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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Fred Hutchinson Cancer Research Center and
University of Washington, Seattle, WA.
Allogeneic peripheral blood stem cell grafts contain about 10 times more T and B cells than marrow grafts. Because these cells may
survive in transplant recipients for a long time, recipients of blood
stem cells may be less immunocompromised than recipients of marrow.
Immune reconstitution was studied in 115 patients randomly assigned to
receive either allogeneic marrow or filgrastim-mobilized blood stem
cell transplantation. Between day 30 and 365 after transplantation,
counts of most lymphocyte subsets were higher in the blood stem cell
recipients. The difference was most striking for CD4 T cells (about
4-fold higher counts for CD45RAhigh CD4 T cells and about
2-fold higher counts for CD45RAlow/ Allogeneic bone marrow transplantation is a
recognized treatment for certain hematologic malignant diseases,
aplastic anemia, and inborn errors of cells originating from
hematopoietic stem cells.1,2 Immune deficiency leading to
increased susceptibility to infections follows transplantation and
lasts for more than a year.3-8 Although infections that
occur in the first month after grafting likely result from a deficiency
of both granulocytes and mononuclear cell (MNC) subsets,
postengraftment infections are probably due to a deficiency in MNC
subsets, primarily CD4 T cells and B cells.9-11
Postengraftment infections cause substantial morbidity and mortality.
Atkinson et al3 showed that 87% of allograft recipients
had at least one postengraftment infection and 48% had at least 3 (excluding upper respiratory tract infections) during a 2-year period.
A similar incidence of postengraftment infections was observed by Ochs
et al,7 who also noted that occurrence of postengraftment
infection was the dominant independent factor associated with increased
nonrelapse mortality (relative risk = 5.5;
P = .0001).
Recipients of blood stem cells receive at least 10 times more
lymphocytes than recipients of marrow.12,13 The lifespan of human T cells is months to years.14-16 Therefore, we
hypothesized that the large lymphocyte inoculum given to blood stem
cell recipients might result in higher T-cell counts in the first year
after transplantation. Results of small nonrandomized studies of blood
stem cell recipients compared with marrow recipients support this
hypothesis.12,13 We also hypothesized that higher
lymphocyte counts in blood stem cell recipients could lead to lower
infection rates. Thus, the purpose of this randomized study was to
analyze MNC-subset recovery and postengraftment infection rates in
marrow grafting compared with blood stem cell grafting.
Patients
Enumeration of MNC subsets
Lymphoproliferation assays Herpes simplex virus (HSV)-specific, varicella zoster virus (VZV)-specific T-helper-cell function and phytohemagglutinin (PHA)-stimulated T-cell proliferation were assessed as described previously.29,30 Briefly, MNCs separated by a Ficoll device were suspended at a concentration of 2 × 106 cells/mL in RPMI with 10% human AB serum, glutamine (4 mM), penicillin (100 U/mL), streptomycin (0.1 mg/mL), and amphotericin B (250 ng/mL). One hundred microliters of the peripheral blood mononuclear cell suspension was dispensed into wells of 96 round-bottomed plates. VZV and HSV antigens were prepared by sonication and heat inactivation of virus grown on foreskin fibroblasts. HSV or VZV antigen or PHA (final concentration, 10 µg/mL) was added to triplicate wells containing MNCs on day zero. The plates were incubated at 37°C in a humidified 5% carbon dioxide atmosphere for 4 days. Eighteen to 24 hours before harvest, tritium thymidine (0.074 MBq [2 µCi]) was added to each well. Cells were harvested by using a semiautomated harvester, and counts per minute (cpm) were determined in a -scintillation counter.
The mean cpm of cells exposed to the antigen minus the mean cpm of
cells incubated with medium alone ( cpm) was calculated. Because the
percentage of CD4 cells, as well as total T cells, among MNCs was
higher in the blood stem cell recipients than in the marrow recipients,
results were expressed as cpm per 1000 CD4 T cells (HSV and VZV
assessment) or per 1000 T cells (PHA assessment).
