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• W2012973463 abstract "IntroductionAdvances in supportive care have led to significant improvements in hematopoietic cell transplant (HCT) outcomes over the last decade. Although children with acute leukemia previously had rates of 1-year transplant-related mortality (TRM) following unrelated donor HCT approaching 40%, in a more recent era, these rates have fallen by more than half to approximately 15% [1MacMillan M. Davies S. Nelson G. et al.Twenty years of unrelated donor bone marrow transplantation for pediatric acute leukemia facilitated by the National Marrow Donor Program.Biol Blood Marrow Transplant. 2008; 14: 16-22Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar]. This has led to significantly more alternative donor HCTs being performed for a wide variety of nonmalignant diseases, including primary immunodeficiencies (of T cells and/or phagocytes), hemoglobinopathies, bone marrow failure syndromes, and metabolic syndromes. Unlike a typical patient with leukemia, who enters HCT having received months of immunosuppressive chemotherapy, many patients with a nonmalignant disorder will begin the conditioning regimen with a fully intact immune system. This places those patients at very high risk for graft rejection, which forces transplant physicians to employ preparative regimens that are highly immunoablative. Even patients who enter HCT with defective immune systems, such as those with severe aplastic anemia or hemophagocytic lymphohistiocytosis, tend to require significant immunoablation because of an underlying disposition toward attacking bone marrow elements such as transplanted hematopoietic stem cells.This increased pre-HCT immunoablation often leads to delays in post-HCT immune reconstitution, which in turn is associated with significant complications, including autoimmune cytopenias, opportunistic infections, and Epstein-Barr virus (EBV)-related posttransplant lymphoproliferative disease (PTLD).Autoimmune Cytopenias Following HCT for Nonmalignant DisordersAutoimmune cytopenias occurring before and after allogeneic HCT are common, whereas the literature on the topic is sparse. In part, this is because the diagnosis is not always suspected (cytopenias are often seen in the early posttransplant period and may be multifactorial), and the diagnostic workup is not entirely straightforward. In some circumstances, watchful waiting with minimal intervention, even over a period of months, is appropriate. In other cases, multiagent therapy is indicated, as with life-threatening neutropenia or thrombocytopenia.PathophysiologyBone marrow transplantation can both transmit and eliminate autoimmune disease. Imbalance between autoreactive and autoregulatory lymphocytes underlies the development and persistence of autoimmune cytopenias.PretransplantMany patients with nonmalignant disorders show evidence of autoimmune cytopenias pretransplant [2Arkwright P.D. Abinun M. Cant A.J. Autoimmunity in human primary immunodeficiency diseases.Blood. 2002; 99: 2694-2702Crossref PubMed Scopus (158) Google Scholar, 3Elhasid R. Bergman R. Etzioni A. Autoimmunity in severe combined immunodeficiency (SCID).Blood. 2002; 100 (author reply 8-9): 2677-2678Crossref PubMed Google Scholar, 4Etzioni A. Immune deficiency and autoimmunity.Science. 2003; : 364-369Google Scholar, 5Goyal R. Bulua A.C. Nikolov N.P. Schwartzberg P.L. Siegel R.M. Rheumatologic and autoimmune manifestations of primary immunodeficiency disorders.Curr Opin Rheumatol. 2009; 21: 78-84Crossref PubMed Scopus (46) Google Scholar, 6Sherer Y. Shoenfeld Y. Autoimmune diseases and autoimmunity post-bone marrow transplantation.Bone Marrow Transplant. 1998; 22: 873-881Crossref PubMed Scopus (176) Google Scholar]. Perhaps the most challenging disorder in this regard is ALPS (autoimmune lymphoproliferative syndrome). ALPS, caused by defective lymphocyte homeostasis because of mutations in multiple genes, but most commonly fetal alcohol syndrome, is characterized by nonmalignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism), autoimmune disease mostly directed toward blood cells, and life-long increased risk of both Hodgkin and non-Hodgkin lymphoma. Pretransplant, the patients may require two or more immunosuppressive agents to control autoimmunity. To date, HCT has been performed only in the most severe and drug-resistant cases. In the experience at Cincinnati Children’s, severe posttransplant immune cytopenias can persist for 2 years or more despite treatment with multiple agents and plasmapheresis—but the patients finally recover and splenomegaly resolves.Other immunodeficiency disorders associated with a high incidence