|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-07-2110.
TRANSPLANTATION
From the Section of Bone Marrow Transplantation and
Leukemia, Washington University School of Medicine, St Louis; and
Division of Pediatric Hematology Oncology, Washington University School
of Medicine, St Louis, MO.
We studied the impact of donor cytomegalovirus (CMV)
serologic status on CMV viremia and disease when prophylactic
granulocyte colony-stimulating factor (G-CSF)-mobilized
granulocyte transfusions (GTs) were given following allogeneic
peripheral blood stem cell (AlloPBSC) transplantation. A cohort of
83 patients who received 2 prophylactic GTs from ABO-compatible stem
cell donors following AlloPBSC transplantation was compared with a
cohort of 142 patients who did not. AlloPBSC donors were eligible for
granulocyte donation irrespective of their CMV serostatus. Recipients
received no prophylactic therapy for CMV. Donor CMV serostatus had no
impact on CMV viremia and disease in the 2 cohorts. Our data show that
in an era of effective surveillance and preemptive therapy for CMV,
AlloPBSC recipients can safely receive 2 transfusions of prophylactic
G-CSF-mobilized granulocyte components from CMV-seropositive
AlloPBSC donors. This knowledge may help expand the donor pool in areas
with a high prevalence of CMV in the general population.
(Blood. 2003;101:2067-2069) In the neutropenic phase following allogeneic
peripheral blood stem cell (AlloPBSC) transplantation, recipients
are at risk for life-threatening infections. The ability to collect an
increased number of granulocytes from donors stimulated with
granulocyte colony-stimulating factor (G-CSF) has rekindled interest in
granulocyte transfusions (GTs) as a possible approach to this
problem.1,2 Preliminary data from our institution have
suggested that prophylactic G-CSF-mobilized HLA-matched
GTs from the PBSC donor may reduce antibiotic utilization and
febrile days in neutropenic AlloPBSC recipients and may improve
survival.3,4
However, granulocytes and peripheral blood mononuclear cells
(MNCs) are thought to be reservoirs for cytomegalovirus
(CMV).5-7 Despite the introduction of intensive CMV
surveillance strategies and prophylactic/preemptive antiviral therapy,
CMV infection remains a major cause of morbidity after allogeneic
transplantation.8-12 Traditionally, CMV-seropositive
individuals are excluded as granulocyte donors, especially for
CMV-seronegative recipients.13 With the prevalence of CMV
seropositivity in the general population being as high as 70% in
certain geographic areas, this exclusion criteria alone results in a
substantial diminution of the pool of potential granulocyte donors. The
published literature on the effect of GTs on CMV infection is limited,
and most antedate the era of G-CSF-mobilized GTs, the use of AlloPBSCs
and, most importantly, the availability of effective
prophylactic/preemptive therapy for CMV.14,15 We therefore
chose to study whether donor CMV serologic status had any effect on CMV
infection in a large cohort of AlloPBSC recipients following
infusion of G-CSF-mobilized prophylactic granulocyte components
obtained from AlloPBSC donors.
Related donor AlloPBSC recipients were scheduled to receive or
not receive HLA-matched G-CSF-mobilized prophylactic GTs on a
prospective study approved by the Institutional Review Board of
Washington University. Randomization was biologic, determined by
availability of an ABO-compatible AlloPBSC donor. The same ABO-compatible sibling served as both the AlloPBSC and granulocyte donor. Granulocyte donors were selected without regard to donor CMV
serologic status. G-CSF (10 µg/kg) was administered to
granulocyte donors 12 hours prior to each leukapheresis. Granulocyte
components were collected and irradiated as previously
reported.16 GTs were administered on day +3 and +6 or on
day +5 and +7 based on the conditioning regimen employed. To avoid
human error, all AlloPBSC recipients received CMV-seronegative or
filtered red cells and platelets irrespective of recipient CMV
serologic status. Recipients were monitored for CMV viremia every 2 weeks (from engraftment to day + 180) by shell vial/tube culture.
Preemptive therapy with intravenous gancyclovir 5 mg/kg once daily for
21 days was instituted following initial detection of CMV viremia.
Patients received acyclovir for herpes simplex virus and
trimethoprim-sulphamethoxazole for Pneumocystis
carinii prophylaxis.
A total of 225 patients underwent AlloPBSC transplantation.
Conditioning regimens were cyclophosphamide (CY)/total body irradiation (TBI) (129), etoposide/CY/TBI (58), busulfan/CY (15), and other (23).
