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Infectious complications after hematopoietic stem cell transplantation: current status and future perspectives in Korea

Article information

Korean J Intern Med. 2018;33(2):256-276
Publication date (electronic) : 2018 February 27
doi : https://doi.org/10.3904/kjim.2018.036
Sung-Yeon Cho1,2,3, Hyeon-Jeong Lee1, Dong-Gun Lee1,2,3
1Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
2The Catholic Blood and Marrow Transplantation Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
3Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
Correspondence to Dong-Gun Lee, M.D. Division of Infectious Diseases, Department of Internal Medicine, The Catholic Blood and Marrow Transplantation Centre, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea Tel: +82-2-2258-6003 Fax: +82-2-535-2494 E-mail: symonlee@catholic.ac.kr
Received 2018 February 12; Accepted 2018 February 18.

Abstract

Hematopoietic stem cell transplantation (HSCT) is a treatment for hematologic malignancies, immune deficiencies, or genetic diseases, ect. Recently, the number of HSCTs performed in Korea has increased and the outcomes have improved. However, infectious complications account for most of the morbidity and mortality after HSCT. Post-HSCT infectious complications are usually classified according to the time after HSCT: pre-engraftment, immediate post-engraftment, and late post-engraftment period. In addition, the types and risk factors of infectious complications differ according to the stem cell source, donor type, conditioning intensity, region, prophylaxis strategy, and comorbidities, such as graft-versushost disease and invasive fungal infection. In this review, we summarize infectious complications after HSCT, focusing on the Korean perspectives.

Keywords: Hematopoietic stem cell transplantation; Immunocompromised host; Infectious diseases; Opportunistic infections

INTRODUCTION

Hematopoietic stem cell transplantation (HSCT), known previously as bone marrow transplantation, is performed to treat two broad categories of diseases. The first category consists of functional failure of bone marrow or marrow-derived cells, including aplastic anemia, myelodysplastic syndrome, immunodeficiency syndromes (severe combined immune deficiency or chronic granulomatous disease), genetic diseases (mucopolysaccharidosis, glycogen storage diseases, etc.), or hemoglobinopathies (thalassemia, sickle cell anemia, etc.). In such cases, HSCT is applied to replace the defective, non-functional bone marrow tissues. Diseases in the second category—which includes hematologic malignancies such as acute or chronic leukemia, multiple myeloma, lymphomas, and myeloproliferative neoplasms—are more common indications for HSCT, the performance of which aims (1) to restore the myelosuppressive or myeloablative effect of cytotoxic treatment (such as intensive chemotherapy and/or total body irradiation [TBI]) to eliminate malignant cells, and (2) to induce a graft-versus-leukemic effect by providing anti-neoplastic immune cells expressing tumor-specific or -associated antigens [1,2].

Until the 1970s, HSCTs were simply classified as autologous or allogeneic according to their donor status, and survival rates were very low. Since the introduction of the human leukocyte antigen (HLA) concept, the incidence of graft failure and/or graft-versus-host disease (GVHD) has decreased. In recent years, allogeneic HSCT has involved various sources of hematopoietic stem cells (bone marrow, peripheral stem cell, cord blood, and mesenchymal cells), donors (sibling, unrelated, haploidentical), and conditioning regimens (standard [myeloablative], reduced intensity). Supportive therapies such as transfusion, colony stimulating factors, and antimicrobial agents have also been developed. Although various early diagnosis and therapeutic techniques have been developed to improve transplant performance, infectious diseases still affect the prognosis of HSCT recipients [2-4].

In Korea, HSCT was first performed in 1983 [5], and the number of transplants has rapidly increased over the past 30 years. In addition to being susceptible to infectious diseases due to neutropenia immediately after HSCT, delayed immune recovery is evident over a long period of time after engraftment, depending on the type of HSCT, immunosuppressants, and acute or chronic GVHD. Because the prevalent infectious diseases vary geographically and over time, state-of-the-art knowledge is needed [6-8]. In this manuscript, infectious complications after HSCT, particularly those common in Korea, are reviewed, as well as the epidemiology, diagnosis, preventive or therapeutic strategies, and novel drugs for improving outcomes of patients.

IMMUNE RECONSTITUTION AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION

The post-HSCT period is usually divided into the (1) pre-engraftment period (day 0 to days 15–45), (2) immediate post-engraftment period (engraftment to day 100), and (3) late post‑engraftment period (days 100 to 365). In general, the neutrophil count recovers 2 to 3 weeks after HSCT. However, the functional recovery of various cell types is also important. Immunological recovery takes 3 to 6 months for NK cells, 6 to 12 months for B-cells and CD8 T-cells, and 1 to 2 years for CD4 T-cells [9]. The use of T-cell-depleting agents (anti-thymocyte globulin [ATG], alemtuzumab, etc.) to reduce the risk of GVHD and graft failure could improve the outcomes of transplantation but may delay immune recovery [10]. Recipients of T‑cell-depleted transplantation may be vulnerable to viral infections—such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), or adenovirus—and adoptive immunotherapy may be applied [11].