of pretransplant immune cytopenias include Omenn syndrome (sometimes referred to as “leaky” severe combined immunodeficiency [SCID]) and Wiskott Aldrich syndrome (WAS). Omenn syndrome is most often caused by hypomorphic mutations in recombinase genes RAG-1 and RAG-2, which impair but do not eliminate recombination of variable, diversity, and joining segments of TCR and Ig genes. Many other SCID defects have also been associated with immune cytopenias pretransplant. Omenn syndrome is no longer viewed as a specific form of SCID but rather as an aberrant inflammatory condition that can significantly impair (but not abolish) T cell development in the thymus. In this way, it resembles some features of chronic graft-versus-host disease (cGVHD) (information to follow).Immune cytopenias have been documented in high proportions of untransplanted patients with WAS, usually apparent before 5 years of age. Reported incidence ranges between the reports from the Necker Hospital, Paris: autoimmune hemolytic anemia (36%), autoimmune neutropenia (25%) [7Dupuis-Girod S. Medioni J. Haddad E. et al.Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients.Pediatrics. 2003; 111: e622-e627Crossref PubMed Scopus (268) Google Scholar], to 50% of patients experiencing one or more autoimmune cytopenias pretransplant in the current era (experience of the Cincinnati Children’s Hospital Medical Center). Severe thrombocytopenia in WAS may not only be because of the intrinsic defect in platelet production but additionally to the development of antiplatelet autoantibodies. Severe thrombocytopenia recurring after splenectomy is particularly ominous in regard to heightened risk of life-threatening hemorrhage. The etiology of the high risk of developing autoimmunity in WAS is not yet fully understood but may involve a combination of factors resulting from the underlying gene defect including defective motility and polarization of a number of hematologic cells, decreased number and function of regulatory T cells (Tregs), susceptibility to autoimmune triggers such as cytomegalovirus (CMV) infection, and a chronically inflamed milieu.In addition to the disorders previously mentioned, pretransplant autoimmune cytopenias can be seen in IPEX syndrome (failure to generate Tregs) and a variety of marrow failure syndromes some of which demonstrate significant deficiencies in B and natural killer (NK) cells.PosttransplantCauses of posttransplant immune cytopenias are multiple. In a minority of cases, transfer of “pathologic” lymphocytes from an autoimmune-prone donor can occur. More commonly, host plasma cells persist and continue to manufacture autoantibodies for many months in the bone marrow and lymphoid tissues despite myeloablative conditioning therapy. Regulatory control of existing or emerging autoimmune lymphocytes is also not established until the latter part of the first posttransplant year, or later, specifically the emergence of significant numbers of natural Tregs. Many of the immunosuppressive agents frequently used to prevent acute GVHD such as steroids and calcineurin inhibitors are not fully effective in controlling the autoimmunity.Acute GVHD and cGVHD contribute to the development of an autoimmune-prone milieu [8Chen X. Vodanovic-Jankovic S. Johnson B. Keller M. Komorowski R. Drobyski W.R. Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease.Blood. 2007; 110: 3804-3813Crossref PubMed Scopus (195) Google Scholar]. GVHD-attributable autoimmunity is associated with a paucity of CD4+CD25+Foxp3+ regulatory T cells. In animal models, this favors the expansion of donor-derived CD4+ T cells of the Th1 and Th17 proinflammatory cytokine phenotypes. These T cells interact with donor-derived antigen-presenting cells, favoring and sustaining an immunologic environment that favors de novo development of autoantibodies to donor-derived hematopoietic cells [9Tivol E. Komorowski R. Drobyski W.R. Emergent autoimmunity in graft-versus-host disease.Blood. 2005; 105: 4885-4891Crossref PubMed Scopus (103) Google Scholar].The incidence of posttransplant autoimmune cytopenias has not been described for most nonmalignant disorders. One exception is infants with SCID undergoing nonmyeloablative HCT [10Horn B. Viele M. Mentzer W. Mogck N. DeSantes K. Cowan M. Autoimmune hemolytic anemia in patients with SCID after T cell-depleted BM and PBSC transplantation.Bone Marrow Transplant. 1999; 24: 1009-1013Crossref PubMed Scopus (60) Google Scholar]. WAS is the other exception. In a recent retrospective review of 194 patients transplanted for WAS from multiple centers around the world between 1980 and 2009, retrospective analysis of lineage-specific donor cell engraftment showed that stable full-donor chimerism was attained by 72.3% of the patients who survived for at least 1 year after HCT. Mixed chimerism was associated with an increased risk of incomplete reconstitution of lymphocyte count and post-HCT autoimmunity [11Moratto D. Giliani S. Bonfim C. et al.Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study.Blood. 2011; 118: 1675-1684Crossref PubMed Scopus (225) Google Scholar]. This is in accordance with an earlier report from the European Bone Marrow Transplant Group reporting on 96 patients who underwent transplantation between 1979 and 2001 who survived at least 2 years [12Ozsahin H. Cavazzana-Calvo M. Notarangelo L.D. et al.Long-term outcome following hematopoietic stem-cell transplantation in Wiskott-Aldrich syndrome: collaborative study of the European Society for Immunodeficiencies and European Group for Blood and Marrow Transplantation.Blood. 2008; 111: 439-445Crossref PubMed Scopus (178) Google Scholar]. Autoimmunity independent of cGVHD was associated with persistent mixed chimerism (note: there is significant overlap of subjects between the two studies).The incidence of post-HCT autoimmune cytopenias was recently analyzed in the series of patients with WAS transplanted during 2001 to 2009 at Cincinnati Children’s Hospital Medical Center when screening for autoimmune cytopenias was routinely performed. Seventeen of 31 patients (55%) had clinically evident immune-mediated cytopenias documented by analysis for relevant autoantibodies. Trilineage cytopenias were detected in one of 31 patients (3%), dual cytopenias were detected in eight of 31(26%), and single cytopenias were detected in eight of 31 patients (26%). The most common cytopenia detected was thrombocytopenia in 13 of 31 (42%), followed by autoimmune neutropenia in 11 of 31 (35%) patients, and autoimmune hemolytic anemia in three of 31 (10%). Time of diagnosis of immune-mediated cytopenias varied with a median of 148 days (range, 33-467 days) but typically occurring within the first 6 months post-HCT. Occurrence of autoimmune cytopenias did not correlate with the presence of acute GVHD (grades II-IV, P = .71), cGVHD (P = .12) or with mixed chimerism (P = .50; all Fisher exact test). Fourteen of 17 patients developed autoantibodies independent of cGVHD. Autoimmune cytopenias resolved in the majority of patients with complete resolution in 11/17 (65%) patients at present and ongoing improvement in four more recent patients. The median time to recovery of normal blood counts in this group was 429 days (range, 131-979 days) from the time of HCT, indicating that management of posttransplantation autoimmune complications need be prolonged in this population but that resolution can be obtained in the majority of patients.DiagnosisImmune cytopenias are suspected when levels of hemoglobin, neutrophils, and/or platelets do not rise as expected weeks or months after HCT, or, once recovered or normalized, the levels begin to decline. It is helpful to check the level of overall or lineage-specific engraftment with some regularity, because many patients with nonmalignant disorders receive reduced-intensity conditioning, and information regarding the status of engraftment may influence the intervention that is ultimately selected.An elevated reticulocyte count is consistent with AIHA. Bone marrow biopsies are often performed: if there is robust cellularity—peripheral destruction is highly likely. However, the finding of a hypoplastic marrow does not preclude an autoimmune process. Testing for antibodies against the patient’s neutrophil and platelet-specific antigens largely confirms the diagnosis. Such autoantibody testing is performed in a few specialty laboratories in North America, and may require a 2- to 3-week turnaround.TherapySimilar approaches are used and have similar efficacy in both the pre- and posttransplantation setting. Conventional measures include corticosteroid dosing to 2 mg/kg and infusion of high doses of intravenous immunoglobulin to achieve a minimum sustained trough level of around 2,000 intended to reduce rapid splenic uptake of autoantibody-coated cells.Rituximab, typically administered as four weekly doses, is now commonly administered both pre- and posttransplantation, especially in cases of primary immunodeficiencies [13Bonduel M. Zelazko M. Figueroa C. Magaldi G. Rossi J. del Pozo A. Successful treatment of autoimmune hemolytic anemia with rituximab in a child with severe combined immunodeficiency following nonidentical T-cell-depleted bone marrow transplantation.Bone Marrow Transplant. 