Advertisement

Risks and Epidemiology of Infections After Hematopoietic Stem Cell Transplantation

  • Juan Gea-BanaclocheEmail author
Chapter

Abstract

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.

Keywords

Stem cell transplantation Prevention Risk factors GVHD EBV CMV Vaccinations 

6.1 Introduction

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 specific recommendations for prophylaxis and management of infections after HCT [1, 2, 3, 4, 5, 6, 7, 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.

6.2 Individual Characteristics and the Risk of Infection

Different indications for HCT are associated with their own infectious risks. Primary immunodeficiencies (PID), hemoglobinopathies, and hematologic malignancies present different challenges. Even in hematologic malignancies, the risk may vary depending on the specific 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 significant risk for the disease. Prior invasive fungal infections may reactivate following transplant, and secondary prophylaxis is required [13, 14, 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 influence 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 confirmed, but they hold the promise of a more individualized approach to infectious prophylaxis.

6.3 Time Course of Infections After Allogeneic Stem Cell Transplantation

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 significant mucositis, which results in increased risk of bacterial infections from the resident gastrointestinal flora, 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.

6.4 Types of Allogeneic Hematopoietic Stem Cell Transplantation (HCT)

Not all allogeneic stem cell transplantations are the same. Several characteristics of the transplant influence 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.
Table 6-1.

Type of transplant and infectious disease risk

Factor

Type of transplant

Risk of infection

Conditioning regimen

Myeloablative

In general, there are less early infections (mainly bacterial) with nonmyeloablative transplants, but different regimens may have very different risks

Reduced intensity

Nonmyeloablative regimens do not seem to result in less late infections

Nonmyeloablative

 

HLA match

HLA-matched sibling

With higher degree of mismatch, more immunosuppression is required, immune reconstitution is delayed, and the risk of infection is higher. Haploidentical and partially matched transplants often incorporate T cell depletion

HLA-matched unrelated (URD or MUD)

 

Haploidentical

Haploidentical transplants using posttransplant cyclophosphamide seem to have good immune reconstitution

Partially matched

 

Source of stem cells

Bone marrow

G-CSF-mobilized peripheral blood stem cells often result in shorter neutropenia, but may be associated with higher risk of chronic GVHD. Conflicting data on CMV risk

G-CSF-mobilized peripheral blood stem cells

UCD transplants result in long-lasting neutropenia and prolonged immunodeficiency, with higher risk of infection

Cord blood (UCD)

High risk of viral infections with cord transplants

GVHD prophylaxis (posttransplant immunosuppression)

T cell depletion (in vitro via CD34+ cell selection or in vivo with ATG or alemtuzumab)

T cell depletion results in increased risk for infections. ATG and alemtuzumab may result in prolonged lymphopenia and immunodeficiency, depending on the dose used. Viral infections, EBV-related PTLD, and toxoplasmosis seem to be more common after T cell depletion

Immunosuppressive agents

Differences between pharmacological immunosuppressive regimens are not well defined; sirolimus may be associated with less CMV reactivation

G-CSF granulocyte-colony-stimulating factor, GVHD graft-versus-host disease, CMV cytomegalovirus, ATG anti-thymocyte immunoglobulin, EBV-related PTLD Epstein–Barr virus-related posttransplant lymphoproliferative disorder.

6.4.1 Preparative (Conditioning) Regimen

The conditioning regimen administered before the infusion of stem cells has some influence on the risk of infection through its effect on neutropenia, mucosal damage, and GVHD. The conditioning regimen has several goals: reduction of the malignancy (when there is one), creation of space in the bone marrow to provide a selective advantage to the infused stem cells, and elimination of the recipient’s immune system to minimize the risk of rejection. Different conditioning regimens may be more appropriate depending on the disease and the general status of the recipient [22]. Myeloablative, reduced intensity, and nonmyeloablative are the general categories, but within each one there are substantial differences that may be relevant. In general, fully myeloablative regimens result in more prolonged neutropenia and more severe mucosal barrier damage, which may impact the infectious risk during the pre-engraftment period [23].

6.4.2 Degree of HLA Similarity Between Donor and Recipient

Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) indicate that there is a direct association between the number of donor–recipient HLA mismatches and the risk for mortality [24]. The current standard aims for high-resolution matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1 (i.e., an “8 out of 8” match), but only about 30% of transplant candidates will have a perfectly matched sibling or unrelated donor (MUD). If a mismatch is unavoidable, a single-locus mismatched donor can be used [24]. Other alternatives include haploidentical and umbilical cord blood (UCB) transplants.

Haploidentical transplants are one special type of mismatched transplant, where the donor shares at least one complete haplotype with the recipient. Most candidates for transplant have a potential haploidentical donor. The successful use of a regimen of posttransplant cyclophosphamide to prevent GVHD in the haploidentical setting has resulted in an increasing number of this type of transplant being performed during the last decade [25]. Interestingly, early data suggest haploidentical transplants do not result in delayed immune reconstitution or increased infections [26].

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 immunodeficiency, 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 × 106 kg−1), neutrophil recovery proceeds at the standard pace and there is no increased risk of neutropenia-related infections.

The problems with UCB transplants include a markedly decreased stem cell dose (often <1 × 105 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-specific 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 third-party donor [28].

6.4.3 Source of Stem Cells

Stem cells may be given using the bone marrow, G-CSF-mobilized 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 confirmed that chronic GVHD is more common with mobilized PBSC [29]. The particular features of UCD transplants were discussed on the preceding paragraph.

6.4.4 Strategy to Prevent GVHD: 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 × 106 kg−1 when bone marrow is used and 300 × 106 kg−1 when PBSCs are used [30]. Reductions in the amount of T cells of 2–3 log10 are possible, and in some haploidentical transplant regimens, as few as 12.5 × 103 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 half-life 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.

6.5 Graft-Versus-Host Disease

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 significant mortality. The treatment of choice is high-dose systemic corticosteroids. GVHD is associated with significant 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 defined chronologically: GVHD starting after day 100. It has been classified 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 first 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 classification 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 first 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, infliximab, 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 first 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-confirmed bloodstream infection or MBI-LCBI) or the intravascular catheter (central line-associated bloodstream infections or CLABSIs) [56].

The relative frequency of Gram-positive and Gram-negative 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 fluoroquinolones seem to have less detrimental effects on biodiversity of the fecal flora than beta-lactams. Levofloxacin 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].

6.6.2 Early Bacterial Infections 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 Gram-negative 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 efficacious and cost-effective 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 [65].

6.6.3 Late Infections: Streptococcus pneumoniae and Others

HCT recipients are at high risk for Streptococcus pneumoniae infections (2–8.6/1000 patients transplanted) [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 efficacy. 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 levofloxacin) 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 identified. 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 difficult 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 specificity 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) [74].

6.7 Risks and Epidemiology of Fungal Infections After Allogeneic HCT

It is necessary to separate invasive candidiasis and candidemia (often related to neutropenia or to the intravenous catheter) from invasive mold infection (of which invasive aspergillosis (IA) is by far the most frequent) [75] (Table 6-2). When deciding on a prophylaxis strategy, it is recommended to consider what kind of fungal infection one is trying to prevent.
Table 6-2.

Risk factors and epidemiology of fungal infections after HCT

Pathogen

Risk factors

Comment

Candida spp.

Neutropenia, mucositis, indwelling catheter, heavy colonization, TBI

Non-albicans Candida is increasing; Candida albicans breakthrough is usually associated with fluconazole resistance

Aspergillus spp.

