key: cord-019009-3ngfv96u
authors: Gea-Banacloche, Juan
title: Risks and Epidemiology of Infections After Hematopoietic Stem Cell Transplantation
date: 2016-02-15
journal: Transplant Infections
DOI: 10.1007/978-3-319-28797-3_6
sha: 
doc_id: 19009
cord_uid: 3ngfv96u

Infections following HCT are frequently related to risk factors caused by the procedure itself. Neutropenia and mucositis predispose to bacterial infections. Prolonged neutropenia increases the likelihood of invasive fungal infection. GVHD and its treatment create the most important easily identifiable risk period for a variety of infectious complications, particularly mold infections. Profound, prolonged T cell immunodeficiency, present after T cell-depleted or cord blood transplants, is the main risk factor for viral problems like disseminated adenovirus disease or EBV-related posttransplant lymphoproliferative disorder.

Understanding the epidemiology of infections after allogeneic hematopoietic stem cell transplantation (HCT) is important to implement appropriate preventive strategies as well as to effectively diagnose and treat individual patients.

Several groups of experts and professional organizations publish guidelines that provide specifi c recommendations for prophylaxis and management of infections after HCT [ 1 -8 ] , including vaccinations [ 1 , 9 , 10 ] . Many of these recommendations are necessarily based on low-quality evidence and rely heavily on expert opinion. Guidelines should not be followed blindly, but understood as tools that may help to provide the best possible care.

Risk factors for infection include individual characteristics (e.g., indication for HCT, prior infections, CMV serostatus, particular genetic traits) and type of transplant (based on conditioning regimen, stem cell source, degree of HLA homology, and immunosuppression). The development of graft-versus-host disease (GVHD) is frequently the decisive contributor to infectious morbidity and mortality.

Different indications for HCT are associated with their own infectious risks. Primary immunodefi ciencies (PID), hemoglobinopathies, and hematologic malignancies present different challenges. Even in hematologic malignancies, the risk may vary depending on the specifi c condition: patients with chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL) present different risks based on both the biology of the disease and prior treatment. These factors should be considered when assessing individual patients. Prior infections must be considered. A history of infection or colonization with a multidrug-resistant organism (MDRO) like carbapenem-resistant enterobacteria (CRE), extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria, vancomycin-resistant enterococcus (VRE), or methicillin-resistant Staphylococcus aureus (MRSA) has implications regarding optimal management of fever during neutropenia [ 6 , 11 , 12 ] , which is a common complication of HCT. Transplant candidates are routinely screened for serologic evidence of latent infections that may reactivate (HSV, VZV, CMV, EBV, hepatitis B and C, toxoplasmosis); some of these will be discussed later in this chapter. Some transplant centers will perform screening for tuberculosis with tuberculin skin test (TST) or interferon-gamma release assay (IGRA), at least for patients who are considered at signifi cant risk for the disease. Prior invasive fungal infections may reactivate following transplant, and secondary prophylaxis is required [ 13 -15 ] . Even active fungal infection has been reported to be controllable. There are, however, cases of progression of prior aspergillosis after transplant; myeloablative conditioning, prolonged neutropenia, cytomegalovirus (CMV) disease, and graft-versus-host disease (GVHD) are risk factors [ 15 , 16 ] .

As the correlates of native and adaptive immunity are better understood, genetic associations are coming to light. There is evidence that some donor haplotypes of TLR4 , the gene that encodes the toll-like receptor protein 4 (TLR4) are associated with increased risk of invasive aspergillosis after HCT [ 17 ] . Recipient's mutations in MBL2 , the gene that encodes mannose-binding lectin (MBL), have been associated with increased risk of infection after neutrophil recovery following myeloablative transplant [ 18 ] . Other polymorphisms of MBL2 may be important for infection through a direct infl uence on the risk of developing GVHD [ 19 , 20 ] . Different genotypes of activated killer immunoglobulin-like receptors (aKIR) in the donor have been found to protect from CMV reactivation [ 21 ] . Many of these associations are preliminary and require more data to be confi rmed, but they hold the promise of a more individualized approach to infectious prophylaxis.

From a practical standpoint, it is helpful to consider three distinct periods during transplant: pre-engraftment (until neutrophil recovery), early post-engraftment (from engraftment until day 100) , and late post-engraftment (after day 100) . This framework originated with myeloablative transplants, and is eminently pragmatic. The pre-engraftment phase may be accompanied by profound neutropenia and signifi cant mucositis, which results in increased risk of bacterial infections from the resident gastrointestinal fl ora, candidiasis, aspergillosis (in cases of prolonged neutropenia) and herpes simplex virus reactivation. After engraftment, with neutropenia no longer being a factor, many infections are related to the profound defect in cellular immunity caused by the conditioning regimen and the immunosuppression administered to prevent GVHD. CMV reactivation and the development of acute GVHD and its treatment play a central role during this time. The day 100 landmark derives from the standard time at which immunosuppression (e.g., cyclosporine A or tacrolimus) is frequently tapered. Infections after this point would be primarily related to lack of immune reconstitution and, in the absence of GVHD, become progressively less common.

Not all allogeneic stem cell transplantations are the same. Several characteristics of the transplant infl uence the risk of infection: the conditioning preparative regimen, the source of stem cells, the degree of HLA identity between donor and recipient, and the prophylactic strategy adopted to prevent GVHD (use of T cell depletion or immunosuppressive medications). Table 6 -1 summarizes the impact of these factors on infections. Matching for UCB transplants focuses on three loci (HLA-A, HLA-B, and HLA-DRB1). The majority of UCB transplants are mismatched by at least one locus (often two). Among transplants mismatched at two loci, mismatching at HLA-C and HLA-DRB1 was associated with the highest risk of mortality [ 24 ] .

