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Related Collections Transplantation Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 November 2000, Vol. 96, No. 9, pp. 3290-3293 BRIEF REPORT Low B-cell and monocyte counts on day 80 are associated with high infection rates between days 100 and 365 after allogeneic marrow transplantation Jan Storek, German Espino, Monja A. Dawson, Barry Storer, Mary E. D. Flowers, and David G. Maloney From the Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA.     Abstract Top Abstract Introduction Study design Results and discussion References To ascertain which mononuclear cell subset deficiency plays a role in the marrow transplant recipient's susceptibility to infections, mononuclear cell subset counts were prospectively determined in 108 patients on day 80. Infections occurring between day 100 and 365 were recorded by an investigator blinded to the subset counts. In univariate analyses, the counts of the following subsets showed a significant inverse correlation with infection rates: total B cells, IgD+ B cells, IgD B cells, total CD4 T cells, CD28+ CD4 T cells, CD28 CD4 T cells, CD45RAlow/ CD4 T cells and monocytes. In multivariate analyses, the counts of the following subsets remained significantly inversely correlated with the infection rates: total B cells (P = .0004) and monocytes (P = .009). CD28 CD8 T-cell counts showed no correlation with infection rates. In conclusion, the susceptibility of patients to infections late posttransplant may be due in part to the slow reconstitution of B cells and monocytes. (Blood. 2000;96:3290-3293) © 2000 by The American Society of Hematology.     Introduction Top Abstract Introduction Study design Results and discussion References Infections are frequent after marrow transplantation, even after neutrophil engraftment.1-6 Ochs et al5 noted that the occurrence of postengraftment infection(s) was the dominant independent factor associated with increased nonrelapse mortality (RR = 5.5, P = .0001). Quantitative deficiencies of lymphocytes and their subsets have been described in transplant recipients surviving past engraftment.6 For example, low memory B-cell counts are frequently detected in the first year and low CD4 T-cell counts (both naive and memory) are frequently detected in the first 5 years after transplant.7,8 However, which cell subset deficiency plays the most crucial role in the susceptibility of patients to late infections is unknown. Therefore, we evaluated mononuclear cell (MNC) subset counts and determined their correlations with the rate of late infections (occurring between day 100 and day 365).     Study design Top Abstract Introduction Study design Results and discussion References   MNC subset counts were determined in 108 allogeneic marrow recipients transplanted between May 1996 and August 1997, who were outpatients and had no signs of relapse around day 80. Three of the 108 patients subsequently died before day 100 and were not evaluable for day 100-365 infections. The demographic and clinical information on the evaluable 105 patients is given in Table 1. Prophylaxis of late infections included sulfamethoxazole/trimethoprim until day 180. A longer course of sulfamethoxazole/trimethoprim, usually with penicillin, was given to patients in whom clinical extensive chronic graft-vs-host disease (GVHD) developed. Six patients received intravenous immunoglobulin between day 100 and 365.                                 View this table: [in this window] [in a new window]   Table 1. Patient characteristics Blood was drawn on approximately day 80 under an IRB-approved protocol and MNC subsets were enumerated as described.9 Day 100-365 infections were counted by a chart reviewer blinded to the MNC subset counts (G.E.) and associations between the MNC subset counts and the infection rate were statistically tested (Table 2, footnotes).                                