IgG levels Serum IgG levels were determined by standard rate nephelometry.Enumeration of infections The goal of this study was to determine whether higher lymphocyte counts after blood stem cell grafting would be associated with an infection rate lower than that after marrow grafting. Because blood stem cell grafting is associated with earlier neutrophil engraftment,17 only postengraftment infections were counted. These were defined as infections diagnosed between day 30 and day 365, since both marrow recipients and blood stem cell recipients achieved neutrophil engraftment by day 30 (Table 1) and the minimum follow-up period was 365 days.Definite infection was defined as an illness with symptoms and signs consistent with an infection and microbiological documentation of a pathogen, except in cases of dermatomal zoster, for which a clinical diagnosis was considered sufficient to classify an infection as definite. Microbiological documentation of an infection consisted of isolation of the pathogen by culture from a sterile or nonsterile site (if from a nonsterile site, the organism had to be clinically judged to be pathogenic) or histologic or immunohistologic evidence. Culture-documented viremia, bacteremia, or fungemia was considered a definite infection even if the patient had no symptoms or signs of infection. Oral candidiasis was not considered a definite infection because it could not be reliably distinguished from oral graft-versus-host disease (GVHD) with candidal colonization. Clinical infection (no microorganism identified) was defined as illness with symptoms and signs consistent with an infection. Presumed oral, gastrointestinal, conjunctival, and respiratory tract infections were not included, however, because they could not be reliably distinguished from GVHD or allergy. Hemorrhagic cystitis was not included because it could not be differentiated from conditioning-regimen-induced cystitis. Fever of presumed infectious cause was included only if the patient's body temperature was above 38.5°C and the condition responded to antibiotic therapy within 3 days. Sinusitis and pneumonia were included only if documented radiologically. A chronic infection was counted as one infection. A recurrent infection was counted as multiple infections only if episodes were clearly separated by an asymptomatic period of longer than 4 weeks. A polymicrobial infection of one organ or several adjacent organs was considered one infection (due to the organism judged to be the major pathogen). Infections with one microorganism in 2 nonadjacent organs were counted as 2 infections. The respiratory tract was considered adjacent to the paranasal sinuses and lungs. Lungs and paranasal sinuses were considered nonadjacent. An organ infection with viremia, bacteremia, or fungemia was counted only as the organ infection. Severe infections were defined as infections treated in a hospital. Nonsevere infections were treated in an outpatient setting. Death associated with a definite infection was defined as (1) autopsy findings consistent with an infection and detection of the pathogen in an autopsy specimen, or (2) death after a definite infection that was judged to have caused the death either directly (eg, pneumonia) or indirectly (eg, sepsis with subsequent adult respiratory distress syndrome). Statistical analysis The significance of differences between marrow recipients and blood stem cell recipients in MNC-subset counts, cpm, and serum IgG
levels at each time point was tested by the Mann-Whitney rank sum test.
The significance of differences in infection rates was determined by
the likelihood ratio test. The number of infections was treated as a
Poisson random variable. Regression models were fit with the SAS Genmod
(SAS Institute, Cary, NC) procedure using the log of the number of days
at risk as a fixed predictor (offset). Days at risk were calculated as
365 or the day after transplantation of death or relapse (whatever
occurred first) minus 30.
MNC subsets Compared with marrow recipients, blood stem cell recipients received significantly higher numbers of all subsets of MNCs with the graft, except for B-cell progenitors and plasma cells (Table 3). In the first year after grafting, counts of the following MNC subsets were significantly higher in blood stem cell recipients at 3 or more time points (Figure 1): total CD4 T cells and their CD45RAhigh (naive), CD45RAlow/
(memory/effector) and CD28+ subpopulations, CD8 T cells and
their CD11alow (naive) and CD28+
subpopulations, and CD4CD8 T cells. Subsets
not significantly different at any time point after transplantation
included CD28CD8 T cells and monocytes. MNC subsets with
significantly greater numbers in marrow recipients than in blood stem
cell recipients early (on day 30 or day 80) but not late (on day 180 or
day 365) after transplantation included total B cells and their
IgD+ (naive) and IgD (memory) subsets,
CD11ahigh (memory/effector) CD8 T cells, and natural killer
(NK) cells. Conversely, CD28CD4 T-cell counts and
CD4+CD8+ T cell counts were similar in the 2 groups of recipients early after transplantation but higher in blood
stem cell recipients later. MNC-subset counts in marrow donors and
those in blood stem cell donors (before use of filgrastim) were similar
(P > 0.1 for all the subsets). The data from donors were
pooled and are shown in Figure 1 as the normal reference
values.