The degree of mismatch between the donor and the recipient affects the infectious risk mainly through the likelihood of GVHD. More GVHD usually results in more infections. To prevent GVHD in a mismatched transplant, more potent immunosuppression may be required, increasing the risk of infection. It is also possible that immune reconstitution proceeds more slowly (even with the same immunosuppressive regimen) after a URD HCT. These factors may result in increased risk of infections associated with T cell immunodefi ciency, like CMV, Pneumocystis jirovecii pneumonia (PCP), and Epstein-Barr virus (EBV)-related posttransplant lymphoproliferative disorder (PTLD).

However, provided the number of stem cells administered is the usual (>3 × 10 6 kg −1 ), neutrophil recovery proceeds at the standard pace and there is no increased risk of neutropeniarelated infections.

The problems with UCB transplants include a markedly decreased stem cell dose (often <1 × 10 5 kg −1 ) which results in prolonged neutropenia (up to 6 weeks), with the attendant risk of bacterial and fungal infections [ 27 ] . In addition, the cord blood does not have antigen-specifi c memory T cells that can expand in a thymus-independent fashion to provide protection against viruses and opportunistic pathogens. This results in high frequency of late severe infections following cord transplantation, even when the neutropenic period is shortened by coadministration of stem cells from a thirdparty donor [ 28 ].

Stem cells may be given using the bone marrow, G-CSFmobilized peripheral blood stem cells (PBSCs), or UCB. Frequently bone marrow will result in more prolonged neutropenia compared with PBSC, and increased infections during neutropenia should be expected. However, a multicenter randomized trial comparing peripheral blood stem cells with the bone marrow from unrelated donors showed no difference in the relapse or infectious mortality between both groups, but confi rmed that chronic GVHD is more common with mobilized PBSC [ 29 ] . The particular features of UCD transplants were discussed on the preceding paragraph.

Manipulation of the Stem Cells, Immunosuppressive Drugs, or a Combination GVHD may be prevented by decreasing the amount donor T cells or by limiting T cell function with immunosuppressive agents. The stem cells, whether from the bone marrow or the periphery, may be administered unmanipulated (sometimes called "T cell replete") or enriched by CD34 selection (also called "T cell depleted"). If unmanipulated bone marrow or PBSCs are used, the dose of CD3+ T cells administered with the graft varies between 24 × 10 6 kg −1 when bone marrow is used and 300 × 10 6 kg −1 when PBSCs are used [ 30 ] .

Reductions in the amount of T cells of 2-3 log 10 are possible, and in some haploidentical transplant regimens, as few as 12.5 × 10 3 CD3+ cells are given, which still results in detectable immune reconstitution starting 2-3 months after transplant [ 31 ] . T cell depletion may minimize or altogether prevent GVHD but may result in prolonged immunodeficiency, depending on the degree of depletion. If an unmanipulated product is used, T cell depletion may be attained in vivo by using alemtuzumab or ATG. These agents produce a profound depletion of T cells in vivo, and their long halflife makes them still be present and active in the recipient when the stem cell product is administered. If no in vitro or in vivo T cell depletion is used, one of a variety of immunosuppressive regimens will be given to prevent GVHD (e.g., tacrolimus + methotrexate, tacrolimus plus mycophenolate mofetil, cyclosporine A, sirolimus, posttransplant cyclophosphamide). A randomized controlled trial documented more infections in patients randomized to (moderate) T cell depletion than in the group who received pharmacologic immunosuppression [ 32 ] . T cell depletion in vivo with alemtuzumab has been associated with increased risk of infection [ 33 ] . It is possible that different pharmacological regimens may result in different infectious risks, but this has not been adequately studied. Preliminary evidence suggests that a sirolimus-based regimen may result in less CMV reactivation [ 34 ] and that posttransplant cyclophosphamide result in relatively decreased risk of PTLD [ 35 ].

The above categories may combine in several ways, compounding the risk of infection. These variations should be considered both when designing a regimen of anti-infective prophylaxis and when considering an individual patient who may have an infection.

GVHD is the most important cause of non-relapse mortality following HCT, and it is frequently complicated by infection. GVHD is categorized as acute or chronic based on its time of onset. Acute GVHD develops before day 100 and is characterized by gastrointestinal disease (secretory diarrhea, nausea, vomiting), liver dysfunction, and skin rash. Stages of GVHD in the skin, gut, and liver combine to give a grade (I-IV) of the severity of the disease. Acute GVHD grades III-IV is associated with signifi cant mortality. The treatment of choice is high-dose systemic corticosteroids. GVHD is associated with signifi cant immune dysregulation [ 36 , 37 ] and is frequently accompanied by CMV reactivation [ 38 ] . The combination of disruption of the GI mucosa (and sometimes skin) and high-dose corticosteroids (in addition to the immunosuppressive agents concurrently given, like tacrolimus and MMF) constitute a high-risk setting for infection. Bacterial, fungal, and viral infections are common under these circumstances.

Chronic graft-versus-host disease (cGVHD) has been traditionally defi ned chronologically: GVHD starting after day 100. It has been classifi ed based on its relation to prior GVHD (progressive when acute GVHD continues after day 100, quiescent when there is a period of time during which the patient is free of GVHD, or de novo when chronic GVHD is the fi rst manifestation of GVHD) and its extension (limited or extensive, reformulated as clinical limited, or clinical extensive). The clinical syndrome of typical chronic GVHD is quite distinct from the acute form, and a new classifi cation focusing on the clinical characteristics of the disease as well as on the timing is being increasingly used [ 39 ] . From the standpoint of infectious diseases, the important consideration is that the presence of chronic GVHD is associated with high risk of infection [ 40 , 41 ] . Multiple immune defects have been described during chronic GVHD, involving humoral and cellular immunity [ 42 , 43 ] as well as functional hyposplenism [ 44 , 45 ] . Besides these abnormalities, that result in delayed immune reconstitution and poor response to immunizations, the risk is of infection is increased by the treatment of extensive cGVHD [ 41 ], which typically includes systemic corticosteroids and a variety of steroid-sparing agents. Notably, cGVHD is a well-documented risk for pneumococcal infections [ 45 , 46 ] , fungal infections, and late CMV disease. However, all types of infections are more common during cGVHD, particularly during the fi rst few months [ 47 ] .