View this table: [in this window] [in a new window]   Table 2. Significance of associations between day 80 MNC subset counts and day 100-365 infection rates     Results and discussion Top Abstract Introduction Study design Results and discussion References On day 80, the counts of all MNC subsets studied (Table 2) were significantly lower compared with the MNC subset counts in 103 healthy adult volunteers (P < .001, Mann-Whitney test). Between day 100 and day 365 or the day of relapse or death (whichever occurred first), a total of 168 infections developed (average, 1.6 per patient). In univariate analyses, the counts of the following MNC subsets inversely correlated with the rate of all infections (P < .05): total B cells, IgD+ B cells, IgD B cells, total CD4 T cells, CD45RAlow/ CD4 T cells, CD28+ CD4 T cells, CD28 CD4 T cells, CD28+ CD8 T cells, and monocytes (Table 2). In multivariate analyses, factors other than the MNC cell subsets possibly influencing the rate of infections were considered as confounders (Table 2, footnote). Of all the potential confounders, only the use of corticosteroids in the first 3 months after transplant was associated with significantly increased rate of all day 100-365 infections in univariate analyses (P = .04). However, in the multivariate analyses, only low total B-cell count and low monocyte count remained significantly associated with increased rate of infections (P = .0004 for B cells, P = .009 for monocytes). Both the univariate and the multivariate analyses were also performed separately for severe infections (defined as infections requiring hospitalization), viral infections, bacterial infections, and fungal infections. In the univariate analyses, the rates of severe, viral, bacterial, and fungal infections tended to inversely correlate with the same MNC subset counts, as the rates of all infections (Table 2). In the multivariate analyses, the low IgD B-cell count remained significantly associated with increased rates of severe infections (P = .003) and bacterial infections (P = .03), the low monocyte count remained significantly associated with increased rate of viral infections (P = .004), and the low total B-cell count remained significantly associated with increased rate of fungal infections (P = .0003). We also evaluated whether a day 80 MNC subset count was associated with relapse rate or nonrelapse mortality before day 365, using a Mann-Whitney test. No MNC subset count was significantly different in the patients who relapsed compared with those who did not. The total B-cell count was lower in the patients who died without relapse (median, 0.9 × 106/L) than in the patients who did not (median, 2.5 × 106/L), (2-sided P = .092, 1-sided P = .046); whereas the other MNC subset counts were not different. These data are insufficient to resolve the question of whether the association between B cell and monocyte counts and infections reflects the importance of B cells and monocytes for decreasing susceptibility to infections or that the B cell and monocyte counts may be merely surrogate markers for the quality of the marrow graft. We attempted to determine this by evaluating absolute neutrophil count as a measure of graft function. Day 80 neutrophil counts showed no correlation with infections (Spearman rank correlation coefficient r = 0.05) and no correlation with B-cell counts. In contrast, day 80 IgG level showed a trend toward inverse correlation with infections (Spearman rank correlation coefficient r = 0.40), suggesting that the B cells themselves may be important. As the IgG level was available for only 34 patients who did not receive intravenous immunoglobulin between day 0 and day 80, this was not statistically significant. Other data also support B-cell function as important. Riches et al10 described 3.5 times greater incidence of late infections in patients with low compared with those with normal serum IgG2 and IgG4 levels. Among marrow transplant recipients participating in our randomized trial of placebo versus intravenous immunoglobulin that did not contain IgA,11 there was a significant inverse correlation between day 100 serum IgA level and the rate of late infections (P = .01) (unpublished data). Sheridan et al12 described significant association between low serum IgG2 and IgG4 levels and the incidence of late pneumococcal infections. Thus, given the lack of an association between day 80 neutrophil counts and late infections and given the probable association between day 80 immunoglobulin