key: cord-0042640-dnxdamsu
authors: Pergam, Steven A.; Mattson, Debra K.; Boeckh, Michael
title: Infections in Leukemia and Hematopoietic Stem Cell Transplantation
date: 2011-11-26
journal: Leukemia and Related Disorders
DOI: 10.1007/978-1-60761-565-1_12
sha: 0103baf3e4e8e7465d9630386da01100ba071cd8
doc_id: 42640
cord_uid: dnxdamsu

Infections are one of the most common complications in patients diagnosed with leukemia and serve as a major obstacle to treatment. Through the early 1970s, infections were the most common cause of death in patients diagnosed with acute leukemia, but improvement in treatment and supportive care over the past few decades, coupled with expanded prophylaxis and prevention regimens, have led to reduction in both the frequency and severity of infections. Regardless, due in part to an aging cancer population and the diversity of cancer treatments and procedures, infectious diseases remain a major cause of morbidity and mortality in patients with leukemia.

Infections are one of the most common complications in patients diagnosed with leukemia and serve as a major obstacle to treatment [ 1 ] . Through the early 1970s, infections were the most common cause of death in patients diagnosed with acute leukemia [ 2, 3 ] , but improvement in treatment and supportive care over the past few decades, coupled with expanded prophylaxis and prevention regimens, have led to reduction in both the frequency and severity of infections [4] [5] [6] . Regardless, due in part to an aging cancer population and the diversity of cancer treatments and procedures, infectious diseases remain a major cause of morbidity and mortality in patients with leukemia.

Leukemia is associated with marked alterations in humoral and cellular immunity which enhance the ability of microorganisms to evade detection and destruction. As the bone marrow is replaced with malignant cells, myeloid and lymphoid cell production fall, and those available have weakened responses to pathogens. Peripheral leukocytes in patients with acute leukemia have impaired phagocytosis [ 7, 8 ] which can lead to increased risk of bacterial and fungal infections, while chronic leukemias demonstrate reduced immunoglobulin production [ 9, 10 ] . Due to these immune defi cits, it is not uncommon for infections to be a primary reason for patients to seek care, and uncontrolled or uncommon infections are known to portend an undiagnosed hematologic malignancy [ 11 ] .

In addition to direct effects, treatment leads to further decrements in the ability of patients to fi ght infection. Chemotherapy-associated marrow toxicity is unavoidable, and neutropenia and/or lymphopenia is nearly universal during therapy for acute leukemia. Protracted periods of agranulocytosis and delayed recovery of adaptive immunity are more common following aggressive therapy for relapsed disease and/or conditioning prior to hematopoietic cell transplantation (HCT) [12] [13] [14] . Furthermore, alterations in normal gut fl ora [ 15 ] , destruction of mucosal barriers [ 16, 17 ] , transfusion-associated iron overload [ 18 ] , and loss of skin integrity further increase the risk of infection. All told, the multiple negative effects of therapy further compromise the immune response, placing these patients at added risk for severe and life-threatening infections.

The development of prophylactic strategies for viral [ 6, 19, 20 ] and bacterial infections [ 4 ] , as well as broad-spectrum antifungals [ 21, 22 ] , has improved prevention and treatment options for these high-risk patients. Novel laboratory techniques, such as molecular diagnostics for viral infections [ 23 ] , have also allowed for earlier detection of major infections [ 24 ] . Hematologic support through the use of colonystimulating factors has helped to shorten neutropenia and further limit infectious complications [ 25 ] . However, even as diagnostic and therapeutic options have evolved, novel treatment options for leukemia, biologic immune-modulating therapies, expanded transplant protocols for high-risk patients, and alternate stem cell donor sources have led to additional immune dysfunction and infectious risk. Not surprisingly, prevention regimens have also led to the emergence of drugresistant pathogens [26] [27] [28] [29] [30] , many of which are associated with increased infection-related mortality.

In this chapter, we review the most prevalent infections seen in leukemia, but we will focus primarily on transplant-associated infections. We review timing of infections and then common infections by organ systems. We also discuss the management of neutropenic fever and assess important prevention strategies. This chapter should serve as a reference for clinicians on common infectious complications; however, the sheer number of potential infections is too large to allow for a comprehensive review. In addition, when addressing this topic, there is a large variation on the strength of clinical evidence in the literature. Randomized clinical trials evaluating treatment and prevention of infections, for example, are the strongest for cytomegalovirus (CMV) and fungal infections, but the majority of data are based either on retrospective clinical studies or on expert opinion. In this overview, we do not address the strength of evidence and instead refer you to more comprehensive guidelines and reviews whenever possible throughout the chapter [ 31, 32 ] . Finally, when providing care for these complex patients, we recommend close collaboration with colleagues in Infectious Diseases, Pulmonary/Critical Care, Surgery, and with local Clinical Microbiology and Virology laboratories.

Patients with underlying leukemia are at high risk for infections, and many present to primary care providers with infections as the fi rst sign of their underlying hematologic malignancy. Prolonged neutropenia prior to transplant has also been shown to be a predictor of posttransplant infectious risk and mortality [ 33 ] . Providers must assess patients at presentation for infection symptoms such as recurrent fevers, chronic cough, skin nodules, or upper respiratory symptoms prior to starting treatment, and all patients with infectious symptoms should undergo pretransplant evaluation. Some infections may even require delay in transplant conditioning (e.g., respiratory syncytial virus [RSV] ) [34] [35] [36] . All patients should also have standard pretransplant serologic testing as recommended in updated guidelines [ 31 ] .

During the early period postchemotherapy and conditioning, patients have abnormalities in barrier and innate responses which dramatically increase the risk of infection. Signifi cant mucositis, long-term catheters, and prolonged periods of hospitalization all increase risk. Early bacterial infections are typically associated with mucositis, such as Streptococcus species and enteric gram-negative rods (GNRs), or related to central catheters. Viral infections are infrequent in the early preengraftment phase, except for HSV and HHV-6, which commonly occur in this time frame. Respiratory pathogens are less frequent during this period due to the more limited outpatient exposure. Patients are at high risk for Candida and invasive moulds during this period [ 31 ] .

In this period after neutrophil recovery, adaptive and humoral immune responses remain impaired [ 31 ] . Patients continue to be at risk for bacteremia with grampositive and GNR organisms, but viral and fungal infections become more prominent. Cytomegalovirus (CMV) usually occurs in weeks 3-4, and EBV in the second and third months posttransplant [ 37 ] . Respiratory viral infections increase in frequency with the move to more outpatient therapy. Aspergillus, Candida, and other fungal infections continue through the postengraftment phase due to the development of graft-versus-host disease (GVHD) and associated treatments.

After day 100, patients more commonly develop infections with encapsulated (e.g., Streptococcus pneumoniae ) and community-acquired bacterial infections. Respiratory viruses remain major pathogens. Late T-cell recovery and lymphopenia also allow for continued development of CMV and other viral-related complications. Varicella-zoster virus (VZV) reactivation primarily occurs as a late complication [ 37 ] . Late fungal infections occur in patients with ongoing GVHD issues. Pneumocystis jiroveci (PCP) occurs in posttransplant patients not receiving appropriate PCP prophylaxis.

Empiric therapy for neutropenic fever during leukemia treatment and transplantation is reviewed in detail in other sources [ 31, 32, 39 ] . In order to address the multiple possible infections that can occur during treatment for leukemia, we have divided infections into specifi c organ systems ( Fig. 12.1 ). In this section, we focus on clinical signs/symptoms, differential diagnosis, and diagnostic strategies, followed by a brief review of treatment options.

Patients who develop bloodstream infections present with a wide spectrum of symptoms which vary from asymptomatic (usually detected by surveillance cultures) [ 40 ] to fulminant septic shock. Patients with bloodstream infections are usually febrile, but fever may be masked in some patients on immunosuppression, particularly those on high-dose steroids. Hypothermia is an infrequent presentation. Careful examination of the central venous catheter (CVC) may provide visual clues that suggest infection, such as erythema or purulence around the line or exit site; some patients may complain of chest wall pain or numbness at sites of catheter placement. A thorough skin exam is also important, as some patients develop skin nodules, ecthyma gangrenosum, or other lesions during episodes of bacteremia [ 41, 42 ] or fungemia [ 43, 44 ] . The development of hypoxia, renal insuffi ciency, and liver function abnormalities are ominous signs of developing septic shock and multiorgan failure.

Less frequent gram-positive species such as Corynebacterium jeikeium can also cause disease in this population [ 70 ] .

A variety of GNR organisms cause bloodstream infections, but Pseudomonas aeruginosa remains one of the most important GNRs. P. aeruginosa 's intrinsic virulence leads to additional mortality, and it is often associated with high-level resistance [ 71, 72 ] . Stenotrophomonas maltophilia is resistant to carbepenems and other standard neutropenic treatment options and is often preferentially selected in this population [73] [74] [75] . With the continued emergence of multidrug-resistant GNR pathogens, providers need to be cautious in choosing empiric regimens [ 52, 72 ] as these organisms are associated with prolonged bacteremia and increased morbidity and mortality [ 76 ] . Due to bacterial translocation during episodes of severe mucositis and gut GVHD, enteric GNRs and gram-positive clostridial species are more frequent. In particular, C. perfringens bacteremia can lead to severe life-threatening intravascular hemolysis [ 77 ] , and C. septicum bacteremia is associated with gastrointestinal complications [ 78 ] .

Candida species can also lead to bloodstream infections, particularly in patients who either are receiving broad-spectrum antibiotics or have clinically signifi cant mucositis [ 79 ] . Candida species that are detected in patients receiving antifungal prophylaxis are more likely to be resistant species, particularly C. krusei and C. glabrata [ 79, 80 ] . Data suggest that rates of candidemia may be decreasing [ 81 ] . Other yeasts, such as Rhodotorula [ 78 ] , are a less frequent cause of bloodstream infections.

Although moulds can spread hematogenously, they are rare causes of bloodstream infections [ 82, 83 ] . Fusarium , however, are the one mould species that routinely can present with fungemia [ 84 ] . Typical "banana-shaped" conidia seen on gram stain from blood cultures are pathognomonic for fusariosis. At sites of skin breakdown, fungal infections can invade damaged tissue, so exit infections can sometimes be caused by fungal pathogens [ 85, 86 ] .

Blood cultures are the mainstay of any work-up for patients suspected of having an infection. It is recommended that patients with central catheters have cultures drawn from their lines; peripheral cultures should also be drawn if possible [ 51 ] . A metaanalysis found that line cultures were a better diagnostic test for bacteremia with better sensitivity and negative predictive value when compared to a peripheral culture [ 87 ] . Current guidelines suggest that if a peripheral culture is not possible, it is recommended that ³ 2 blood samples should be drawn from each catheter lumen [ 51, 88 ] . Differential time to positivity and quantitative blood cultures are other techniques to help identify catheter-associated infections that are beyond the scope of this chapter but are reviewed elsewhere [89] [90] [91] .

Line tips should be sent for culture at the time of removal if at all possible [ 51 ] . Skin biopsies can also be helpful in patients with suspicious skin lesions in some infections [ 70 ] .

Treatment options vary by pathogen and site (see Table 12 .1 ). Tunnel infections require line removal [ 51 ] , but exit-site infections can sometimes be managed with antibiotic therapy, particularly if they are not associated with bacteremia. Exit-site infections that do not improve with systemic antibiotic therapy should lead to line removal [ 51 ] . Antibiotic therapy for any bloodstream infections should be based on culture and sensitivity testing, and patients should have repeat cultures to assure that the organism has cleared. Most bacterial infections require at least 2 weeks of IV therapy, but some pathogens (e.g., Listeria monocytogenes ) may need more prolonged courses. Patients with NTM should be treated for at least 3 months with a combination of at least 2-3 agents [ 55 ] . Patients with candidemia should be treated with fl uconazole, lipid amphotericin B formulations, or an echinocandin, and any central catheter should be removed [ 92 ] . All patients with candidemia should undergo an ophthalmologic evaluation. Recommendations regarding the management of Candida infections are reviewed in reference by Pappas et al. [ 92 ] . Decisions regarding tunneled line or port removal should be done in collaboration with Infectious Diseases, Interventional Radiology, or Surgery and are reviewed by Mermel [ 51 ] .

Patients undergoing HCT and those who are receiving leukemia therapy are more likely to have neurologic complications [ 93 ] . Up to 30% of patients undergoing HCT can develop delirium during follow-up, with the nearly half occurring in the fi rst 4 weeks posttransplant [ 94 ] . Infections may present with symptoms that are subtle (e.g., mild confusion) and rarely may be asymptomatic [ 95 ] . More common manifestations are headache, memory loss, focal weakness, or imbalance. Patients with eye infections can present with visual loss, eye pain, proptosis, changes in ocular movements (e.g., cranial nerve dysfunction), pupillary changes, or periorbital edema, all of which should lead to urgent ophthalmologic evaluation.