During the pre-engraftment period, the risk of opportunistic infection varies depending on the type of anticancer drugs used, conditioning intensity (myeloablative or reduced intensity), and presence of acute GVHD. Autologous HSCT leads to more rapid recovery of immune function than allogeneic HSCT. In the post-engraftment period, the immune system is reconstituted and recovered in autologous HSCT recipients. However, allogeneic HSCT recipients undergoing long-term immunosuppressive therapy for chronic GVHD remain at risk of infection. Table 1 shows the risk factors for, and infectious diseases commonly encountered after, HSCT.

Common infectious diseases and risk factors according to the various time periods after hematopoietic stem cell transplantation

BACTERIA

Epidemiology

As shown in Table 1, the infectious diseases that occur before the engraftment are similar to those that develop during the neutropenic phase after chemotherapy [2,12]. Neutrophils are important in innate immunity against microorganisms. A decrease in the number of neutrophils increases the susceptibility to infection. In addition, patients with neutropenia have a reduced number of leukocytes. Therefore, inflammatory findings, which are common in patients with normal leukocyte counts, are not often seen, with the exception of fever, which is difficult to diagnose, so the appropriate time to start treatment may be missed [13]. The main sources of bacterial infections in the pre-engraftment phase are the normal gastrointestinal flora and indwelling vascular catheters. Gram-negative bacilli (GNB) are common pathogens in the former, while Gram-positive cocci (GPC) are more common in the latter [14]. In general, microbiologically defined infections (MDIs) account for only 30% to 40% of cases of neutropenic fever [15].

The distribution of causative organisms in febrile neutropenic patients varies geographically. In the United States and Europe, GPC accounted for 60% to 70% of MDI until the early 1990s, while the proportion of GNB increased after the mid-2000s. In a multicenter epidemiological survey, the proportions of Gram-positive and -negative cases were 55% (range, 30% to 85%) and 45% (range, 15% to 70%), respectively [16-18]. Enterobacteriaceae was the most common causative organism, accounting for 30% (range, 8% to 56%). The second most common organism was coagulase-negative staphylococci (24% [range, 7% to 51%]). In Korean studies, GNB were also more common until the mid-2000s, which is consistent with other reports from the Asia-Pacific region [19]. Intestinal bacteria such as Escherichia coli, Klebsiella pneumoniaei, and Pseudomonas aeruginosa are frequently reported GNB, and Enterococcus, Streptococcus, and Staphylococcus species are common among GPC [6-8,20-22]. Because the epidemiology of bacterial pathogens and the resistance profiles varies, early empirical antimicrobial agents must be selected according to the distributions and susceptibilities of the frequently detected bacterial taxa in that center [13,15,19].

In the late post-engraftment phase after autologous HSCT, the immune system is reconstituted and restored, which is consistent with the time at which chronic GVHD typically develops after allogeneic HSCT. Therefore, autologous transplant recipients rarely experience opportunistic infections at this time, but allogeneic HSCT recipients (who take chronic immunosuppressive drugs for several months) are at risk of infection. In this period, infectious diseases may continue to develop. In addition, the immune deficiency resulting from chronic GVHD is associated with infections by encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis [2,12]. Deficiencies in immunoglobulin G2 (IgG2) and IgG4 have been reported in patients with chronic and severe GVHD, and are associated with severe pneumonia, meningitis, and sepsis due to S. pneumoniae [23]. Early diagnosis and treatment are essential, and vaccination should be emphasized in this high-risk group of patients. Immunization after HSCT will be described in a separate section of this review.

Resistance

Over the past decade, the frequency of detection of resistant bacteria has increased worldwide, including in patients with neutropenic fever and hematologic malignancies [24]. Among extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae, K. pneumoniae comprises around two-thirds, and E. coli about one-thirds (range, 11% to 69%), depending on the region [18,25-27]. In the late 2000s, 26% of E. coli and K. pneumoniae bacteremia isolates from neutropenic patients were ESBL-producing strains in a single-center study [26]. The incidence of infections caused by carbapenem-resistant Enterobacteriaceae (CRE), along with ESBL-producing Enterobacteriaceae, is increasing in hematologic malignancy patients [18,28-31]. K. pneumoniae, E. coli, P. aeruginosa, and Acinetobacter baumannii are clinically important strains associated with the acquisition of carbapenem resistance. A study of prior colonization by CRE as a risk factor for CRE bloodstream infections found that 45% of neutropenic patients with carbapenem-resistant K. pneumoniae rectal colonization experienced bloodstream infection by an identical strain [30]. There is no multicenter study of CRE in HSCT recipients. However, a single-center, retrospective cohort study performed in Korea reported that the incidence of carbapenem‑resistant A. baumannii bacteremia was 0.53 cases per 10,000 patient-days; post-engraftment infection by this organism can be fatal [31].