Lymphoproliferation in vitro To assess whether the functional capacity of T cells was different in blood stem cell recipients compared with marrow recipients, PHA-stimulated proliferation of MNCs corrected for the percentage of T cells among MNCs was evaluated. The median corrected cpm was 1.5 times higher in blood stem cell recipients on day 30 (P = .04) and not significantly different on day 80, 180, or 365 (Figure 2). This suggests that
during most of the first year after transplantation, the functional
capacity of single T cells is similar in marrow recipients and blood
stem cell recipients.
T-helper-cell function was assessed by observing proliferation on
stimulation with HSV and VZV proteins. We focused on recipients with a
latent or active infection whose donors had an infection because
uninfected recipients with uninfected donors are not expected to mount
a lymphoproliferative response. Infection can be assessed indirectly by
detection of antiviral antibodies or, in healthy persons, detection of
antiviral T cells, by lymphoproliferation.31 HSV-specific
lymphoproliferation was evaluated in HSV-seropositive patients with
HSV-lymphoproliferation-positive donors (13 marrow recipients and 21 blood stem cell recipients), and VZV-specific lymphoproliferation was
evaluated in VZV-seropositive patients with
VZV-lymphoproliferation-positive donors (17 marrow recipients and 19 blood stem cell recipients). For both HSV and VZV, the median corrected
Interestingly, when uncorrected Serum IgG Measurements of total serum IgG levels on day 80 after transplantation were available for 44 marrow recipients and 44 blood stem cell recipients who did not have multiple myeloma and did not receive intravenous immunoglobulin between day 0 and day 80. The levels were similar (median, 5.70 g/L in marrow recipients and 5.45 g/L in blood stem cell recipients; P = .99). Determinations of day 365 IgG levels were available for 31 marrow recipients and 39 blood stem cell recipients who did not have multiple myeloma and had not received intravenous immunoglobulin within 2 months before the evaluation on day 365. Levels were also similar at that time (median, 6.32 g/L in marrow recipients and 5.65 g/L in blood stem cell recipients; P = .56). Our normal range (5th-95th percentile) is 6.94 to 15.18 g/L. Thus, the degree of IgG deficiency was similar in the 2 groups of patients.Infections The rate of total infections was 1.4 times higher in marrow recipients than in blood stem cell recipients (P .01;
Table 4). The rate of total definite
infections was 1.7 times higher in marrow recipients
(P .001). Importantly, the difference was more striking
for severe definite infections (2.4 times higher rate in marrow
recipients) than for nonsevere definite infections (1.4 times higher
rate in marrow recipients). The difference was more striking for
bacterial infections (1.7 times higher rate) and fungal infections (5.5 times higher rate) than for viral infections (1.4 times higher rate).
The rate of clinical infections was similar in the 2 groups. Details on
the infections are shown in Table 5.
There was no difference in the posttransplantation day of diagnosis of the infections (median, day 78 for marrow recipients [25th-75th percentile, day 52-day 168] and day 98 for blood stem cell
recipients [25th-75th percentile, day 50-day 182];
P = .43; Figure 3).