2005; 35: 819-821Crossref PubMed Scopus (5) Google Scholar, 14Raj K. Narayanan S. Augustson B. et al.Rituximab is effective in the management of refractory autoimmune cytopenias occurring after allogeneic stem cell transplantation.Bone Marrow Transplant. 2005; 35: 299-301Crossref PubMed Scopus (43) Google Scholar]. In refractory cases, rituximab has been combined with plasmapheresis with anecdotal success in pediatric HCT. Sirolimus, shown to be useful in ALPS, also appears to benefit some cases of post-HCT immune cytopenias [15Valentini R.P. Imam A. Warrier I. et al.Sirolimus rescue for tacrolimus-associated post-transplant autoimmune hemolytic anemia.Pediatr Transplant. 2006; 10: 358-361Crossref PubMed Scopus (39) Google Scholar, 16Teachey D.T. Greiner R. Seif A. et al.Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome.Br J Haematol. 2009; 145: 101-106Crossref PubMed Scopus (129) Google Scholar].The newest approach to be considered is bortezomib, a proteasome inhibitor, combined with plasmapheresis, administered in repeated cycles. This is the first effective treatment to block pathologic plasma cells. It has shown promise in reversing allosensitization in solid-organ transplantation [17Trivedi H.L. Terasaki P.I. Feroz A. et al.Abrogation of anti-HLA antibodies via proteasome inhibition.Transplantation. 2009; 87: 1555-1561Crossref PubMed Scopus (134) Google Scholar]. Trials to control autoimmune cytopenias in the HCT setting are just beginning.Opportunistic Infections: Toward Risk-Adapted Prophylaxis StrategiesInfections with opportunistic organisms are one of the most common posttransplantation complications. Multiple therapy-induced alterations of host defenses contribute to this risk [18Lehrnbecher T. Foster C. Vázquez N. Mackall C. Chanock S. Therapy-induced alterations in host defense in children receiving therapy for cancer.J Pediatr Hematol Oncol. 1997; 19: 399-417Crossref PubMed Scopus (116) Google Scholar]. The three major contributors to the development of an opportunistic infection (OI) are breakdown in natural barriers (such as indwelling catheter and mucositis), defects in cell-mediated immunity (lymphopenia from corticosteroids and other anti-T cell cytotoxic agents), and deficient numbers of phagocytes (because of myeloablative chemotherapy). Classically, three phases of infections have been noted: (1) prior to engraftment (mainly bacteremias, herpes simplex virus, candidemia, and invasive aspergillosis [IA]); (2) the early postengraftment period until approximately day +100 (mainly Gram-positive bacteremias, candidemia, and CMV and other double-strand [ds] DNA viruses); and (3) the late period following day +100 (mainly encapsulated bacteria, IA, Pneumocystis jiroveci, and continuing problems with dsDNA viruses) [19Tomblyn M. Chiller T. Einsele H. et al.Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective.Biol Blood Marrow Transplant. 2009; 15: 1143-1238Abstract Full Text Full Text PDF PubMed Scopus (1166) Google Scholar].In addition to causing significant morbidity and prolonged hospitalizations, OIs cause 37% to 40% of TRM following allogeneic HCT [20Pasquini M, Wang Z. Current use and outcome of hematopoietic stem cell transplantation. CIBMTR Summary Slides. 2010. Available at: http://www.cibmtr.org.Google Scholar]. The first step toward preventing OI in patients with nonmalignant disease lies in defining risk groups. For example, one of the simplest ways to segregate HCT recipients is by the donor stem cell source (bone marrow versus peripheral blood stem cell versus umbilical cord blood [UCB]). The recipients of more mismatched allogeneic donors tend to be much more immunosuppressed, initially in order to overcome HLA barriers and to hopefully prevent the development of GVHD and then later, when undergoing treatment for GVHD. This, in turn, leads to more OI, as is seen in both recipients of UCB transplants (reviewed in [21Szabolcs P. Niedzwiecki D. Immune reconstitution after unrelated cord blood transplantation.Cytotherapy. 2007; 9: 111-122Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar]), as well as those undergoing ex vivo T cell depletion, where a prospective trial found a significantly higher incidence of severe CMV and IA compared with those receiving standard cyclosporine and methotrexate for GVHD prophylaxis [22van Burik J. Carter S. Freifeld A. et al.Higher risk of cytomegalovirus and aspergillus infections in recipients of T cell-depleted unrelated bone marrow: analysis of infectious complications in patients treated with T cell depletion versus immunosuppressive therapy to prevent graft-versus-host disease.Biol Blood Marrow Transplant. 