When GVHD is not controlled by corticosteroids, it is called " steroid refractory ," and there is currently no universally accepted standard treatment. This situation is important from the infectious disease standpoint because patients are usually treated with a variety of highly immunosuppressive regimens (e.g., ATG, cyclophosphamide, MMF, infl iximab, daclizumab, alefacept, alemtuzumab, sirolimus, visilizumab, denileukin diftitox, and others) [ 48 ] that result in a wide array of infectious complications. Reactivation of CMV is very common, as are fungal infections [ 49 , 50 ] , Epstein-Barr virus-related PTLD [ 51 ] , as well as human herpesvirus 6 (HHV-6) [ 52 ] and adenovirus [ 53 ] . There are no controlled studies to support any particular infection prevention strategy during this period of increased immunosuppression, but some authors have emphasized that early use of prophylactic antibiotics and antifungals is an essential part of a successful approach to this problem [ 54 ] . Unfortunately, this is a condition for which controlled trials are unlikely to be performed, and different centers will have to decide on a particular approach of close monitoring versus prophylaxis based on local experience and published case series.

In the following sections, the epidemiology of bacterial, fungal, viral, and parasitic diseases will be discussed. The implications for prophylaxis and management will be mentioned. Immunizations for transplant recipients, (as well as their caregivers and immediate contacts) are discussed in Chap. 48 6.6 Risks and Epidemiology of Bacterial Infections After Allogeneic HCT 6.6.1 Early Bacterial Infections: Pre-engraftment Approximately 20% of HCT recipients will experience at least one episode of bacteremia during the fi rst few weeks, and a similar proportion after engraftment [ 55 ] . These infections are usually related to either neutropenia with subsequent bacterial translocation through the GI mucosa (mucosal barrier injury laboratory-confi rmed bloodstream infection or MBI-LCBI) or the intravascular catheter (central lineassociated bloodstream infections or CLABSIs) [ 56 ] .

The relative frequency of Gram-positive and Gramnegative infections during neutropenia varies in different series and with the use of prophylactic antibiotics. In some centers, the most frequent Gram-positive isolates are viridans group Streptococcus [ 55 ] ; this may be a function of the conditioning regimen or the patient population. Enterococcus faecium , frequently VRE, is another Gram-positive organism that tends to cause bloodstream infection relatively early, although this seems to be rather institution dependent [ 57 ] . The Gram-negative bacteria are commonly Enterobacteriaceae . These infections are generally related to the disruption of the GI mucosa due to the preparative regimen. The role of reduced diversity of the microbiota with subsequent bacterial domination and ultimately bacteremia is an area of intense study [ 58 ] . The risk of bacteremia during neutropenia may be decreased by the use of prophylactic antibiotics [ 59 , 60 ] . This had been shown in multiple studies over the years, but the recommendation of using antibiotics did not become part of practice guidelines until recently. It is not clear whether this recommendation will continue amidst the increasing concern over the role of antibiotic-induced decreased microbiome diversity on the outcome of HCT [ 61 ] . In this regard it is of interest that fl uoroquinolones seem to have less detrimental effects on biodiversity of the fecal fl ora than beta-lactams. Levofl oxacin at a dose of 500 mg/d for patients who are going to be profoundly neutropenic for longer than 1 week is the current recommendation of the IDSA [ 11 ].

Following Engraftment

In a large study from the Sloan Kettering Cancer Center, the risk factors for post-engraftment bacteremia included acute GVHD, renal dysfunction, hepatic dysfunction, and neutropenia [ 55 ] . Enterococcus (VRE) and coagulase-negative Staphylococcus were the most common Gram-positive isolates. Enterobacteriaceae and non-fermentative Gram-negative bacteria (including Pseudomonas , Stenotrophomonas , and Acinetobacter , possibly related to the indwelling catheter) were the most common Gramnegative isolates. Bacteremia following engraftment often happens in the setting of patients with a complicated clinical course, acute GVHD, and multiple medical problems or else is catheter related.

Daily bathing with chlorhexidine-impregnated washcloths decreased the risk of acquisition of MDROs and development of hospital-acquired bloodstream infections in transplant recipients in a randomized trial [ 62 ] , and this practice should be considered by every transplant program.

The advantages and disadvantages of active screening for colonization by resistant pathogens have not been adequately studied in HCT recipients. It is likely that local epidemiology determines whether screening is an effi cacious and costeffective approach to either prevent infection or improve outcomes. A retrospective study on VRE bacteremia from the Sloan Kettering Cancer Center showed that VRE carriage was predictive of subsequent VRE bacteremia, but failed to detect the pathogen in many patients [ 63 ] . Performing surveillance cultures for resistant organisms in vulnerable patient populations is part of the CDC recommendations "Management of Multidrug-Resistant Organisms in Healthcare Settings, 2006" [ 64 ] , and has been vigorously advocated by some experts [ [ 66 , 67 ] . Both early and late (beyond day 100) pneumococcal disease has been reported, with late infections strongly associated with active cGVHD [ 46 ] . These have been attributed to inadequate antibody production and functional hyposplenism [ 44 , 67 ] . Vaccination against S. pneumoniae should be given to all HCT recipients, starting 3-6 months after transplant and using the 13-valent conjugate vaccine [ 9 ] (see Chap. 48 for details). Four doses of the vaccine result in enhanced antibody response and tolerable side effects [ 68 ] . Antibiotic prophylaxis against S. pneumoniae prophylaxis for adults with active cGVHD has been recommended [ 69 ] , although there is only weak evidence supporting its effi cacy. Penicillin V-K is safe and well tolerated, but the local patterns of penicillin resistance may make other antibiotics (e.g., trimethoprim, sulfamethoxazole, azithromycin, or levofl oxacin) preferable, although their long-term safety is not well established. Late bacterial infections often involve the respiratory tract. Pneumonia is the most common cause of fatal late infection [ 40 , 70 ] . Chronic GVHD is the risk factor most commonly identifi ed. Besides S. pneumoniae , multiple other pathogens have been reported. Nocardia also tends to occur late and in patients with cGVHD [ 71 , 72 ] . Mycobacterial infections are uncommon and diffi cult to diagnose [ 73 ] . Risk factors for the development of active TB include GVHD, corticosteroid treatment, and total body irradiation (TBI) [ 74 ] . The need for universal testing for tuberculosis is controversial, given the unknown sensitivity and specifi city of the tests in this population and the fact that tuberculosis is a relatively uncommon complication after HCT (albeit still approximately three times higher than in the general population) [ Invasive candidiasis follows prior colonization and favorable conditions for the yeast: disruption of the GI mucosa during chemotherapy or acute GVHD, overgrowth in the presence of broad-spectrum antibiotics, and/or presence of indwelling catheters (the catheter seems to be the main risk factor in the case of C. parapsilosis ). Early studies showed that fl uconazole during the pre-engraftment period could decrease the incidence of invasive candidiasis [ 76 , 77 ] . Accordingly, fl uconazole is recommended as part of the standard prophylactic regimen during the pre-engraftment period. The prevalent use of fl uconazole has resulted in substantial decrease in the incidence of infections caused by C. albicans with relative increases in the incidence of other species of Candida with decreased susceptibility to this agent (e.g., C. glabrata , C. krusei ) [ 78 ] .