Prolonged neutropenia

Aspergillus is the most common mold infection in a proportion 7:1 to 9:1 in most series. Antifungal prophylaxis with voriconazole or echinocandins increases the likelihood of non-aspergillus molds

Type of transplant: cord blood, T cell depletion, partially matched transplant

Not all species of Aspergillus are equally invasive or equally susceptible to antifungal agents

GVHD, acute GVHD and chronic extensive GVHD; systemic corticosteroids

 

CMV disease

 

Other molds

Mucormycosis (formerly zygomycosis)

Prophylaxis with voriconazole

Simultaneous disease of sinuses and the lung was identified as suggestive of mucormycosis in a case–control study

Fusarium spp.

HLA-mismatched transplant

Paronychia and positive blood cultures common

Prolonged neutropenia

Smoking

Scedosporium spp.

Neutropenia, GVHD, environmental exposure, voriconazole

Scedosporium prolificans more invasive and refractory to treatment than S. apiospermum

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 fluconazole during the pre-engraftment period could decrease the incidence of invasive candidiasis [76, 77]. Accordingly, fluconazole is recommended as part of the standard prophylactic regimen during the pre-engraftment period. The prevalent use of fluconazole 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 specific “at risk” periods following HCT, with a first 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 identified over the years, but the most consistently found to be significant in multivariate analyses are acute GVHD, chronic extensive GVHD, and CMV disease [80, 81, 82]. Systemic corticosteroids are almost always present as part of the treatment of acute and chronic GVHD.
Figure 6-1.

Time from transplant to diagnosis of aspergillosis in days (From Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 1997, Jun;175(6):1459–66, with permission).

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 fluconazole is a safe and well-established intervention during the pre-engraftment 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 fluconazole in a randomized controlled trial [85], and the same question (what kind of transplant patient would benefit most) applies.

Regarding the duration of antifungal prophylaxis, fluconazole 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 fluconazole during periods when the main fungal infection is aspergillosis. Several randomized controlled trials have compared fluconazole 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 fluconazole in preventing IA, but the benefit 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 fluconazole 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.

6.8 Risks and Epidemiology of Viral 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 defined 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.
Table 6-3.

Risk factors and epidemiology of viral infections after HCT

Pathogen

Risk factors

Comment

Respiratory virus

Respiratory syncytial virus (RSV)

Pre-engraftment

Progression to pneumonia is associated with older age and lymphopenia

Lymphopenia

It may be less common in nonmyeloablative or reduced intensity transplants

Preexisting obstructive airway disease

 

Parainfluenza

Unrelated donor (URD) transplant

Progression to pneumonia (less common than in RSV) is associated with corticosteroid use and lymphopenia

CD4+ lymphopenia

Influenza

Advanced disease

Progression to pneumonia seems less in patients who are receiving corticosteroids

Female sex

Transplantation during influenza season

Adenovirus

Lymphopenia (T cell depletion), anti-T cell antibodies, umbilical cord blood transplants, mismatched transplants (other than DRB1), haploidentical transplants

Both reactivation of latent adenovirus and new infections occur. Plasma viremia is an important predictor of disease

Refractory GVHD

GVHD on corticosteroids

Others (metapneumovirus rhinovirus, coronavirus, enterovirus, bocavirus)

Risk factors not well defined

 

Herpesvirus

HSV

HSV + serology in the recipient

 

Acyclovir-resistant HSV

Low-dose prophylaxis

 

Intermittent treatment

HSV-seronegative donors

Varicella zoster virus (VZV)

VZV + serology

Clinical reactivation of 25% in the first year after stopping acyclovir prophylaxis

HCT recipients with multidermatomal zoster should be on airborne and contact precautions

CMV (early disease)

CMV + serology in recipient

Rate of CMV infection in seronegative recipients of seropositive donor (R−/D+) is very low if leucodepleted products are used

URD transplants and mismatched transplants (in some studies)

T cell depletion {Holmberg, 1999 #131}

CMV (late disease)

Chronic GVHD

 

Corticosteroids

CD4+ lymphopenia (<50)

Unrelated transplants

Haploidentical transplants

Umbilical cord blood transplants

T cell-depleted transplants

Epstein–Barr virus (EBV)-related posttransplant lymphoproliferative disorder (PTLD)

Profound T cell cytopenia

 

T cell depletion

Anti-T cell antibodies

UCB transplants

Haploidentical transplants

Human herpesvirus 6 (HHV-6)

UCB

Reactivation after transplant is very common; disease is rare; multiple disease associations described

Unrelated donor transplant

Mismatched transplant

GVHD

BK virus

Reactivation almost universal after allo-HCT

High-level viremia associated with disease

6.8.1 Herpesviruses

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 defined, although multiple associations have been described. HHV-8 infection and disease (primary effusion lymphoma and Kaposi’s sarcoma) occur only infrequently after HCT.

6.8.1.1 Herpes Simplex Virus

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.

6.8.1.2 Varicella Zoster Virus

VZV predictably reactivates following transplant (approximately 25% in the first 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.

6.8.1.3 Cytomegalovirus (CMV)

CMV remains latent in a variety of human cells. CMV-seropositive 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-specific immunity in the donor. The rate of CMV infection in the donor–recipient (D/R) pairs often follows the progression \( \mathrm{D}\hbox{--} /\mathrm{R}+>\mathrm{D}+/\mathrm{R}+\gg \mathrm{D}+/\mathrm{R}\hbox{--} >\mathrm{D}\hbox{--} /\mathrm{R}\hbox{--} \), suggesting that CMV-specific 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 significant 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).

6.8.1.4 Epstein–Barr Virus and Posttransplant Lymphoproliferative Disorder

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 infiltration 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 insufficient 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, 109, 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).
Figure 6-2.

EBV-related lymphoproliferative disorder after a matched unrelated donor transplant. A 24-year-old man with Hodgkin lymphoma underwent a syngeneic HCT followed by MUD HCT (cyclophosphamide + fludarabine followed by alemtuzumab and cyclosporine). His day-28 CT/PET showed a mixed response: improvement in the intrathoracic lesions and cervical lymph nodes but appearance of new PET+ lesions in the liver, pharynx, and stomach. EBV viral load had been increasing slowly. Biopsies of the PET+ liver and stomach lesions showed a polyclonal EBV+ B cell infiltrate. The disease responded to rituximab and cyclosporine taper.

6.8.1.5 Human Herpesvirus 6

HHV-6 is acquired early in life, when it may cause roseola infantum and nonspecific 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, 114, 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].

6.8.2 Respiratory Viruses

Respiratory viruses, a heterogeneous group of virus that is responsible for most upper acute respiratory infections in normal hosts, result in significant morbidity and mortality after HCT, particularly during the first 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], influenza, parainfluenza virus (PIV) [124], rhinovirus [125], and adenovirus, newly identified viruses including metapneumovirus [126], coronavirus [127], and bocavirus [128] have emerged as significant pathogens. These infections present significant 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 insufficiency, 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]. Long-term, 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 airflow obstruction [131]. The most significant 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 parainfluenza infections but not so in influenza [129, 130] (see Table 6-3).

6.8.3 Adenovirus

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 different 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, 135, 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].
Figure 6-3.

Adenovirus pneumonia in the setting of disseminated disease. A 48-year-old man received HLA-matched sibling donor nonmyeloablative HCT for myelodysplastic syndrome in transformation. Leukemia recurred immediately after transplant. He received several donor lymphocyte infusions/stem cell boosts and then induction treatment for AML with FLAG (fludarabine + cytarabine + G-CSF) followed by donor stem cells. Graft-versus-host disease involving the skin and gut had been documented being treated with methylprednisolone 1 mg/kg/day. After the patient recovered from neutropenia, he developed spiking fever and progressive shortness of breath. Adenovirus was isolated from tears, respiratory secretions, and urine. PCR in the blood was positive for adenovirus, and the autopsy showed only disseminated adenovirus disease.

6.8.4 Polyomavirus: BK and JC Virus

6.8.4.1 BK Virus

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].

6.8.4.2 JC Virus

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 demyelination 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 difficult 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.

6.9 Risks and Epidemiology of Pneumocystis After Allogeneic HCT

PCP is an opportunistic infection of patients with profound cellular immunodeficiency, 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 infiltrates 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 deficiency. 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 difficult. Absorption is better in the presence of significant 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].
Figure 6-4.

Pneumocystis pneumonia. A 23-year-old man with Ph + ALL s/p matched sibling allo-HCT presented for his 1-year posttransplant visit complaining of worsening fever and cough over the last 2 weeks, despite oral levofloxacin. He was in complete remission. A month earlier, abnormal liver enzymes had prompted the initiation of sirolimus for suspected chronic GVHD. He was on prophylaxis with acyclovir and atovaquone. The CT showed multifocal infiltrates. The bronchoalveolar lavage showed abundant Pneumocystis. After 1 week of treatment with trimethoprim/sulfamethoxazole, the radiographic pattern became characteristic of pneumocystis pneumonia. Atovaquone failures are well documented. The radiographic features of PCP after allogeneic transplant may be atypical.

6.10 Risks and Epidemiology of Toxoplasmosis After Allogeneic HCT

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 first 6 months after transplant, but it can happen later in the presence of persistent immunosuppression [160, 161, 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 efficacy 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 PCR-detected reactivation seems to precede symptoms by 4–16 days [162]. Retrospective data suggest this strategy may result in improved outcome [164].

6.11 Summary

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 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 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 benefits of antimicrobial prophylaxis and reduce the cost, both direct and indirect, associated with this life-saving practice.

References

  1. 1.
    Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15(10):1143–238.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Groll AH, Castagnola E, Cesaro S, Dalle JH, Engelhard D, Hope W, et al. Fourth european conference on infections in leukaemia (ECIL-4): guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation. Lancet Oncol. 2014;15(8):e327–40.PubMedCrossRefGoogle Scholar
  3. 3.
    Maertens J, Marchetti O, Herbrecht R, Cornely OA, Flückiger U, Frêre P, et al. European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3—2009 update. Bone Marrow Transplant. 2011;46(5):709–18.PubMedCrossRefGoogle Scholar
  4. 4.
    Engelhard D, Mohty B, de la Camara R, Cordonnier C, Ljungman P. European guidelines for prevention and management of influenza in hematopoietic stem cell transplantation and leukemia patients: summary of ECIL-4 (2011), on behalf of ECIL, a joint venture of EBMT, EORTC, ICHS, and ELN. Transpl Infect Dis. 2013;15(3):219–32.PubMedCrossRefGoogle Scholar
  5. 5.
    Averbuch D, Cordonnier C, Livermore DM, Mikulska M, Orasch C, Viscoli C, et al. Targeted therapy against multi-resistant bacteria in leukemic and hematopoietic stem cell transplant recipients: guidelines of the 4th european conference on infections in leukemia (ECIL-4, 2011). Haematologica. 2013;98(12):1836–47.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Averbuch D, Orasch C, Cordonnier C, Livermore DM, Mikulska M, Viscoli C, et al. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th european conference on infections in leukemia. Haematologica. 2013;98(12):1826–35.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Styczynski J, Reusser P, Einsele H, de la Camara R, Cordonnier C, Ward KN, et al. Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the second european conference on infections in leukemia. Bone Marrow Transplant. 2009;43(10):757–70.PubMedCrossRefGoogle Scholar
  8. 8.
    Matthes-Martin S, Feuchtinger T, Shaw PJ, Engelhard D, Hirsch HH, Cordonnier C, et al. European guidelines for diagnosis and treatment of adenovirus infection in leukemia and stem cell transplantation: summary of ECIL-4 (2011). Transpl Infect Dis. 2012;14(6):555–63.PubMedCrossRefGoogle Scholar
  9. 9.
    Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tomblyn M, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58(3):e44–100.PubMedCrossRefGoogle Scholar
  10. 10.
    Hilgendorf I, Freund M, Jilg W, Einsele H, Gea-Banacloche J, Greinix H, et al. Vaccination of allogeneic haematopoietic stem cell transplant recipients: report from the international consensus conference on clinical practice in chronic GVHD. Vaccine. 2011;29(16):2825–33.PubMedCrossRefGoogle Scholar
  11. 11.
    Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011;52(4):e56–93.PubMedCrossRefGoogle Scholar
  12. 12.
    Lehrnbecher T, Phillips R, Alexander S, Alvaro F, Carlesse F, Fisher B, et al. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol. 2012;30(35):4427–38.PubMedCrossRefGoogle Scholar
  13. 13.
    Cordonnier C, Maury S, Pautas C, Bastié JN, Chehata S, Castaigne S, et al. Secondary antifungal prophylaxis with voriconazole to adhere to scheduled treatment in leukemic patients and stem cell transplant recipients. Bone Marrow Transplant. 2004;33(9):943–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Aki ZS, Sucak GT, Yeğin ZA, Güzel O, Erbaş G, Senol E. Hematopoietic stem cell transplantation in patients with active fungal infection: not a contraindication for transplantation. Transplant Proc. 2008;40(5):1579–85.PubMedCrossRefGoogle Scholar
  15. 15.
    Liu F, Wu T, Wang JB, Cao XY, Yin YM, Zhao YL, Lu DP. Risk factors for recurrence of invasive fungal infection during secondary antifungal prophylaxis in allogeneic hematopoietic stem cell transplant recipients. Transpl Infect Dis. 2013;15(3):243–50.PubMedCrossRefGoogle Scholar
  16. 16.
    Martino R, Parody R, Fukuda T, Maertens J, Theunissen K, Ho A, et al. 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. Blood. 2006;108(9):2928–36.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Bochud PY, Eggiman P, Calandra T, Van Melle G, Saghafi L, Francioli P. Bacteremia due to viridans streptococcus in neutropenic patients with cancer: clinical spectrum and risk factors. Clin Infect Dis. 1994;18(1):25–31.PubMedCrossRefGoogle Scholar
  18. 18.
    Mullighan CG, Heatley SL, Danner S, Dean MM, Doherty K, Hahn U, et al. Mannose-binding lectin status is associated with risk of major infection following myeloablative sibling allogeneic hematopoietic stem cell transplantation. Blood. 2008;112(5):2120–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Harkensee C, Oka A, Onizuka M, Middleton PG, Inoko H, Nakaoka H, et al. Microsatellite scanning of the immunogenome associates MAPK14 and ELTD1 with graft-versus-host disease in hematopoietic stem cell transplantation. Immunogenetics. 2013;65(6):417–27.PubMedCrossRefGoogle Scholar
  20. 20.
    Dickinson AM, Charron D. Non-HLA immunogenetics in hematopoietic stem cell transplantation. Curr Opin Immunol. 2005;17(5):517–25.PubMedCrossRefGoogle Scholar
  21. 21.
    Zaia JA, Sun JY, Gallez-Hawkins GM, Thao L, Oki A, Lacey SF, et al. The effect of single and combined activating killer immunoglobulin-like receptor genotypes on cytomegalovirus infection and immunity after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2009;15(3):315–25.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood. 2014;124(3):344–53.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Junghanss C, Marr KA, Carter RA, Sandmaier BM, Maris MB, Maloney DG, et al. Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant. 2002;8(9):512–20.PubMedCrossRefGoogle Scholar
  24. 24.
    Spellman SR, Eapen M, Logan BR, Mueller C, Rubinstein P, Setterholm MI, et al. A perspective on the selection of unrelated donors and cord blood units for transplantation. Blood. 2012;120(2):259–65.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Luznik L, O’Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14(6):641–50.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Cieri N, Peccatori J. Tracking T cell dynamics in the first month after haplo-HSCT with post-transplant cyclophosphamide reveals a predominant contribution of memory stem T cells to the early phase of immune reconstitution. Blood. 2013;122(11):4615.Google Scholar
  27. 27.
    Safdar A, Rodriguez GH, De Lima MJ, Petropoulos D, Chemaly RF, Worth LL, et al. Infections in 100 cord blood transplantations: spectrum of early and late posttransplant infections in adult and pediatric patients 1996-2005. Medicine (Baltimore). 2007;86(6):324–33.CrossRefGoogle Scholar
  28. 28.
    Martino R, Bautista G, Parody R, García I, Esquirol A, Rovira M, et al. Severe infections after single umbilical cord blood transplantation in adults with or without the co-infusion of CD34(+) cells from a third-party donor: results of a multicenter study from the grupo español de trasplante hematopoyético (GETH). Transpl Infect Dis. 2015;17(2):221–33.PubMedCrossRefGoogle Scholar
  29. 29.
    Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012;367(16):1487–96.PubMedCrossRefGoogle Scholar
  30. 30.
    Körbling M, Anderlini P. Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter? Blood. 2001;98(10):2900–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Eyrich M, Lang P, Lal S, Bader P, Handgretinger R, Klingebiel T, et al. A prospective analysis of the pattern of immune reconstitution in a paediatric cohort following transplantation of positively selected human leucocyte antigen-disparate haematopoietic stem cells from parental donors. Br J Haematol. 2001;114(2):422–32.PubMedCrossRefGoogle Scholar
  32. 32.
    van Burik JA, Carter SL, Freifeld AG, High KP, Godder KT, Papanicolaou GA, 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(12):1487–98.PubMedCrossRefGoogle Scholar
  33. 33.
    Pérez-Simón JA, Kottaridis PD, Martino R, Craddock C, Caballero D, Chopra R, et al. Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. Blood. 2002;100(9):3121–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Marty FM, Bryar J, Browne SK, Schwarzberg T, Ho VT, Bassett IV, et al. Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis. Blood. 2007;110(2):490–500.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Kanakry JA, Kasamon YL, Bolaños-Meade J, Borrello IM, Brodsky RA, Fuchs EJ, et al. Absence of post-transplantation lymphoproliferative disorder after allogeneic blood or marrow transplantation using post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant. 2013;19(10):1514–7.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Ferrara JL, Levy R, Chao NJ. Pathophysiologic mechanisms of acute graft-vs.-host disease. Biol Blood Marrow Transplant. 1999;5(6):347–56.PubMedCrossRefGoogle Scholar
  37. 37.
    Chu YW, Gress RE. Murine models of chronic graft-versus-host disease: insights and unresolved issues. Biol Blood Marrow Transplant. 2008;14(4):365–78.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Boeckh M, Nichols WG, Papanicolaou G, Rubin R, Wingard JR, Zaia J. Cytomegalovirus in hematopoietic stem cell transplant recipients: current status, known challenges, and future strategies. Biol Blood Marrow Transplant. 2003;9(9):543–58.PubMedCrossRefGoogle Scholar
  39. 39.
    Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005;11(12):945–56.PubMedCrossRefGoogle Scholar
  40. 40.
    Bjorklund A, Aschan J, Labopin M, Remberger M, Ringden O, Winiarski J, Ljungman P. Risk factors for fatal infectious complications developing late after allogeneic stem cell transplantation. Bone Marrow Transplant. 2007;40(11):1055–62.PubMedCrossRefGoogle Scholar
  41. 41.
    Yamasaki S, Heike Y, Mori S, Fukuda T, Maruyama D, Kato R, et al. Infectious complications in chronic graft-versus-host disease: a retrospective study of 145 recipients of allogeneic hematopoietic stem cell transplantation with reduced- and conventional-intensity conditioning regimens. Transpl Infect Dis. 2008;10(4):252–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Storek J, Witherspoon RP, Webb D, Storb R. Lack of B cells precursors in marrow transplant recipients with chronic graft-versus-host disease. Am J Hematol. 1996;52(2):82–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Storek J, Gooley T, Witherspoon RP, Sullivan KM, Storb R. Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am J Hematol. 1997;54(2):131–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Kalhs P, Panzer S, Kletter K, Minar E, Stain-Kos M, Walter R, et al. Functional asplenia after bone marrow transplantation. A late complication related to extensive chronic graft-versus-host disease. Ann Intern Med. 1988;109(6):461–4.PubMedCrossRefGoogle Scholar
  45. 45.
    Dahut W, Georgiadis M. Pneumococcal arthritis and functional asplenia after allogeneic bone marrow transplantation. Bone Marrow Transplant. 1995;15(1):161.PubMedGoogle Scholar
  46. 46.
    Kulkarni S, Powles R, Treleaven J, Riley U, Singhal S, Horton C, et al. Chronic graft versus host disease is associated with long-term risk for pneumococcal infections in recipients of bone marrow transplants. Blood. 2000;95(12):3683–6.PubMedGoogle Scholar
  47. 47.
    Arora M, Burns LJ, Davies SM, Macmillan ML, Defor TE, Miller WJ, Weisdorf DJ. Chronic graft-versus-host disease: a prospective cohort study. Biol Blood Marrow Transplant. 2003;9(1):38–45.PubMedCrossRefGoogle Scholar
  48. 48.
    Martin PJ, Inamoto Y, Flowers ME, Carpenter PA. Secondary treatment of acute graft-versus-host disease: a critical review. Biol Blood Marrow Transplant. 2012;18(7):982–8.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Couriel D, Saliba R, Hicks K, Ippoliti C, de Lima M, Hosing C, et al. Tumor necrosis factor-alpha blockade for the treatment of acute GVHD. Blood. 2004;104(3):649–54.PubMedCrossRefGoogle Scholar
  50. 50.
    Marty FM, Lee SJ, Fahey MM, Alyea EP, Soiffer RJ, Antin JH, Baden LR. Infliximab use in patients with severe graft-versus-host disease and other emerging risk factors of non-candida invasive fungal infections in allogeneic hematopoietic stem cell transplant recipients: a cohort study. Blood. 2003;102(8):2768–76.PubMedCrossRefGoogle Scholar
  51. 51.
    Carpenter PA, Appelbaum FR, Corey L, Deeg HJ, Doney K, Gooley T, et al. A humanized non-FcR-binding anti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versus-host disease. Blood. 2002;99(8):2712–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Seeley WW, Marty FM, Holmes TM, Upchurch K, Soiffer RJ, Antin JH, et al. Post-transplant acute limbic encephalitis: clinical features and relationship to HHV6. Neurology. 2007;69(2):156–65.PubMedCrossRefGoogle Scholar
  53. 53.
    Khandelwal P, Lawrence J, Filipovich AH, Davies SM, Bleesing JJ, Jordan MB, et al. The successful use of alemtuzumab for treatment of steroid-refractory acute graft-versus-host disease in pediatric patients. Pediatr Transplant. 2014;18(1):94–102.PubMedCrossRefGoogle Scholar
  54. 54.
    Srinivasan R, Chakrabarti S, Walsh T, Igarashi T, Takahashi Y, Kleiner D, et al. Improved survival in steroid-refractory acute graft versus host disease after non-myeloablative allogeneic transplantation using a daclizumab-based strategy with comprehensive infection prophylaxis. Br J Haematol. 2004;124(6):777–86.PubMedCrossRefGoogle Scholar
  55. 55.
    Almyroudis NG, Fuller A, Jakubowski A, Sepkowitz K, Jaffe D, Small TN, et al. Pre- and post-engraftment bloodstream infection rates and associated mortality in allogeneic hematopoietic stem cell transplant recipients. Transpl Infect Dis. 2005;7(1):11–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Metzger KE, Rucker Y, Callaghan M, Churchill M, Jovanovic BD, Zembower TR, Bolon MK. The burden of mucosal barrier injury laboratory-confirmed bloodstream infection among hematology, oncology, and stem cell transplant patients. Infect Control Hosp Epidemiol. 2015;36(2):119–24.PubMedCrossRefGoogle Scholar
  57. 57.
    Weinstock DM, Conlon M, Iovino C, Aubrey T, Gudiol C, Riedel E, et al. Colonization, bloodstream infection, and mortality caused by vancomycin-resistant enterococcus early after allogeneic hematopoietic stem cell transplant. Biol Blood Marrow Transplant. 2007;13(5):615–21.PubMedCrossRefGoogle Scholar
  58. 58.
    Taur Y, Xavier JB, Lipuma L, Ubeda C, Goldberg J, Gobourne A, et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2012;55(7):905–14.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Bucaneve G, Micozzi A, Menichetti F, Martino P, Dionisi MS, Martinelli G, et al. Levofloxacin to prevent bacterial infection in patients with cancer and neutropenia. N Engl J Med. 2005;353(10):977–87.PubMedCrossRefGoogle Scholar
  60. 60.
    Gafter-Gvili A, Fraser A, Paul M, Vidal L, Lawrie TA, van de Wetering MD, et al. Antibiotic prophylaxis for bacterial infections in afebrile neutropenic patients following chemotherapy. Cochrane Database Syst Rev. 2012;1:CD004386.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Taur Y, Jenq RR, Perales MA, Littmann ER, Morjaria S, Ling L, et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood. 2014;124(7):1174–82.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Climo MW, Yokoe DS, Warren DK, Perl TM, Bolon M, Herwaldt LA, et al. Effect of daily chlorhexidine bathing on hospital-acquired infection. N Engl J Med. 2013;368(6):533–42.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Kamboj M, Chung D, Seo SK, Pamer EG, Sepkowitz KA, Jakubowski AA, Papanicolaou G. The changing epidemiology of vancomycin-resistant enterococcus (VRE) bacteremia in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Biol Blood Marrow Transplant. 2010;16(11):1576–81.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Siegel JD, Rhinehart E, Jackson M, Chiarello L, Healthcare Infection Control Practices Advisory Committee. Management of multidrug-resistant organisms in health care settings, 2006. Am J Infect Control. 2007;35(10 Suppl 2):S165–93.PubMedCrossRefGoogle Scholar
  65. 65.
    Farr BM. What to think if the results of the national institutes of health randomized trial of methicillin-resistant staphylococcus aureus and vancomycin-resistant enterococcus control measures are negative (and other advice to young epidemiologists): a review and an au revoir. Infect Control Hosp Epidemiol. 2006;27(10):1096–106.PubMedCrossRefGoogle Scholar
  66. 66.
    Youssef S, Rodriguez G, Rolston KV, Champlin RE, Raad II, Safdar A. Streptococcus pneumoniae infections in 47 hematopoietic stem cell transplantation recipients: clinical characteristics of infections and vaccine-breakthrough infections, 1989-2005. Medicine (Baltimore). 2007;86(2):69–77.CrossRefGoogle Scholar
  67. 67.
    Engelhard D, Cordonnier C, Shaw PJ, Parkalli T, Guenther C, Martino R, et al. Early and late invasive pneumococcal infection following stem cell transplantation: a European bone marrow transplantation survey. Br J Haematol. 2002;117(2):444–50.PubMedCrossRefGoogle Scholar
  68. 68.
    Cordonnier C, Ljungman P, Juergens C, Maertens J, Selleslag D, Sundaraiyer V, et al. 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. Clin Infect Dis. 2015;61(3):313–23.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Carpenter PA, Kitko CL, Elad S, Flowers ME, Gea-Banacloche JC, Halter JP, et al. National institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: V. The 2014 ancillary therapy and supportive care working group report. Biol Blood Marrow Transplant. 2015;21(7):1167–87.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Ochs L, Shu XO, Miller J, Enright H, Wagner J, Filipovich A, et al. Late infections after allogeneic bone marrow transplantations: comparison of incidence in related and unrelated donor transplant recipients. Blood. 1995;86(10):3979–86.PubMedGoogle Scholar
  71. 71.
    van Burik JA, Hackman RC, Nadeem SQ, Hiemenz JW, White MH, Flowers ME, Bowden RA. Nocardiosis after bone marrow transplantation: a retrospective study. Clin Infect Dis. 1997;24(6):1154–60.PubMedCrossRefGoogle Scholar
  72. 72.
    Daly AS, McGeer A, Lipton JH. Systemic nocardiosis following allogeneic bone marrow transplantation. Transpl Infect Dis. 2003;5(1):16–20.PubMedCrossRefGoogle Scholar
  73. 73.
    Cordonnier C, Martino R, Trabasso P, Held TK, Akan H, Ward MS, et al. Mycobacterial infection: a difficult and late diagnosis in stem cell transplant recipients. Clin Infect Dis. 2004;38(9):1229–36.PubMedCrossRefGoogle Scholar
  74. 74.
    de la Cámara R, Martino R, Granados E, Rodriguez-Salvanés FJ, Rovira M, Cabrera R, et al. Tuberculosis after hematopoietic stem cell transplantation: incidence, clinical characteristics and outcome. Spanish group on infectious complications in hematopoietic transplantation. Bone Marrow Transplant. 2000;26(3):291–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Camps IR. Risk factors for invasive fungal infections in haematopoietic stem cell transplantation. Int J Antimicrob Agents. 2008;32 Suppl 2:S119–23.PubMedCrossRefGoogle Scholar
  76. 76.
    Goodman JL, Winston DJ, Greenfield RA, Chandrasekar PH, Fox B, Kaizer H, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med. 1992;326(13):845–51.PubMedCrossRefGoogle Scholar
  77. 77.
    Slavin MA, Osborne B, Adams R, Levenstein MJ, Schoch HG, Feldman AR, 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(6):1545–52.PubMedCrossRefGoogle Scholar
  78. 78.
    Marr KA, Seidel K, White TC, Bowden RA. Candidemia in allogeneic blood and marrow transplant recipients: evolution of risk factors after the adoption of prophylactic fluconazole. J Infect Dis. 2000;181(1):309–16.PubMedCrossRefGoogle Scholar
  79. 79.
    Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis. 1997;175(6):1459–66.PubMedCrossRefGoogle Scholar
  80. 80.
    Marr KA, Carter RA, Boeckh M, Martin P, Corey L. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood. 2002;100(13):4358–66.PubMedCrossRefGoogle Scholar
  81. 81.
    Fukuda T, Boeckh M, Carter RA, Sandmaier BM, Maris MB, Maloney DG, et al. Invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplantation after nonmyeloablative conditioning: risks and outcomes. Blood. 2003;10:10.Google Scholar
  82. 82.
    Barnes PD, Marr KA. Risks, diagnosis and outcomes of invasive fungal infections in haematopoietic stem cell transplant recipients. Br J Haematol. 2007;139(4):519–31.PubMedCrossRefGoogle Scholar
  83. 83.
    Corzo-León DE, Satlin MJ, Soave R, Shore TB, Schuetz AN, Jacobs SE, Walsh TJ. Epidemiology and outcomes of invasive fungal infections in allogeneic haematopoietic stem cell transplant recipients in the era of antifungal prophylaxis: a single-centre study with focus on emerging pathogens. Mycoses. 2015;58(6):325–36.PubMedCrossRefGoogle Scholar
  84. 84.
    Kontoyiannis DP, Lionakis MS, Lewis RE, Chamilos G, Healy M, Perego C, et al. Zygomycosis in a tertiary-care cancer center in the era of aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases. J Infect Dis. 2005;191(8):1350–60.PubMedCrossRefGoogle Scholar
  85. 85.
    van Burik JA, Ratanatharathorn V, Stepan DE, Miller CB, Lipton JH, Vesole DH, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis. 2004;39(10):1407–16.PubMedCrossRefGoogle Scholar
  86. 86.
    Marr KA, Seidel K, Slavin MA, Bowden RA, Schoch HG, Flowers ME, et al. Prolonged fluconazole 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. Blood. 2000;96(6):2055–61.PubMedGoogle Scholar
  87. 87.
    Winston DJ, Maziarz RT, Chandrasekar PH, Lazarus HM, Goldman M, Blumer JL, et al. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial. Ann Intern Med. 2003;138(9):705–13.PubMedCrossRefGoogle Scholar
  88. 88.
    Marr KA, Crippa F, Leisenring W, Hoyle M, Boeckh M, Balajee SA, et al. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood. 2004;103(4):1527–33.PubMedCrossRefGoogle Scholar
  89. 89.
    Wingard JR, Carter SL, Walsh TJ, Kurtzberg J, Small TN, Baden LR, et al. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood. 2010;116(24):5111–8.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356(4):335–47.PubMedCrossRefGoogle Scholar
  91. 91.
    Ping B, Zhu Y, Gao Y, Yue C, Wu B. Second- versus first-generation azoles for antifungal prophylaxis in hematology patients: a systematic review and meta-analysis. Ann Hematol. 2013;92(6):831–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007;356(4):348–59.PubMedCrossRefGoogle Scholar
  93. 93.
    Inazawa N, Hori T, Hatakeyama N, Yamamoto M, Yoto Y, Nojima M, et al. Large-scale multiplex polymerase chain reaction assay for diagnosis of viral reactivations after allogeneic hematopoietic stem cell transplantation. J Med Virol. 2015;87(8):1427–35.PubMedCrossRefGoogle Scholar
  94. 94.
    Milano F, Pergam SA, Xie H, Leisenring WM, Gutman JA, Riffkin I, et al. Intensive strategy to prevent cytomegalovirus disease in seropositive umbilical cord blood transplant recipients. Blood. 2011;118(20):5689–96.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Boeckh M, Kim HW, Flowers ME, Meyers JD, Bowden RA. Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantation—a randomized double-blind placebo-controlled study. Blood. 2006;107(5):1800–5.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Erard V, Wald A, Corey L, Leisenring WM, Boeckh M. Use of long-term suppressive acyclovir after hematopoietic stem-cell transplantation: impact on herpes simplex virus (HSV) disease and drug-resistant HSV disease. J Infect Dis. 2007;196(2):266–70.PubMedCrossRefGoogle Scholar
  97. 97.
    Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA. Cytomegalovirus pp 65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood. 1996;88(10):4063–71.PubMedGoogle Scholar
  98. 98.
    Jeon S, Lee WK, Lee Y, Lee DG, Lee JW. Risk factors for cytomegalovirus retinitis in patients with cytomegalovirus viremia after hematopoietic stem cell transplantation. Ophthalmology. 2012;119(9):1892–8.PubMedCrossRefGoogle Scholar
  99. 99.
    Reddy SM, Winston DJ, Territo MC, Schiller GJ. CMV central nervous system disease in stem-cell transplant recipients: an increasing complication of drug-resistant CMV infection and protracted immunodeficiency. Bone Marrow Transplant. 2010;45(6):979–84.PubMedCrossRefGoogle Scholar
  100. 100.
    Jeong TD, Sung H, Choi SH, Lee SO, Yoon HK, Kim MN, Im HJ. Cytomegalovirus ventriculoencephalitis with compartmentalization of antiviral-resistant cytomegalovirus in a T cell-depleted haploidentical peripheral blood stem cell transplant recipient. Diagn Microbiol Infect Dis. 2012;74(3):307–10.PubMedCrossRefGoogle Scholar
  101. 101.
    Nichols WG, Price TH, Gooley T, Corey L, Boeckh M. Transfusion-transmitted cytomegalovirus infection after receipt of leukoreduced blood products. Blood. 2003;101(10):4195–200.PubMedCrossRefGoogle Scholar
  102. 102.
    Boeckh M, Bowden RA, Gooley T, Myerson D, Corey L. Successful modification of a pp 65 antigenemia-based early treatment strategy for prevention of cytomegalovirus disease in allogeneic marrow transplant recipients [letter]. Blood. 1999;93(5):1781–2.PubMedGoogle Scholar
  103. 103.
    Boeckh M, Leisenring W, Riddell SR, Bowden RA, Huang ML, Myerson D, et al. Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and t-cell immunity. Blood. 2003;101(2):407–14.PubMedCrossRefGoogle Scholar
  104. 104.
    Boeckh M, Nichols WG, Chemaly RF, Papanicolaou GA, Wingard JR, Xie H, et al. Valganciclovir for the prevention of complications of late cytomegalovirus infection after allogeneic hematopoietic cell transplantation: a randomized trial. Ann Intern Med. 2015;162(1):1–10.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Ljungman P. The role of cytomegalovirus serostatus on outcome of hematopoietic stem cell transplantation. Curr Opin Hematol. 2014;21(6):466–9.PubMedCrossRefGoogle Scholar
  106. 106.
    Singavi AK, Harrington AM, Fenske TS. Post-transplant lymphoproliferative disorders. Cancer Treat Res. 2015;165:305–27.PubMedCrossRefGoogle Scholar
  107. 107.
    Foot AB, Garin YJ, Ribaud P, Devergie A, Derouin F, Gluckman E. Prophylaxis of toxoplasmosis infection with pyrimethamine/sulfadoxine (fansidar) in bone marrow transplant recipients. Bone Marrow Transplant. 1994;14(2):241–5.PubMedGoogle Scholar
  108. 108.
    Landgren O, Gilbert ES, Rizzo JD, Socié G, Banks PM, Sobocinski KA, et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood. 2009;113(20):4992–5001.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Sanz J, Arango M, Senent L, Jarque I, Montesinos P, Sempere A, et al. EBV-associated post-transplant lymphoproliferative disorder after umbilical cord blood transplantation in adults with hematological diseases. Bone Marrow Transplant. 2013;49(3):397–402.PubMedCrossRefGoogle Scholar
  110. 110.
    Fox CP, Burns D, Parker AN, Peggs KS, Harvey CM, Natarajan S, et al. 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. Bone Marrow Transplant. 2013;11.Google Scholar
  111. 111.
    García-Cadenas I, Castillo N, Martino R, Barba P, Esquirol A, Novelli S, et al. Impact of Epstein Barr virus-related complications after high-risk allo-SCT in the era of pre-emptive rituximab. Bone Marrow Transplant. 2015;50(4):579–84.PubMedCrossRefGoogle Scholar
  112. 112.
    Cone RW, Huang ML, Corey L, Zeh J, Ashley R, Bowden R. Human herpesvirus 6 infections after bone marrow transplantation: clinical and virologic manifestations. J Infect Dis. 1999;179(2):311–8.PubMedCrossRefGoogle Scholar
  113. 113.
    Ljungman P, Wang FZ, Clark DA, Emery VC, Remberger M, Ringdén O, Linde A. High levels of human herpesvirus 6 DNA in peripheral blood leucocytes are correlated to platelet engraftment and disease in allogeneic stem cell transplant patients. Br J Haematol. 2000;111(3):774–81.PubMedGoogle Scholar
  114. 114.
    Zerr DM, Corey L, Kim HW, Huang ML, Nguy L, Boeckh M. Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation. Clin Infect Dis. 2005;40(7):932–40.PubMedCrossRefGoogle Scholar
  115. 115.
    Gotoh M, Yoshizawa S, Katagiri S, Suguro T, Asano M, Kitahara T, et al. Human herpesvirus 6 reactivation on the 30th day after allogeneic hematopoietic stem cell transplantation can predict grade 2-4 acute graft-versus-host disease. Transpl Infect Dis. 2014;16(3):440–9.PubMedCrossRefGoogle Scholar
  116. 116.
    Ogata M, Fukuda T, Teshima T. Human herpesvirus-6 encephalitis after allogeneic hematopoietic cell transplantation: what we do and do not know. Bone Marrow Transplant. 2015;50(8):1030–6.PubMedCrossRefGoogle Scholar
  117. 117.
    Ogata M, Satou T, Kadota J-I, Saito N, Yoshida T, Okumura H, et al. Human herpesvirus 6 (HHV-6) reactivation and HHV-6 encephalitis after allogeneic hematopoietic cell transplantation: a multicenter, prospective study. Clin Infect Dis. 2013;57(5):671–81.PubMedCrossRefGoogle Scholar
  118. 118.
    Olson AL, Dahi PB, Zheng J, Devlin SM, Lubin M, Gonzales AM, et al. Frequent human herpesvirus-6 viremia but low incidence of encephalitis in double-unit cord blood recipients transplanted without antithymocyte globulin. Biol Blood Marrow Transplant. 2014;20(6):787–93.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Ogata M, Satou T, Inoue Y, Takano K, Ikebe T, Ando T, et al. Foscarnet against human herpesvirus (HHV)-6 reactivation after allo-SCT: breakthrough HHV-6 encephalitis following antiviral prophylaxis. Bone Marrow Transplant. 2013;48(2):257–64.PubMedCrossRefGoogle Scholar
  120. 120.
    Ljungman P, de la Camara R, Cordonnier C, Einsele H, Engelhard D, Reusser P, et al. Management of CMV, HHV-6, HHV-7 and kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT. Bone Marrow Transplant. 2008;42(4):227–40.PubMedCrossRefGoogle Scholar
  121. 121.
    Boeckh M. The challenge of respiratory virus infections in hematopoietic cell transplant recipients. Br J Haematol. 2008;143(4):455–67.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Campbell AP, Guthrie KA, Englund JA, Farney RM, Minerich EL, Kuypers J, et al. Clinical outcomes associated with respiratory virus detection before allogeneic hematopoietic stem cell transplantation. Clin Infect Dis. 2015;61(2):192–202.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Waghmare A, Campbell AP, Xie H, Seo S, Kuypers J, Leisenring W, et al. Respiratory syncytial virus lower respiratory disease in hematopoietic cell transplant recipients: viral RNA detection in blood, antiviral treatment, and clinical outcomes. Clin Infect Dis. 2013;57(12):1731–41.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Nichols WG, Corey L, Gooley T, Davis C, Boeckh M. Parainfluenza virus infections after hematopoietic stem cell transplantation: risk factors, response to antiviral therapy, and effect on transplant outcome. Blood. 2001;98(3):573–8.PubMedCrossRefGoogle Scholar
  125. 125.
    Ison MG, Hayden FG, Kaiser L, Corey L, Boeckh M. Rhinovirus infections in hematopoietic stem cell transplant recipients with pneumonia. Clin Infect Dis. 2003;36(9):1139–43.PubMedCrossRefGoogle Scholar
  126. 126.
    Renaud C, Xie H, Seo S, Kuypers J, Cent A, Corey L, et al. Mortality rates of human metapneumovirus and respiratory syncytial virus lower respiratory tract infections in hematopoietic cell transplantation recipients. Biol Blood Marrow Transplant. 2013;19(8):1220–6.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Milano F, Campbell AP, Guthrie KA, Kuypers J, Englund JA, Corey L, Boeckh M. Human rhinovirus and coronavirus detection among allogeneic hematopoietic stem cell transplantation recipients. Blood. 2010;115(10):2088–94.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Schenk T, Strahm B, Kontny U, Hufnagel M, Neumann-Haefelin D, Falcone V. Disseminated bocavirus infection after stem cell transplant. Emerg Infect Dis. 2007;13(9):1425–7.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Nichols WG, Guthrie KA, Corey L, Boeckh M. Influenza infections after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of antiviral therapy. Clin Infect Dis. 2004;39(9):1300–6.PubMedCrossRefGoogle Scholar
  130. 130.
    Ustun C, Slabý J, Shanley RM, Vydra J, Smith AR, Wagner JE, et al. Human parainfluenza virus infection after hematopoietic stem cell transplantation: risk factors, management, mortality, and changes over time. Biol Blood Marrow Transplant. 2012;18(10):1580–8.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Erard V, Chien JW, Kim HW, Nichols WG, Flowers ME, Martin PJ, et al. Airflow decline after myeloablative allogeneic hematopoietic cell transplantation: the role of community respiratory viruses. J Infect Dis. 2006;193(12):1619–25.PubMedCrossRefGoogle Scholar
  132. 132.
    Kim YJ, Guthrie KA, Waghmare A, Walsh EE, Falsey AR, Kuypers J, et al. Respiratory syncytial virus in hematopoietic cell transplant recipients: factors determining progression to lower respiratory tract disease. J Infect Dis. 2013;209(8):1195–204.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Feghoul L, Chevret S, Cuinet A, Dalle JH, Ouachée M, Yacouben K, et al. Adenovirus infection and disease in pediatric hematopoietic stem cell transplant patients: clues for antiviral preemptive treatment. Clin Microbiol Infect. 2015;21(7):701–19.PubMedCrossRefGoogle Scholar
  134. 134.
    Myers GD, Krance RA, Weiss H, Kuehnle I, Demmler G, Heslop HE, Bollard CM. Adenovirus infection rates in pediatric recipients of alternate donor allogeneic bone marrow transplants receiving either antithymocyte globulin (ATG) or alemtuzumab (campath). Bone Marrow Transplant. 2005;36(11):1001–8.PubMedCrossRefGoogle Scholar
  135. 135.
    Chakrabarti S, Mautner V, Osman H, Collingham KE, Fegan CD, Klapper PE, et al. Adenovirus infections following allogeneic stem cell transplantation: incidence and outcome in relation to graft manipulation, immunosuppression, and immune recovery. Blood. 2002;100(5):1619–27.PubMedCrossRefGoogle Scholar
  136. 136.
    Symeonidis N, Jakubowski A, Pierre-Louis S, Jaffe D, Pamer E, Sepkowitz K, et al. Invasive adenoviral infections in t-cell-depleted allogeneic hematopoietic stem cell transplantation: high mortality in the era of cidofovir. Transpl Infect Dis. 2007;9(2):108–13.PubMedCrossRefGoogle Scholar
  137. 137.
    Erard V, Huang ML, Ferrenberg J, Nguy L, Stevens-Ayers TL, Hackman RC, et al. 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. Clin Infect Dis. 2007;45(8):958–65.PubMedCrossRefGoogle Scholar
  138. 138.
    Ljungman P, Ribaud P, Eyrich M, Matthes-Martin S, Einsele H, Bleakley M, et al. 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. Bone Marrow Transplant. 2003;31(6):481–6.PubMedCrossRefGoogle Scholar
  139. 139.
    Dropulic LK, Jones RJ. Polyomavirus BK infection in blood and marrow transplant recipients. Bone Marrow Transplant. 2008;41(1):11–8.PubMedCrossRefGoogle Scholar
  140. 140.
    Erard V, Kim HW, Corey L, Limaye A, Huang ML, Myerson D, et al. BK DNA viral load in plasma: evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients. Blood. 2005;106(3):1130–2.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Oshrine B, Bunin N, Li Y, Furth S, Laskin BL. Kidney and bladder outcomes in children with hemorrhagic cystitis and BK virus infection after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19(12):1702–7.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Verghese PS, Finn LS, Englund JA, Sanders JE, Hingorani SR. BK nephropathy in pediatric hematopoietic stem cell transplant recipients. Pediatr Transplant. 2009;13(7):913–8.PubMedCrossRefGoogle Scholar
  143. 143.
    Yapa HM, McLornan DP, Raj K, Streetly M, Kazmi M, Cuthill K, et al. Pneumonitis post-haematopoeitic stem cell transplant—cytopathology clinches diagnosis. J Clin Virol. 2012;55(3):278–81.PubMedCrossRefGoogle Scholar
  144. 144.
    Wittmann T, Horowitz N, Benyamini N, Henig I, Zuckerman T, Rowe JM, et al. JC polyomavirus reactivation is common following allogeneic stem cell transplantation and its preemptive detection may prevent lethal complications. Bone Marrow Transplant. 2015;50(7):984–91.PubMedCrossRefGoogle Scholar
  145. 145.
    Tuan IZ, Dennison D, Weisdorf DJ. Pneumocystis carinii pneumonitis following bone marrow transplantation. Bone Marrow Transplant. 1992;10(3):267–72.PubMedGoogle Scholar
  146. 146.
    De Castro N, Neuville S, Sarfati C, Ribaud P, Derouin F, Gluckman E, et al. Occurrence of pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study. Bone Marrow Transplant. 2005;36(10):879–83.PubMedCrossRefGoogle Scholar
  147. 147.
    Lyytikäinen O, Ruutu T, Volin L, Lautenschlager I, Jokipii L, Tiittanen L, Ruutu P. Late onset pneumocystis carinii pneumonia following allogeneic bone marrow transplantation. Bone Marrow Transplant. 1996;17(6):1057–9.PubMedGoogle Scholar
  148. 148.
    Torres HA, Chemaly RF, Storey R, Aguilera EA, Nogueras GM, Safdar A, et al. Influence of type of cancer and hematopoietic stem cell transplantation on clinical presentation of pneumocystis jiroveci pneumonia in cancer patients. Eur J Clin Microbiol Infect Dis. 2006;25(6):382–8.PubMedCrossRefGoogle Scholar
  149. 149.
    El-Sadr WM, Luskin-Hawk R, Yurik TM, Walker J, Abrams D, John SL, et al. A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for the prevention of pneumocystis carinii pneumonia in human immunodeficiency virus-infected persons. Terry beirn community programs for clinical research on AIDS (CPCRA). Clin Infect Dis. 1999;29(4):775–83.PubMedCrossRefGoogle Scholar
  150. 150.
    Vasconcelles MJ, Bernardo MV, King C, Weller EA, Antin JH. 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. Biol Blood Marrow Transplant. 2000;6(1):35–43.PubMedCrossRefGoogle Scholar
  151. 151.
    Sangiolo D, Storer B, Nash R, Corey L, Davis C, Flowers M, et al. Toxicity and efficacy of daily dapsone as pneumocystis jiroveci prophylaxis after hematopoietic stem cell transplantation: a case-control study. Biol Blood Marrow Transplant. 2005;11(7):521–9.PubMedCrossRefGoogle Scholar
  152. 152.
    Souza JP, Boeckh M, Gooley TA, Flowers ME, Crawford SW. High rates of pneumocystis carinii pneumonia in allogeneic blood and marrow transplant recipients receiving dapsone prophylaxis. Clin Infect Dis. 1999;29(6):1467–71.PubMedCrossRefGoogle Scholar
  153. 153.
    Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia: a retrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore). 2004;83(5):265–73.CrossRefGoogle Scholar
  154. 154.
    Colby C, McAfee S, Sackstein R, Finkelstein D, Fishman J, Spitzer T. 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. Bone Marrow Transplant. 1999;24(8):897–902.PubMedCrossRefGoogle Scholar
  155. 155.
    Chan C, Montaner J, Lefebvre EA, Morey G, Dohn M, McIvor RA, et al. Atovaquone suspension compared with aerosolized pentamidine for prevention of pneumocystis carinii pneumonia in human immunodeficiency virus-infected subjects intolerant of trimethoprim or sulfonamides. J Infect Dis. 1999;180(2):369–76.PubMedCrossRefGoogle Scholar
  156. 156.
    Gea-Banacloche J, Masur H, Arns da Cunha C, Chiller T, Kirchhoff LV, et al. Regionally limited or rare infections: prevention after hematopoietic cell transplantation. Bone Marrow Transplant. 2009;44(8):489–94.PubMedCrossRefGoogle Scholar
  157. 157.
    Jurges E, Young Y, Eltumi M, Holliman RE, Vellodi A, Rogers TR, Hobbs JR. Transmission of toxoplasmosis by bone marrow transplant associated with campath-1g. Bone Marrow Transplant. 1992;9(1):65–6.PubMedGoogle Scholar
  158. 158.
    Chandrasekar PH, Momin F. Disseminated toxoplasmosis in marrow recipients: a report of three cases and a review of the literature. Bone marrow transplant team. Bone Marrow Transplant. 1997;19(7):685–9.PubMedCrossRefGoogle Scholar
  159. 159.
    Osthoff M, Chew E, Bajel A, Kelsey G, Panek-Hudson Y, Mason K, et al. Disseminated toxoplasmosis after allogeneic stem cell transplantation in a seronegative recipient. Transpl Infect Dis. 2013;15(1):E14–9.PubMedCrossRefGoogle Scholar
  160. 160.
    Martino R, Maertens J, Bretagne S, Rovira M, Deconinck E, Ullmann AJ, et al. Toxoplasmosis after hematopoietic stem cell transplantation. Clin Infect Dis. 2000;31(5):1188–95.PubMedCrossRefGoogle Scholar
  161. 161.
    Martino R, Bretagne S, Rovira M, Ullmann AJ, Maertens J, Held T, et al. Toxoplasmosis after hematopoietic stem transplantation. Report of a 5-year survey from the infectious diseases working party of the european group for blood and marrow transplantation. Bone Marrow Transplant. 2000;25(10):1111–4.PubMedCrossRefGoogle Scholar
  162. 162.
    Martino R, Bretagne S, Einsele H, Maertens J, Ullmann AJ, Parody R, et al. Early detection of toxoplasma infection by molecular monitoring of toxoplasma gondii in peripheral blood samples after allogeneic stem cell transplantation. Clin Infect Dis. 2005;40(1):67–78.PubMedCrossRefGoogle Scholar
  163. 163.
    Mendorf A, Klyuchnikov E, Langebrake C, Rohde H, Ayuk F, Regier M, et al. Atovaquone for prophylaxis of toxoplasmosis after allogeneic hematopoietic stem cell transplantation. Acta Haematol. 2015;134(3):146–54.PubMedCrossRefGoogle Scholar
  164. 164.
    Robert-Gangneux F, Sterkers Y, Yera H, Accoceberry I, Menotti J, Cassaing S, et al. Molecular diagnosis of toxoplasmosis in immunocompromised patients: a three-year multicenter retrospective study. J Clin Microbiol. 2015;53(5):1677–84.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Open Access This chapter is distributed under the terms of the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Authors and Affiliations

  1. 1.NIH Clinical CenterBethesdaUSA

Personalised recommendations