The rate of methicillin-resistant coagulase-negative staphylococci is reportedly higher than 50% in most centers, while the incidence rate of Staphylococcus aureus in HSCT patients is low with a high methicillin-resistance rate of median 56% (range, 18% to 100%) [18]. In the late 2000s, coagulase-negative staphylococci were reported to have a methicillin resistance rate of more than 90% and S. aureus a rate of more than 60% [22]. The incidence of Enterococcus bloodstream infections was 1.76 cases per 1,000 patient-days, with vancomycin-resistant Enterococcus (VRE) accounting for 20.6% [22,32]. Most VRE bloodstream infections are caused by E. faecium and are associated with long-term hospitalization and an underlying medical condition, but the resistance itself has not been associated with mortality [32].

The epidemiology of drug-resistant pathogens is important for establishing strategies for prophylaxis and initial empirical antimicrobial therapy. Because domestic data are limited to single-institution and retrospective studies, multicenter nationwide studies of the epidemiology of bacterial infections in Korea are required.

Prophylaxis strategies

Prophylaxis plays an important role during the pre-engraftment phase (Table 2). Oral fluoroquinolone prophylaxis can reduce febrile neutropenic episodes and related mortality in allogeneic HSCT recipients [33,34]. According to the guidelines from the Infectious Diseases Society of America and Infectious Diseases Working Party of the German Society of Hematology and Oncology, ciprofloxacin and levofloxacin are equally effective, but levofloxacin may be more effective in terms of broader coverage of viridans streptococci when oral mucositis is present [15,35]. Although fluoroquinolone prophylaxis has led to an increase in the frequency of drug-resistant (including quinolones) pathogens, the benefit reportedly outweighs the risk [33]. Fluoroquinolone prophylaxis decreased the rate of identification of P. aeruginosa [22]. However, fluoroquinolone prophylaxis is reportedly correlated with resistance development and Clostridium difficile-associated diarrhea [36-41]. Moreover, fluoroquinolone prophylaxis may reduce the rate of bloodstream infections, but not the overall mortality rate [42]. Therefore, the benefit of routine fluoroquinolone prophylaxis should be weighed against its toxicity and effect on the local epidemiology.

Overall infection risk and needs for antimicrobial prophylaxis after HSCT

Empirical therapy: escalation vs. de-escalation therapy

In neutropenic patients during the pre-engraftment phase, infections can progress rapidly. In addition, as it is difficult to distinguish between bacterial infection and non-infectious fever in the early stages, empirical antimicrobial therapy is recommended immediately in all patients with febrile neutropenic episodes. Except for the presence of definite infection foci, the broad-spectrum β-lactam antibiotics ceftazidime, cefepime, piperacillin/tazobactam, and carbapenem are recommended as they have activity against Gram-positive and -negative bacteria, including P. aeruginosa [13,15,43,44]. Step-down therapy can be considered after an initial regimen comprising two or more antimicrobial agents, depending on the local epidemiology and resistance profiles.

The de-escalation approach is generally recommended when high incidence of resistant pathogens in neutropenic fever, or high colonization rates of multiple drug resistance bacteria, or if the patient has a history of infection with drug-resistant pathogens [13,24,44]. However, the data on cut-offs for resistance are insufficient to formulate such a strategy. In addition, no randomized controlled study has compared the therapeutic efficacy of the escalation and de-escalation approaches in HSCT recipients. Selection of the appropriate strategy should take into account the patient’s condition and the prevalence of resistant organisms in the center.

FUNGI

Aspergillus species are the most common causes of invasive fungal infections (IFIs) in patients with hematologic diseases, followed by Candida spp. and rare fungi [45]. The causative fungi are not different after HSCT [46,47]. The characteristics of, and risk factors for, fungal infections differ according to the phase after transplantation. During the pre-engraftment period, neutropenia and mucosal damage are risk factors for invasive candidiasis [4]. Antifungal prophylaxis regimens used during and/or after HSCT are listed in Table 3 [13,48]. Recent advances in the use of prophylactic antifungal agents during HSCT have led to changes in the epidemiology of candidiasis [49]. The Korean epidemiologic data show that the incidence of Candida albicans infection is markedly reduced by antifungal prophylaxis [22]. Nonetheless, the incidence of C. albicans has been decreased by the increasing prophylactic use of fluconazole or echinocandins, and attention should be paid to the selection of antifungal agents for empirical or targeted therapy for invasive candidiasis [50,51]. Post-engraftment, the risk of candida infection decreases with the recovery of neutropenia and mucosal skin loss, but the risk of aspergillosis remains [52].