2007; 13: 1487-1498Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar].Current Prophylaxis Strategies: Medications versus Cellular TherapyCurrent strategies used for post-HCT prophylaxis of OIs generally utilize antimicrobial medications, although there is significant interest in developing adoptive immunotherapy for potential future use as OI prevention.Antibacterial prophylaxis has been widely used in adult patients undergoing HCT. A meta-analysis of 95 randomized trials showed that, in adults, antibacterial prophylaxis significantly decreased the risk of all-cause mortality [23Gafter-Gvili A. Fraser A. Paul M. et al.Meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients.Ann Intern Med. 2005; 142: 979-995Crossref PubMed Google Scholar], so that the combined HCT guidelines state that prophylaxis with a fluoroquinolone should be strongly considered [19Tomblyn M. Chiller T. Einsele H. et al.Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective.Biol Blood Marrow Transplant. 2009; 15: 1143-1238Abstract Full Text Full Text PDF PubMed Scopus (1166) Google Scholar]. Because the data in children are so limited, no recommendation could be made. Therefore, in mid-2011, the Children’s Oncology Group (COG) embarked upon a prospective trial designed to definitively answer the question of the utility of this strategy. Given the known risk of neutropenia contributing to the development of bacteremia, another approach would be to use prophylactic granulocyte transfusions during the first several weeks post-HCT. However, a meta-analysis of 10 older trials evaluating this approach in adults failed to show improvement in mortality [24Massey E. Paulus U. Doree C. Stanworth S. Granulocyte transfusions for preventing infections in patients with neutropenia or neutrophil dysfunction.Cochrane Database Syst Rev. 2009; 21: CD005341Google Scholar]; however, given interval advances in supportive care, it is still conceivable that a carefully designed trial with large granulocyte doses could show a benefit.Conversely, antifungal prophylaxis is widely used in pediatric HCT recipients, despite the fact that there are almost no data in children <12 years of age. Based on two pivotal trials published over 15 years ago [25Goodman J. Winston D. Greenfield R. et al.A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation.N Engl J Med. 1992; 326: 845-851Crossref PubMed Scopus (1072) Google Scholar, 26Slavin M. Osborne B. Adams R. et al.Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation—a prospective, randomized, double-blind study.J Infect Dis. 1995; 171: 1545-1552Crossref PubMed Scopus (727) Google Scholar], fluconazole is still the most common agent of choice, even in higher-risk alternative donor HCT, although more centers are now using theoretically superior mold-active agents, despite a paucity of data demonstrating actual superiority (56% of centers use fluconazole, 28% use voriconazole, 11% use an echinocandin, and 5% use a liposomal form of amphotericin B; C. Dvorak, unpublished data from 2011 survey of COG HCT centers). Because of the profound lack of pediatric-specific data, in late 2011, the COG plans to initiate a prospective trial of caspofungin prophylaxis compared with fluconazole or voriconazole in alternative donor HCT. Another interesting approach lies in the creation of Aspergillus-specific T cells, which in haploidentical HCT recipients has been shown to improve resolution rates of documented IA [27Perruccio K. Tosti A. Burchielli E. et al.Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation.Blood. 2005; 106: 4397-4406Crossref PubMed Scopus (305) Google Scholar].Other than the use of early acyclovir to prevent HSV reactivation, medication-based prophylactic strategies for viral infections post-HCT have been limited by the toxicities of the available agents. As of 2005, only 15% of pediatric HCT centers used ganciclovir in a prophylactic strategy against CMV, with the majority using preemptive treatment guided by highly sensitive polymerase chain reaction (PCR) monitoring [28Lee S. Astigarraga C. Eapen M. et al.Variation in supportive care practices in hematopoietic cell transplantation.Biol Blood Marrow Transplant. 2008; 14: 1231-1238Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar]. However, the advent of CMX-001, a potentially less-toxic lipid formulation of cidofovir, an agent with broad activity against dsDNA viruses, has reopened the door regarding the utility of a prophylaxis strategy in high-risk patients. Adult studies of this agent are underway, and a pediatric trial is being planned. In addition, significant strides have been made in the creation of donor T cell-specific dsDNA viruses have shown an ability to prevent reactivation of CMV [27Perruccio K. Tosti A. Burchielli E. et al.Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation.Blood. 