AlloPBSC products were infused without T-cell depletion. Graft-versus-host disease (GVHD) prophylaxis consisted of
cyclosporine (CSA) and prednisone in 96 patients and CSA alone in 129 patients. Eighty-three patients received prophylactic GTs (cohort A),
and 142 patients did not (cohort B). Data on patient characteristics and leukocyte subsets administered in the 2 cohorts are summarized in
Tables 1-2. It is
of particular relevance that there were no statistically significant
differences with respect to observed rates of acute GVHD in the 2 cohorts. As expected, cohort A received a greater number of
neutrophils. This cohort also received a greater number of T cells
(CD3+), T-cell subsets (CD4+ and
CD8+), and natural killer (NK) cells
(CD16+CD56+).
The overall incidence of CMV viremia was not different between
recipients in cohorts A and B: 26 of 83 (31%) (95% confidence interval [CI], 22%, 42%) versus 49 of 142 (34%) (95% CI, 27%, 43%), respectively. The median time to detection of viremia was similar in cohort A (median, 35 days; range, 17-53 days) and cohort B
(median, 36 days; range, 17-77 days). There was also no difference in
the overall incidence of CMV disease between recipients in cohorts A
and B: 6 of 83 (7.2%) (95% CI, 1.2%, 8.0%) versus 5 of 142 (3.5%)
(95% CI, 2.7%, 15%), respectively. A detailed analysis of 4 subgroups based on donor and recipient CMV serostatus showed that
within each subgroup prophylactic GTs had no effect on the incidence of
CMV viremia (Table 3). In particular, the
incidence of CMV viremia between cohorts A and B was not different in
the CMV-seronegative recipients who had CMV-seropositive donors
(subgroup 2).
Two reports in the early 1980s found an increased incidence of CMV infection in seronegative recipients of GTs and formed the basis of the general policy of excluding CMV-seropositive individuals as granulocyte donors for immunocompromised CMV-seronegative recipients. The report of Winston et al was limited by a small and heterogeneous group of patients that received GTs from multiple granulocyte donors, most of whom did not have CMV serologic data available.15 Although seronegative granulocyte recipients did have a statistically higher prevalence of CMV infection, this was mainly accounted for by a higher incidence of asymptomatic seroconversion in the cohort receiving GTs. The rate of CMV disease among patients who did or did not receive GTs was the same. Hersman et al reported a higher incidence of CMV infection in seronegative recipients of GTs from seropositive granulocyte donors when compared with seronegative patients who did not receive GTs or seronegative patients who received GTs from seronegative donors.14 However, it appears that CMV-seronegative patients were permitted to receive red cell and platelet transfusions from donors irrespective of donor CMV serostatus. This potentially confounding variable could explain why an extremely high proportion (35%) of seronegative patients who received GTs from seronegative donors developed CMV infection. Recently, the debate on this issue has been rekindled with Narvios et al suggesting that screening of potential granulocyte donors for CMV antibody is not warranted, whereas Nichols et al disagree.17,18 As expected, our analysis of the cohort that did not receive prophylactic GTs showed that a seronegative recipient of AlloPBSCs from a seropositive donor had a greater risk of CMV viremia compared with a seronegative recipient who received AlloPBSCs from a seronegative PBSC donor (30.8 vs 2.7%) (Table 3). However, the additional transfusion of granulocyte components from CMV-seropositive donors to CMV-seronegative recipients did not significantly increase the risk of CMV viremia over that observed in similar donor-recipient CMV serostatus pairs given AlloPBSCs alone (33.3% vs 30.8%) (Table 3). Although granulocyte components were not tested for the CMV genome and the power of the subgroup analysis based on donor and recipient serostatus is limited by the small sample size, it appears that most of the risk of CMV viremia was derived from the transfusion of the AlloPBSC product from a CMV-seropositive donor. The transfusion of granulocyte components collected from CMV-seropositive donors did not add substantially to this risk. This may be due to passive transfer of immunity to CMV by the large numbers of immune effector cells in the granulocyte components. Our data show that in an era of effective surveillance and preemptive therapy for CMV, AlloPBSC recipients can safely receive 2 transfusions of prophylactic G-CSF-mobilized granulocyte components from CMV-seropositive AlloPBSC donors. This knowledge may help expand the donor pool in areas with a high prevalence of CMV in the general population.
Submitted July 15, 2002; accepted October 10, 2002.
Prepublished online as Blood First Edition Paper, October 24, 2002; DOI 10.1182/blood-2002-07-2110.
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: Ravi Vij, Section of Bone Marrow Transplantation and Leukemia, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8007, St Louis, MO 63110-1093; e-mail: rvij{at}im.wustl.edu.