While certain symptoms such as anterograde amnesia [ 96 ] and personality changes [ 97 ] are classically associated with specifi c infections (HHV-6 and HSV, respectively), symptoms are not diagnostic of the underlying disorder. Patients with more severe infections can present with more ominous symptoms such as seizures, encephalitis, or focal weakness. Perhaps most importantly, fever may not always be present to suggest an infectious etiology [ 98, 99 ] . Since these patients have numerous noninfectious etiologies that can lead to CNS dysfunction, it is even more important to aggressively pursue a diagnosis.

Bacterial infections are a relatively uncommon cause of CNS infections in an age where prophylactic antibiotics are standard practice. Gram-negative and gram-positive organisms can get into the CNS and lead to meningitis during treatment, and although rare, resistant bacteria may be more common due to prior antibiotic exposure. Communityacquired meningitis caused by bacteria such as S. pneumoniae is infrequent, but due to alterations in humoral immunity, emerging microbial resistance and a move to more outpatient care can occur late posttransplant and during periods of treatment for GHVD [ 100, 101 ] . Rothia mucilaginosa , a gram-positive organism that is a commensal organism in oral fl ora, is associated with a rare, but severe, meningitis that occurs almost exclusively during periods of severe mucositis [ 102 ] . Central line-associated bacteremia rarely leads to ophthalmic infection causing sight-threatening endophthalmitis or brain involvement [ 103, 104 ] , and even less frequently, bacteria can gain access through intracranial interventions such as Ommaya port placement [ 105 ] . Some bacteria have a known predilection for the CNS and may not be addressed by standard prophylaxis strategies. Listeria monocytogenes is a non-spore-forming gram-positive rod that is most commonly acquired as a food-borne illness with a particular penchant for involving the CNS [ 106 ] . Nearly 50% of immunocompromised patients who develop listeriosis develop CNS disease [ 107 ] , which can present as acute cerebritis or brain abscesses ( Fig. 12. 2 ). Nocardia species are fi lamentous bacteria that usually lead to pulmonary infections, of which over 30% develop CNS lesions; most commonly single or multiple abscesses. Many with CNS involvement are asymptomatic at the time of diagnosis, so routine brain imaging is recommended in all patients diagnosed with Nocardia [ 108 ] .

Cryptococcus neoformans is a cause of meningitis in immunocompromised hosts and leads to occasional infections in leukemic patients [ 109 ] . Fluconazole prophylaxis has limited this infection, but late disease can occur in transplant recipients. Similarly, Candida species ophthalmic infections (endophthalmitis or retinitis) can occur in leukemia patients undergoing chemotherapy or transplant, but CNS infections are almost universally associated with systemic fungemia. Resistant species, such as C. krusei and C. glabrata , should be considered in patients who develop CNS involvement while on prophylactic therapy [ 110 ] .

Mould infections, particularly Aspergillus species, can also lead to serious and lifethreatening CNS infections. Involvement of the CNS usually develops from a primary pulmonary source, through hematogenous spread or through direct invasion from involved sinuses. Mould infections primarily lead to space-occupying lesions, but can also present as cerebral infarctions or meningitis [ 111, 112 ] . Retrospective reviews of brain abscesses in transplant patients suggest that Aspergillus is the most common cause [ 99, 113, 114 ] and that fungal etiologies make up close to 90% of episodes [ 113, 114 ] . While Aspergillus may be the most common fungus, CNS infection can also be caused by other opportunistic moulds such as the Mucorales (zygomyces) species [ 115, 116 ] and Scedosporium [ 117 ] . Rhinocerebral involvement and cavernous sinus involvement are unique presentations nearly always associated with the Mucorales [ 118 ] . Endemic moulds, such as Histoplasma capsulatum [ 119 ] and Coccidiodomycosis immitis [ 120 ] , are infrequent and develop only in patients with travel or residence in areas of endemicity [121] [122] [123] .

Latent viruses can cause CNS-related disease, particularly in patients undergoing HCT [ 124 ] . During the early posttransplant period, HHV-6 is the most common viral cause of CNS infection [ 94, 124 ] . HHV-6 reactivation usually occurs between 2 and weakness. An MRI of the brain demonstrated an abscess ( yellow arrow ) with surrounding edema. Blood cultures were positive for gram-positive rods which were later indentifi ed to be Listeria monocytogenes. Symptoms improved after institution of ampicillin and gentamicin therapy. The patient improved after a prolonged course of antibiotics 4 weeks posttransplant, and symptoms can range from mild delirium and cognitive dysfunction to seizures and encephalitis [ 125 ] . Varicella-zoster virus (VZV) is another neurotropic virus primarily associated with encephalitis, though vasculopathy can also be associated with CNS involvement [ 126 ] . Interestingly, although VZV reactivation usually presents with prominent skin involvement (herpes zoster), patients with CNS disease may present without rash [ 127, 128 ] . Herpes simplex (HSV) encephalitis can also occur in leukemia and transplant recipients, though patients are more likely to present with personality changes and focal abnormalities [ 129 ] . Additionally, both HSV and VZV can present with involvement in the otic branch presenting with unilateral facial paralysis, ear pain, and vesicles in the auditory canal and auricle (Ramsay Hunt syndrome) [ 130, 131 ] . CNS involvement of both VZV and HSV usually occurs only after the discontinuation of prophylactic acyclovir; such prophylaxis has not been shown to prevent HHV-6. Other latent herpesvirus infections, such as Epstein-Barr virus (EBV) [ 132 ] and cytomegalovirus (CMV) [ 133, 134 ] , can also cause CNS disease and, in EBV's case, can be associated with both encephalitis and posttransplant lymphoproliferative disorder (PTLD) [ 37, 135 ] .

The polyomaviruses, particularly JC virus, are less frequent CNS pathogens in this population. JC virus is the causative agent of progressive multifocal leukoencephalopathy (PML), which occurs late in the posttransplant period and presents with focal neurologic fi ndings and altered mental status as a result of white matter demyelination [136] [137] [138] . Other viral pathogens such as West Nile virus [ 139, 140 ] and enteroviruses [ 141 ] cause sporadic cases of CNS disease.

Toxoplasmosis is most commonly found in patients who are seropositive prior to starting therapy [ 142 ] , but has been rarely reported in patients who were seronegative [ 143, 144 ] . When toxoplasmosis does develop in the posttransplant period, nearly all cases are associated with CNS involvement [ 144 ] . Symptoms are varied, diagnosis is diffi cult, and outcomes are very poor [ 144, 145 ] . Strongyloides stercoralis hyperinfection, which occurs from a reactivation of a clinically silent infection, can lead to a polymicrobial meningitis and direct parasite invasion into the CNS [ 146, 147 ] . Patients with prior exposure to areas of high endemicity of Strongyloides are at risk, but this is a rare complication.

The mainstay of any work-up for CNS-related symptoms is fi rst and foremost a thorough neurologic exam. Early fi ndings can be subtle and missed on cursory review, but a focal neurologic exam can identify subtle cranial nerve abnormalities, unsuspected confusion, and/or focal weakness. It is important to pay special attention to the oropharynx, sinuses, auditory canals, and nasal passageways, as lesions in these locations (e.g., a black eschar or vesicles) can suggest either a route of infection and/or a specifi c pathogen. Patients with nuchal rigidity, mental status changes, fever, and other classic signs for bacterial meningitis should be considered for urgent lumbar puncture and empiric antibiotics to avoid major delays in treatment.

Radiologic imaging is critical to assessing high-risk immunocompromised patients, as clinical symptoms vary in these patients. Both computed tomography (CT) and magnetic resonance imaging (MRI) provide important diagnostic data; an MRI provides better resolution, but CT scans are often more readily available. Radiologic imaging can evaluate for space-occupying lesions or evidence of increased intracranial pressure which would preclude cerebrospinal fl uid (CSF) analyses. Specifi c radiologic manifestations of certain infections, such as herpes simplex (temporal lobe involvement), HHV-6 (mesial temporal lobes, limbic encephalitis) [ 148 ] , and JC virus (single or multifocal white matter lesions without mass effect) [ 149 ] , can be suggestive of the underlying diagnosis. These patients may also present with atypical fi ndings on imaging. Toxoplasmosis for example, may not present with classic ring-enhancing lesions [ 150, 151 ] . Additionally, imaging can suggest other noninfectious etiologies which can lead to CNS symptoms. An excellent review of radiologic fi ndings associated with hematopoietic transplantation is reviewed by Nishiguchi [ 151 ] .

CSF analyses are critically important for a diagnosis. Standard cell counts, glucose, total protein as well as gram stain, cultures, polymerase chain reaction (PCR) testing, and molecular analyses can potentially lead to a diagnosis. Specifi c tests that can be considered during CSF analysis are listed in Table 12. 3 . Serologic tests can be benefi cial in patients who are considered to be at risk for endemic mycoses or parasitic disease, and blood cultures can provide additional data for potential bacterial and fungal processes. Patients with symptoms at other locations (e.g., cough) should undergo additional imaging to help complete a diagnostic work-up. Other data to rule out other noninfectious etiologies should also be considered, such as drug levels to assess for CNS drug toxicity and CSF cytologic review and fl ow cytometry to assess for CNS involvement of leukemia if appropriate. Toxoplasmosis PCR from serum should be assessed in patients who are known to be seropositive for toxoplasmosis [ 152 ] . Finally, brain biopsy may be necessary in some rare cases to make the diagnosis.

Due to the poor outcome of infections that occur in the CNS, it is important to consider early antimicrobial therapy while awaiting the results of diagnostic testing, as delay can lead to major morbidity with severe infections. Bacterial infections need aggressive IV therapy with duration dependent on the diagnosis (see Table 12 .1 ). Dual therapy for CNS Nocardia species infections should be considered initially (e.g., trimethoprim/ sulfamethoxazole and imipenem) and long-term therapy based on sensitivity testing once available. Length of therapy is dependent on CT resolution, but most feel that at least a year of therapy is needed [ 153 ] . Usual antimicrobial coverage for bacterial meningitis (vancomycin, cephalosporins, and aminoglycosides) will not treat Listeria monocytogenes . All immunosuppressed patients with presumed meningitis should have IV ampicillin added to the underlying empiric regimen. Patients with proven listeriosis require prolonged IV ampicillin therapy. Aspergillus CNS infections should be guided by sensitivity testing when possible, but usual treatment includes either voriconazole or lipid amphotericin B formulations; treatment guidelines are reviewed by Walsh et al. [ 154 ] . Voriconazole, in particular, is known to get excellent CNS penetra- This list is not completely inclusive, and decisions should be made based on clinical symptoms and history. Primary and secondary options may be different depending on presentation b Opening pressure should be determined at the time of lumbar puncture whenever possible c May not be necessary in patients taking prophylactic acyclovir d Drug levels will depend on patients' current medications e Brain biopsy may be necessary in some cases to make the diagnosis, but this should be reserved for patients with severe and life-threatening symptoms when possible tion [ 155, 156 ] . Patients with CNS infection with any of the Mucorales species should be treated with either lipid amphotericin B formulations or posaconazole, but overall outcomes are poor [ 116 ] . Endemic fungal CNS infections' treatment options are reviewed in references by Wheat et al. [ 119 ] , Galgiani et al. [ 120 ] , and Perfect et al. [ 109 ] . HSV and VZV CNS infections require high-dose IV acyclovir, and patients with HHV-6 encephalitis should receive either IV foscarnet or IV ganciclovir [ 157 ] . Patients with toxoplasmosis should receive intensive therapy with pyrimethamine, sulfadiazine, and folinic acid or high-dose trimethoprim/sulfamethoxazole [ 158 ] .

The sinopulmonary system is one of the most frequent sites of infection during leukemia therapy. Symptoms vary depending on the involved site, particularly since both upper and lower tract infections can occur. Classic symptom presentations, however, normally seen in immunocompetent patients are uncommon in this population. Upper tract infection symptoms often involve the sinuses and nasopharynx, including: rhinorrhea, sore throat, facial pain/pressure, headaches, cough, disturbances in taste and smell, among others. Classic symptoms that are consistent with the common cold or sinusitis are not infrequent in mild cases, but the development of bloody/ black nasal discharge, lesions on the palate, facial weakness, periorbital erythema, or proptosis are signs of severe invasive disease.

With lower tract parenchymal involvement, symptoms may include cough, sputum production, shortness of breath, and wheezing. Focal chest pain or hemoptysis are more ominous signs of an invasive fungal infection, and hypoxia can be a harbinger of the development of acute respiratory distress. Still, specifi c symptoms in transplant are not always pathognomonic for a specifi c infectious etiology, and patients receiving corticosteroids may have less prominent symptoms. Occasional patients may be asymptomatic with lesions found only on imaging. Noninfectious etiologies such as diffuse alveolar hemorrhage, idiopathic pneumonia syndrome, cryptogenic organizing pneumonia, and drug toxicity can cause symptoms and even radiographic changes that mimic infections, making a prompt diagnosis even more challenging [ 159, 160 ] .