Invasive aspergillosis occurs during specifi c "at risk" periods following HCT, with a fi rst peak around the time of neutropenia pre-engraftment, a second peak between days 40 and 70 (the time of acute GVHD and its treatment), and a third peak late after transplant, usually in the midst of actively treated cGVHD [ 79 ] (Figure 6-1 ) . A variety of risk factors for invasive aspergillosis have been identifi ed over the years, but the most consistently found to be signifi cant in multivariate analyses are acute GVHD, chronic extensive GVHD, and CMV disease [ 80 -82 ] . Systemic corticosteroids are almost always present as part of the treatment of acute and chronic GVHD.

Non-aspergillus mold infections (e.g., fusariosis, mucormycosis, scedosporiosis), sometimes referred to as emerging mold infections, have been reported with increasing frequency [ 83 ] . The increased use of prophylaxis with activity against Aspergillus would be expected to result in a relative increase of other opportunistic mycoses like mucormycosis [ 84 ] .

Considering the diversity of fungal infections after transplant and the current antifungal armamentarium, it is controversial which antifungal prophylaxis is appropriate at what point during transplant. For instance, although fl uconazole is a safe and well-established intervention during the preengraftment period of myeloablative transplants [ 76 , 77 ] , it is reasonable to question how necessary it is in transplants with conditioning regimens that result in shorter neutropenia. Micafungin showed to be equivalent to fl uconazole in a randomized controlled trial [ 85 ] , and the same question (what kind of transplant patient would benefi t most) applies.

Regarding the duration of antifungal prophylaxis, fl uconazole up to day 75 posttransplant was associated with improved survival mainly due to decreased incidence of systemic candidiasis [ 86 ] , but it is uncertain whether this strategy should be used for all patients or should be received for some selected subgroups considered at higher risk. Similarly, it is reasonable to question the indication for fl uconazole during periods when the main fungal infection is aspergillosis. Several randomized controlled trials have compared fl uconazole with another azole with activity against molds (itraconazole [ 87 , 88 ] , voriconazole [ 89 ] , or posaconazole [ 90 ] ) either as standard posttransplant prophylaxis or during periods of increased risk. The general conclusion of these trials is that the aspergillus-active drugs are, indeed, more effective than fl uconazole in preventing IA, but the benefi t in survival in the context of a clinical trial with careful monitoring of galactomannan antigen is hard to demonstrate [ 91 ] . The 2009 ASBMT/EBMT Guidelines recommend posaconazole or voriconazole as antifungal prophylaxis in the setting of GVHD and micafungin in the setting of prolonged neutropenia [ 1 ] . Of note, posaconazole prophylaxis was superior to fl uconazole or itraconazole and improved survival in prolonged neutropenia in non-transplant patients [ 92 ] . Now, there are even more options of mold-active prophylaxis with posaconazole delayed-release tablets, intravenous posaconazole, and the new agent isavuconazole.

Infections After Allogeneic HCT Viral infections remain a challenge because newer transplant modalities result in severe prolonged T cell immunodeficiency and because the current antiviral armamentarium is very limited. Multiple latent viruses may reactivate following HCT [ 93 ] . The role of monitoring by PCR is well defi ned mainly for CMV. Latent viral reactivation is of particular concern in recipients of cord [ 94 ] or T cell-depleted transplants. Table 6 -3 presents a summary of this section.

Members of the herpesvirus family that have caused significant disease after transplant include HSV-1, HSV-2, VZV, EBV, CMV, and HHV-6. Posttransplant complications of HHV-7 are not well defi ned, although multiple associations have been described. HHV-8 infection and disease (primary effusion lymphoma and Kaposi's sarcoma) occur only infrequently after HCT.

HSV-1 and HSV-2 may reactivate following the preparative regimen and complicate chemotherapy-induced mucositis, so it is customary to administer prophylaxis with acyclovir or valacyclovir at least until engraftment. In patients with common recurrences, long-term suppression may be appropriate. 

VZV predictably reactivates following transplant (approximately 25% in the fi rst year), either as shingles, multidermatomal, disseminated, or even without a rash ("zoster sine herpete"). In patients who are at risk for VZV reactivation, the use of long-term acyclovir safely prevents the occurrence of VZV disease [ 95 , 96 ] , and currently it is recommended for at least 1 year following HCT. CMV remains latent in a variety of human cells. CMVseropositive HCT recipients are at risk for CMV reactivation and disease after transplant. The term "CMV infection" is used to denote the presence of CMV in the blood detected by PCR or pp65 antigenemia [ 97 ] . Following reactivation, CMV may cause disease typically in the form of pneumonia and/or gastrointestinal disease (most commonly colitis).