Although all patients had a sustained absolute neutrophil count of 0.5 × 109/L by day 28 after transplantation (Table 1), absolute neutrophil counts were significantly higher in blood stem cell recipients compared with marrow recipients until day 48. To eliminate any influence of the different neutrophil counts, we compared infection rates between day 60 and day 365. The rate of total infections was significantly higher in marrow recipients (unadjusted rate ratio, 1.48 [P = .02], and adjusted rate ratio, 1.53 [P = .01]). The rate of total definite infections was also significantly higher in marrow recipients (unadjusted rate ratio, 1.90 [P = .002], and adjusted rate ratio, 1.99 [P = .001]). Therefore, the differences in infection rates between day 30 and day 365 in the 2 groups of patients were most likely due to the differences in lymphocyte-subset counts and not neutrophil counts. Death associated with a definite infection diagnosed between day 30 and
day 365 occurred between day 30 and day 365 in 9 marrow recipients and
3 blood stem cell recipients (P = .17 by X2 test). Details on these infections are provided in Table
6. There were 9 deaths associated with a
bacterial or fungal infection among marrow recipients and none among
blood stem cell recipients (P = .008 by X2
test).
The important findings of this study were that (1) compared with marrow recipients, blood stem cell recipients had higher counts of T cells (particularly CD4 T cells); (2) T cells were equally functional in the 2 patient groups; and (3) improving the quantitative lymphocyte deficiency in recipients of hematopoietic transplants may result in fewer infections. The higher counts of certain lymphocyte subsets in blood stem cell recipients were anticipated because of the results of smaller nonrandomized studies and have been attributed to the larger lymphocyte inoculum.12,13 It is reasonable to attribute the higher posttransplantation counts of T cells, particularly naive T cells, to the large inoculum because T cells, especially naive T cells, are extremely long-lived.14-16 Also, few T cells are produced from stem cells in adult transplant recipients in the first year after transplantation because of age- and allografting-associated thymic atrophy; therefore, most T cells in patients in this year originate from the T cells infused with the graft.8,32-35 This idea is in agreement with the observation that naive T-cell counts but not CD34 cell counts in the grafts correlate with naive T-cell counts after transplantation (J. S. et al, unpublished data, March 2001). We found that even though blood stem cell grafts contained more monocytes, NK cells, and B cells than marrow grafts, reconstitution of these cell populations was similar in marrow recipients and blood stem cell recipients. The numbers of monocytes and NK cells had already reached the normal range by day 30, suggesting that reconstitution of these populations occurs rapidly and is not limited by the number of cells in the graft. B-cell counts were higher during the first 3 months after blood stem cell transplantation compared with marrow transplantation. This finding is consistent with the presence of much higher numbers of naive and memory B cells in blood stem cell grafts than in marrow grafts. However, the rate of B-cell recovery was faster in marrow recipients, as indicated by the steeper slope during the first 3 months after grafting (Figure 1). This might have been due to the higher number of B-cell progenitors in the marrow grafts (Table 3). Total IgG levels were similar in the 2 patient groups, suggesting that humoral immunity is not improved after blood stem cell grafting compared with marrow grafting. After marrow grafting, IgG is frequently composed of monoclonal or oligoclonal immunoglobulins of unclear specificity (not against infectious agents)36-50 and therefore the protective value of these immunoglobulins in marrow recipients is low. Qualitative comparisons of immunoglobulins will be needed to assess the contribution of humoral immunity to preventing infection after blood stem cell transplantation. The presence of higher numbers of plasma cells in the marrow inoculum (Table 3) raises the question of whether the immunoglobulins produced by the infused plasma cells markedly contribute to the total IgG levels. If they do, this could be why IgG levels are not higher in blood stem cell recipients than in marrow recipients, even though B-cell counts are higher. The difference in the rates of total definite infections cannot be attributed to differences in clinical patient characteristics because those were balanced between the 2 patient groups (Table 1). Adjustment for minor imbalances in pretransplantation characteristics (splenectomy, disease/disease stage, and CMV serostatus) only strengthened the significance of the differences (Table 4). We did not adjust for minor imbalances in posttransplantation characteristics because those may have been associated with the main treatment (blood stem cell grafting or marrow grafting). Nevertheless, the higher infection rates in the marrow recipients cannot be attributed to a weaker graft, since the incidence