2005; 106: 4397-4406Crossref PubMed Scopus (305) Google Scholar] and EBV [29Leen A. Christin A. Myers G. et al.Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation.Blood. 2009; 114: 4283-4292Crossref PubMed Scopus (263) Google Scholar] following high-risk HCT, and this approach could also be applied to adenovirus [29Leen A. Christin A. Myers G. et al.Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation.Blood. 2009; 114: 4283-4292Crossref PubMed Scopus (263) Google Scholar].The most significant problem with the creation of infection-specific T cells is that a different T cell product needs to be developed for each potential infection that a patient may encounter, which can be time consuming and expensive. Thus, most trials of these cells are currently being done in patients to treat an active infection. Although certainly a “cocktail” containing a mixture of several different virus-specific T cells could be produced [30Hanley P. Shaffer D. Cruz C. et al.Expansion of T cells targeting multiple antigens of cytomegalovirus, Epstein-Barr virus and adenovirus to provide broad antiviral specificity after stem cell transplantation.Cytotherapy. 2011; ([Epub ahead of print])PubMed Google Scholar], others have evaluated the possibility of utilized infusions of alloreactive-depleted T cells [31Amrolia P. Muccioli-Casadei G. Huls H. et al.Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation.Blood. 2006; 108: 1797-1808Crossref PubMed Scopus (203) Google Scholar].Finally, although some of the newer antimicrobial agents and the virus-specific T cells are quite exciting, it is unlikely that any of these agents will prove to be completely free of unintended side effects. Therefore, the question must be asked: Should everyone receive antimicrobial prophylaxis, or can we begin to determine who exactly are the highest-risk patients and target our prophylaxis strategies upon them?Bacteremia: Gram-Negative Rods and BeyondBacteremia, most importantly from Gram-negative rods, is commonly encountered during the neutropenic period post-HCT, with incidences ranging from as low as 21% for matched related donors to as high as 76% for alternative donor recipients and with an appreciable mortality rate of 11% to 18% [32Castagnola E. Bagnasco F. Faraci M. et al.Incidence of bacteremias and invasive mycoses in children undergoing allogeneic hematopoietic stem cell transplantation: a single center experience.Bone Marrow Transplant. 2008; 41: 339-347Crossref PubMed Scopus (44) Google Scholar, 33Mullen C.A. Nair J. Sandesh S. Chan K.W. Fever and neutropenia in pediatric hematopoietic stem cell transplant patients.Bone Marrow Transplant. 2000; 25: 59-65Crossref PubMed Scopus (41) Google Scholar]. As noted previously, efforts are underway to determine if pediatric patients would benefit from the administration of prophylactic antibiotics post-HCT; however, any pharmaceutical prophylaxis regimen will always carry a risk of inducing the development of resistant organisms. Clearly, the optimal strategy would be to identify which patients, are at highest risk and only utilize prophylaxis in those individuals. However, besides neutropenia and the presence of central venous catheters, there are few accepted risk factors for the development of bacteremia. One commonly held belief is that bacteremia is more common in those with impaired mucosal integrity because of cytoreductive chemo- or radiotherapy. However, other than the known risk of α-hemolytic Streptococcal infections following cytarabine therapy, individuals appear to have variable susceptibilities to conditioning agents, and there is no easy method for measuring mucosal damage outside of the mouth, making broad associations of bacteremia to specific agents difficult. Several studies have shown that either host or donor polymorphisms in genes responsible for immunity contribute to the risk of bacterial infections (Table 1) [34Rocha V. Franco R. Porcher R. et al.Host defense and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation.Blood. 2002; 100: 3908-3918Crossref PubMed Scopus (165) Google Scholar, 35Azarian M. Busson M. 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• W2012973463 created "2016-06-24" @default.
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• W2012973463 date "2012-01-01" @default.
• W2012973463 modified "2023-09-27" @default.
• W2012973463 title "Complications of Transplant for Nonmalignant Disorders: Autoimmune Cytopenias, Opportunistic Infections, and PTLD" @default.
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• W2012973463 doi "https://doi.org/10.1016/j.bbmt.2011.10.024" @default.
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