Other CMV diseases like retinitis or CNS involvement are rare after HCT but have been described: retinitis has been associated with high CMV viral load [ 98 ] sometimes in the context of chronic GVHD and CNS disease (encephalitis and ventriculitis), sometimes with resistant virus in the CNS [ 99 , 100 ] . The risk for reactivation may be related to the presence of CMV-specifi c immunity in the donor. The rate of CMV infection in the donor-recipient (D/R) pairs often follows the progression D R D R D R D R -+ + + + -

, suggesting that CMV-specifi c memory T cells administered with the stem cells may play a role in preventing reactivation and disease. CMV infection or disease in CMV-seronegative recipients of seronegative donors (R−/D−) is rare when leucodepleted or CMV-negative blood products are used [ 101 ] .

Every transplant program must decide on a strategy to monitor CMV and prevent disease. Depending on a variety of factors, either universal prophylaxis with ganciclovir up to day 100 or a preemptive strategy of weekly monitoring and early therapy may be used. Both approaches resulted in similar overall mortality when compared in a randomized controlled trial, but universal prophylaxis was followed by more cases of late CMV disease [ 97 , 102 ] . Late CMV disease has emerged as a signifi cant problem, as it occurs when patients are not being under close monitoring by the transplant center. Risk factors include lymphopenia and chronic GVHD [ 103 ] . Preventing late CMV disease may be accomplished by either prophylaxis with valganciclovir or the preemptive approach with weekly CMV PCR monitoring [ 104 ] . The effect of CMV serostatus of donor and recipient on overall survival is complex (for a review, see [ 105 ] and Chap. 24 ).

PTLD is a spectrum of lymphoid proliferations that may happen after solid organ or allogeneic stem cell transplantation, usually (but not always) driven by EBV [ 106 ] . Pathologically the spectrum goes from polymorphic, polyclonal tissue infi ltration of lymphocytes to monomorphic involvement with high-grade B cell lymphoma. After allogeneic HCT, the proliferating cells may be from donor (most commonly) or recipient origin. This disorder is typically related to insuffi cient or abnormal T cell responses against EBV [ 107 ] , and accordingly it is more common in the setting of HLA-mismatched transplants, T cell depletion, or intense immunosuppression for the treatment of GVHD [ 108 -110 ] . Some cases have followed the use of alemtuzumab for in vivo T cell depletion or GVHD prophylaxis [ 110 ] , despite the fact that anti-CD52 also results in depletion of B cells and earlier had been reported to be associated with relatively less risk. Interestingly, the use of posttransplant cyclophosphamide to prevent GVHD seems to be associated with lower risk of PTLD [ 35 ] . Monitoring of EBV viral load by quantitative PCR is now recommended in those transplants considered at high risk. Preemptive management of increasing EBV viral load in patients at risk has been associated with good outcomes [ 111 ] , although it is not clear when exactly this treatment should be given. A CT/PET may be useful to localize areas amenable to biopsy (Figure 6 -2 ).

HHV-6 is acquired early in life, when it may cause roseola infantum and nonspecifi c febrile illnesses. It frequently reactivates following HCT. Using quantitative PCR, HHV-6 can often be detected in peripheral blood 2-5 weeks after transplant. Most of the time the reactivation seems to be asymptomatic [ 112 ] , but a number of associations (rash, delayed engraftment, GVHD, thrombocytopenia, increased overall mortality) as well as actual clinicopathological entities (hepatitis, pneumonitis, encephalitis) have been described [ 113 -115 ] . HHV-6 is possibly the most common cause of infectious encephalitis after HCT [ 116 ] . It seems to be particularly frequent after cord blood transplant. Cases of encephalitis tend to be accompanied by higher viral loads of HHV-6 in plasma [ 117 ] , but the role of systematic monitoring of HHV-6 in plasma is unknown at this time, as reactivation seems much more common than disease [ 118 ] and attempts to use a preemptive strategy using foscarnet have not been successful [ 119 ] . The European Conference on Infections in Leukemia has proposed evidence-based guidelines to address the diagnostic and therapeutic uncertainties related to this infection [ 120 ] .

Respiratory viruses , a heterogeneous group of virus that is responsible for most upper acute respiratory infections in normal hosts, result in signifi cant morbidity and mortality after HCT, particularly during the fi rst 3 months following transplant [ 121 ] . Even asymptomatic carriage of respiratory viruses at the time of transplant has been reported to result in increased risk of unfavorable outcomes [ 122 ] . Besides respiratory syncytial virus (RSV) [ 123 ] , infl uenza, parainfl uenza virus (PIV) [ 124 ] , rhinovirus [ 125 ] , and adenovirus, newly identifi ed viruses including metapneumovirus [ 126 ] , coronavirus [ 127 ] , and bocavirus [ 128 ] have emerged as signifi cant pathogens. These infections present signifi cant risks both acutely and in the long term. During the acute infection, HCT recipients are at risk of developing viral pneumonia that sometimes progresses to respiratory insuffi ciency, mechanical ventilation and death, and also at risk of concomitant or secondary bacterial or fungal infections that are associated with increased mortality [ 124 , 129 , 130 ] . Longterm, there seems to be an association between early infection (pre-day 100) with some of these viruses (most notably PIV and RSV) and later development of chronic airfl ow obstruction [ 131 ] . The most signifi cant risk factor overall for progression of these infections from the upper respiratory tract to the lungs seems to be lymphopenia [ 132 ] . Corticosteroid use seems to contribute to progression to pneumonia in RSV and parainfl uenza infections but not so in infl uenza [ 129 , 130 ] (see Table 6 -3 ).

