Infections in Hematopoietic Stem Cell Transplant Recipients

SECTION 4 Infections in the Immunocompromised Host

80 

Infections in Hematopoietic Stem Cell Transplant Recipients KIEREN A. MARR

KEY CONCEPTS • Type of transplant, including type of stem cells, conditioning regimens and post-transplant immunosuppression, affects risks and timing of infections. • Infectious risks have expanded late after allogeneic hematopoietic stem cell transplantation (HSCT). • Preventive practices that have decreased infection caused by gram-negative bacteria, herpesviruses and fungi have improved survival after HSCT and should be routinely employed. • Bacterial infections can occur both early and late after HSCT, with risks associated with GI tract damage and neutropenia (early), and poor antibody responses (late). • Infections can be caused by both latent (e.g. herpesviruses) and exogenously acquired (e.g. influenza) viruses, with implications on prevention strategies.

Hematopoietic Stem Cell Transplantation: Background and Current Practices Hematopoietic stem cell transplantation (HSCT) is increasingly used to treat hematologic and nonhematologic malignancies and inherited immunodeficiencies. Multiple practices, including conditioning regimens, stem cell sources and supportive care strategies, impact on the severity and duration of infectious risks, key determinants of outcomes. In order to allow for donor hematopoiesis to establish in the recipient, a conditioning regimen must be applied before infusion of stem cells. The primary aim of the conditioning regimen is to suppress recipient T cells that could ultimately mediate rejection of the graft. With the goal of eliminating residual malignant disease, conventional regimens aim to be highly myeloablative, potentially employing total body irradiation (TBI) and high-dose chemotherapy (e.g. busulphan, cyclophosphamide). In this setting, severe and protracted neutropenia, and regimen-related organ toxicities contribute risks for infectious complications. New, alternative, reduced-intensity, or nonmyeloablative regimens are increasingly employed. Success relies on the therapeutic potential of graft-versus-host effects, which are produced when donor-derived immune cells recognize and destroy host tumor cells and tissues, sometimes to a degree that can result in complete remission.1,2 A number of alternative conditioning regimens that have fewer organ toxicities (e.g. gastrointestinal tract mucositis) and shorter (if any) neutropenia have been developed.3–7 Suitable donors that are matched for human leukocyte antigens (HLA) are available in only approximately 30% of people. New technologies have allowed for expansion of the donor pool, especially with use of alternative stem cells (cord blood) and with transplantation using HLA-mismatched and related, haplo-identical donors. Type of donor, post-transplant immunosuppressive regimens and types of stem cells impact immune reconstitution and risks for graft-versus-



host disease (GVHD). Practices aimed to decrease infection must then consider the primary risk periods, with consideration of the pace of immune reconstitution and how that impacts on risks.

Risk for Infections: Impact of the Graft, the Host and Transplant Complications The risk of infections post-HSCT is associated with a number of factors, defined largely by the type of graft received, and host and transplant complications – all determinants of the ‘net state of immunosuppression’.

THE GRAFT AND TYPE OF TRANSPLANT Donor and HLA-matching of the graft impact risks for infection, primarily by dictating the likelihood and severity of GVHD and the need for and intensity of immunosuppressive therapy. The cellular composition of the graft (stem cell source and ex vivo manipulation) similarly affects the risk for infection, with a variable pace of engraftment resultant from differing stem cell sources (bone marrow, peripheral blood stem cells or cord blood), and ex vivo manipulation (e.g. T-cell depletion). Transplantation with stem cells harvested from peripheral blood of G-CSF-treated donors (PBSCs) may yield faster reconstitution of platelets, CD4+ T cells, neutrophils and monocytes compared to bone marrow, and possibly, different infectious risks.8–12 In a large comparative study, lymphocyte subsets (especially CD4+ T cells) were higher in PBSC compared to bone marrow transplant recipients, accompanied by fewer bacterial and fungal infections.12 However, there is concern that the success of PBSC transplant, especially from unrelated or HLAmismatched donors, may be limited by a more rapid onset of severe GVHD.8,9 Cord blood transplantation, which is increasingly performed in patients who lack suitable related donors, is associated with delayed hematopoietic recovery. With this, slow engraftment and impaired neutrophil function may work together to increase the risk of infection, particularly early after transplantation.13–16 Studies have reported high risk for aspergillosis, candidiasis and infections caused by adenovirus and human herpesvirus 6 (HHV-6) in cord blood transplant recipients.13,17,18 Patients who receive cord blood after non-myeloablative conditioning regimens that incorporate antithymocyte globulin (ATG) appear to be at particularly high risk for Epstein–Barr virus (EBV)-related complications.19 On the other hand, the low rates of GVHD may confer a relative protection from infection later after transplantation.20 Although T-cell depletion (TCD) decreases the pace and severity of GVHD, TCD itself is associated with delayed immune reconstitution and an increased risk for infections.21–24 A large study comparing infectious complications in patients treated with TCD bone marrow from unrelated donors to those of patients treated with GVHD suppressive therapies found that TCD was associated with a particularly high risk for both cytomegalovirus (CMV) infection and aspergillosis.25 Because CD34+ selection results in removal of T cells, natural killer (NK) cells and monocytes, this practice may increase the risk for infections after transplantation.26,27

739

740

SECTION 4  Infections in the Immunocompromised Host

It appears that immune reconstitution is similar after nonmyeloablative and myeloablative HSCT, although few large comparative studies have been performed, and reconstitution depends on multiple host and therapeutic variables.28,29 Results of at least one study suggested that non-myeloablative HSCT may be associated with more rapid reconstitution of immune responses assessed in vitro.29 Results of another study suggested that although the total numbers of lymphocytes and antibodies was not different during the first 180 days after non-myeloablative and myeloablative HLA-identical HSCT, recipients of non-myeloablative regimens had relatively higher numbers of CMV T-helper cells during the early time period, raising the possibility of a protective effect of donor T cells that survive the less ablative conditioning regimen.30 Of course, the short duration of neutropenia and differences in organ toxicities are important determinants of infectious risks. One case–control study suggested fewer early bacterial and candidal infections after non-myeloablative conditioning.5,31 Late-onset GVHD after non-myeloablative HSCT poses increased risks for late CMV disease and aspergillosis.5,31,32

HOST FACTORS THAT IMPACT ON INFECTION RISKS Underlying disease impacts risk for infection post-HSCT. Patients who receive HSCT for a hematologic malignancy beyond first remission, for aplastic anemia and for myelodysplastic syndromes, have higher risks for aspergillosis.17,33–37 Patients who have protracted courses of primary immunodeficiencies may also have increased risks. Multiple studies have reported that older people have increased risks for infections after HSCT.17,33,36 Although it is not clear why older age predicts higher risks, factors that have been suggested include cumulative exposure to previous cytotoxic therapy, underlying disease, severity of GVHD, baseline organ dysfunction, previous microbial exposure and waning cellular immunity. On the other hand, youth presents increased risks for other infections, with the classic example being adenovirus.38,39 Genetic factors modulate risks for infectious complications, especially those that impact innate immunity. Polymorphisms in specific genes of both recipients and donors have been associated with posttransplant risks for infection. For instance, risks for infectious complications after chemotherapy and HSCT have been reported to be associated with polymorphisms in the Fc gamma receptor, myeloperoxidase gene promoter, CXCL10, interleukin-10, DC-SIGN and multiple Toll-like receptors (TLR).40–43 Donor and recipient genotypes have been implicated. For instance, recipients of stem cells from HLA matched-related donors who have polymorphisms in TLR4 have high risks for invasive aspergillosis.43 On the other hand, stem cell transplant recipients who have polymorphisms in the gene that codes for the pattern recognition receptor pentraxin 3 also have high risks for invasive aspergillosis,44 with impaired neutrophilic fungal clearance. One may envision a future in which post-transplant risks, and preventive strategies, may be personalized based on genetic variability.

TRANSPLANT COMPLICATIONS THAT IMPACT ON INFECTION RISKS Multiple complications that occur after HSCT alter the risk for infections. Early after HSCT, breakdown of the mucosa of the gut is a primary mode of entry for bacteria and Candida spp. that colonize the GI tract. Other, subtle manifestations of organ toxicities may also lead to subsequent infection risks. Patients with renal or hepatic dysfunction may not tolerate typical doses of prophylactic or empiric antibiotics or antifungals. Other biologic variables such as iron overload or metal chelating therapy may have an effect, especially on bacterial and filamentous fungal infections.45 GVHD and corticosteroid-based therapies impact risks for all infections – bacterial, fungal and viral. Corticosteroids administered for other post-HSCT complications, such as bronchiolitis obliterans and ‘idiopathic’ pulmonary syndromes, may also lead to equivalent, high risks for infections. The negative impact of corticosteroid expo-

sure is not limited to the above risks; cumulative exposure to high-dose corticosteroids is an important variable predicting persistent infection and poor prognosis of treatment for viral or fungal disease.46–48 It has been hypothesized that infection with herpesviruses, especially CMV, may directly impact on the risk for other infections by modulating immune responses. High risk for subsequent bacterial and fungal infections has been noted in patients with active CMV disease or latent CMV infection, even after controlling for secondary neutropenia in multivariable models.17,37,49 Cytomegalovirus-seronegative recipients of stem cells from seropositive donors (D+/R−) have increased risk for both bacterial and fungal infections, even in the absence of CMV-specific therapy.50 Donor or recipient seropositivity may have the most impact on survival in patients who receive HSCT from unrelated donors.51 Thus, multiple factors related to both host and transplant contribute to the ‘net state of immunosuppression’. This net state, which changes according to the timing of the transplant and to exposures, dictates overall infectious risk, as summarized in Table 80-1 and Figure 80-1. Knowing risks for infections according to timing after HSCT has enabled development of effective strategies to prevent complications – and to improve survival. For instance, a large analysis of HSCT outcomes in one center showed that effective prevention of fungal infections (Candida spp. and molds), CMV, and gram-negative bacteria, led to sequential improvements in survival over time.52 Commonly employed prevention strategies for different types of infection are outlined in Table 80-2, and a more detailed discussion pertaining to diagnostic and therapeutic approaches for infectious complications is presented in other chapters.

Bacterial Infections in HSCT Patients: Epidemiology, Manifestations and Management Patients have high risks for bacterial infections early after HSCT, with GI tract mucositis and neutropenia leading to translocation of endogenous pathogens, and during the later periods of GVHD, when risks for encapsulated organisms are particularly prominent. Bacteria most frequently become blood-borne through the GI tract and/or intravenous catheter, or through the respiratory tract or breaks in the integument. Risks are related to antibacterial prophylaxis patterns, degree of GI tract mucositis and presence of indwelling intravenous catheters. Late after HSCT, the epidemiology of infection largely depends on the severity of GVHD, application of prolonged prophylaxis and efficacy of immunization. Numerous aerobic and anaerobic bacteria cause infection in these patients, as outlined in more depth in Chapter 79. Overall risks are dependent on the type of transplant, degree of immunosuppression and post-transplant complications, and exposure; general estimates are provided in Table 80-1. The epidemiology of bacterial infections has changed over two decades, with large European and North American studies suggesting an increase in the incidence of infections caused by gram-positive bacteria concurrent with a decrease in infections caused by gramnegative bacteria.53,54 More recent studies demonstrated a potential reversal in trends, with more infections caused by gram-negative bacteria.55 Some of this increase may be associated with high rates of infection caused by multidrug-resistant (MDR) bacteria; a large multicenter Brazilian study showed that 37% of gram-negative bacteria recovered from HSCT recipients were MDR; risks for these infections were increased with use of third-generation cephalosporins.56 Outcomes can be particularly poor, especially in the setting of severe GVHD; for instance, Pseudomonas aeruginosa infections (lung and bloodstream) recur in 16% of patients who are treated with 14-day courses of appropriate antibiotics, with associated mortality estimated at 36%.57 Bacterial infections involving the GI tract, such as neutropenic enterocolitis, or typhlitis, are relatively common in the setting of neutropenia after cytotoxic therapy. Diarrhea is also common after



Chapter 80  Infections in Hematopoietic Stem Cell Transplant Recipients

TABLE 80-1 

Approximate Incidence of Selected Infectious Complications in Hematopoietic Stem Cell Transplant (HSCT) Recipients

Infection

Autologous HSCT

Allogeneic HSCT

Gram-positive

5–10

10–20

Gram-negative

5–10

5–10

Mycobacterium tuberculosis

<2

<2

Nontuberculous

<2

<5

Candida spp.

<2

<5

Aspergillus spp.

<10

5–15

Pneumocystis jirovecii

<2

<3

Cytomegalovirus infection*   R+ (auto)/R+/D+ or D− (allo)   R− (auto)/R−/D+ (allo)   R−/D− (allo)

25–40 3–5 NA

70 15–25 3–5

Cytomegalovirus disease*   R+ (auto)/R+/D+ or D− (allo)   R− (auto)/R−/D+ (allo)   R−/D− (allo)

5–7 1–3 NA

35–40 10 1–3

60–80

60–80

BACTERIAL*

MYCOBACTERIAL

FUNGAL*

VIRAL

Herpes simplex virus (HSV)*   Without prophylaxis, HSV+ Varicella-zoster virus (VZV)*   Without prophylaxis, VZV+

20–40

17–60

Influenza virus†

<5

<5

Respiratory syncitial virus†

<5

5–15

<5

5–10

Adenovirus

<5

5–20

BK virus

<5

5–40

Epstein–Barr virus

<5

5–25

Human herpesvirus 6   Infection   Disease

35–60 <3

35–60 <3–12

<2

<2

Parainfluenza virus

†

PARASITIC Toxoplasma gondii*

Shown are estimates of disease incidence (%), unless indicated otherwise.75,78,90,92,117–126 *Dependent on prophylaxis. † Episodic incidence during the year. NA, not applicable.

conditioning therapy for HSCT; recent reports suggest that 47–100% of autologous or allogeneic HSCT recipients develop diarrhea at some point during therapy.58–63 Conventional bacterial pathogens, parasitic pathogens and viruses cause diarrhea in these patients; however, in allogeneic HSCT recipients, GVHD impacts the duration and magnitude of risks for infectious colitis and the differential diagnosis of diarrhea. For instance, GVHD has been reported to be an important risk factor for Clostridium difficile-associated disease (CDAD) in allogeneic HSCT recipients, and recent studies demonstrate that CDAD may also present risks for GVHD.60,61,64,65 This observation raises concern for microbial GI infection driving an alloreactive response; much research is currently focused on resolving how microbial flora, and specific infections, impact transplant outcomes such as GVHD.

741

Finally, management of allogeneic HSCT patients with acute diarrhea is more complex, as the differential diagnosis includes GVHD involving the GI tract; in a study of 169 HSCT recipients, an infectious cause of diarrhea was documented in only 45 (29%).66 GVHD can be indistinguishable from infectious diarrhea using signs and symptoms alone; empiric immunosuppressive therapies often exacerbate and ‘uncover’ infectious causes (e.g. CMV, discussed below). Recent attention has been focused on the role of difficult to diagnose viruses – such as norovirus – in causing diarrheal illnesses that ‘mimic’ GVHD.67

Viral Infections in HSCT Patients: Epidemiology, Manifestations and Management Infections caused by endogenous viruses (e.g. herpesviruses) and exogenous viruses (e.g. those acquired through the GI and respiratory tracts) are common in the HSCT population (see Table 80-1). The incidence of disease thus depends on mode of infection, recipient and donor CMV seropositivities, and immunosuppression. These host– pathogen interactions dictate the risk, timing and incidence of infection caused by latent herpesviruses, while exposure impacts the epidemiology of exogenously acquired viruses. In the latter group, degree of immunosuppression more often impacts the severity of infection (i.e. whether a virus is contained within the upper respiratory tract or invades lung tissue).

HERPESVIRUS INFECTIONS Herpesviruses are exceedingly important in HSCT recipients, with clinically significant infections caused by CMV, herpes simplex virus (HSV), varicella-zoster virus (VZV), EBV and HHV-6 and -8. Perhaps the most important infectious complication is caused by CMV. The risk of CMV disease is primarily related to reactivation of infected recipient or donor cells during periods of low CMV-specific T-lymphocyte function. Allogeneic HSCT recipients, who have the highest risk during GVHD, most commonly develop interstitial pneumonitis and gastroenteritis, and less commonly, other manifestations such as retinitis, isolated fever, pancytopenia, hepatitis and encephalitis. However, retinitis appears to be increasingly recognized, especially late after allogeneic HSCT in the setting of severe GVHD and recurrent CMV reactivation.68 Infection caused by CMV has also been associated with ‘indirect effects’, which include higher mortality related to other infections.50 For these reasons, prevention strategies have been an active area of research, especially in recipients of allogeneic HSCT (see Table 80-2). Antiviral drug strategies, which include both universal prophylaxis and preemptive therapy, are effective and have lowered CMV-related mortality; however, both prophylaxis and pre-emptive therapies have limitations, including emergence of drug resistance and toxicities associated with antiviral drugs. Unfortunately, no strategy is 100% effective, largely because the duration of time at risk for CMV disease is progressively extended in patients who receive suppressive therapies without effective immune reconstitution. CMV resistance to ganciclovir during prophylaxis or pre-emptive therapy has been reported, but appears to be less common than in other populations, such as in organ transplant recipients. The kinetics of viral reactivation, dictated by pathogen-specific cellular immunity and antiviral exposure, impacts the likelihood of viral resistance, especially in the setting in which resistance mutations impact viral ‘fitness’.69 As control of CMV infection and risk for development of disease are primarily associated with both CD8+ and CD4+ T-cell immune responses, efforts are under way to develop strategies to enhance immunity, both as an effort to augment therapy of disease (e.g. cellular immunotherapy), and to develop preventive strategies (e.g. vaccines). Both HSV and VZV infections occur and cause localized disease in seropositive hosts; reactivation and primary infection can also cause disseminated disease (e.g. hepatitis, pneumonitis, encephalitis).

742

SECTION 4  Infections in the Immunocompromised Host

Primary risk periods for infections after HSCT

Aspergillosis, cytomegalovirus Herpes simplex virus

Encapsulated bacteria

Mucositis-related bacteremia

Allogeneic

Line-related bacteremia, candidemia

Myeloablative (with GVHD)

Human herpesvirus 6 Adenovirus

Epstein– Barr virus

Varicella-zoster virus

Aspergillosis, cytomegalovirus, varicella-zoster virus

Nonmyeloablative (with GVHD)

Line-related bacteremia, candidemia

Encapsulated bacteria

Herpes simplex virus Aspergillosis, human herpesvirus 6

Cord blood

Adenovirus

Candidemia Bacteremia

Line-related bacteremia, candidemia Cytomegalovirus, varicella-zoster virus

Aspergillosis Candidemia

Autologous**

Cellular immunity/acute GVHD†

Neutropenia

Risks

Mucositis associated with GVHD

Mucositis

Cellular and humoral immunity/chronic GVHD

Intravascular line

0 High incidence

50

100

360 Days after transplant

Low incidence

†

Risk increased in recipients of T-lymphocyte depleted grafts **Risks may be increased after CD34 selection Respiratory virus infections can occur at any time after HSCT, with episodic incidence

Figure 80-1  Primary risk periods for infections after hematopoietic stem cell transplantation. Typical risk periods for the most common infections after each type of HSCT are shown. Risks are based on typical prophylaxis strategies, which include trimethoprim–sulfamethoxazole for Pneumocystis jirovecii, screened or filtered blood products and ganciclovir for cytomegalovirus, aciclovir for herpes simplex virus, and fluconazole for candidemia. (Courtesy of R. Bowden. In: Armstrong D.C., Cohen J., ed. Infectious diseases. London: Mosby; 1999:4.4.3.)

Prolonged antiviral prophylaxis is usually employed in seropositive patients; one randomized trial documented a decrease in VZV disease with one year of prophylaxis after allogeneic HSCT.70 Rebound disease, and HSV and VZV antiviral resistance appear to be infrequent in this population.71,72 An inactivated varicella vaccine given before receipt of autologous stem cells and 90 days thereafter has been shown to reduce the risk of VZV disease.73 Human herpesvirus 6 (HHV-6), the cause of exanthem subitum, infects nearly everyone by 3 years of age and becomes latent. This virus (especially variant B) has been increasingly implicated in disease in adult and pediatric HSCT recipients. Although early reports associated HHV-6 with pneumonitis, rash, bone marrow suppression (especially involving megakaryotic lineage) and fever, most recent studies have shown more definitive associations with neurologic manifestations, including seizures, multifocal encephalitis and ‘post-transplant acute limbic encephalitis’. The latter, ‘PALE’, is a syndrome characterized by anterograde amnesia, syndrome of inappropriate production of antidiuretic hormone (SIADH), mild cerebrospinal fluid (CSF) pleocytosis and temporal EEG abnormalities.74 Multiple issues surrounding HHV-6, including pathogenesis of disease, epidemiology and prevention, and the role of antiviral therapies remain under current investigation. One interesting observation is that this virus can be transmitted from a donor to an HSCT recipient by means of chromosomally integrated virus, also confounding the interpretation of HHV-6 viremia.75

COMMUNITY-ACQUIRED RESPIRATORY VIRUSES Respiratory viruses, acquired within the community or nosocomially in association with institutional outbreaks, impose a significant burden of morbidity and mortality in this population. Biology of the viruses, pathogenesis of disease, diagnosis and therapies are discussed elsewhere in this text (Chapters 172 and 173). There are a few concepts specific to this population that are worthy of discussion. Approximated incidence of respiratory tract ‘infection’ is listed in Table 80-1. However, incidence of pneumonia and related mortality is variable for specific viruses and is largely impacted by underlying immunity. Respiratory syncytial virus (RSV), influenza and parainfluenza (especially parainfluenza 3) have been reported to have the highest rates of pneumonia and related mortality in HSCT patients. These three viruses account for the bulk of diagnosed infections, progressing to pneumonia in 35% of patients.76 Progression from upper to lower respiratory tract infection with RSV is dependent on lymphopenia, older age, allogeneic HSCT and degree of GVHD, but outcomes are also particularly poor when infection is established early after HSCT.77 In contemporary studies,76,78–80 associated mortality is estimated to be about 18–30%. Definitive recommendations of how to prevent progression of pneumonia are elusive in the absence of large randomized trials. Methods that have been explored and reported to be safe include systemic and aerosolized administration of ribavirin, administration of intravenous immunoglobulin and use of neutralizing antibody, palivizumab.78,81 Similarly, although no randomized trials



Chapter 80  Infections in Hematopoietic Stem Cell Transplant Recipients

TABLE 80-2 

Prevention Strategies Commonly Employed in HSCT Recipients

Indication

Strategy

Decreased duration of neutropenia

Colony-stimulating factors WBC transfusions

Bacterial infections

Antibiotic prophylaxis during neutropenia Antibiotic prophylaxis during GVHD IVIG Vaccination

Cytomegalovirus disease

Screening (or filtering) of blood products in seronegative recipients Antiviral prophylaxis PCR or antigen-based screening for reactivation with pre-emptive therapy IVIG Safe sex practices Vaccination (experimental)

Herpes simplex virus (HSV) -1 and -2

Antiviral prophylaxis Safe sex practices

Varicella-zoster virus

Antiviral prophylaxis Postexposure prophylaxis IVIG Immunization

Epstein–Barr virus (EBV)/ post-transplant lymphoproliferative disorders

PCR screening for reactivation, reduce immunosuppression if possible, consider rituximab and therapy with EBV-specific cytotoxic T lymphocytes (experimental)

Adenovirus infections

PCR screening for reactivation with preemptive therapy

BK infection

PCR screening for reactivation, reduce immunosuppression if possible, pre-emptive strategies

Respiratory virus infections

Enhanced infection control measures Prophylaxis, pre-emptive therapy for influenza Vaccination

Fungal infections

Antifungal prophylaxis Prophylaxis to prevent Pneumocystis jirovecii pneumonia

Toxoplasmosis

Prophylaxis with seropositivity and GVHD

Other

Infection control measures to prevent food-borne illness and respiratory acquisition of infection

Listed are strategies that are in common use or have suggested potential in recent clinical studies. GVHD, graft-versus-host disease; IVIG, intravenous immunoglobulin; PCR, polymerase chain reaction; WBC, white blood cell.

a

b

743

have been performed to establish efficacy, oseltamivir is tolerated by HSCT recipients and used frequently to prevent disease caused by influenza viruses in outbreak settings.82 Resistance to oseltamivir has been noted in 2009 pandemic influenza (H1N1) strains infecting HSCT recipients, possibly developing as a result of prolonged viral excretion with inconsistent exposure to oral drug.83,84 Human metapneumovirus has been recognized as a cause of previously undiagnosed ‘idiopathic pneumonia’ in HSCT recipients.79,85 This virus, as well as influenza and parainfluenza 3, can persist in respiratory secretions for extended periods of time in asymptomatic HSCT recipients,86,87 presenting challenges to both diagnostics and effective infection control. One caveat complicating the care of these patients is that diagnostic parsimony does not always apply in patients with diagnosed upper respiratory tract infections and pulmonary abnormalities. Both parainfluenza and influenza lower respiratory tract infections are frequently associated with ‘co-pathogens’, including bacteria and fungi, which require different therapies. In one study, parainfluenza 3 pneumonia was associated with other pathogens in 53% of cases.88,89 Diagnostic bronchoscopy is wise, when feasible. Adenovirus can cause disease after primary infection (gastroenteritis, interstitial pneumonitis) and after reactivation, with propensity to cause disease in the kidneys and liver. Incidence is variable and dependent on age, with higher rates in the young and older age groups, and degree of T-cell dysfunction related to cellular depletion or GVHD.90 Lower respiratory tract disease caused by respiratory viruses can present differently with different diagnostic imaging techniques. Disease may be unapparent on chest radiograph (Figure 80-2a), with early pneumonia better shown on computed tomography (CT) scan (Figure 80-2b); CT scan can also show both nodular and ‘ground glass’ infiltrates, representative of bronchiolitis and pneumonia (Figure 80-2c,d).

BK VIRUS Reactivation of polyoma BK virus (BKV) has been associated with post-engraftment hemorrhagic cystitis in allogeneic HSCT recipients.91 Frequency of disease is dependent on the type of transplant and HLA match, type of conditioning regimen, GVHD and pretransplant serologies.92–95 Disease may be preceded by viral reactivation in urine and serum, presenting options for monitoring and ‘preemptive’ therapy.96 Unlike renal transplant recipients, interstitial nephritis appears rarely (for a detailed discussion about BK virus, see Chapter 168).

HEPATITIS VIRUSES Hepatitis virus infections can be acquired from infected stem cell donors, although rates of transmission are variable and dependent on donor viral reactivation at time of stem cell recovery; effective prevention by treating donors with antiviral drugs and recipient vaccination has been reported.97 Hepatitis C virus (HCV) has recently been recognized as one of the two most common viral infections (with VZV) late

c

d

Figure 80-2  Respiratory virus infections. (a, b) Chest radiograph and CT scan of documented human metapneumovirus infection in a patient with acute myelogenous leukemia. (c, d) CT scans of adenoviral infection complicating severe GVHD in a recipient of an HLA-matched unrelated donor transplant. In these scans, taken on the same day, both centrilobular nodules (left) and ground glass infiltrates (right) were apparent.

744

SECTION 4  Infections in the Immunocompromised Host

after HSCT. In one series 10% of long-term survivors of allogeneic HSCT recipients developed HCV from matched related donors.98

Fungal Infections in HSCT Patients: Epidemiology, Manifestations and Management Overall risks for fungal infections are contingent upon variables that modulate the pace of immune reconstitution, organ toxicities and microbial exposures.

INFECTIONS CAUSED BY CANDIDA SPECIES The vast majority of superficial and invasive yeast infections are caused by Candida spp., with invasive Candida infections separated into two primary syndromes: acute candidiasis (bloodstream infection) and chronic candidiasis (hepatosplenic infection). The pathogenesis and clinical characteristics of candidiasis are discussed in Chapter 189. In this population, bloodstream infections occur either through an indwelling intravascular catheter or through a damaged GI tract. Acute infection usually manifests as fever and signs of sepsis. Adequate antifungal therapy is essential, not only to cure the acute episode, but also to decrease the likelihood of late embolic manifestations (e.g. chorioretinitis, endocarditis).99 The widespread use of fluconazole, which is supported by numerous randomized trials carried out in the early 1990s,100,101 has decreased the incidence and mortality rate attributable to both acute and chronic infections caused by Candida albicans.37,102,103 This practice has resulted in improved overall survival in allogeneic HSCT patients.100 However, the decreased incidence of early candidiasis due to azole-susceptible species (C. albicans and C. tropicalis) and improved survival late after HSCT with GVHD has allowed for an increase in infections due to fluconazole-resistant Candida spp., such as C. glabrata and C. krusei.37,103–106 There has also been a shift from Candida spp. to molds as the primary fungal pathogens. Thus, the appearance of azoleresistant organisms is not a failure of prophylaxis but reflects the success of supportive care strategies.

INFECTIONS CAUSED BY FILAMENTOUS FUNGI Infections with filamentous fungi are usually acquired through the respiratory route, although filamentous fungi can also invade through a damaged GI tract.107–109 The most common cause of fungal infection in HSCT patients is currently Aspergillus fumigatus.33,110 The day of onset of aspergillosis has changed, from primarily the early neutropenic period to later after allogeneic transplant.4,17,33 Risks for early and late disease are different; risks for early disease are primarily those that impact on the pace of engraftment, such as the specific stem cell product. There is also some indication that a portion of patients who present with aspergillosis early after HSCT may have been exposed to the organism before conditioning therapy. This may explain some of the impact of ‘host’ variables, such as age and underlying diseases on the risk of aspergillosis. Risks during the late period are largely those associated with GVHD and its therapies. Other infections, such as CMV disease, may pose both direct and indirect risks for subsequent disease. There has been an increase in invasive infections caused by zygomycetes and Fusarium spp.110 Most recent efforts have been directed towards preventing mold infections by using universal or targeted prophylaxis with different mold-active drugs (e.g. azoles, echinocandins or polyenes) or ‘pre-emptive therapy’ driven by screening for fungal antigens or nucleic acids. Success has been reported in large randomized trials applying azole antifungals, although there is concern of breakthrough infection with organisms that demonstrate innate or acquired drug resistance.111–113 Currently, there are many issues of debate concerning preventive therapies, including which antifungal drug is best, which patients benefit and the optimal duration of therapy. Fungal infections present with the typical appearance of nodular infiltrates on radiographs. In neutropenic patients, who have been studied most extensively, resolution of neutropenia may result in increased size of lesions and cavitation. Fungal pneumonia that occurs in non-neutropenic hosts can present with multiple radiographic abnormalities, including focal or multifocal consolidation and airway disease, characterized by ‘tree in bud’ abnormalities. Nodular lesions and consolidations have multiple infectious and noninfectious etiologies (Figure 80-3); bronchoscopic examination is necessary in order to

a

b

c

d

e

f

Figure 80-3  Pneumonia. Multiple CT scans representative of documented infections. (a) Stenotrophomonas spp. infection presenting as a nodular lesion in patient with acute myelogenous leukemia (AML) and neutropenic fever. (b) Nodular lesion in a patient with AML and documented aspergillosis. (c) Cytomegalovirus pneumonitis presenting with focal, ‘patchy’, nodular infiltrate in a patient with graft-versus-host disease (GVHD). (d) Necrotic lesion diagnosed as Aspergillus fumigatus in a patient with Hodgkin’s lymphoma. (e, f) Progression of scattered patchy peripheral ground glass infiltrate (e), followed by diffuse airway thickening and mild bronchiectasis (f) in a patient with GVHD after nonmyeloablative HSCT, who presented with obstructive symptoms and had A. fumigatus tracheobronchitis.



Chapter 80  Infections in Hematopoietic Stem Cell Transplant Recipients

745

optimize therapy. Recently, immune reconstitution syndrome has been recognized as a cause of progressive infiltrates in HSCT recipients with pulmonary aspergillosis.114

PNEUMOCYSTIS INFECTIONS In the absence of prophylaxis, Pneumocystis jirovecii pneumonia (PJP) is a common cause of infection after allogeneic HSCT, particularly during lymphopenia and GVHD. Infections may manifest with multiple typical and atypical abnormalities, including ground glass infiltrates, pneumothorax, pleural effusions and nodular infiltrates.115 Death attributable to PCP is particularly high after HSCT, emphasizing the importance of effective prevention. Trimethoprim–sulfamethoxazole is most frequently administered using a twice-weekly algorithm, although the drug is only moderately tolerated due to allergic manifestations and bone marrow toxicity. Alternatives explored included pentamidine (aerosolized and intravenous), dapsone and atovaquone, although the latter strategies may not be as effective.116 Importantly, patients who do not receive the trimethoprim–sulfamethoxazole formulation also do not have the added benefits of prevention of other pathogens, such as Nocardia spp. and Toxoplasma gondii infection; these patients can present with combined pulmonary and CNS lesions (Figure 80-4).

Summary Infections remain a leading cause of death in HSCT patients, but the timing of onset and the spectrum of pathogens have evolved over the past two decades. Changes in transplantation practices, different hosts and the development of effective strategies to prevent early CMV

a

b

Figure 80-4  (a, b) Toxoplasmosis. Nodular lung lesions and multiple foci of enhancement with associated edema in a patient treated with rituximab for mantle cell lymphoma who developed fevers and confusion as presenting symptoms of toxoplasmosis.

disease and candidiasis have increased survival rates. Late after transplantation, severe GVHD dominates the clinical presentation and is often accompanied by the emergence of other organisms, such as molds and other opportunistic pathogens. The approach to this patient population requires not only an understanding of the pathogens, but also a complete appreciation for the host and associated immunosuppression, which defines risk periods, differential diagnosis and appropriate therapies. References available online at expertconsult.com.

KEY REFERENCES Bochud P.Y., Chien J.W., Marr K.A., et al.: Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med 2008; 359:1766-1777. Boeckh M., Kim H.W., Flowers M.E., et al.: Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantation – a randomized double-blind placebo-controlled study. Blood 2006; 107:1800-1805. Cunha C., Aversa F., Lacerda J.F., et al.: Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. N Engl J Med 2014; 370:421-432. Giralt S., Estey E., Albitar M., et al.: Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graftversus-leukemia without myeloablative therapy. Blood 1997; 89:4531-4536. Gluckman E., Rocha V., Boyer-Chammard A., et al.: Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med 1997; 337:373-381.

Gooley T.A., Chien J.W., Pergam S.A., et al.: Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363:2091-2101. Hata A., Asanuma H., Rinki M., et al.: Use of an inactivated varicella vaccine in recipients of hematopoietic-cell transplants. N Engl J Med 2002; 347:26-34. Marr K.A., Carter R.A., Boeckh M., et al.: Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 2002; 100: 4358-4366. McSweeney P.A., Niederwieser D., Shizuru J.A., et al.: Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97:3390-3400. Powles R., Mehta J., Kulkarni S., et al.: Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: a randomised trial. Lancet 2000; 355:1231-1237. Rocha V., Wagner J.E. Jr, Sobocinski K.A., et al.: Graftversus-host disease in children who have received a

cord-blood or bone marrow transplant from an HLAidentical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. N Engl J Med 2000; 342:1846-1854. Schwartz S., Vergoulidou M., Schreier E., et al.: Norovirus gastroenteritis causes severe and lethal complications after chemotherapy and hematopoietic stem cell transplantation. Blood 2011; 117:5850-5856. Small T.N., Papadopoulos E.B., Boulad F., et al.: Comparison of immune reconstitution after unrelated and related T-cell-depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions. Blood 1999; 93:467-480. Ullmann A.J., Lipton J.H., Vesole D.H., et al.: Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007; 356:335-347.

Chapter 80  Infections in Hematopoietic Stem Cell Transplant Recipients 745.e1

REFERENCES 1. Champlin R., Khouri I., Kornblau S., et al.: Allogeneic hematopoietic transplantation as adoptive immunotherapy. Induction of graft-versus-malignancy as primary therapy. Hematol Oncol Clin North Am 1999; 13:1041-1057, vii-viii. 2. Collins R.H. Jr, Shpilberg O., Drobyski W.R., et al.: Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997; 15:433-444. 3. Giralt S., Estey E., Albitar M., et al.: Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graftversus-leukemia without myeloablative therapy. Blood 1997; 89:4531-4536. 4. Junghanss C., Marr K.A.: Infectious risks and outcomes after stem cell transplantation: are nonmyeloablative transplants changing the picture? Curr Opin Infect Dis 2002; 15:347-353. 5. Junghanss C., Marr K.A., Carter R.A., 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; 8:512-520. 6. Khouri I.F., Saliba R.M., Giralt S.A., et al.: Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 2001; 98:35953599. 7. McSweeney P.A., Niederwieser D., Shizuru J.A., et al.: Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97:3390-3400. 8. Fauser A.A., Basara N., Blau I.W., et al.: A comparative study of peripheral blood stem cell vs bone marrow transplantation from unrelated donors (MUD): a single center study. Bone Marrow Transplant 2000; 25(Suppl. 2):S27-S31. 9. Blau I.W., Basara N., Lentini G., et al.: Feasibility and safety of peripheral blood stem cell transplantation from unrelated donors: results of a single-center study. Bone Marrow Transplant 2001; 27:27-33. 10. Remberger M., Ringden O., Blau I.W., et al.: No difference in graft-versus-host disease, relapse, and survival comparing peripheral stem cells to bone marrow using unrelated donors. Blood 2001; 98:1739-1745. 11. Powles R., Mehta J., Kulkarni S., et al.: Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: a randomised trial. Lancet 2000; 355:1231-1237. 12. Storek J., Dawson M.A., Storer B., et al.: Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood 2001; 97:3380-3389. 13. Benjamin D.K., Miller W.C., Bayliff S., et al.: Infections diagnosed in the first year after pediatric stem cell transplantation. Pediatr Infect Dis J 2002; 21:227-234. 14. Gluckman E., Rocha V., Boyer-Chammard A., et al.: Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med 1997; 337:373-381. 15. Gluckman E., Rocha V., Chevret S.: Results of unrelated umbilical cord blood hematopoietic stem cell transplant. Transfus Clin Biol 2001; 8:146-154. 16. Wagner J.E., Barker J.N., DeFor T.E., et al.: Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood 2002; 100:1611-1618. 17. Marr K.A., Carter R.A., Boeckh M., et al.: Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 2002; 100:4358-4366. 18. Sashihara J., Tanaka-Taya K., Tanaka S., et al.: High incidence of human herpesvirus 6 infection with a high viral load in cord blood stem cell transplant recipients. Blood 2002; 100:2005-2011. 19. Brunstein C.G., Weisdorf D.J., DeFor T., et al.: Marked increased risk of Epstein–Barr virus-related complica-

tions with the addition of antithymocyte globulin to a nonmyeloablative conditioning prior to unrelated umbilical cord blood transplantation. Blood 2006; 108:2874-2880. 20. Rocha V., Wagner J.E. Jr, Sobocinski K.A., et al.: Graftversus-host disease in children who have received a cord-blood or bone marrow transplant from an HLAidentical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. N Engl J Med 2000; 342:1846-1854. 21. Chakrabarti S., Collingham K.E., Marshall T., et al.: Respiratory virus infections in adult T cell-depleted transplant recipients: the role of cellular immunity. Transplantation 2001; 72:1460-1463. 22. Davison G.M., Novitzky N., Kline A., et al.: Immune reconstitution after allogeneic bone marrow transplantation depleted of T cells. Transplantation 2000; 69:1341-1347. 23. Eyrich M., Lang P., Lal S., 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; 114:422-432. 24. Small T.N., Papadopoulos E.B., Boulad F., et al.: Comparison of immune reconstitution after unrelated and related T-cell-depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions. Blood 1999; 93:467-480. 25. van Burik J.A., Carter S.L., Freifeld A.G., 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; 13:14871498. 26. Holmberg L.A., Boeckh M., Hooper H., et al.: Increased incidence of cytomegalovirus disease after autologous CD34-selected peripheral blood stem cell transplantation. Blood 1999; 94:4029-4035. 27. Crippa F., Holmberg L., Carter R.A., et al.: Infectious complications after autologous CD34-selected peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 2002; 8:281-289. 28. Aubert G., Hassan-Walker A.F., Madrigal J.A., et al.: Cytomegalovirus-specific cellular immune responses and viremia in recipients of allogeneic stem cell transplants. J Infect Dis 2001; 184:955-963. 29. Morecki S., Gelfand Y., Nagler A., et al.: Immune reconstitution following allogeneic stem cell transplantation in recipients conditioned by low intensity vs myeloablative regimen. Bone Marrow Transplant 2001; 28:243-249. 30. Maris M., Boeckh M., Storer B., et al.: Immunologic recovery after hematopoietic cell transplantation with nonmyeloablative conditioning. Exp Hematol 2003; 31:941-952. 31. Mossad S.B., Avery R.K., Longworth D.L., et al.: Infectious complications within the first year after nonmyeloablative allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant 2001; 28:491-495. 32. Junghanss C., Boeckh M., Carter R.A., et al.: Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study. Blood 2002; 99:1978-1985. 33. Grow W.B., Moreb J.S., Roque D., et al.: Late onset of invasive aspergillus infection in bone marrow transplant patients at a university hospital. Bone Marrow Transplant 2002; 29:15-19. 34. Wald A., Leisenring W., van Burik J.A., et al.: Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 1997; 175:1459-1466. 35. Jantunen E., Ruutu P., Niskanen L., et al.: Incidence and risk factors for invasive fungal infections in allogeneic BMT recipients. Bone Marrow Transplant 1997; 19:801-808. 36. Goodrich J.M., Reed E.C., Mori M., et al.: Clinical features and analysis of risk factors for invasive candidal

infection after marrow transplantation. J Infect Dis 1991; 164:731-740. 37. Marr K.A., Seidel K., White T.C., et al.: Candidemia in allogeneic blood and marrow transplant recipients: evolution of risk factors after the adoption of prophylactic fluconazole. J Infect Dis 2000; 181:309-316. 38. Carrigan D.R.: Adenovirus infections in immunocompromised patients. Am J Med 1997; 102:71-74. 39. Howard D.S., Phillips I.G., Reece D.E., et al.: Adenovirus infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 1999; 29:1494-1501. 40. Mezger M., Steffens M., Beyer M., et al.: Polymorphisms in the chemokine (C-X-C motif) ligand 10 are associated with invasive aspergillosis after allogeneic stem-cell transplantation and influence CXCL10 expression in monocyte-derived dendritic cells. Blood 2008; 111:534-536. 41. Mezger M., Steffens M., Semmler C., et al.: Investigation of promoter variations in dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN) (CD209) and their relevance for human cytomegalovirus reactivation and disease after allogeneic stem-cell transplantation. Clin Microbiol Infect 2008; 14:228-234. 42. Molle I., Ostergaard M., Melsvik D., et al.: Infectious complications after chemotherapy and stem cell transplantation in multiple myeloma: implications of Fc gamma receptor and myeloperoxidase promoter polymorphisms. Leuk Lymphoma 2008; 49:1116-1122. 43. Bochud P.Y., Chien J.W., Marr K.A., et al.: Toll-like receptor 4 polymorphisms and aspergillosis in stemcell transplantation. N Engl J Med 2008; 359:17661777. 44. Cunha C., Aversa F., Lacerda J.F., et al.: Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. N Engl J Med 2014; 370:421-432. 45. Majhail N.S., Lazarus H.M., Burns L.J.: Iron overload in hematopoietic cell transplantation. Bone Marrow Transplant 2008; 41:997-1003. 46. Einsele H., Hebart H., Kauffmann-Schneider C., et al.: Risk factors for treatment failures in patients receiving PCR-based preemptive therapy for CMV infection. Bone Marrow Transplant 2000; 25:757-763. 47. Nichols W.G., Corey L., Gooley T., et al.: Rising pp65 antigenemia during preemptive anticytomegalovirus therapy after allogeneic hematopoietic stem cell transplantation: risk factors, correlation with DNA load, and outcomes. Blood 2001; 97:867-874. 48. Ribaud P., Chastang C., Latge J.P., et al.: Survival and prognostic factors of invasive aspergillosis after allogeneic bone marrow transplantation. Clin Infect Dis 1999; 28:322-330. 49. Morrison V.A., Haake R.J., Weisdorf D.J.: NonCandida fungal infections after bone marrow transplantation: risk factors and outcome. Am J Med 1994; 96:497-503. 50. Nichols W.G., Corey L., Gooley T., et al.: High risk of death due to bacterial and fungal infection among cytomegalovirus (CMV)-seronegative recipients of stem cell transplants from seropositive donors: evidence for indirect effects of primary CMV infection. J Infect Dis 2002; 185:273-282. 51. Meijer E., Dekker A.W., Rozenberg-Arska M., et al.: Influence of cytomegalovirus seropositivity on outcome after T cell-depleted bone marrow transplantation: contrasting results between recipients of grafts from related and unrelated donors. Clin Infect Dis 2002; 35:703-712. 52. Gooley T.A., Chien J.W., Pergam S.A., et al.: Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010; 363:2091-2101. 53. Zinner S.H.: Changing epidemiology of infections in patients with neutropenia and cancer: emphasis on gram-positive and resistant bacteria. Clin Infect Dis 1999; 29:490-494. 54. Buchheidt D., Hiddemann W., Schiel X., et al.: European surveillance of infections and risk factors in cancer patients. Eur J Clin Microbiol Infect Dis 1999; 18:161-163. 55. Viscoli C., Castagnola E.: Treatment of febrile neutropenia: what is new? Curr Opin Infect Dis 2002; 15:377382. 56. Oliveira A.L., de Souza M., Carvalho-Dias V.M., et al.: Epidemiology of bacteremia and factors associated

745.e2 SECTION 4 

Infections in the Immunocompromised Host

with multi-drug-resistant gram-negative bacteremia in hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2007; 39:775-781. 57. Hakki M., Limaye A.P., Kim H.W., et al.: Invasive Pseudomonas aeruginosa infections: high rate of recurrence and mortality after hematopoietic cell transplantation. Bone Marrow Transplant 2007; 39:687-693. 58. Bilgrami S., Feingold J.M., Dorsky D., et al.: Incidence and outcome of Clostridium difficile infection following autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 1999; 23:1039-1042. 59. Arango J.I., Restrepo A., Schneider D.L., et al.: Incidence of Clostridium difficile-associated diarrhea before and after autologous peripheral blood stem cell transplantation for lymphoma and multiple myeloma. Bone Marrow Transplant 2006; 37:517-521. 60. Dubberke E.R., Sadhu J., Gatti R., et al.: Severity of Clostridium difficile-associated disease (CDAD) in allogeneic stem cell transplant recipients: evaluation of a CDAD severity grading system. Infect Control Hosp Epidemiol 2007; 28:208-211. 61. Chakrabarti S., Lees A., Jones S.G., et al.: Clostridium difficile infection in allogeneic stem cell transplant recipients is associated with severe graft-versus-host disease and non-relapse mortality. Bone Marrow Transplant 2000; 26:871-876. 62. van Kraaij M.G., Dekker A.W., Verdonck L.F., et al.: Infectious gastro-enteritis: an uncommon cause of diarrhoea in adult allogeneic and autologous stem cell transplant recipients. Bone Marrow Transplant 2000; 26:299-303. 63. Alonso C.D., Dufresne S.F., Hanna D.B., et al.: Clostridium difficile infection after adult autologous stem cell transplantation: a multicenter study of epidemiology and risk factors. Biol Blood Marrow Transplant 2013; 19:1502-1508. 64. Alonso C.D., Treadway S.B., Hanna D.B., et al.: Epidemiology and outcomes of Clostridium difficile infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2012; 54:1053-1063. 65. Willems L., Porcher R., Lafaurie M., et al.: Clostridium difficile infection after allogeneic hematopoietic stem cell transplantation: incidence, risk factors, and outcome. Biol Blood Marrow Transplant 2012; 18:12951301. 66. Kamboj M., Mihu C.N., Sepkowitz K., et al.: Work-up for infectious diarrhea after allogeneic hematopoietic stem cell transplantation: single specimen testing results in cost savings without compromising diagnostic yield. Transpl Infect Dis 2007; 9:265-269. 67. Schwartz S., Vergoulidou M., Schreier E., et al.: Norovirus gastroenteritis causes severe and lethal complications after chemotherapy and hematopoietic stem cell transplantation. Blood 2011; 117:5850-5856. 68. Xhaard A., Robin M., Scieux C., et al.: Increased incidence of cytomegalovirus retinitis after allogeneic hematopoietic stem cell transplantation. Transplantation 2007; 83:80-83. 69. Springer K.L., Chou S., Li S., et al.: How evolution of mutations conferring drug resistance affects viral dynamics and clinical outcomes of cytomegalovirusinfected hematopoietic cell transplant recipients. J Clin Microbiol 2005; 43:208-213. 70. Boeckh M., Kim H.W., Flowers M.E., et al.: Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantation – a randomized double-blind placebo-controlled study. Blood 2006; 107:1800-1805. 71. Erard V., Wald A., Corey L., et al.: 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; 196:266-270. 72. Erard V., Guthrie K.A., Varley C., et al.: One-year acyclovir prophylaxis for preventing varicella-zoster virus disease after hematopoietic cell transplantation: no evidence of rebound varicella-zoster virus disease after drug discontinuation. Blood 2007; 110:3071-3077. 73. Hata A., Asanuma H., Rinki M., et al.: Use of an inactivated varicella vaccine in recipients of hematopoieticcell transplants. N Engl J Med 2002; 347:26-34. 74. Seeley W.W., Marty F.M., Holmes T.M., et al.: Posttransplant acute limbic encephalitis: clinical features and relationship to HHV6. Neurology 2007; 69: 156-165.

75. Kamble R.T., Clark D.A., Leong H.N., et al.: Transmission of integrated human herpesvirus-6 in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2007; 40:563-566. 76. Chemaly R.F., Ghosh S., Bodey G.P., et al.: Respiratory viral infections in adults with hematologic malignancies and human stem cell transplantation recipients: a retrospective study at a major cancer center. Medicine (Baltimore) 2006; 85:278-287. 77. Kim Y.J., Guthrie K.A., Waghmare A., et al.: Respiratory syncytial virus in hematopoietic cell transplant recipients: factors determining progression to lower respiratory tract disease. J Infect Dis 2014; 209:11951204. 78. Khanna N., Widmer A.F., Decker M., et al.: Respiratory syncytial virus infection in patients with hematological diseases: single-center study and review of the literature. Clin Infect Dis 2008; 46:402-412. 79. Martino R., Porras R.P., Rabella N., et al.: Prospective study of the incidence, clinical features, and outcome of symptomatic upper and lower respiratory tract infections by respiratory viruses in adult recipients of hematopoietic stem cell transplants for hematologic malignancies. Biol Blood Marrow Transplant 2005; 11:781-796. 80. Waghmare A., Campbell A.P., Xie H., 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; 57:1731-1741. 81. Boeckh M., Englund J., Li Y., et al.: Randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hematopoietic cell transplant recipients. Clin Infect Dis 2007; 44:245-249. 82. Vu D., Peck A.J., Nichols W.G., et al.: Safety and tolerability of oseltamivir prophylaxis in hematopoietic stem cell transplant recipients: a retrospective case–control study. Clin Infect Dis 2007; 45:187193. 83. Renaud C., Boudreault A.A., Kuypers J., et al.: H275Y mutant pandemic (H1N1) 2009 virus in immunocompromised patients. Emerg Infect Dis 2011; 17:653660, quiz 765. 84. Ljungman P., de la Camara R., Perez-Bercoff L., et al.: Outcome of pandemic H1N1 infections in hematopoietic stem cell transplant recipients. Haematologica 2011; 96:1231-1235. 85. Englund J.A., Boeckh M., Kuypers J., et al.: Brief communication: fatal human metapneumovirus infection in stem-cell transplant recipients. Ann Intern Med 2006; 144:344-349. 86. Peck A.J., Englund J.A., Kuypers J., et al.: Respiratory virus infection among hematopoietic cell transplant recipients: evidence for asymptomatic parainfluenza virus infection. Blood 2007; 110:1681-1688. 87. Debiaggi M., Canducci F., Sampaolo M., et al.: Persistent symptomless human metapneumovirus infection in hematopoietic stem cell transplant recipients. J Infect Dis 2006; 194:474-478. 88. Nichols W.G., Corey L., Gooley T., et al.: Parainfluenza virus infections after hematopoietic stem cell transplantation: risk factors, response to antiviral therapy, and effect on transplant outcome. Blood 2001; 98:573578. 89. Martino R., Pinana J.L., Parody R., et al.: Lower respiratory tract respiratory virus infections increase the risk of invasive aspergillosis after a reduced-intensity allogeneic hematopoietic SCT. Bone Marrow Transplant 2009; 44:749-756. 90. Chakrabarti S., Mautner V., Osman H., et al.: Adenovirus infections following allogeneic stem cell transplantation: incidence and outcome in relation to graft manipulation, immunosuppression, and immune recovery. Blood 2002; 100:1619-1627. 91. Leung A.Y., Yuen K.Y., Kwong Y.L.: Polyoma BK virus and haemorrhagic cystitis in haematopoietic stem cell transplantation: a changing paradigm. Bone Marrow Transplant 2005; 36:929-937. 92. Giraud G., Priftakis P., Bogdanovic G., et al.: BK-viruria and haemorrhagic cystitis are more frequent in allogeneic haematopoietic stem cell transplant patients receiving full conditioning and unrelated-HLA-mismatched grafts. Bone Marrow Transplant 2008; 41:737-742.

93. Wong A.S., Chan K.H., Cheng V.C., et al.: Relationship of pretransplantation polyoma BK virus serologic findings and BK viral reactivation after hematopoietic stem cell transplantation. Clin Infect Dis 2007; 44:830837. 94. Erard V., Storer B., Corey L., et al.: BK virus infection in hematopoietic stem cell transplant recipients: frequency, risk factors, and association with postengraftment hemorrhagic cystitis. Clin Infect Dis 2004; 39:1861-1865. 95. Erard V., Kim H.W., Corey L., et al.: BK DNA viral load in plasma: evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients. Blood 2005; 106:1130-1132. 96. Cesaro S., Facchin C., Tridello G., et al.: A prospective study of BK-virus-associated haemorrhagic cystitis in paediatric patients undergoing allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant 2008; 41:363-370. 97. Piekarska A., Zaucha J.M., Hellmann A., et al.: Prevention of hepatitis B virus transmission from an infected stem cell donor. Bone Marrow Transplant 2007; 40:399-400. 98. Robin M., Porcher R., De Castro Araujo R., et al.: Risk factors for late infections after allogeneic hematopoietic stem cell transplantation from a matched related donor. Biol Blood Marrow Transplant 2007; 13:13041312. 99. Rex J.H., Walsh T.J., Sobel J.D., et al.: Practice guidelines for the treatment of candidiasis. Infectious Diseases Society of America. Clin Infect Dis 2000; 30:662-678. 100. Goodman J.L., Winston D.J., Greenfield R.A., et al.: A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992; 326:845-851. 101. Slavin M.A., Osborne B., Adams R., et al.: Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation – a prospective, randomized, double-blind study. J Infect Dis 1995; 171:15451552. 102. Marr K.A., Seidel K., Slavin M.A., 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; 96:2055-2061. 103. van Burik J.H., Leisenring W., Myerson D., et al.: The effect of prophylactic fluconazole on the clinical spectrum of fungal diseases in bone marrow transplant recipients with special attention to hepatic candidiasis: an autopsy study of 355 patients. Medicine (Baltimore) 1998; 77:246-254. 104. Wingard J.R.: Importance of Candida species other than C. albicans as pathogens in oncology patients. Clin Infect Dis 1995; 20:115-125. 105. Wingard J.R., Merz W.G., Rinaldi M.G., et al.: Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. N Engl J Med 1991; 325:1274-1277. 106. Wingard J.R., Merz W.G., Rinaldi M.G., et al.: Association of Torulopsis glabrata infections with fluconazole prophylaxis in neutropenic bone marrow transplant patients. Antimicrob Agents Chemother 1993; 37:1847-1849. 107. Catalano L., Picardi M., Anzivino D., et al.: Small bowel infarction by Aspergillus. Haematologica 1997; 82:182-183. 108. Oliver M.R., Van Voorhis W.C., Boeckh M., et al.: Hepatic mucormycosis in a bone marrow transplant recipient who ingested naturopathic medicine. Clin Infect Dis 1996; 22:521-524. 109. Kazan E., Maertens J., Herbrecht R., et al.: A retrospective series of gut aspergillosis in haematology patients. Clin Microbiol Infect 2011; 17:588-594. 110. Marr K.A., Carter R.A., Crippa F., et al.: Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002; 34:909-917. 111. Ullmann A.J., Lipton J.H., Vesole D.H., et al.: Posaconazole or fluconazole for prophylaxis in severe graftversus-host disease. N Engl J Med 2007; 356:335-347. 112. Marty F.M., Cosimi L.A., Baden L.R.: Breakthrough zygomycosis after voriconazole treatment in recipients

of hematopoietic stem-cell transplants. N Engl J Med 2004; 350:950-952. 113. Wingard J.R., Carter S.L., Walsh T.J., et al.: Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood 2010; 116:5111-5118. 114. Miceli M.H., Maertens J., Buve K., et al.: Immune reconstitution inflammatory syndrome in cancer patients with pulmonary aspergillosis recovering from neutropenia: proof of principle, description, and clinical and research implications. Cancer 2007; 110:112120. 115. Torres H.A., Chemaly R.F., Storey R., 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; 25:382-388. 116. Souza J.P., Boeckh M., Gooley T.A., et al.: High rates of Pneumocystis carinii pneumonia in allogeneic blood and marrow transplant recipients receiving dapsone prophylaxis. Clin Infect Dis 1999; 29:1467-1471.

Chapter 80  Infections in Hematopoietic Stem Cell Transplant Recipients 745.e3 117. Puig N., de la Rubia J., Jarque I., et al.: A study of incidence and characteristics of infections in 476 patients from a single center undergoing autologous blood stem cell transplantation. Int J Hematol 2007; 86:186-192. 118. Poutsiaka D.D., Price L.L., Ucuzian A., et al.: Blood stream infection after hematopoietic stem cell transplantation is associated with increased mortality. Bone Marrow Transplant 2007; 40:63-70. 119. Busca A., Locatelli F., Barbui A., et al.: Infectious complications following nonmyeloablative allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2003; 5:132-139. 120. Pagano L., Caira M., Nosari A., et al.: Fungal infections in recipients of hematopoietic stem cell transplants: results of the SEIFEM B-2004 study – Sorveglianza Epidemiologica Infezioni Fungine Nelle Emopatie Maligne. Clin Infect Dis 2007; 45:1161-1170. 121. De Castro N., Neuville S., Sarfati C., et al.: Occurrence of Pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study. Bone Marrow Transplant 2005; 36:879-883.

122. Chen C.S., Boeckh M., Seidel K., et al.: Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation. Bone Marrow Transplant 2003; 32:515-522. 123. Boeckh M., Nichols W.G.: The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood 2004; 103:2003-2008. 124. Ljungman P.: Respiratory virus infections in bone marrow transplant recipients: the European perspective. Am J Med 1997; 102:44-47. 125. Vu T., Carrum G., Hutton G., et al.: Human herpesvirus-6 encephalitis following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2007; 39:705-709. 126. Imbert-Marcille B.M., Tang X.W., Lepelletier D., et al.: Human herpesvirus 6 infection after autologous or allogeneic stem cell transplantation: a single-center prospective longitudinal study of 92 patients. Clin Infect Dis 2000; 31:881-886.