of severe neutropenia between day 30 and day 365 was not significantly higher in those patients (Table 1). Also, day 60 to day 365 infection rates, which were not influenced by the higher neutrophil counts in blood stem cell recipients up to day 48, were significantly higher in marrow recipients. Use of glucocorticoids is unlikely to have been responsible for the observed differences in infection rates because the number of patients treated with glucocorticoids was similar in the 2 groups. The differences also cannot be attributed to GVHD, since the incidence of grade 2 to 4 acute GVHD was similar in the 2 patient groups and there was a trend toward a lower incidence of clinical extensive chronic GVHD among the marrow recipients. Infection prophylaxis strategies were also similar in the 2 groups. The only difference was a trend toward a greater use of prophylactic acyclovir in marrow recipients (Table 1), a finding that may explain why the incidence of HSV and VZV infections among blood stem cell recipients was not lower than that among marrow recipients. The difference in total definite infection rates was attributable primarily to differences in the rates of bacterial and fungal infections. Also, blood stem cell recipients had fewer fatal bacterial and fungal infections. This may seem puzzling because the major difference between the marrow recipients and the blood stem cell recipients appeared to be in their T-cell counts and T cells have traditionally been considered to play a much less important role than neutrophils in host defense against extracellular bacteria and fungi (particularly molds). Perhaps the importance of T cells in host defense against extracellular bacteria and fungi (particularly molds) has been underestimated. Adoptively transferred T cells from immune donors to naive hosts have been found to protect rodents against infection with Bacteroides fragilis, Pseudomonas aeruginosa, Candida albicans, or Aspergillus fumigatus.51-54 The concurrence of higher T-cell counts and, in part, B-cell and NK
cell counts and the lower infection rates in the blood stem cell
recipients suggests but does not prove that the higher lymphocyte-subset counts resulted in lower infection rates. However, this is likely because previous studies showed inverse correlations between CD4 T-cell or B-cell counts and postengraftment infection rates.9-11 Moreover, in the marrow recipients in our
study, there was a trend toward inverse correlations between day 30, 80, 180, and 365 total CD4 T-cell counts and day 30 to day 365 infection rates; between day 30, 80, 180, and 365 total B-cell counts
and day 30 to day 365 infection rates; and between day 30, 80, and 180 NK cell counts and day 30 to day 365 infection rates (by Spearman rank
correlation; data not shown). The most striking correlations in marrow
recipients were those between day 80 total B-cell counts and total
definite infections (r = It would not be prudent to interpret the finding of lower day 30 to day 365 infection rates in blood stem cell recipients as a recommendation for discontinuing marrow transplantation. Other end points, such as relapse and survival, must also be taken into consideration. Moreover, if chronic GVHD is more prevalent or more severe (requiring more immunosuppressive treatment) after blood stem cell grafting than after marrow grafting,55-57 it is possible that infection rates after day 365 in blood stem cell recipients will be equal to or even higher than those in marrow recipients. In summary, we found that blood stem cell recipients have fewer day 30 to day 365 infections than marrow recipients. This might be because of improved lymphocyte-subset counts after blood stem cell grafting, an improvement that may result from the high numbers of lymphocytes in blood stem cell grafts.
We thank Patrick Sudour, Kristen White, Erica Ryberg, Amber Wyman, Hana Gage, and the dedicated staff of the FHCRC Cryobiology Laboratory for excellent technical assistance; the study nurse, Terri Cunningham; the patients who agreed to participate in the study; and the staff of the FHCRC Long- Term Follow-Up Department, who diligently gathered clinical information.
Submitted October 10, 2000; accepted January 31, 2001.
Supported by National Institutes of Health grants CA68496, CA18221, CA18029, CA15704, HL36444, and AI46108.
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: Jan Storek, FHCRC, D1-100, 1100 Fairview Ave N, Seattle, WA 98109-1024; e-mail: jstorek{at}fhcrc.org.
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J. M. Zaucha, T. Gooley, W. I. Bensinger, S. Heimfeld, T. R. Chauncey, R. Zaucha, P. J. Martin, M. E. D. Flowers, J. Storek, G. Georges, et al. CD34 cell dose in granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell grafts affects engraftment kinetics and development of extensive chronic graft-versus-host disease after human leukocyte antigen-identical sibling transplantation Blood, December 1, 2001; 98(12): 3221 - 3227. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
0.43; P = .006), day 80 IgD+ B-cell counts and total definite infections
(r = 
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