Besides its role among the community-acquired respiratory virus, adenovirus may cause disease in transplant recipients following reactivation in the gastrointestinal tract followed by dissemination and end-organ damage [ 133 ] . De novo acquisition of adenovirus may also result in disseminated disease. There are more than 60 types of human adenovirus, with dif-ferent tropisms and possibly varying susceptibilities to antiviral agents. They can cause a variety of diseases, including upper and lower respiratory tract infection, colitis, hemorrhagic cystitis (HC), nephropathy, and CNS disease. Systemic adenovirus disease seems to be more common in children, particularly in recipients of cord blood or T cell-depleted transplants [ 134 -136 ] . Patients with GVHD on treatment with high-dose corticosteroids are also at risk (Figure 6-3 ) . Some studies have documented that sustained high levels of adenoviremia are associated with disease [ 137 ] . It is not known yet whether a preemptive approach with cidofovir can successfully prevent disseminated disease and death [ 133 , 138 ] .

BK virus infects 90% of humans by age 12. It predictably reactivates in most patients following HCT and causes hemorrhagic cystitis (HC) in a minority of them [ 139 ] . Detection of high levels of BK in the peripheral blood seems to correlate with the presence of BK-induced HC [ 140 , 141 ] . In a large study from the Fred Hutchinson Cancer Research Center (FHCRC), no association was found between BK virus-associated HC and lymphopenia, corticosteroid use, and GVHD-the typical risk factors for viral infections after HCT [ 140 ] . In contrast, other smaller studies have found an association with GVHD. The pathogenesis of this disease remains unexplained. BK-induced nephropathy, a common problem after kidney transplant, remains infrequent after HCT and does seem to be related to profound immunosuppression [ 142 ] . BK pneumonitis has also been described, but it is distinctly rare [ 143 ] .

JC virus is also acquired by most people during childhood. In immunocompromised hosts, it may cause encephalitis (JC encephalitis, previously called progressive multifocal leukoencephalopathy (PML)) with multiple areas of demyelin-ation without edema detectable by MRI. Some studies have suggested that detectable viral load after HCT may be more common than currently thought [ 144 ] . Ascertaining risk factors for this disease is diffi cult because some transplant recipients may have conditions known to be associated with it and also received medications like MMF, rituximab, or brentuximab, which have been associated with PML even in the absence of allo-HCT.

PCP is an opportunistic infection of patients with profound cellular immunodefi ciency, and prophylaxis is recommended after HCT. It is now relatively uncommon: 1.3-2.4% of patients transplanted from several series [ 145 , 146 ] Most cases seem to occur relatively late, after discontinuing prophylaxis or during periods of intensive immunosuppression for the treatment of GVHD [ 147 ] . Hypoxemia is characteristic at presentation. Atypical radiological manifestations, including nodular infi ltrates and pleural effusions (in contrast to typical interstitial pneumonitis), are described frequently, as is the presence of co-pathogens [ 148 ] . The preferred prophylaxis is trimethoprim/sulfamethoxazole (TMP/SMX) , and several dosing regimens are effective (one single-strength tablet daily, one double-strength tablet daily, or one double-strength tablet three times/week) [ 149 ] . TMP/ SMX may be poorly tolerated because of hematologic toxicity, skin rash and/or gastrointestinal toxicity [ 150 ] . It is unclear which is the prophylaxis of choice if TMP/ SMX cannot be used. Aerosolized pentamidine is convenient, obviates the problem of compliance, and is less toxic than dapsone and better tolerated than atovaquone. However, it has been reportedly associated with more failures than dapsone [ 150 ] . Dapsone seemed to be effective and well tolerated in one study [ 151 ] but not in another when it was given only three times per week [ 152 ] . Dapsone should not be given to patients with G6PD defi ciency. Methemoglobinemia is a well-known complication of dapsone [ 153 ] that should be considered in the presence of unexplained shortness of breath. Atovaquone suspension 1500 mg/d may be used, but published experience in HSCT recipients is limited [ 154 , 155 ] . Atovaquone is expensive and poor tolerance has made compliance for some patients diffi cult. Absorption is better in the presence of signifi cant amount of fat, and breakthroughs are well documented ( Figure 6-4 ) . PCP prophylaxis is recommended at least until all immunosuppression has been stopped but it is unclear how much longer to continue it [ 156 ] .

Most cases of toxoplasmosis after HCT represent reactivation, although rare cases of transmission with bone marrow transplant have been suspected [ 157 ] . Recipients should be tested for anti-toxoplasma IgG antibody, and if they are found to be positive, prophylaxis is recommended. Rare cases of toxoplasmosis after HCT have occurred in seronegative recipients [ 158 , 159 ] . The disease tends to occur within the fi rst 6 months after transplant, but it can happen later in the presence of persistent immunosuppression [ 160 -162 ] . The risk of toxoplasmosis varies with the type of transplant and the immunosuppression: cord blood and use of ATG were found to be risk factors for disease in a prospective study [ 162 ] ; most cases in another series occurred in URD or mismatched transplants [ 107 ] . TMP/SMX as given for PCP prophylaxis is considered adequate to prevent toxoplasmosis, although there have been cases on HCT recipients who were receiving it [ 162 ] . The best alternative for patients who are intolerant to TMP/SMX is unknown. Dapsone and atovaquone showed some effi cacy in HIV-infected patients and there is increasing experience after HCT [ 163 ] , although failures have been reported. Other regimens include clindamycin with pyrimethamine and leucovorin, pyrimethamine with sulfadiazine, or pyrimethamine and sulfadoxine and leucovorin [ 107 ] . If a reliable quantitative PCR assay is available, frequent monitoring and preemptive treatment may be appropriate, since PCRdetected reactivation seems to precede symptoms by 4-16 days [ 162 ] . Retrospective data suggest this strategy may result in improved outcome [ 164 ] .

In summary, infections following HCT are frequently related to risk factors caused by the procedure itself. Neutropenia and mucositis predispose to bacterial infections. Prolonged neutropenia increases the likelihood of invasive fungal infection. GVHD and its treatment create the most important easily identifi able risk period for a variety of infectious complications, particularly mold infections. Profound, prolonged T cell immunodefi ciency, present after T cell-depleted or cord blood transplants, is the main risk factor for viral problems like disseminated adenovirus disease or EBVrelated PTLD.

Besides all these "procedure-related" risk factors, there are individual characteristics that only now are starting to be investigated and understood. Future epidemiological and basic studies will likely result in truly personalized prophylactic regimens that will increase the unquestionable benefi ts of antimicrobial prophylaxis and reduce the cost, both direct and indirect, associated with this life-saving practice. 

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Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation

Secondary antifungal prophylaxis with voriconazole to adhere to scheduled treatment in leukemic patients and stem cell transplant recipients

Hematopoietic stem cell transplantation in patients with active fungal infection: not a contraindication for transplantation

Risk factors for recurrence of invasive fungal infection during secondary antifungal prophylaxis in allogeneic hematopoietic stem cell transplant recipients

Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: a retrospective survey of the infectious diseases working party of the european group for blood and marrow transplantation

Lack of B cells precursors in marrow transplant recipients with chronic graftversus-host disease

Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts

Functional asplenia after bone marrow transplantation. A late complication related to extensive chronic graft-versushost disease

Pneumococcal arthritis and functional asplenia after allogeneic bone marrow transplantation

Chronic graft versus host disease is associated with long-term risk for pneumococcal infections in recipients of bone marrow transplants

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Secondary treatment of acute graft-versus-host disease: a critical review

Tumor necrosis factor-alpha blockade for the treatment of acute GVHD

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Post-transplant acute limbic encephalitis: clinical features and relationship to HHV6

The successful use of alemtuzumab for treatment of steroid-refractory acute graft-versushost disease in pediatric patients

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The burden of mucosal barrier injury laboratory-confi rmed bloodstream infection among hematology, oncology, and stem cell transplant patients

Colonization, bloodstream infection, and mortality caused by vancomycin-resistant enterococcus early after allogeneic hematopoietic stem cell transplant

Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation

Levofl oxacin to prevent bacterial infection in patients with cancer and neutropenia

Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy

The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation

Effect of daily chlorhexidine bathing on hospital-acquired infection

The changing epidemiology of vancomycin-resistant enterococcus (VRE) bacteremia in allogeneic hematopoietic stem cell transplant (HSCT) recipients

Healthcare Infection Control Practices Advisory Committee. Management of multidrug-resistant organisms in health care settings

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Immunogenicity, safety, and tolerability of 13-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine in recipients of allogeneic hematopoietic stem cell transplant aged ≥2 years: an open-label study

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Systemic nocardiosis following allogeneic bone marrow transplantation

Mycobacterial infection: a diffi cult and late diagnosis in stem cell transplant recipients

Tuberculosis after hematopoietic stem cell transplantation: incidence, clinical characteristics and outcome. Spanish group on infectious complications in hematopoietic transplantation

Risk factors for invasive fungal infections in haematopoietic stem cell transplantation

A controlled trial of fl uconazole to prevent fungal infections in patients undergoing bone marrow transplantation

Effi cacy and safety of fl uconazole prophylaxis for fungal infections after marrow transplantation-a prospective, randomized, double-blind study

Candidemia in allogeneic blood and marrow transplant recipients: evolution of risk factors after the adoption of prophylactic fl uconazole

Epidemiology of aspergillus infections in a large cohort of patients undergoing bone marrow transplantation

Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors

Invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplantation after nonmyeloablative conditioning: risks and outcomes

Risks, diagnosis and outcomes of invasive fungal infections in haematopoietic stem cell transplant recipients

Epidemiology and outcomes of invasive fungal infections in allogeneic haematopoietic stem cell transplant recipients in the era of antifungal prophylaxis: a singlecentre study with focus on emerging pathogens

Zygomycosis in a tertiary-care cancer center in the era of aspergillus-active antifungal therapy: a casecontrol observational study of 27 recent cases

Micafungin versus fl uconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation

Prolonged fl uconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial

Intravenous and oral itraconazole versus intravenous and oral fl uconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial

Itraconazole versus fl uconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants

Randomized, double-blind trial of fl uconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation

Posaconazole or fl uconazole for prophylaxis in severe graft-versus-host disease

Second-versus fi rstgeneration azoles for antifungal prophylaxis in hematology patients: a systematic review and meta-analysis

Posaconazole vs. fl uconazole or itraconazole prophylaxis in patients with neutropenia

Large-scale multiplex polymerase chain reaction assay for diagnosis of viral reactivations after allogeneic hematopoietic stem cell transplantation

Intensive strategy to prevent cytomegalovirus disease in seropositive umbilical cord blood transplant recipients

Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantation-a randomized double-blind placebo-controlled study

Use of long-term suppressive acyclovir after hematopoietic stem-cell transplantation: impact on herpes simplex virus (HSV) disease and drug-resistant HSV disease

Cytomegalovirus pp 65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study

Risk factors for cytomegalovirus retinitis in patients with cytomegalovirus viremia after hematopoietic stem cell transplantation

CMV central nervous system disease in stem-cell transplant recipients: an increasing complication of drug-resistant CMV infection and protracted immunodefi ciency

Cytomegalovirus ventriculoencephalitis with compartmentalization of antiviral-resistant cytomegalovirus in a T cell-depleted haploidentical peripheral blood stem cell transplant recipient

Transfusion-transmitted cytomegalovirus infection after receipt of leukoreduced blood products

Successful modifi cation of a pp 65 antigenemia-based early treatment strategy for prevention of cytomegalovirus disease in allogeneic marrow transplant recipients

Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and t-cell immunity

Valganciclovir for the prevention of complications of late cytomegalovirus infection after allogeneic hematopoietic cell transplantation: a randomized trial

The role of cytomegalovirus serostatus on outcome of hematopoietic stem cell transplantation

Post-transplant lymphoproliferative disorders

Prophylaxis of toxoplasmosis infection with pyrimethamine/sulfadoxine (fansidar) in bone marrow transplant recipients

Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation

EBV-associated post-transplant lymphoproliferative disorder after umbilical cord blood transplantation in adults with hematological diseases

EBV-associated post-transplant lymphoproliferative disorder following in vivo t-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era

Impact of Epstein Barr virus-related complications after high-risk allo-SCT in the era of pre-emptive rituximab

Human herpesvirus 6 infections after bone marrow transplantation: clinical and virologic manifestations

High levels of human herpesvirus 6 DNA in peripheral blood leucocytes are correlated to platelet engraftment and disease in allogeneic stem cell transplant patients

Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation

Human herpesvirus 6 reactivation on the 30th day after allogeneic hematopoietic stem cell transplantation can predict grade 2-4 acute graft-versus-host disease

Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: what we do and do not know

Human herpesvirus 6 (HHV-6) reactivation and HHV-6 encephalitis after allogeneic hematopoietic cell transplantation: a multicenter, prospective study

Frequent human herpesvirus-6 viremia but low incidence of encephalitis in double-unit cord blood recipients transplanted without antithymocyte globulin

Foscarnet against human herpesvirus (HHV)-6 reactivation after allo-SCT: breakthrough HHV-6 encephalitis following antiviral prophylaxis

Management of CMV, HHV-6, HHV-7 and kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT

The challenge of respiratory virus infections in hematopoietic cell transplant recipients

Risks and Epidemiology of Infections After Hematopoietic Stem Cell Transplantation with respiratory virus detection before allogeneic hematopoietic stem cell transplantation

Respiratory syncytial virus lower respiratory disease in hematopoietic cell transplant recipients: viral RNA detection in blood, antiviral treatment, and clinical outcomes

Parainfl uenza virus infections after hematopoietic stem cell transplantation: risk factors, response to antiviral therapy, and effect on transplant outcome

Rhinovirus infections in hematopoietic stem cell transplant recipients with pneumonia

Mortality rates of human metapneumovirus and respiratory syncytial virus lower respiratory tract infections in hematopoietic cell transplantation recipients

Human rhinovirus and coronavirus detection among allogeneic hematopoietic stem cell transplantation recipients

Disseminated bocavirus infection after stem cell transplant

Infl uenza infections after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of antiviral therapy

Human parainfl uenza virus infection after hematopoietic stem cell transplantation: risk factors, management, mortality, and changes over time

Airfl ow decline after myeloablative allogeneic hematopoietic cell transplantation: the role of community respiratory viruses

Respiratory syncytial virus in hematopoietic cell transplant recipients: factors determining progression to lower respiratory tract disease

Adenovirus infection and disease in pediatric hematopoietic stem cell transplant patients: clues for antiviral preemptive treatment

Adenovirus infection rates in pediatric recipients of alternate donor allogeneic bone marrow transplants receiving either antithymocyte globulin (ATG) or alemtuzumab (campath)

Adenovirus infections following allogeneic stem cell transplantation: incidence and outcome in relation to graft manipulation, immunosuppression, and immune recovery

Invasive adenoviral infections in t-celldepleted allogeneic hematopoietic stem cell transplantation: high mortality in the era of cidofovir

Quantitative real-time polymerase chain reaction for detection of adenovirus after T cell-replete hematopoietic cell transplantation: viral load as a marker for invasive disease

Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the infectious diseases working party of the European group for blood and marrow transplantation

Polyomavirus BK infection in blood and marrow transplant recipients

BK DNA viral load in plasma: evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients

Kidney and bladder outcomes in children with hemorrhagic cystitis and BK virus infection after allogeneic hematopoietic stem cell transplantation

BK nephropathy in pediatric hematopoietic stem cell transplant recipients

Pneumonitis post-haematopoeitic stem cell transplant-cytopathology clinches diagnosis

JC polyomavirus reactivation is common following allogeneic stem cell transplantation and its preemptive detection may prevent lethal complications

Pneumocystis carinii pneumonitis following bone marrow transplantation

Occurrence of pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study

Late onset pneumocystis carinii pneumonia following allogeneic bone marrow transplantation

Infl uence of type of cancer and hematopoietic stem cell transplantation on clinical presentation of pneumocystis jiroveci pneumonia in cancer patients

A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for the prevention of pneumocystis carinii pneumonia in human immunodefi ciency virusinfected persons. Terry beirn community programs for clinical research on AIDS (CPCRA)

Aerosolized pentamidine as pneumocystis prophylaxis after bone marrow transplantation is inferior to other regimens and is associated with decreased survival and an increased risk of other infections

Toxicity and effi cacy of daily dapsone as pneumocystis jiroveci prophylaxis after hematopoietic stem cell transplantation: a case-control study

High rates of pneumocystis carinii pneumonia in allogeneic blood and marrow transplant recipients receiving dapsone prophylaxis

Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals

A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation

Atovaquone suspension compared with aerosolized pentamidine for prevention of pneumocystis carinii pneumonia in human immunodefi ciency virus-infected subjects intolerant of trimethoprim or sulfonamides

Regionally limited or rare infections: prevention after hematopoietic cell transplantation

Transmission of toxoplasmosis by bone marrow transplant associated with campath-1g

Disseminated toxoplasmosis in marrow recipients: a report of three cases and a review of the literature. Bone marrow transplant team

Disseminated toxoplasmosis after allogeneic stem cell transplantation in a seronegative recipient

Toxoplasmosis after hematopoietic stem cell transplantation

Report of a 5-year survey from the infectious diseases working party of the european group for blood and marrow transplantation

Early detection of toxoplasma infection by molecular monitoring of toxoplasma gondii in peripheral blood samples after allogeneic stem cell transplantation

Atovaquone for prophylaxis of toxoplasmosis after allogeneic hematopoietic stem cell transplantation

Molecular diagnosis of toxoplasmosis in immunocompromised patients: a three-year multicenter retrospective study

Risks and Epidemiology of Infections After Hematopoietic Stem Cell Transplantation