1. Bensinger WI, Price TH, Dale DC, et al. The effects of daily recombinant human granulocyte colony-stimulating factor administration on normal granulocyte donors undergoing leukapheresis. Blood. 1993;81:1883-1888[Abstract]. 2. Strauss RG. Therapeutic granulocyte transfusions in 1993. Blood. 1993;81:1675-1678[Medline] [Order article via Infotrieve]. 3. Adkins D, Goodnough LT, Moellering J, et al. Reduction in antibiotic utilization and in febrile days by transfusion of G-CSF mobilized prophylactic granulocyte components: a randomized study [abstract]. Blood. 1999;94:590a. 4. Blum W, Hallem C, Vij R, et al. Improved survival in allogeneic peripheral blood stem cell (PBSC) transplant patients who received prophylactic granulocyte transfusions from HLA-matched donors: long term follow-up [abstract]. Blood. 2001;98:58a. 5. Brytting M, Mousavi-Jazi M, Bostrom L, et al. Cytomegalovirus DNA in peripheral blood leukocytes and plasma from bone marrow transplant recipients. Transplantation. 1995;60:961-965[Medline] [Order article via Infotrieve]. 6. Hamprecht K, Steinmassl M, Einsele L, Jahn G. Discordant detection of human cytomegalovirus DNA from peripheral blood mononuclear cells, granulocytes and plasma: correlation to viremia and HCMV infection. J Clin Virol. 1998;11:125-136[CrossRef][Medline] [Order article via Infotrieve]. 7. von Laer D, Serr A, Meyer-Konig U, Kriste G, Hufert FT, Haller O. Human cytomegalovirus immediate early and late transcripts are expressed in all major leukocyte populations in vivo. J Infect Dis. 1995;172:365-370[Medline] [Order article via Infotrieve]. 8. Yakushiji K, Gondo H, Kamezaki K, et al. Monitoring of cytomegalovirus reactivation after allogeneic stem cell transplantation: comparison of an antigenemia assay and quantitative real-time polymerase chain reaction. Bone Marrow Transplant. 2002;29:599-606[CrossRef][Medline] [Order article via Infotrieve]. 9. Machado CM, Menezes RX, Macedo MC, et al. Extended antigenemia surveillance and late cytomegalovirus infection after allogeneic BMT. Bone Marrow Transplant. 2001;28:1053-1059[CrossRef][Medline] [Order article via Infotrieve].
10.
Kanda Y, Mineishi S, Nakai K, Sait OT, Tanosaki R, Takaue Y.
Frequent detection of rising cytomegalovirus antigenemia after allogeneic stem cell transplantation following a regimen containing antithymocyte globulin.
Blood.
2001;97:3676-3677
11.
Junghanss C, Boeckh M, Carter RA, et al.
Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study.
Blood.
2002;99:1978-1985
12.
Broers AE, van Der Holt R, van Esser JW, et al.
Increased transplant-related morbidity and mortality in CMV-seropositive patients despite highly effective prevention of CMV disease after allogeneic T-cell-depleted stem cell transplantation.
Blood.
2000;95:2240-2245 13. America's Blood Centers. Granulocyte transfusions. Blood Bull. 2000;2. Available at: http://66.155.15.152/medical/bulletin_v2_n4.htm. 14. Hersman J, Meyers JD, Thomas ED, Buckner CD, Clift R. The effect of granulocyte transfusions on the incidence of cytomegalovirus infection after allogeneic marrow transplantation. Ann Intern Med. 1982;96:149-152[Medline] [Order article via Infotrieve]. 15. Winston DJ, Ho WG, Howell CL, et al. Cytomegalovirus infections associated with leukocyte transfusions. Ann Intern Med. 1980;93:671-675[Medline] [Order article via Infotrieve].
16.
Adkins D, Goodnough LT, Shenoy S, et al.
Effect of leukocyte compatibility on neutrophil increment after transfusion of granulocyte colony-stimulating factor-mobilized prophylactic granulocyte transfusions and on clinical outcomes after stem cell transplantation.
Blood.
2000;95:3605-3612
17.
Narvios A, Pena E, Han XY, Lichtiger B.
Cytomegalovirus infection in cancer patients receiving granulocyte transfusions.
Blood.
2002;99:390-391
18.
Nichols WG, Price T, Boeckh M.
Cytomegalovirus infections in cancer patients receiving granulocyte transfusions.
Blood.
2002;99:3483-3484
© 2003 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  W. G. Nichols, T. Price, M. Boeckh, R. Vij, J. DiPersio, H. Khoury, L. T. Goodnough, S. M. Devine, W. Blum, and D. Adkins Donor serostatus and CMV infection and disease among recipients of prophylactic granulocyte transfusions Blood, June 15, 2003; 101(12): 5091 - 5092. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2003 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction