - 6902. [Abstract] [Full Text] [PDF]
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 J. D. Roback Vaccine-Enhanced Donor Lymphocyte Infusion (veDLI) Hematology, January 1, 2006; 2006(1): 486 - 491. [Abstract] [Full Text] [PDF]
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 M. Saijo, T. Suzutani, S. Morikawa, and I. Kurane Genotypic Characterization of the DNA Polymerase and Sensitivity to Antiviral Compounds of Foscarnet-Resistant Herpes Simplex Virus Type 1 (HSV-1) Derived from a Foscarnet-Sensitive HSV-1 Strain Antimicrob. Agents Chemother., February 1, 2005; 49(2): 606 - 611. [Abstract] [Full Text] [PDF]
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 C. Danve-Szatanek, M. Aymard, D. Thouvenot, F. Morfin, G. Agius, I. Bertin, S. Billaudel, B. Chanzy, M. Coste-Burel, L. Finkielsztejn, et al. Surveillance Network for Herpes Simplex Virus Resistance to Antiviral Drugs: 3-Year Follow-Up J. Clin. Microbiol., January 1, 2004; 42(1): 242 - 249. [Abstract] [Full Text] [PDF]
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 F. J. Jenkins, D. T. Rowe, and C. R. Rinaldo Jr. Herpesvirus Infections in Organ Transplant Recipients Clin. Vaccine Immunol., January 1, 2003; 10(1): 1 - 7. [Full Text] [PDF]
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Top
Abstract
Introduction
10 and consisted of fractionated total body irradiation,
thiotepa, fludarabine, and antithymocyte globulin (ATG; 13 patients),
or busulfan, cyclophosphamide, fludarabine, and ATG (1 patient). Donors
underwent leukopheresis for 2 to 5 days after subcutaneous administration of granulocyte colony-stimulating factor (G-CSF; 10 µg/kg per day). Donor pheresis products were stringently depleted of
T and B cells by a combination of CD34+ selection
and T- and B-cell-negative selection using the Isolex 300i system
(version 2.5; Baxter HCC, Roundlake, IL), and immediately administered to the recipient through a central venous catheter. No
posttransplantation immunosuppression was given for graft-versus-host disease prophylaxis. Patients with positive pretransplantation serologies for HSV-1, HSV-2, or varicella zoster virus (VZV) received prophylactic acyclovir (5 mg/kg intravenously every 8 hours) from day