Numerous bacterial pathogens can lead to sinusitis. In immunocompetent hosts, sinusitis is caused by predominantly respiratory pathogens such as S. pneumoniae , Haemophilus infl uenzae , and Moraxella catarrhalis , but in transplantation, other GNR, resistant organisms, and polymicrobial infections are more frequent etiologies [ 75, 161 ] . Patients with preexisting disease or those with a history of chronic sinus infections prior to transplant are likely at higher risk [ 162 ] . Specifi c pathogens cannot always be identifi ed, and most patients are treated empirically with broad-spectrum antibiotics.

Pneumonia can be caused by a variety of bacterial organisms in leukemic patients, although after transplant, bacterial pneumonias are less frequent [ 163 ] . Patients with prolonged neutropenia or undergoing salvage chemotherapy are not surprisingly at higher risk for developing this complication. There are a wide variety of gram-positive and GNR species that can lead to pneumonia in this immunocompromised population, but providers should be aware of specifi c bacterial pathogens that are more specifi c to these patients. The gram-positive fi lamentous bacteria Nocardia is an opportunistic infection that after inhalation can develop into pulmonary disease. Nocardia are usually resistant to standard antimicrobial prophylaxis regimens, are more frequent in patients not on trimethoprim/sulfamethoxazole prophylaxis [ 164 ] and those receiving steroids [ 165 ] . Nocardia species can have varied presentations in transplantation, but most frequently appear as nodular pulmonary disease; some patients may have asymptomatic nodules found only on imaging (Fig. 12. 3 ) [ 165 ] . Legionella species can also occur in posttransplant recipients, though nonpneumophila species, particularly L. micdadei , are more frequent [166] [167] [168] . Legionella species can present with lung nodules, mimicking fungal infections, or as pulmonary infi ltrates. Mycoplasma and other atypical organisms are rare [ 169, 170 ] . Mycobacterium avium-intracellulare (MAI) is the most frequently isolated mycobacteria from pulmonary specimens in HCT patients, but since many have colonization, not all warrant treatment [ 55 ] . 

Fungal infections are one of the most common and vexing problems in patients with leukemia and HCT, and most lead to sinopulmonary infections. Fungal sinusitis can particularly be troubling due to the proximity of the infection and risk for invasion into the CNS and can present initially with similar features to bacterial cases. A high index of suspicion is needed to prevent life-threatening complications particularly in patients who worsen after treatment for bacterial sinusitis or in patients on steroids. Aspergillus species are the most common cause of fungal sinusitis [ 171, 172 ] , but less frequent fungal organisms, such as Scopulariopsis [ 173 ] and Paecilomyces [ 174 ] , among others, can also lead to sinus disease. The Mucorales are notorious for leading to life-threatening sinus disease [ 115, 116, 118, 175 ] .

Pulmonary fungal infections are even more common in this patient population, where invasive Aspergillus remains the most common etiology [176] [177] [178] . Patients with known GVHD, high-dose steroids, iron overload, CMV infection, and prolonged neutropenia are at increased risk for fungal infections [179] [180] [181] [182] [183] [184] . Iron overload is particularly associated with the Mucorales, which may also be more prevalent in patients who are treated or undergo prophylaxis with voriconazole [ 185, 186 ] . Because of the severity of immunosuppression, multiple other fungal species manifest as pulmonary disease in hematopoietic transplant recipients [ 187, 188 ] . Yeast less commonly causes pulmonary disease, with the exception of Cryptococcus species, which can lead to pulmonary nodules [ 189 ] . Although resistant Candida species can be isolated from bronchoalveolar lavage (BAL) cultures, Candida pneumonia is a rare complication, even more so with the addition of standardized antifungal prophylaxis [ 190 ] .

The other unique pulmonary fungal pathogen in these patients is PCP. PCP is more common in patients on high-dose steroids and in those who do not receive or discontinue trimethoprim/sulfamethoxazole prophylaxis [ 191, 192 ] . Disease usually occurs as a late complication due to current prevention strategies [ 191 ] . Even with appropriate treatment and diagnostics, patients who develop PCP can develop major complications [ 193 ] .

Multiple viral pathogens lead to sinopulmonary complications during therapy for leukemia. These break down into two main categories: reactivation from latency and community acquisition. Latent herpesviruses, particularly CMV, can lead to invasive pulmonary disease in transplant recipients. Patients typically present with shortness of breath and hypoxia, and most have evidence of CMV reactivation from other sites. Risk factors for the development of CMV pneumonia include: lymphopenia, GVHD, and high-dose steroids, among others [ 194 ] . Patients who undergo umbilical cord blood transplant or T-cell depletion are at signifi cantly higher risk [ 195, 196 ] . Early CMV pneumonia/pneumonitis is seen within the fi rst 3 months posttransplantation during the period of greatest immunosuppression. Late CMV disease occurs more than 3 months after HSCT, and likely as a result of residual defi cits in cell-mediated immunity [ 194, 197, 198 ] . HSV, VZV, and other herpesviruses can also rarely lead to pulmonary complications in patients [ 199 ] . EBV-associated posttransplant related lymphoproliferative disease (PTLD) can manifest in the lungs as pulmonary nodules [ 200 ] . Adenovirus can be latent in the lung and reactivate during the posttransplant period [ 201 ] , leading to severe pulmonary complications and dissemination [ 202, 203 ] .

Respiratory viral pathogens are the most frequent sinopulmonary infection in these patients, with up to 30% of patients developing at least one infection (mostly upper respiratory events) during follow-up [ 204, 205 ] . These viruses can cause a spectrum of disease, including upper respiratory infection, pneumonia, and/or even late airfl ow obstruction [ 206 ] , and are a cause of signifi cant morbidity and mortality [ 205 ] . Infl uenza A and B, parainfl uenza virus, metapneumovirus, and RSV can all be associated with both upper and severe lower tract disease. Infl uenza viruses and RSV are seasonal, while parainfl uenza can occur year round. Community-acquired adenovirus can also be associated with high rates of mortality when associated with lower tract disease [ 207 ] . Rhinovirus and coronavirus are the most common respiratory viral infections, often limited to only upper respiratory disease [ 204 ] . They have been rarely associated with pulmonary complications in transplant recipients [ 208 ] . Other novel and emerging respiratory pathogens' (e.g., human bocavirus, WU and KI polyomaviruses) epidemiology in this population has not been well described to date [ 209 ] .

Radiologic imaging of the sinopulmonary system has become an important part of any diagnostic evaluation in this population. Bacterial, viral, and fungal infections can opacify sinus spaces on plain fi lm or CT, but more invasive fi ndings, such as bony erosion, suggest fungal sinusitis. Bacterial infections typically present as lobar consolidations or infi ltrates. Fungal infections typically present on CT as solitary or multiple pulmonary nodules, and a classic "halo sign" on CT is very suggestive of an underlying fungal nodule (Fig. 12.4 ) [ 210, 211 ] . Lobar consolidation and cavitary disease are less frequent CT presentations [ 210 ] . International criteria for the diagnosis of fungal infections, which include radiologic fi ndings, can help providers determine which patients should receive antifungal therapy [ 212 ] . Lower tract viral infections primarily present with diffuse interstitial disease or ground-glass infi ltrates; other infections such as PCP can have a similar appearance. Pulmonary consolidation [ 213 ] and nodular disease [ 214 ] have also been described for viral infections (e.g., CMV, HMPV). Since multiple pathogens can occur in a single patient, radiologic fi ndings are only suggestive and need confi rmatory testing.

Noninvasive modalities are available for viral and fungal infections. Serum galactomannan (GM) testing has improved diagnostics specifi cally for Aspergillus species and has become an important tool for screening [215] [216] [217] . The serum (1 → 3)-betad -glucan assay has also been used for detecting fungal infections in transplant patients [ 218 ] . Similar to GM, this assay does not identify Mucorales species but may be useful in diagnosing PCP [ 219 ] . Serum cryptococcal antigen testing can be useful in patients where Cryptococcus is a diagnostic possibility.

CMV and adenovirus pneumonia are typically associated with dissemination, so viremia is often found during and before pulmonary infection. Upper respiratory viral infections can be detected by a number of laboratory modalities, including culture, direct fl uorescent antigen (DFA) testing, and other rapid commercial antigen detection kits. Comprehensive or multiplex PCR panels are becoming increasingly utilized at many centers, including ours, since these techniques offer greater sensitivity than standard modalities and can detect coinfection [ 220, 221 ] . The fact that many of these patients develop prolonged shedding, particularly those on steroids [ 222 ] , also suggest that PCR-based methods may enhance infection control practices.

Invasive diagnostic modalities are also needed to diagnose patients, and BAL should be considered in all patients with pulmonary fi ndings [ 216 ] . Cultures, cytology, and antigen testing (e.g., GM from BAL) [ 215 ] can all provide additional microbiologic evidence to avoid the institution of empiric therapies (see Table 12 .2 ). Additionally, this modality may help to evaluate other nonfungal infections, separate specifi c pathogens from each other, detect coinfections, and provide samples for antimicrobial resistance testing. While PCR-based strategies for specifi c fungal pathogens are still under development, PCR-based respiratory testing for viral pathogens from BAL samples is becoming standard at many centers [ 209, 220 ] . PCP is classically diagnosed from induced sputum samples in other immunocompromised populations (e.g., HIV); however, bronchoscopy may enhance diagnosis in transplant recipients due to the low burden of disease [ 223, 224 ] . CMV shell vial assays and cultures from BAL are also necessary criteria for the diagnosis of CMV pneumonia [ 225 ] . A microbiologic diagnosis is important to allow targeted treatment and can help determine the duration of therapy. When a diagnosis of a pulmonary process is not made by BAL, video-assisted thoracoscopic biopsy (VATS) or CT-guided biopsy may be necessary to determine the cause of the pulmonary symptoms. For sinus infections, Otolaryngology evaluation should be obtained in all high-risk patients with sinus symptoms, as early nasal/sinus endoscopy with visual inspection, and biopsy can allow for more prompt diagnosis.

Bacterial pneumonias should be treated when possible as directed by cultures and sensitivities (Table 12 .1 ). Treatment guidelines for community-acquired pneumonia are reviewed by Mandell [ 226 ] , and recommendations for treatment of nosocomial or ventilator-associated pneumonia are reviewed by the American Thoracic Society and the Infectious Diseases Society of America [ 227 ] . In particular, Pseudomonas pneumonia may require prolonged treatment due to the high risk of fatal relapse [ 71 ] . Similar to CNS disease, Nocardia pulmonary disease should be treated with trimethoprim/sulfamethoxazole or based on microbiologic sensitivities for at least These are current strategies used at our center but may not be appropriate at all centers b The KOH preparation dissolves keratin and other cellular in the specimen; calcofl uor is a fl orescent dye that binds to polysaccharides in chitin of fungi c PCR for fungal pathogens are not standardized and not currently considered part of standard diagnostic testing for fungal diagnoses d Specifi c coronavirus species associated with clinical disease e Includes parainfl uenza (1,2,3, and 4) 6 months [ 108 ] . Patients with Legionella pneumonia should receive 3 weeks of a respiratory fl uoroquinolone or azithromycin.

Aspergillus pulmonary infections are most frequently treated with voriconazole or lipid amphotericin B formulations; treatment guidelines are reviewed by Walsh [ 154 ] . There is a lack of randomized clinical trials comparing different agents, and the role of combination therapy is controversial; results from a future trial addressing combination therapy are forthcoming. Patients should typically undergo therapy until pulmonary nodules have completely resolved or stabilized for 2-3 months of immunosuppressive therapy. Patients with Mucorales pulmonary infections should be treated with either lipid amphotericin B formulations or posaconazole; when possible, sensitivity testing can help tailor therapy. Cardiothoracic surgery consultation should be considered in patients failing therapy and can be considered as adjunctive treatment for patients with solitary fungal nodules. Treatment of less frequent fungal infections (e.g., Scedosporium species) should be based on sensitivity testing. Endemic fungal CNS infections' treatment options are reviewed in references by Wheat et al. [ 119 ] , Galgiani et al. [ 120 ] , and Perfect et al. [ 109 ] .

Patients who develop pulmonary CMV should receive IV ganciclovir or foscarnet, with the addition of intravenous immunoglobulin (IVIG) for at least 5 weeks; treatment options are reviewed by Boeckh [ 19 ] . Adenovirus pneumonia has no approved therapy, but many centers will attempt IV cidofovir and IVIG, although neither have been studied prospectively [ 228, 229 ] . Treatment options for patients with infl uenza are reviewed by Casper [ 230 ] but usually include oseltamivir or inhaled zanamivir as primary therapy. Alternate combination therapy can be considered in patients with life-threatening infections [ 230 ] , particularly since the development of resistance can occur during therapy [ 29 ] . RSV is responsive to aerosolized ribavirin, which has been shown to reduce mortality from lower tract disease [ 231 ] . Survival may be improved when aerosolized ribavirin is used in combination therapy with intravenous immunoglobulin or palivizumab [ 29, 205 ] . Few options exist for treatment of other viral respiratory pathogens, so although no randomized data exist, oral or inhaled ribavirin can be considered in patients with parainfl uenza [ 232 ] or metapneumovirus [ 233 ] .

Cardiac infections are relatively infrequent in patients who undergo therapy for leukemia. A diagnostic clue for a cardiovascular infection is the development of persistently positive blood cultures. Patients who receive appropriate antimicrobial therapy and have continued positive cultures after removal of all hardware (e.g., central catheters) should be evaluated for a cardiac or vascular source of infection (e.g., endocarditis, aortitis, or infected thrombophlebitis). Additionally, patients with cardiovascular infections can present with tachycardia, arrhythmias, acute heart block, heart failure or myocardial infarction, painful phlebitis or limb swelling.

The two most common infections associated with cardiopulmonary system are septic thrombophlebitis and endocarditis. Septic thrombophlebitis typically involves the development of bacteremia or fungemia that infects a preexisting thrombus, typically at sites of line placement. Candida species are commonly associated with this phenomenon, but any bacteria can lead to this complication [ 234 ] . Endocarditis in this population is an uncommon outcome following transplantation. These cases are often due to Streptococcus , Staphylococcus , or Enterococcal species, but other rare GNRs and atypical organisms have occasionally been reported [ 235 , 236 ] ; nearly all cases involve the right side of the heart unless patients have known underlying valvular pathology [ 235 ] . Candida or other fungal endocarditis is rare but associated with high rates of morbidity and mortality [237] [238] [239] . Interestingly, noninfectious etiologies of endocardial masses (thrombi or marantic changes) can lead to similar symptoms in this population [ 236, 240 ] . Invasive fungal infections of the myocardium can also occur, but most are associated with primary pulmonary involvement or dissemination [ 241, 242 ] . Rare bacterial and fungal processes can lead to purulent pericarditis [ 243, 244 ] .

Viral cardiac complications are uncommon in patients being treated for leukemia. Rare cases of herpesviruses and sporadic community-acquired viral infections and pericarditis or myocarditis have been reported [ 128, [245] [246] [247] [248] . Noninfectious etiologies and adverse drug side effects are signifi cantly more likely as causes of infl ammatory heart disease [ 249, 250 ] .

Blood cultures remain a staple for the diagnosis of cardiovascular infections. Patients with recurrent bacteremia either during or immediately after completing their antibiotic therapy should be considered for imaging to rule out septic thrombophlebitis. Ultrasound evaluation of veins near either the site of a line placement or involving an edematous limb can help identify suspicious thrombi. Patients who have clinical symptoms concerning for endocarditis should undergo an electrocardiogram and echocardiography. Transthoracic echocardiography can be helpful in diagnosing right-sided endocarditis, but transesophageal echocardiography has higher sensitivity for left-sided lesions and should be pursued in those who are considered high risk [ 251 ] . Guidelines for the diagnosis, treatment, and management of infective endocarditis can be found in Baddour [ 251 ] . Cardiac MRI may be useful in diagnosing invasive fungal infections [ 252 ] , but biopsy is the gold standard for diagnosis. Many patients with invasive cardiac mould infections are only diagnosed at autopsy.

Patients with infected thrombophlebitis should receive extended antibiotic therapy that is based on antimicrobial sensitivity testing of the organism. In addition to prolonged antibiotic therapy, anticoagulation or surgical thrombus removal may be necessary for cure. Patients with endocarditis need appropriate antibiotics for 4-6 weeks following bacterial clearance. Patients who develop additional complications such as heart failure, or who fail antibiotic therapy may need valve replacement. Patients with Candida or other fungal endocarditis need cardiothoracic surgical consultation as few, if any, recover without surgical valve replacement. Treatment and follow-up of patients with endocarditis are reviewed in detail by Baddour [ 251 ] . Patients with invasive cardiac fungal infections have a poor prognosis, but antifungal therapy should be attempted.

Gastrointestinal (GI) symptoms are frequent during the treatment for leukemia as a consequence of chemotherapy, adverse reactions, GVHD, and infections. Diarrhea, for example, occurs in nearly 80% of patients at some during the posttransplant period [ 253 ] . Not surprisingly, it can be diffi cult to separate infectious from noninfectious etiologies. Typical GI symptoms associated with infections are abdominal or perirectal pain, diarrhea, nausea vomiting, dysphagia, or GI bleeding. Signs of an infectious GI process can also include elevated temperature, tachycardia, jaundice, and liver enzyme abnormalities, but many of these are also seen in noninfectious etiologies such as GVHD or sinusoidal obstruction syndrome [ 254 ] .

Bacterial GI complications can occur during treatment of leukemia and during the transplant process. Most community-acquired bacterial causes for diarrhea, such as Salmonella and Shigella , occur only sporadically due to limited oral intake, less frequent exposure, and to standard prophylactic antibiotic therapy [ 255 ] . A more frequent infectious etiology for diarrhea is Clostridium diffi cile infection.

The use of broad-spectrum antibiotic therapy and prolonged exposure to inpatient care increase the risk for C. diffi cile . Usually C. diffi cile -associated diarrhea occurs within the fi rst 30-40 days posttransplant [ 253, 256 ] , but patients are at risk through the transplant process. Episodes of C. diffi cile that occur during neutropenia can develop into life-threatening disease [ 257 ] .

Neutropenic enterocolitis (typhlitis) presents with the triad of right lower quadrant pain, diarrhea, and fever; patients with severe disease may have rebound tenderness and signs of peritonitis ( Fig. 12.5 ) [ 258 ] . This condition involves the cecum and is related to loss of integrity of the bowel wall and subsequent bacterial invasion [ 258 ] . Classically, this condition is associated with Clostridium septicum but likely involves other anaerobic organisms as well [ 259 ] . Perirectal abscesses can occur during early conditioning and mucositis, as neutropenic patients may present with minimal swelling or erythema, a high index of suspicion is needed in patients with rectal pain. Necrotizing fasciitis should be ruled out in patients with perineal involvement (see Skin and Soft Tissue section). Intra-abdominal and hepatic abscesses are infrequent.

Oral candidiasis (thrush) was a frequent complication following transplantation, but is much less common with the addition of fl uconazole to prevention strategies. Thrush can occur as a result of azole-resistant species. Candida esophagitis is less Underwent CT scan of the abdomen which demonstrated bowel wall thickening and edema throughout the cecum and ascending colon with surrounding fat stranding ( yellow arrow ), consistent with neutropenic enterocolitis (typhlitis). Blood cultures from the day of admission were positive for C. septicum . The patient improved with broad-spectrum antibiotic therapy and did not need surgical intervention frequent as it is primarily due to C. albicans [ 260 ] which is reliably sensitive to fl uconazole [ 261 ] . Candida species, primarily C. albicans , can also present as involvement in the liver as hepatosplenic candidiasis. Patients with hepatosplenic candidiasis acquire the disease during periods of neutropenia but may develop fever, right upper quadrant pain, and increasing liver function tests only after neutrophil recovery [ 262 ] . Patients with hepatosplenic candidiasis do not normally have detectable candidemia, and nearly all cases are thought to be due to C. albicans [ 262 ] . Similar to other invasive Candida complications, hepatosplenic candidiasis has become less common since the addition of standardized fl uconazole prophylaxis.

Mould involvement of the gut can be a devastating complication. Most mould infections in the GI tract are thought to be acquired from ingestion during periods of high risk. Unfortunately, these invasive infections are diffi cult to diagnosis premortem, due to nonspecifi c symptoms and imaging (Fig. 12.6 ). Patients typically present with abdominal pain, but others can have only fever or nonspecifi c fi ndings; GI bleeding or perforation can be late signs of invasive involvement. The most frequent GI moulds are Aspergillus species and the Mucorales which can both lead to disease throughout the GI tract [ 263, 264 ] including the liver [ 265 ] . Clinical diagnosis can be very challenging, and such a delay leads to high rates of mortality; many are diagnosed only at autopsy [ 263 ] .

Herpesviruses, particularly CMV, can lead to invasive disease throughout the GI tract. CMV GI disease in transplant recipients resembles gut GVHD and, not infrequently, is found on biopsy in conjunction with a gut GVHD diagnosis. Patients typically present with abdominal pain, diarrhea (lower tract), nausea, and early satiety (upper tract); most patients are either on high-dose steroids or are T-cell-depleted transplant recipients [ 194 ] . The majority of patients have CMV detected in the blood at the time of diagnosis, but since a signifi cant proportion have no blood dissemination, a negative plasma PCR does not preclude invasive CMV disease. GI disease is the most common site of late CMV disease [ 266 ] . CMV rarely leads to severe hepatitis [ 267 ] . HSV can cause erosive esophagitis [ 268 ] and hepatitis [ 269 ] , but the routine use of acyclovir prophylaxis limits these complications.

VZV reactivation can lead to GI disease. Visceral varicella-zoster is unique to this population and is a life-threatening condition that necessitates treatment with high-dose IV acyclovir. This complication must be considered in any leukemic or transplant patient who presents with the triad of abdominal pain, increasing liver function tests, and hyponatremia [ 270, 271 ] . Patients with visceral involvement can also present with hepatitis and pancreatitis as a component of the diagnosis [ 271 ] . Importantly, unlike most episodes of VZV reactivation, this presentation is not always associated with the rash or skin lesions usually associated with herpes zoster [ 272 ] . Empiric therapy should be started immediately if this diagnosis is suspected.

EBV in posttransplant recipients can cause PTLD in high-risk patients and occurs in about 1% of all HCT patients [ 273 ] . PTLD can present anywhere but has a predilection for the gut and liver. Symptoms vary by location, but GI disease can be challenging to diagnose. Risk factors for the development of EBV-associated complications include T-cell depletion, EBV serologic mismatch, splenectomy [ 274 ] , mismatched or unrelated transplantation, and the development of chronic GVHD. 200 PTLD peaks around 2-3 months posttransplant, and most are polymorphic disease [ 200 ] . Umbilical cord blood transplant recipients may be more likely to develop early malignant monomorphic disease [ 275 ] . Interestingly, patients over the age of 50 have an increased rate of PTLD [ 200 ] .

Adenovirus most frequently leads to the development of diarrhea, and in more severe cases lower tract GI bleeding and dissemination [ 229, 276 ] . There is a strong correlation between the detection of viremia and the development of invasive disease [ 277 ] . Adenovirus reactivation occurs most frequently in patients with mismatched grafts and in those who have received T-cell-depleted transplants [ 278 ] . In children, adenovirus occurs more frequently, and earlier posttransplant; invasive disease is more prevalent [ 279 ] . Adenovirus can lead to hepatitis and fulminant hepatic failure [ 280, 281 ] .

Norovirus (Norwalk agent) has been increasingly recognized as a major cause of morbidity and mortality in cancer patients [ 282, 283 ] . These patients are more likely to develop chronic diarrhea which has been associated with signifi cant weight loss and need for parenteral nutrition [ 282, 284 ] . Patients who develop norovirus from the community are likely to shed the virus for extended periods of time [ 284 ] , making infection control practices critical for prevention [ 285 ] . Rotavirus is also recognized as a potential pathogen [ 286, 287 ] .

Finally, hepatitis B (HBV) can be a major problem in patients with prior exposure. During treatment for leukemia, patients with quiescent HBV (HBsAg positive or those with occult HBV) can develop reactivation with the development of hepatitis and even fulminant liver failure [ 288 ] . Prophylaxis and treatment for patients with a prior history of HBV have led to fewer complications related to the disease [289] [290] [291] . While, hepatitis C (HCV) is also known to cause long-term complications in transplant recipients [ 292 ] , it may also be associated with the development of sinusoidal obstruction syndrome [ 293 ] .

Patients who develop GI symptoms, particularly diarrhea and abdominal pain, should be evaluated for infectious etiologies. Routine bacterial cultures and parasite examinations are rarely useful as these pathogens are uncommon [ 286 ] . Samples however should routinely be sent for C. diffi cile testing regardless of prior antibiotic exposure. Elevated liver transaminases and alkaline phosphatase, and rising bilirubin, can also suggest potential etiologies [ 294 ] . Viral testing including adenovirus PCR, norovirus PCR, and rotavirus EIA from stool can be considered for patients. All patients with known HBV exposure should have a HBV PCR at baseline, and if they develop severe transaminitis, have it repeated. Additionally, although CMV, EBV, and adenovirus PCRs from serum can suggest an underlying diagnosis, VZV and HSV PCRs from serum/plasma in the face of symptoms consistent with visceral zoster or acute hepatitis are of critical importance for diagnosis. Serum GM can be sent in patients who are felt to be at risk for gut-related Aspergillus but may be falsely positive in patients with severe mucosal breakdown or in those receiving piperacillin-tazobactam therapy [ 295, 296 ] . All patients receiving intensive chemotherapy should have baseline serologic testing for viral hepatitis.

In patients with abdominal pain, CT scans of the abdomen and pelvis can help evaluate potential etiologies, assess for perforation or abscess, and may help to identify diseases with classic appearance on CT. Hepatosplenic candidiasis, for example, presents with multiple hypodense "bull's eye" lesions in the liver and spleen which are indicative of Candida abscesses within the liver [ 294 ] . Neutropenic enterocolitis typically demonstrates infl ammation and stranding around the cecum (Fig. 12.5 ) . Unfortunately, GI mould infections may be diffi cult to diagnose from imaging [ 264 ] , with many diagnosed following death (Fig. 12.6 ). Intervention may also be important in the work-up of patient's symptoms. In patients at risk for GVHD, gastroenterology consultation is suggested to evaluate by endoscopy. Endoscopic visualization and biopsies can help differentiate between viral infections (CMV and adenovirus) and GVHD and may detect other infectious lesions [ 297 ] . It is important to stress that more than one diagnostic method for CMV detection is needed in the GI tract [ 298 ] and that CMV PCR still needs to be validated as a diagnostic entity for the diagnosis. Surgical intervention or liver biopsy may be necessary particularly in patients without a clear diagnosis or if CT fi ndings are suspicious for a fungal process. Patients with severe neutropenic enterocolitis or those with severe abdominal pain may need emergent surgical consultation [ 258 ] .

Patients who develop C. diffi cile infections should be treated with either oral metronidazole or oral vancomycin (Table 12.1 ) . Patients with severe infections may have better outcomes with oral vancomycin [ 299 ] . Patients with neutropenic enterocolitis and perirectal infections should receive broad-spectrum antibiotics covering anaerobic species (e.g., metronidazole) and GNRs. Surgical consultation should be pursued in all patients with these conditions, as some patients may need early surgical intervention [ 258 ] . Patients with invasive Candida infections should receive prolonged fl uconazole or echinocandin therapy, and patients diagnosed with invasive moulds should receive mould-active therapy depending on the pathogen identifi ed. Voriconazole, lipid amphotericin B formulations, or posaconazole are the most commonly used agents. All patients should also have a surgical consultation. CMV infections should be treated with ganciclovir or foscarnet and HSV/VZV infections with high-dose IV acyclovir. Patients who develop PTLD after HCT are often treated with rituximab but may need additional chemotherapy [ 300, 301 ] . Few options exist for norovirus therapy, but nitazoxanide may be an option [ 302 ] . Treatment of HBV is reviewed in detail by Lok [ 303 ] but typically entails lamivudine, entecavir, or adefovir.

Patients with genitourinary (GU) infections during treatment for leukemia often present with symptoms that are similar to immunocompetent patients: urinary frequency, dysuria, fl ank pain, hematuria, and fevers. These patients are at risk for additional complications and are more likely to develop renal dysfunction and invasive infections. Additionally, side effects of numerous medications and chemother- On broad-spectrum antibiotics, continued to be febrile with increasing abdominal distention and increasing bilirubin despite aggressive antibiotics. Underwent CT scan of the abdomen which demonstrated moderate ascites, but no pneumoperitoneum or obstruction was identifi ed ( above ). The patient developed respiratory distress, anasarca, and dense pulmonary infi ltrates. At autopsy found to have disseminated intra-abdominal Rhizopus species. Mould invaded into celiac axis (with thrombosis) and also involved liver, diaphragm, stomach, pancreas, spleen, and adrenal glands apy agents (e.g., cyclophosphamide and calcineurin inhibitors) can lead to additional GU toxicity. The need for urinary catheters in highly compromised patients may also increase risk. The combination of adverse drug toxicity, GVHD, sepsis, and subsequent multiorgan failure can lead to renal failure and the need for acute renal replacement therapy [ 304, 305 ] .

Patients receiving standard therapy for leukemia and patients undergoing transplantation are at risk for developing urinary tract infections (UTI). The use of standard prophylactic antibiotics has limited UTIs, somewhat, but has led to the development of more resistant nosocomial infections particularly in patients who have prolonged hospitalizations and are catheterized [ 306, 307 ] . Patients undergoing leukemia therapy have Escherichia coli and Klebsiella pneumonia as the predominant species detected from urinary samples [ 307 ] . In patients with urinary catheters, it is important to separate colonization from symptomatic infection [ 308 ] . Patients can also develop complications in the kidney from septic emboli, and more invasive infections of the kidneys and bladder can occur but are infrequent.

Fungal infections of pelvic organs are a relatively infrequent phenomenon. Candida is the most frequent organism to infect the GU tract, with urinary tract infections being the typical presentation, but invasive candidal abscesses can occur during episodes of candidemia [ 309 ] . Patients who develop candiduria typically have anatomic abnormalities of the GU tract, have been treated with broad-spectrum antibiotics, or have a urinary catheter [ 310 ] . Candidal organisms can also lead to asymptomatic colonization of urinary catheters and, in some cases, invasive disease.

GU tract infections are an uncommon manifestation of mould infections. Patients with Aspergillus infection will not infrequently develop parenchymal involvement with disseminated infections [ 242 ] , but occasionally they can be seen as isolated infections in the bladder [ 311 ] or kidney [ 312, 313 ] . The Mucorales and other less common fungal species have also been rarely reported to cause invasive disease in the genitourinary tract [ 314, 315 ] .

BK virus frequently reactivates in the genitourinary system during immunosuppression and can lead to the development of hemorrhagic cystitis (HC) [ 316 ] .

Many patients who have detectable BK virus in the urine may be asymptomatic, but those that develop BK-associated HC present with frequent urination, fl ank pain, frank hematuria, and, in severe cases, the development of severe infl ammation and clotting in the bladder that can lead to urinary obstruction [ 317, 318 ] . Rarely, BK can lead to nephritis in HCT recipients [ 319 ] . Interestingly, the immune response to BK may play an important role in the development of BK-associated symptoms [ 320 ] . Adenovirus also leads to HC [ 320, 321 ] but is a more common cause of nephritis than BK [ 322 ] . Unlike BK virus, risk factors for the development of invasive adenovirus include major changes in immune function, including T-cell depletion [ 202, 320 ] . Adenovirus genitourinary infections are also known to be more common in children and in patients with mismatched grafts [ 202, 229 ] .

Standard urinalysis and urine and blood cultures are important components of the work-up for patients with urinary symptoms. Urine culture results must be interpreted with caution in patients with urinary catheters, as separating colonization versus invasive disease can be challenging (reviewed by Nicolle) [ 308 ] . Viral PCRs for adenovirus and BK, from both blood and urine, can be helpful in evaluating patients with either HC and/or renal failure. A BK viral load in serum ³ 10,000 copies/mL may predict patients with BK-associated HC [ 323 ] . Ultrasound and CT imaging may also help in determining invasive fungal infections. If there is concern for possible nephritis or fungal infection, kidney biopsy or bladder cystoscopy may be necessary to make a defi nitive diagnosis.

Bacterial infections typically require focused therapy based on sensitivity testing, but length of therapy depends on the severity of infection (Table 12.1 ). Patients with catheters should have them replaced prior to starting therapy if possible. Candida infections should be treated with fl uconazole, echinocandin therapy, or lipid amphotericin B formulations, depending on sensitivity testing. Amphotericin bladder washes are used by some centers as adjunctive therapy or for patients with known colonization [ 324 ] . Patients with invasive mould infections should receive voriconazole, lipid amphotericin B formulations, or posaconazole, depending on the pathogen identifi ed; all patients should also have a urology consultation.

BK-virus-related disease is diffi cult to treat, particularly since reductions in immunosuppression are not possible. In patients with severe disease, cidofovir, lefl unomide, IVIG, and fl uoroquinolones have all been suggested as possible therapeutic options, but no randomized trials exist [325] [326] [327] . Adenovirus HC and nephritis are diffi cult to treat, but IV cidofovir can be attempted [ 328 ] .

Leukemia patients can present with a myriad of skin and soft tissue manifestations that can be clues to an underlying infectious etiology. When examining transplant patients and those receiving therapy for leukemia, it is important to do a good skin exam. Cutaneous infections can present in a wide variety of visual appearances as nodules, ulceration, eschars, petechiae, rash/erythema, and/or pustules. Most patients present with fever, but pain suggests a more invasive process. Depending on the appearance and distribution, cutaneous fi ndings can be helpful in making a diagnosis (e.g., dermatomal herpes zoster). Many important noninfectious etiologies such as drug side effects, GVHD, leukemia cutis [ 329 ] , and neutrophilic dermatosis (Sweet's syndrome) [ 330 ] can mimic infectious etiologies. Regardless, any notable lesions or rashes should be promptly evaluated.

Cellulitis is a common manifestation of bacterial infections. The majority of cellulitis cases are due to Streptococcus and Staphylococcus species, but more frequently, no bacterial etiology is identifi ed. Certain bacterial species present with specifi c skin manifestations. Pseudomonas and other GNRs can present with ecthyma gangrenosum, which in the early stage appears as bullae and later slough to classically form a gangrenous ulcer with a black eschar [ 331 ] . C. jeikeium often presents with an erythematous papular eruption during episodes of bacteremia [ 332 ] . Nocardia and other uncommon organisms have also led to cutaneous manifestations in this population [ 333, 334 ] . Gangrenous or necrotizing fasciitis is a life-threatening skin infection and is characterized by necrosis of the deeper subcutaneous fat and fascia. Patients typically present with signs of overwhelming infection, and rates of mortality are very high [ 335 ] . In leukemia, necrotizing fasciitis can be either a polymicrobial process or caused by singular primarily GNR species [ 335 ] . Patients may present with bacteremia and minimal skin fi ndings which may progress rapidly to a more fulminant course [ 336 ] . Clues to this diagnosis include a rapidly expanding cellulitis, black/dusky areas of involvement, pain out of proportion to the cutaneous fi ndings, and laboratory alterations such as an elevated creatinine and lactic acidosis. Surgical consultation and immediate debridement of the affected area are mandatory. A specifi c form of necrotizing fasciitis that involves the perineum, Fournier's gangrene, can be particularly morbid [ 337 ] .

Fungal skin lesions in transplantation can be similar to their bacterial counterparts. Candida species are one of the most common fungal infections to have dermatologic manifestations, and during candidemia, can present with <1 cm scattered erythematous papular nodules with pale centers [ 338 ] . Cryptococcus also can lead to skin nodules in those with disseminated disease [ 339 ] . Solitary nodules are more likely to be caused by moulds, typically Aspergillus and the Mucorales, and initially can be subtle in presentation. Mould infections can occur at sites of trauma, such as sites for bone marrow biopsy or IV placement [ 340 ] . Typically, lesions will progress rapidly without appropriate treatment. Fusarium is the one mould that presents frequently with dermatologic manifestations, usually appearing in greater than 60% of patients with disseminated fusariosis [ 341 ] . Typical lesions are erythematous macules and papules with gray necrotic or ulcerated centers [ 242 ] . Any patient with a cutaneous fungal infection should undergo further evaluation to identify others sites of infection.

HSV is commonly associated with vesicular lesions either around the oropharynx (typically HSV-1) or around anogenital region (HSV-2). Lesions during periods of severe immunosuppression can be much more severe but typically present as erythematous vesicles ("dew drop on a rose petal"). With the standard use of acyclovir, prophylaxis episodes of HSV during transplant and leukemia therapy are less frequent, although acyclovir-resistant cases can occasionally occur, especially in low-dose regimens [ 38 ] . Similar to HSV, VZV can present as herpes zoster or disseminated disease. Typical dermatomal reactivations occur late after transplant, but during active chemotherapy and postconditioning, patients are at risk for dissemination which can have an appearance not unlike primary Varicella (chickenpox) [ 343 ] . Erythematous rashes can be seen in other viral infections [ 344 ] .

As with all infections blood cultures can be helpful in identifying an underlying etiology to skin infections. Dermatology consultation and biopsies can also help in making a diagnosis and may be necessary in some cases that have a large differential diagnosis. Any patient with lesions suspicious for an invasive fungal infection should undergo routine biopsy. In patients with increased concern for necrotizing fasciitis, a high lactate and abnormal chemistry panel (low CO 2 and elevated creatinine) can also be suggestive. Diagnosis must be confi rmed by visual inspection of the fascia and on pathologic review, so an urgent surgical consultation is required. Patients with lesions consistent with HSV or VZV should have lesions unroofed and samples from the base of the lesion sent for DFA, shell vial, and PCR. HSV and VZV PCR levels from serum should also be sent in patients who appear to have disseminated disease.

Bacterial cellulitis is often treated with empiric regimens, as patients rarely have a known causative organism. Vancomycin is often added gram-positive coverage, but GNR treatment should be added in cases of severe of infection. Patients with identifi ed pathogens should have therapy focused on the sensitivity patterns of that organism (Table 12. 1 ). Patients with evidence of necrotizing fasciitis must undergo immediate surgical consultation and debridement; broad coverage is recommended for empiric therapy while awaiting the operating room. Fungal infections should be treated with fl uconazole, echinocandin, voriconazole, lipid amphotericin B formulations, or posaconazole, depending on the species, sensitivities, and severity of disease. Patients with invasive Aspergillus , Mucorales species, or other mould need more extensive surgical debridement to cure the infection. Patients with localized HSV or VZV reactivation should be treated with high-dose acyclovir or valacyclovir.

(Guidelines reviewed in Freifeld [ 39 ] , Tomblyn [ 31 ] , and Baden [ 32 ] )

Neutropenic fever is one of the most common complications following therapy for patients with leukemia occurring in greater than 80% of patients undergoing treatment [ 345 ] . Fever can be caused by numerous etiologies, and only about 20-30% of patients have documented infections during a neutropenic evaluation [ 39 ] . However, due to the high risk for morbidity and mortality associated with infections, most providers give standard prophylaxis during this period of risk. There are numerous risk categories that are reviewed in detail by Freifeld et al. and prevention strategies differ slightly between groups [ 39 ] . Patients receiving therapy for leukemia and transplant recipients are expected to have prolonged periods of neutropenia (>7-10 days) so are considered to be higher risk. Most centers and guidelines recommend the use of fl uoroquinolone prophylaxis in this population, and this appears to be as effective as IV ceftazidime [ 31, 57 ] . Due to the emergence of fl uoroquinolone-resistant S. viridans (particularly ciprofl oxacin) [ 346 ] , some centers add additional penicillin VK or amoxicillin to fl uoroquinolones [ 347, 348 ] and others early vancomycin in patients at high risk for this organism [ 349 ] . Trimethoprim/sulfamethoxazole can be considered in patients who have an allergy to fl uoroquinolones but is often not possible in patients with neutropenia [ 32 ] . Prophylaxis should be stopped after neutrophil recovery. Late strategies to prevent posttransplant S. pneumoniae and encapsulated bacteria in patients with chronic GVHD should be based on local resistance patterns [ 31 ] .

Since VRE and MRSA can be major problems in the treatment phase of leukemia therapy, standard screening for VRE (rectal) and MRSA (nasal) are recommended prior to starting chemotherapy.

Due to the increased risk and signifi cant morbidity associated with fungal infections, most centers use standard antifungal prophylaxis [ 350 ] . Fluconazole prophylaxis has been shown to decrease the rates of major fungal infections [ 351, 352 ] , but its major effect is on prevention of invasive Candida [ 22 ] . Breakthrough candidemia on prophylactic fl uconazole can occur typically in the form of C. glabrata and C. krusei [ 353 ] . The echinocandins, particularly micafungin, have been shown to be useful alternative agents [ 354, 355 ] .

Voriconazole prophylaxis has been shown to be equivalent to fl uconazole in patients undergoing myeloablative HCT, but it did not signifi cantly reduce the number of Aspergillus infections during follow-up in a randomized trial [ 355 ] ; an increase in Mucorales species was not seen. Posaconazole prophylaxis has been shown to decrease the risk of invasive mould infections in high-risk patients with GVHD [ 356 ] and in patients with neutropenia [ 357 ] . Limitation of proton-pump inhibitor use, coadministration with food or acidic beverages, and increases in dosing may prevent the development of insuffi cient drug levels and subsequent breakthrough infections [ 358 ] . Drug levels should be considered in patients receiving voriconazole or posaconazole prophylaxis.

PCP prevention is also an important component of posttransplant prevention. The preferred agent for prevention is postengraftment trimethoprim/sulfamethoxazole [ 31 ] . Trimethoprim/sulfamethoxazole is preferred because of superiority to other preventative agents [ 359 ] and cross-protection for toxoplasmosis and Nocardia. If patients have a known allergy to sulfa drugs, an attempt at desensitization should be attempted. Second-line agents include dapsone, atovaquone, and aerosolized pentamidine, but pentamidine is clearly inferior [ 360 ] , and atovaquone has not been studied prospectively.

Two major prevention strategies are currently used in practice to prevent the development of CMV disease: primary antiviral prophylaxis and preemptive therapy ( Fig. 12.7 ) . Clinical trials of ganciclovir prophylaxis have been performed and shown to decrease CMV disease [ 361, 362 ] , but prophylactic approaches with ganciclovir can cause neutropenia, and increase susceptibility to bacterial or fungal infections [ 363, 364 ] . Prolonged exposure to CMV-specifi c antiviral agents, particularly with minimal immune pressure and subclinical reactivation, can lead to the selection of drug-resistant CMV [ 365 ] .

At many transplant centers, preemptive therapy is used for CMV prevention in HCT [ 350 ] . Although preemptive strategies are similar at most centers, specifi c cutoffs for starting therapy vary between centers. At our institution, transplant recipients are monitored weekly for CMV viremia by quantitative real-time serum PCR for the fi rst 100 days posttransplant [ 23 ] ; other centers use the pp65 CMV antigenemia of whole blood PCR assay. Not all patients with detectable CMV will progress to disease, so centers need to develop viral load thresholds for PCR and antigenemia that will maximize effect and minimize toxicity. Alternatively, some centers use a combined strategy with primary prophylaxis with high-dose acyclovir in addition to preemptive therapy [ 366 ] .

After 100 days posttransplant, PCR surveillance may be discontinued in low-risk patients [ 19 ] . High-risk patient, particularly those with ongoing GVHD therapy, should continue weekly surveillance for late CMV disease until they reach minimal immunosuppressant levels and have at least three consecutive negative weekly tests [ 19 ] . During late surveillance, our threshold for initiation of therapy is 1,000 copies/ mL or greater than fi vefold increase in viral load above the patient's established baseline [ 19 ] .

Some centers screen high-risk posttransplant patients (e.g., T-cell-depleted transplants) by weekly EBV PCR. Numerous testing strategies have been advocated, including whole blood, PBMCs, or cell-free plasma. In general, all of these specimens provide good sensitivity, although comparisons suggest that cell-free plasma may provide superior specifi city for PTLD [ 367 ] . Most authors favor a preemptive therapy similar to what is seen in CMV, in which detection of EBV DNA levels above a certain threshold triggers a reduction in immunosuppression or rituximab therapy [ 368, 369 ] . There are no current guidelines for a threshold for EBV viremia due to variances in testing and in transplant populations [ 31 ] . Other groups use "prompt" therapy in which treatment is triggered only when detection of EBV DNA is accompanied by overt signs of EBV disease. Prompt therapy has shown similar effi cacy to preemptive therapy [ 370 ] . Based on the concern that the delay in treatment may lead to increased complications, many groups still favor preemptive approaches [ 31, 301 ] . T-cell immunotherapeutic regimens are still experimental and not widely available.

Studies using both moderate-and low-dose acyclovir during the posttransplant period have demonstrated a marked decrease in both VZV and HSV complications [ 6, 371 ] . The use of acyclovir or valacyclovir is recommended for at least one year posttransplant and through 6 months after cessation of all immunosuppressive therapies [ 31 ] . Long-term prophylaxis also appears to prevent the emergence of acyclovir-resistant HSV [ 38 ] . Low-dose acyclovir has also shown the ability to prevent both HSV and VZV reactivation in smaller studies [ 371, 372 ] .

Generally, surveillance is not recommended in low-risk patients. Preemptive monitoring has been advocated for adenovirus [ 277, 373, 374 ] , particularly in children undergoing transplantation and in other high-risk adults (e.g., T-cell-depleted transplant recipients). Most often, cidofovir is used as the agent of choice for preemptive therapy [ 374 ] .

Several nonrandomized studies support the use of prophylactic palivizumab for children £ 2 years throughout RSV season [ 375, 376 ] , but adults should not receive palivizumab as prophylaxis. , with drugs such as ganciclovir (IV or oral), is usually given after the point at which patients engraft. Many centers use an antigenemia-based preemptive testing (pp65) strategy ( large medium-gray arrow ). This can be started earlier and has been shown to prevent CMV disease. PCR-based preemptive therapy ( large white arrow ) is the standard at many other centers, including our own, and allows for testing to begin immediately after conditioning. Small white arrows indicate weekly testing by PCR that we do at our center through at least day 100. Small gray arrows indicated weekly antigenemia testing that typically starts near engraftment 

Effect of granulocyte colony-stimulating factor after intensive induction therapy in relapsed or refractory acute leukemia

Causes of death in acute leukemia: a ten-year study of 414 patients from 1954-1963

Causes of death in adults with acute leukemia

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

Reduced mortality after allogeneic hematopoietic-cell transplantation

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

Impaired granulocytic function in patients with acute leukaemia: only partial normalisation after successful remission-inducing treatment

Flow cytometric quantifi cation of phagocytosis in acute myeloid leukemia

The immunodefi ciency of chronic lymphocytic leukaemia

Disease-specifi c complications of chronic lymphocytic leukemia

Recovery of uncommon bacteria from blood: association with neoplastic disease

Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation

T-cell repertoire complexity after allogeneic bone marrow transplantation

Management of infections in patients with chronic lymphocytic leukemia treated with alemtuzumab

Selective suppression of alimentary tract microbial fl ora as prophylaxis during granulocytopenia

Clinical and economic consequences of mucositis induced by chemotherapy and/or radiation therapy

Analysis of factors related to the occurrence of chronic disseminated candidiasis in patients with acute leukemia in a non-bone marrow transplant setting: a follow-up study

Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation

How we treat cytomegalovirus in hematopoietic cell transplant recipients

Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America

The utility of routine surveillance blood cultures in asymptomatic hematopoietic stem cell transplant patients

Ecthyma g angrenosum: a rare cutaneous manifestation caused by Stenotrophomonas maltophilia in a leukemic patient

Infectious granulomatous dermatitis associated with Rothia mucilaginosa bacteremia: a case report

Disseminated fusariosis in immunocompromised patients

Candidemia in acute leukemia patients

Staphylococcus aureus biofi lms prevent macrophage phagocytosis and attenuate infl ammation in vivo

The ability of biofi lm formation does not infl uence virulence of Staphylococcus aureus and host response in a mouse tissue cage infection model

Host defence against Staphylococcus aureus biofi lms infection: phagocytosis of biofi lms by polymorphonuclear neutrophils (PMN)

Host defence against Staphylococcus aureus biofi lms by polymorphonuclear neutrophils: oxygen radical production but not phagocytosis depends on opsonisation with immunoglobulin G

Destruction of bacterial biofi lms by polymorphonuclear neutrophils: relative contribution of phagocytosis, DNA release, and degranulation

Gastro-intestinal toxicity related to bone marrow transplantation: disruption of the intestinal barrier precedes clinical fi ndings

Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America

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

Blood stream infections in allogeneic hematopoietic stem cell transplant recipients: reemergence of Gram-negative rods and increasing antibiotic resistance

Bacterial and fungal bloodstream isolates from 796 hematopoietic stem cell transplant recipients between

Nontuberculous mycobacterial infections in hematopoietic stem cell transplant recipients: characteristics of respiratory and catheter-related infections

Bacteremia after hematopoietic stem cell transplantation: incidence and predictive value of surveillance cultures

The impact of a change in antibacterial prophylaxis from ceftazidime to levofl oxacin in allogeneic hematopoietic cell transplantation

Blood stream infections during chemotherapyinduced neutropenia in adult patients with acute myeloid leukemia: treatment cycle matters

Bacteraemia in hospitalised patients with malignant blood disorders: a retrospective study of causative agents and their resistance profi les during a 14-year period without antibacterial prophylaxis

Risk factors for late Staphylococcus aureus bacteremia after allogeneic hematopoietic stem cell transplantation: a single-institution, nested casecontrolled study

Prevention of peritransplantation viridans streptococcal bacteremia with early vancomycin administration: a single-center observational cohort study

Viridans streptococcal bacteraemia due to penicillinresistant and penicillin-sensitive streptococci: analysis of risk factors and outcome in 60 patients from a single cancer centre before and after penicillin is used for prophylaxis

Clinical features and complications of viridans streptococci bloodstream infection in pediatric hemato-oncology patients

Increased risk for invasive pneumococcal diseases in children with acute lymphoblastic leukaemia

Antibody response to 7-valent conjugated pneumococcal vaccine in patients with chronic lymphocytic leukaemia

Impaired pneumococcal immunity in children after treatment for acute lymphoblastic leukaemia

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

Risk factors for enterococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients

Incidence of vancomycin-resistant enterococci (VRE) infection in high-risk febrile neutropenic patients colonized with VRE

Corynebacterium jeikeium bacteremia in bone marrow transplant patients with Hickman catheters

Invasive Pseudomonas aeruginosa infections: high rate of recurrence and mortality after hematopoietic cell transplantation

Multidrug resistant Pseudomonas aeruginosa infection in children undergoing chemotherapy and hematopoietic stem cell transplantation

Stenotrophomonas maltophilia : an increasing problem in patients with acute leukaemia

Stenotrophomonas maltophilia : changing spectrum of a serious bacterial pathogen in patients with cancer

Clinical characteristics of Stenotrophomonas maltophilia infection in hematopoietic stem cell transplantation recipients: a single center experience

Antibiotic resistance is associated with longer bacteremic episodes and worse outcome in febrile neutropenic children with cancer

Massive intravascular hemolysis: a fatal complication of Clostridium perfringens septicemia in a patient with acute lymphoblastic leukemia

Clinical courses of seven survivors of Clostridium septicum infection and their immunologic responses to alpha toxin

Risk factors and outcome for nosocomial breakthrough candidaemia

Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning

Fungemia due to Rhodotorula mucilaginosa after allogeneic hematopoietic stem cell transplantation

Central venous catheter-associated fungemia secondary to mucormycosis

Nosocomial invasive infection caused by Cunninghamella bertholletiae : case report

Invasive fusariosis in patients with hematologic malignancies at a cancer center

Catheter-associated aspergillosis of the chest wall following allogeneic hematopoietic stem cell transplantation

Cutaneous mucormycosis due to Absidia corymbifera occurring after bone marrow transplantation

Comparison of utility of blood cultures from intravascular catheters and peripheral veins: a systematic review and decision analysis

How many lumens should be cultured in the conservative diagnosis of catheterrelated bloodstream infections?

Difference in time to positivity is useful for the diagnosis of catheter-related bloodstream infection in hematopoietic stem cell transplant recipients

Managing intravascular catheter-related infections in heart transplant patients: how far can we apply IDSA guidelines for immunocompromised patients?

CLABSI rates in immunocompromised patients: a valuable patient centered outcome?

Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America

Neurologic complications of hematopoietic cell transplantation

HHV-6 reactivation and its effect on delirium and cognitive functioning in hematopoietic cell transplantation recipients

Nocardiosis in cancer patients

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

Herpes simplex virus encephalitis: new infection or reactivation?

Varicella-zoster virus encephalitis in a patient undergoing unrelated cord blood transplantation for myelodysplastic syndrome-overt leukemia

Fungal brain abscess in transplant recipients: epidemiologic, microbiologic, and clinical features

Penicillin-resistant Streptococcus pneumoniae septic shock and meningitis complicating chronic graft versus host disease: a case report and review of the literature

Early and late invasive pneumococcal infection following stem cell transplantation: a European bone marrow transplantation survey

Bacterial meningitis from Rothia mucilaginosa in patients with malignancy or undergoing hematopoietic stem cell transplantation

Bacillus cereus bacteremia and meningitis in immunocompromised children

Lactobacillus rhamnosus meningitis following recurrent episodes of bacteremia in a child undergoing allogeneic hematopoietic stem cell transplantation

Ommaya-catheterrelated Staphylococcus epidermidis cerebritis and recurrent bacteremia documented by molecular typing

Listeria and atypical presentations of Listeria in the central nervous system

Human listeriosis in Britain, 1967-85, a summary of 722 cases. 2. Listeriosis in non-pregnant individuals, a changing pattern of infection and seasonal incidence

Actinomycoses and Nocardia pulmonary infections

Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America

Comparison of in vitro susceptibility characteristics of Candida species from cases of invasive candidiasis in solid organ and stem cell transplant recipients: Transplant-Associated Infections Surveillance Network (TRANSNET)

Transplantation of HLA-mismatched CD34+ selected cells in patients with advanced malignancies: severe immunodefi ciency and related complications

Relevant imaging fi ndings of cerebral aspergillosis on MRI: a retrospective case-based study in immunocompromised patients

Brain abscess following marrow transplantation: experience at the Fred Hutchinson Cancer Research Center

Central nervous system infections following bone marrow transplantation: an autopsy report of 27 cases

Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between

Epidemiology and outcome of zygomycosis: a review of 929 reported cases

Infections due to Scedosporium apiospermum and Scedosporium prolifi cans in transplant recipients: clinical characteristics and impact of antifungal agent therapy on outcome

ZYGOMYCOSIS: current approaches to management of patients with haematological malignancies

Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America

Coccidioidomycosis in hematopoietic stem cell transplant recipients

Chronic meningitis by histoplasmosis: report of a child with acute myeloid leukemia

Diagnosis of histoplasmosis in immunosuppressed patients

Viral encephalitis after allogeneic stem cell transplantation: a rare complication with distinct characteristics of different causative agents

Human herpesvirus 6 and central nervous system disease in hematopoietic cell transplantation

Varicella zoster virus vasculopathy: analysis of virus-infected arteries

Acute central nervous system complications in varicella zoster virus infections

Impact of human herpesvirus-6 after haematopoietic stem cell transplantation

Herpes simplex virus encephalitis after allogeneic transplantation: an instructive case

Otological complications of herpes zoster

A case of Ramsay Hunt-like syndrome caused by herpes simplex virus type 2

EBV limbic encephalitis after allogeneic hematopoietic stem cell transplantation

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

Cytomegalovirus ventriculoencephalitis after unrelated double cord blood stem cell transplantation with an alemtuzumab-containing preparative regimen for Philadelphia-positive acute lymphoblastic leukemia

Isolated cerebral manifestation of Epstein-Barr virusassociated post-transplant lymphoproliferative disorder after allogeneic hematopoietic stem cell transplantation: a case of clinical and diagnostic challenges

Progressive multifocal leukoencephalopathy in chronic lymphocytic leukemia: a report of three cases and review of the literature

Two cases of progressive multifocal leukoencephalopathy after allogeneic hematopoietic cell transplantation and a review of the literature

Progressive multifocal leukoencephalopathy in a patient with acute myeloid leukaemia after allogeneic hematopoietic-cell transplantation

Zoonoses in solid-organ and hematopoietic stem cell transplant recipients

Virus encephalopathy in an allogeneic stem cell transplant recipient: use of quantitative PCR for diagnosis and assessment of viral clearance

Outcome of CNS and pulmonary enteroviral infections after hematopoietic cell transplantation

Toxoplasmosis in allo-SCT patients: risk factors and outcomes at a transplantation center with a low incidence

Toxoplasmosis after hematopoietic stem cell transplantation

Disseminated toxoplasmosis following T cell-depleted related and unrelated bone marrow transplantation

Toxoplasmosis, a severe complication in allogeneic hematopoietic stem cell transplantation: successful treatment strategies during a 5-year single-center experience

Parasitic central nervous system infections in immunocompromised hosts

Strongyloides stercoralis hyperinfestation syndrome with Escherichia coli meningitis: report of two cases

Spectrum of imaging fi ndings in immunocompromised patients with HHV-6 infection

Imaging manifestations of progressive multifocal leukoencephalopathy

MR imaging in toxoplasmosis encephalitis after bone marrow transplantation: paucity of enhancement despite fulminant disease

CNS complications of hematopoietic stem cell transplantation

Diagnosis of toxoplasmosis after allogeneic stem cell transplantation: results of DNA detection and serological techniques

Pulmonary nocardiosis: risk factors, clinical features, diagnosis and prognosis

Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America

Improved outcome in central nervous system aspergillosis, using voriconazole treatment

Voriconazole concentrations in the cerebrospinal fl uid and brain tissue of guinea pigs and immunocompromised patients

Human herpesvirus type 6 reactivation after haematopoietic stem cell transplantation

Randomized trial of trimethoprim-sulfamethoxazole versus pyrimethamine-sulfadiazine for therapy of toxoplasmic encephalitis in patients with AIDS. Italian Collaborative Study Group

Risk factors and outcome of pulmonary complications after autologous hematopoietic stem cell transplant (HSCT)

An offi cial American Thoracic Society research statement: noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia syndrome

Microbiology of sinusitis in patients undergoing bone marrow transplantation

Sinus disease in the bone marrow transplant population: incidence, risk factors, and complications

Incidence, risk factors, and mortality from pneumonia developing late after hematopoietic stem cell transplantation

Nocardiosis after bone marrow transplantation: a retrospective study

Pulmonary nocardiosis: risk factors and outcomes

Pneumonia due to Legionella micdadei in bone marrow transplant recipients

Legionella jordanis in hematopoietic SCT patients radiographically mimicking invasive mold infection

Legionellosis in a bone marrow transplant center

Pneumonia due to Mycoplasma pneumoniae in granulocytopenic children with cancer

Chlamydia pneumoniae respiratory infection after allogeneic stem cell transplantation

Invasive fungal sinusitis in patients undergoing bone marrow transplantation

Invasive Aspergillus sinusitis in pediatric bone marrow transplant patients. Evaluation and management

A fatal case of invasive fungal sinusitis by Scopulariopsis acremonium in a bone marrow transplant recipient

Paecilomyces sinusitis in an immunocompromised adult patient: case report and review

Mucormycoses in patients with hematologic malignancies: an emerging fungal infection

Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients

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

Epidemiology and outcome of invasive fungal infection in adult hematopoietic stem cell transplant recipients: analysis of Multicenter Prospective Antifungal Therapy (PATH) Alliance registry

Epidemiology of invasive mold infections in allogeneic stem cell transplant recipients: biological risk factors for infection according to time after transplantation

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

Risk factors for post-engraftment invasive aspergillosis in allogeneic stem cell transplantation

Mucormycosis in allogeneic bone marrow transplant recipients: report of fi ve cases and review of the role of iron overload in the pathogenesis

Risk factors associated with invasive fungal disease in children with cancer and febrile neutropenia: a prospective multicenter evaluation

Invasive fungal disease in adults undergoing remission-induction therapy for acute myeloid leukemia: the pathogenetic role of the antileukemic regimen

Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants

Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole

Fatal disseminated infection due to Scedosporium prolifi cans in a patient with acute myeloid leukemia and posaconazole prophylaxis

Posaconazole salvage therapy allows successful allogeneic hematopoietic stem cell transplantation in patients with refractory invasive mold infections

Cryptococcosis in solid-organ, hematopoietic stem cell, and tissue transplant recipients: evidence-based evolving trends

The effect of prophylactic fl uconazole on the clinical spectrum of fungal diseases in bone marrow transplant recipients with special attention to hepatic candidiasis. An autopsy study of 355 patients

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

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

Acute respiratory failure due to pneumocystis pneumonia in patients without human immunodefi ciency virus infection: outcome and associated features

Cytomegalovirus in hematopoietic stem cell transplant recipients: current status, known challenges, and future strategies

Current status of pediatric umbilical cord blood transplantation in Korea: a multicenter retrospective analysis of 236 cases

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

Late cytomegalovirus disease in marrow transplantation is predicted by virus load in plasma

Screening for CMV-specifi c T cell proliferation to identify patients at risk of developing late onset CMV disease

Pneumonia caused by herpesviruses in recipients of hematopoietic cell transplants

Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation

The impact of adenovirus infection on the immunocompromised host

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

Adenovirus infection after allogeneic stem cell transplantation

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

The challenge of respiratory virus infections in hematopoietic cell transplant recipients

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

Community respiratory virus infections in immunocompromised patients with cancer

Rhinovirus as a cause of fatal lower respiratory tract infection in adult stem cell transplantation patients: a report of two cases

Changing epidemiology of respiratory viral infections in hematopoietic cell transplant recipients and solid organ transplant recipients

Imaging fi ndings in acute invasive pulmonary aspergillosis: clinical signifi cance of the halo sign

The diagnostic value of halo and reversed halo signs for invasive mold infections in compromised hosts

Revised defi nitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group

Chest CT features of community-acquired respiratory viral infections in adult inpatients with lower respiratory tract infections

Cytomegalovirus pneumonitis presenting small nodular opacities

Clinical utility and prognostic value of bronchoalveolar lavage galactomannan in patients with hematologic malignancies

The clinical importance of bronchoalveolar lavage in allogeneic SCT patients with pneumonia

Serum galactomannan strongly correlates with outcome of invasive aspergillosis in acute leukaemia patients

Diagnostic performance of the (1-> 3)-beta-D-glucan assay for invasive fungal disease

-> 3)beta-D-glucan assay positivity in patients with Pneumocystis (carinii) jiroveci pneumonia

Comparison of conventional and molecular detection of respiratory viruses in hematopoietic cell transplant recipients

Comparison of real-time PCR assays with fl uorescent-antibody assays for diagnosis of respiratory virus infections in children

Differences in clinical outcomes after 2009 infl uenza A/H1N1 and seasonal infl uenza among hematopoietic cell transplant recipients

Pneumocystis pneumonia: clinical presentation and diagnosis in patients with and without acquired immune defi ciency syndrome

Pneumocystis pneumonia

Defi nitions of cytomegalovirus infection and disease in transplant recipients

Infectious Diseases Society of America/ American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults

Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia

Treatment of adenovirus infections in patients undergoing allogeneic hematopoietic stem cell transplantation

Adenoviruses in immunocompromised hosts

How I treat infl uenza in patients with hematologic malignancies

Randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hematopoietic cell transplant recipients

Successful treatment of parainfl uenza virus 3 pneumonia with oral ribavirin and methylprednisolone in a bone marrow transplant recipient

Successful treatment of human metapneumovirus pneumonia using combination therapy with intravenous ribavirin and immune globulin

The epidemiology of Candida glabrata and Candida albicans fungemia in immunocompromised patients with cancer

Catheter-related right-sided endocarditis in bone marrow transplant recipients

Characteristics and outcome of patients developing endocarditis following hematopoietic stem cell transplantation

Candida endocarditis in association with myelodysplastic syndromes: review of the literature and report of a case

Aspergillus endocarditis: a review of the literature

Fungal endocarditis in bone marrow transplantation: case report and review of literature

Cardiac involvement in bone marrow transplantation: electrocardiographic changes, arrhythmias, heart failure and autopsy fi ndings

Invasive zygomycosis in transplant recipients

Clinical signifi cance of extra-pulmonary involvement of invasive aspergillosis: a retrospective autopsy-based study of 107 patients

Pericarditis after allogeneic peripheral blood stem cell transplantation caused by Legionella pneumophila (non-serogroup 1)

Purulent pericarditis caused by Candida : report of three cases and identifi cation of high-risk populations as an aid to early diagnosis

Parvovirus B19 infection in pediatric solid-organ and bone marrow transplantation

Fatal cytomegalovirus myocarditis in a seronegative ALL patient

Myocarditis associated with Echo type 7 infection in a leukemic child

Prolonged enteroviral infection in a patient who developed pericarditis and heart failure after bone marrow transplantation

polyserositis with a large pericardial effusion and constrictive pericarditis as manifestations of chronic graft-versus-host disease after non-myeloablative peripheral stem cell transplantation and subsequent donor lymphocyte infusion

Myopericarditis caused by cyclophosphamide used to mobilize peripheral blood stem cells in a myeloma patient with renal failure

Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia

MRI of mycotic sinus of valsalva pseudoaneurysm secondary to Aspergillus pericarditis

Incidence of Clostridium diffi cile infection in patients with acute leukemia and lymphoma after allogeneic hematopoietic stem cell transplantation

Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease)

Nontyphoidal Salmonella infection among recipients of hematopoietic SCT

Recent epidemiology of Clostridium diffi cile infection during hematopoietic stem cell transplantation

Clostridium diffi cile infection in patients with neutropenia

Neutropenic enterocolitis in adults: case series and review of the literature

Clostridium septicum sepsis and neutropenic enterocolitis in a patient treated with intensive chemotherapy for acute myeloid leukemia

Virulence factors of Candida albicans

Stable susceptibility of Candida blood isolates to fl uconazole despite increasing use during the past 10 years

Hepatosplenic candidiasis. A manifestation of chronic disseminated candidiasis

A retrospective series of gut aspergillosis in haematology patients

Clinical presentation of zygomycosis

Two cases of hepatic zygomycosis in allogeneic stem cell transplant recipients and review of literature

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

Pathology of the liver with bone marrow transplantation. Effects of busulfan, carmustine, acute graft-versus-host disease, and cytomegalovirus infection

A prospective study of unexplained nausea and vomiting after marrow transplantation

Hepatitis due to herpes simplex virus in marrow-transplant recipients

Inappropriate antidiuretic hormone secretion, abdominal pain and disseminated varicella-zoster virus infection: an unusual triad in a patient 6 months post mini-allogeneic peripheral stem cell transplant for chronic myeloid leukemia

Triad of severe abdominal pain, inappropriate antidiuretic hormone secretion, and disseminated varicella-zoster virus infection preceding cutaneous manifestations after hematopoietic stem cell transplantation: utility of PCR for early recognition and therapy

Acute abdomen without cutaneous signs of varicella zoster virus infection as a late complication of allogeneic bone marrow transplantation: importance of empiric therapy with acyclovir

Preemptive diagnosis and treatment of Epstein-Barr virus-associated post transplant lymphoproliferative disorder after hematopoietic stem cell transplant: an approach in development

The role of HLA mismatch, splenectomy and recipient Epstein-Barr virus seronegativity as risk factors in post-transplant lymphoproliferative disorder following allogeneic hematopoietic stem cell transplantation

Posttransplantation lymphoproliferative disorder in children: manifestations in hematopoietic cell recipients in comparison with liver recipients

Adenovirus infections in transplant recipients

Adenovirus infections in stem cell transplant recipients: recent developments in understanding of pathogenesis, diagnosis and management

Adenovirus infections in stem cell transplant recipients: recent developments in understanding of pathogenesis, diagnosis and management

Increasing incidence of adenovirus disease in bone marrow transplant recipients

Fulminant adenovirus hepatitis following bone marrow transplantation. A case report and brief review of the literature

Fulminant adenovirus hepatitis following unrelated bone marrow transplantation: failure of intravenous ribavirin therapy

Allogeneic hematopoietic stem cell transplantation and norovirus gastroenteritis: a previously unrecognized cause of morbidity

Norovirus gastroenteritis causes severe and lethal complications after chemotherapy and hematopoietic stem cell transplantation

Chronic norovirus infection in pediatric hematopoietic stem cell transplant recipients: a cause of prolonged intestinal failure requiring intensive nutritional support

Division of Viral Diseases; National Center for Immunization and Respiratory Diseases

Updated norovirus outbreak management and disease prevention guidelines

Work-up for infectious diarrhea after allogeneic hematopoietic stem cell transplantation: single specimen testing results in cost savings without compromising diagnostic yield

Analysis of rotavirus antigenemia in hematopoietic stem cell transplant recipients

HBV disease: HBsAg carrier and occult B infection reactivation in haematological setting

Lamivudine prophylaxis for prevention of chemotherapyinduced hepatitis B virus reactivation in hepatitis B virus carriers with malignancies

Lamivudine prophylaxis and treatment of hepatitis B Virus-exposed recipients receiving reduced intensity conditioning hematopoietic stem cell transplants with alemtuzumab

Extended lamivudine therapy against hepatitis B virus infection in hematopoietic stem cell transplant recipients

Long-term outcome of hepatitis C infection after bone marrow transplantation

Hepatitis C virus infection and bone marrow transplantation: a cohort study with 10-year follow-up

Hepatic candidiasis in cancer patients: the evolving picture of the syndrome

False-positive Aspergillus galactomannan antigenaemia after haematopoietic stem cell transplantation

False positivity of the Aspergillus galactomannan Platelia ELISA because of piperacillin/tazobactam treatment: does it represent a clinical problem?

Green ulcer in the stomach: unusual mucormycosis infection

Recognition and rapid diagnosis of upper gastrointestinal cytomegalovirus infection in marrow transplant recipients. A comparison of seven virologic methods

Comparison of clinical and microbiological response to treatment of Clostridium diffi cile-associated disease with metronidazole and vancomycin

Posttransplant lymphoproliferative disorder

Epstein-Barr virus-associated lymphoproliferative disease after allogeneic haematopoietic stem cell transplantation: molecular monitoring and early treatment of high-risk patients

Nitazoxanide in the treatment of viral gastroenteritis: a randomized double-blind placebo-controlled clinical trial

Chronic hepatitis B: update 2009

Acute renal failure after allogeneic myeloablative stem cell transplantation: retrospective analysis of incidence, risk factors and survival

Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation

Colonization and infection with vancomycin-resistant Enterococcus among patients with cancer

Species distribution and antimicrobial susceptibility of gram-negative aerobic bacteria in hospitalized cancer patients

Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults

Renal Candida tropicalis abscesses in a patient with acute lymphoblastic leukemia

Funguria in cancer patients: analysis of risk factors, clinical presentation and outcome in 50 patients

Aspergillus "fungus ball" of the bladder after hematopoietic transplantation in a pediatric patient: successful treatment with intravesical voriconazole and surgery

Primary renal aspergillosis and renal stones in both kidneys associated with hematopoietic stem cell transplant

Aspergilloma of the renal pelvis in a leukemic child

Invasive zygomycosis in patients with graft-versushost disease after allogeneic stem cell transplantation

Isolated renal mucormycosis

BK virus infection in hematopoietic stem cell transplant recipients: frequency, risk factors, and association with postengraftment hemorrhagic cystitis

Reversible ureteral obstruction due to Polyomavirus infection after percutaneous nephrostomy catheter placement

BK virus: opportunity makes a pathogen

BK virus nephropathy after allogeneic stem cell transplantation: a case report and literature review

Different risk factors related to Adenovirus-or BK virusassociated hemorrhagic cystitis following allogeneic stem cell transplantation

Hematuria due to adenoviral infection in bone marrow transplant recipients

Adenovirus nephritis in hematopoietic stem-cell transplantation

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

Bladder irrigation with amphotericin B and fungal urinary tract infection -systematic review with meta-analysis

Low-dose cidofovir treatment of BK virus-associated hemorrhagic cystitis in recipients of hematopoietic stem cell transplant

The decade of polyomavirus BK-associated nephropathy: state of affairs

Anti-BK virus mechanisms of sirolimus and lefl unomide alone and in combination: toward a new therapy for BK virus infection

Treatment of adenovirus disease in stem cell transplant recipients with cidofovir

An updated approach to the diagnosis of myeloid leukemia cutis

Diagnosis and treatment of the neutrophilic dermatoses (pyoderma gangrenosum, Sweet's syndrome)

Cutaneous manifestations of Corynebacterium jeikeium sepsis

Disseminated subcutaneous Nocardia asteroides abscesses in a patient after bone marrow transplantation

Nontuberculous mycobacterial infection in hematopoietic stem cell and solid organ transplant recipients

Necrotizing fasciitis in two children with acute lymphoblastic leukemia

Gangrenous cellulitis associated with gram-negative bacilli in pancytopenic patients: dilemma with respect to effective therapy

Fatal Fournier's gangrene in a young adult with acute lymphoblastic leukemia. Pediatr Blood Cancer

Cutaneous manifestations of disseminated candidiasis

A case of disseminated Cryptococcosis with skin eruption in a patient with acute leukemia

Cutaneous mucormycosis in a leukemic patient

Disseminated Fusarium solani infection

Fusarium, a signifi cant emerging pathogen in patients with hematologic malignancy: ten years' experience at a cancer center and implications for management

Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir

Human herpesvirus 6 infection after hematopoietic cell transplntation: is routine surveillance necessary?

Management of fever in neutropenic patients with different risks of complications

Emergence of quinolone resistance among viridans group streptococci isolated from the oropharynx of neutropenic peripheral blood stem cell transplant patients receiving quinolone antimicrobial prophylaxis

A double-blind comparison of empirical oral and intravenous antibiotic therapy for low-risk febrile patients with neutropenia during cancer chemotherapy

Ciprofl oxacin vs an aminoglycoside in combination with a beta-lactam for the treatment of febrile neutropenia: a meta-analysis of randomized controlled trials

Reappraisal with metaanalysis of the addition of Gram-positive prophylaxis to fl uoroquinolone in neutropenic patients

An international comparison of current strategies to prevent herpesvirus and fungal infections in hematopoietic cell transplant recipients

Fluconazole prophylaxis of fungal infections in patients with acute leukemia. Results of a randomized placebo-controlled, doubleblind, multicenter trial

Randomized placebocontrolled trial of fl uconazole prophylaxis for neutropenic cancer patients: benefi t based on purpose and intensity of cytotoxic therapy. The Canadian Fluconazole Prophylaxis Study Group

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

Antifungal prophylaxis with micafungin in neutropenic patients with hematological malignancies

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

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

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

Effi cacy, safety, and breakthrough infections associated with standard long-term posaconazole antifungal prophylaxis in allogeneic stem cell transplantation recipients

Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials

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

Prophylactic use of ganciclovir in allogeneic bone marrow transplantation: absence of clinical cytomegalovirus infection

Ganciclovir prophylaxis of cytomegalovirus infection and disease in allogeneic bone marrow transplant recipients. Results of a placebo-controlled, double-blind trial

Neutropenia in allogeneic marrow transplant recipients receiving ganciclovir for prevention of cytomegalovirus disease: risk factors and outcome

Randomized clinical trial of ganciclovir vs acyclovir for prevention of cytomegalovirus antigenemia after allogeneic transplantation

Emergence of drug-resistant cytomegalovirus in the era of valganciclovir prophylaxis: therapeutic implications and outcomes

Randomized study of valacyclovir as prophylaxis against cytomegalovirus reactivation in recipients of allogeneic bone marrow transplants

Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantifi cation of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction

Rituximab treatment for Epstein-Barr virus DNAemia after alternative-donor hematopoietic stem cell transplantation

Monitoring and preemptive rituximab therapy for Epstein-Barr virus reactivation after antithymocyte globulin containing nonmyeloablative conditioning for umbilical cord blood transplantation

Prompt versus preemptive intervention for EBV lymphoproliferative disease

Long-term ultra-low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation

Low-dose acyclovir against reactivation of varicella zoster virus after unrelated cord blood transplantation

High-risk adenovirus-infected pediatric allogeneic hematopoietic progenitor cell transplant recipients and preemptive cidofovir therapy

How I treat adenovirus in hematopoietic stem cell transplant recipients

Palivizumab prophylaxis to prevent respiratory syncytial virus mortality after pediatric bone marrow transplantation: a decision analysis model

Respiratory syncytial virus infection and prophylaxis with palivizumab in immunosuppressed children: the experience of a large Italian neonatal care setting

The authors wish to thank Kyoko Kurosawa for the excellent illustrations.