levels and late infections, we favor the explanation that the slow reconstitution of B cells themselves plays an important role in susceptiblity to infections. Interestingly, low monocyte counts were also associated with infections. However, monocyte deficiency was not as dramatic as B-cell deficiency (median monocyte count was 291 vs 391 × 106/L in patients and normals, respectively; whereas median B-cell count was 2 vs 253 × 106/L). It is possible that the association of monocyte counts with infections could be due to the importance of monocyte/macrophage-mediated phagocytosis, antigen presentation, or secretion of monokines such as interleukin-1. The primary goal of this study was to identify an MNC subset associated with infections. However, the data also provide the opportunity to ask which MNC subsets are not associated with infections. Of the subsets listed in Table 2, the count of the CD28 CD8 T cells was the least associated with the rate of all infections (Spearman rank correlation coefficient r = 0.01, P = .84). This is not surprising, as CD28 CD8 T cells in vitro do not readily proliferate on CD3 cross-linking and are considered anergic.13,14 Thus, the lack of association between CD28 CD8 T-cell counts and infections suggests that the CD28 CD8 T cells are also anergic in vivo. We conclude that the reconstitution of B cells and monocytes may play an important role in marrow transplant recipient defense against microorganisms. This may be tested by adoptively transferring donor B cells and/or monocytes. Alternatively, the use of donor peripheral blood stem cells instead of marrow may provide a larger B-cell/monocyte inoculum, or these cells may be augmented by the use of growth factors.     Acknowledgments We are indebted to the hard work of the staff of the Fred Hutchinson Cancer Research Center Long-Term Follow-Up Department and the staff of the Fred Hutchinson Cancer Research Center Outpatient Department.     Footnotes Submitted February 23, 2000; accepted July 7, 2000. Supported by National Institutes of Health grants Nos. CA68496 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.     References Top Abstract Introduction Study design Results and discussion References 1. Atkinson K, Farewell V, Storb R, et al. Analysis of late infections after human bone marrow transplantation: role of genotypic nonidentity between marrow donor and recipient and of nonspecific suppressor cells in patients with chronic graft-versus-host disease. Blood. 1982;60:714-720[Abstract/Free Full Text]. 2. Marks DI, Cullis JO, Ward KN, et al. Allogeneic bone marrow transplantation for chronic myeloid leukemia using sibling and volunteer unrelated donors: a comparison of complications in the first 2 years. Ann Intern Med. 1993;119:207-214[Abstract/Free Full Text]. 3. Sullivan KM, Mori M, Sanders J, et al. Late complications of allogeneic and autologous marrow transplantation. Bone Marrow Transplant. 1992;10(Suppl 1):127-134. 4. Morrison VA, Haake RJ, Weisdorf DJ. Non-Candida fungal infections after bone marrow transplantation: risk factors and outcome. Am J Med. 1994;96:497-503[Medline] [Order article via Infotrieve]. 5. Ochs L, Shu XO, Miller J, et al. Late infections after allogeneic bone marrow transplantation: comparison of incidence in related and unrelated donor transplant recipients. Blood. 1995;86:3979-3986[Abstract/Free Full Text]. 6. Storek J, Witherspoon RP. Immunologic reconstitution after hematopoietic stem cell transplantation. In: Atkinson K, ed. Clinical Bone Marrow and Blood Stem Cell Transplantation. 2nd ed. Cambridge, MA: Cambridge University Press; 2000:111-146. 7. Storek J, Witherspoon RP, Storb R. Reconstitution of membrane IgD (mIgD) B cells after marrow transplantation lags behind the reconstitution of mIgD+ B cells [letter]. Blood. 1997;89:350-351[Free Full Text]. 8. Storek J, Witherspoon RP, Storb R. T cell reconstitution after bone marrow transplantation into adult patients does not resemble T cell development in early life. Bone Marrow Transplant. 1995;16:413-425[Medline] [Order article via Infotrieve]. 9. Storek J, Dawson MA, Maloney DG. Normal T, B, and NK cell counts in healthy donors at 1 year after blood stem cell harvesting [letter]. Blood. 2000;95:2993-2994[Free Full Text]. 10. Riches PG, Walker SA, Rogers TR, Hobbs JR. Relative deficiency of serum IgA, IgG2 and IgG4 during reconstitution following BMT: relationship to infection. Bone Marrow Transplant. 1986;1(Suppl 1):53[Medline] [Order article via Infotrieve]. 11. Sullivan KM, Storek J, Kopecky KJ, et al. A controlled trial of long-term administration of intravenous immunoglobulin to prevent late infection and chronic GVHD following marrow transplantation: clinical outcome and effect on subsequent immune recovery. Biol Blood Marrow Transplant. 1996;2:44-53[Medline] [Order article via Infotrieve]. 12. Sheridan JF. Immunoglobulin G subclass deficiency and pneumococcal infection after allogeneic BMT. Blood. 1990;75:1583-1586[Abstract/Free Full Text]. 13. Azuma M, Phillips JH, Lanier LL. CD28 T lymphocytes: antigenic and functional properties. J Immunol. 1993;150:1147-1159[Abstract]. 14. Lake RA, O'Hehir RE, Verhoef A, Lamb JR. CD28 mRNA rapidly decays when activated T cells are functionally anergized with specific peptide. Int Immunol. 1993;5:461-466[Abstract/Free Full Text]. 15. Klein U, Kuppers R, Rajewsky K. Human IgM+IgD+ B cells, the major B cell subset in the peripheral blood, express V-kappa genes with no or little somatic mutation throughout life. Eur J Immunol. 1993;23:3272-3277[Medline] [Order article via Infotrieve]. 16. Suzuki I, Milner ECB, Glas AM, et al. Immunoglobulin heavy chain variable region gene usage in bone marrow transplant recipients: lack of somatic mutation indicates a maturational arrest. Blood. 1996;87:1873-1880[Abstract/Free Full Text]. 17. Klein U, Rajewsky K, Kuppers R. Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J Exp Med. 1998;188:1679-1689[Abstract/Free Full Text]. 18. Douek DC, McFarland RD, Keiser PH, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature. 1998;396:690-695[Medline] [Order article via Infotrieve]. 19. Dumont-Girard F, Roux E, van Lier RA, et al. Reconstitution of the T-cell compartment after bone marrow transplantation: restoration of the repertoire by thymic emigrants [In Process Citation]. Blood. 1998;92:4464-4471[Abstract/Free Full Text]. 20. Okumura M, Fujii Y, Inada K, Nakahara K, Matsuda H. Both CD45RA+ and CD45RA subpopulations of CD8+ T cells contain cells with high levels of lymphocyte function-associated antigen-1 expression, a phenotype of primed T cells. J Immunol. 1993;150:429-437[Abstract]. 21. Okumura M, Fujii Y, Takeuchi Y, Inada K, Nakahara K, Matsuda H. Age-related accumulation of LFA-1 high cells in a CD8+CD45RA high T cell population. Eur J Immunol. 1993;23:1057-1063[Medline] [Order article via Infotrieve]. 22. Chambers CA, Allison JP. Costimulatory regulation of T cell function. Curr Opin Cell Biol. 1999;11:203-210[Medline] [Order article via Infotrieve]. 23. Boeckh M, Bowden RA, Goodrich JM, Pettinger M, Meyers JD. Cytomegalovirus antigen detection in peripheral blood leukocytes after allogeneic marrow transplantation. Blood. 1992;80:1358-1364[Abstract/Free Full Text]. © 2000 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. Buza-Vidas, M. Cheng, S. Duarte, H. Nozad, S. E. W. Jacobsen, and E. Sitnicka Crucial role of FLT3 ligand in immune reconstitution after bone marrow transplantation and high-dose chemotherapy Blood, July 1, 2007; 110(1): 424 - 432. [Abstract] [Full Text] [PDF] M. Blazik, P. Hutchinson, M. D. Jose, K. R. Polkinghorne, S. R. Holdsworth, R. C. Atkins, and S. J. Chadban Leukocyte phenotype and function predicts infection risk in renal transplant recipients Nephrol. Dial. Transplant., October 1, 2005; 20(10): 2226 - 2230. [Abstract] [Full Text] [PDF] S. Kaminogawa and M. Nanno Modulation of Immune Functions by Foods Evid. Based Complement. Altern. 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Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation Blood, June 1, 2001; 97(11): 3380 - 3389. [Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Storek, J. Articles by Maloney, D. G. Search for Related Content PubMed PubMed Citation Articles by Storek, J. Articles by Maloney, D. G. Related Collections Transplantation Brief Reports Clinical Trials and Observations Social Bookmarking                   What's this?