Suggested anti-fungal prophylaxis after HSCT

Invasive aspergillosis (IA) that develops during the neutropenic period typically involves angioinvasion due to host immunosuppression. In contrast, IA that occurs in non‑neutropenic patients, usually due to long-term use of steroids or immunosuppressive agents for GVHD, is more likely to be caused by local inflammation (i.e., airway invasiveness) than by vascular invasion [53]. In the SEIFEM B-2004 study, the most frequent etiological agents of IFI were Aspergillus (70.1%) and Candida (24.8%) species. The IFI-attributable mortality rate was 65.3% (72.4% for allogeneic HSCT recipients and 34.7% for autologous HSCT recipients) [46]. In a prospective observational study performed in the Asia-Pacific region, IA accounted for 65.9% of IFI, followed by 26.7% of invasive candidiasis. Interestingly, Aspergillus spp. was not the major fungal pathogen in centers in Thailand and Vietnam, probably because galactomannan testing was unavailable. The heterogeneity of diagnostic, prophylactic, and therapeutic approaches for IFI necessitates local epidemiological data [54].

The incidence of IFI is higher in allogeneic than in autologous HSCT, and the established risk factors include chronic GVHD and steroid use [3]. According to a recent multicenter study performed in Korea (RISK study), the cumulative incidence of IFI after transplantation is 15.36% per year. Notably, the risk factors were different according to the time after transplantation. Prolonged neutropenia (hazard ratio [HR], 12.61; 95% confidence interval [CI], 4.30 to 36.97, in the early phase), CMV reactivation (HR, 21.44; 95% CI, 2.64 to 173.90, in the late phase), secondary neutropenia (HR, 5.29; 95% CI, 1.14 to 24.49, in the very late phase), and use of secondary immunosuppressive agents due to refractory GVHD (i.e., tumor necrosis factor-α inhibitors) (HR, 37.93; 95% CI, 3.79 to 379.45, in the very late phase) are risk factors for IFIs after HSCT [47]. Therefore, active anti-mold prophylaxis should be considered in patients with those risk factors. Currently, voriconazole is available in Korea for secondary prophylaxis of IA after HSCT, and posaconazole for patients on significant immunosuppressive agents for GVHD.

The diagnosis of IFI after HSCT is not markedly different from that before engraftment. However, the computed tomography (CT) findings of invasive pulmonary aspergillosis in patients with hematologic diseases may differ depending on the time of neutropenia and the time of neutrophil recovery after HSCT, suggesting that the diagnostic criteria may need to be redefined [55]. To diagnose IFIs, radiologic examinations such as chest X-ray and CT, and microbiological studies including fungal culture, and galactomannan and β-D-glucan assays should be performed periodically. For accurate diagnosis, bronchoscopy and bronchoalveolar lavage (BAL) fluid examination, lung biopsy, and culture are required.

Voriconazole is the drug of choice for treating IA. Voriconazole therapeutic drug monitoring can be used in many centers, and the target trough level is 1 to 5.5 mg/L. The CYP2C19 polymorphism affects the pharmacokinetics of voriconazole. Among Korean hematologic patients, 28% are extensive metabolizers (EMs), 48% are heterozygous EMs, and 14% are poor metabolizers. While subtherapeutic initial trough levels were common in EMs, there was no significant relationship between CYP2C19 genotype and the clinical outcomes of IA or the toxicity of voriconazole [56]. Isavuconazole is non-inferior to voriconazole for the primary treatment of suspected invasive mold disease, with fewer drug-related adverse events [57,58]. Salvage therapy includes liposomal amphotericin B, caspofungin, posaconazole, and itraconazole, or a combination of them [58]. Treatment duration is at least 6 to 12 weeks, which should be individualized according to the changes in radiologic, microbiologic, and immunologic parameters.

IFIs can occur during treatment with anti-mold agents. Patients with GVHD under long-term immunosuppressive therapy should be on antifungal agents to prevent IFIs (Table 3). In particular, there is a risk of IFIs other than aspergillosis, such as mucormycosis or other rare molds [48,59,60]. A retrospective single-center study reported that the prevalence and incidence of voriconazole-breakthrough IFIs were 2.25% and 0.22 cases per year, respectively. The overall mortality rate was 44.4% [61]. The possible causes of breakthrough IFI during voriconazole treatment were persistent immunodeficiency, neutropenia, low voriconazole concentration, or poor vascular supply (i.e., abscess or necrotic tissue) [61]. In voriconazole-refractory IA, clinicians should consider the following: misdiagnosis or coinfection with another mold, inadequate blood voriconazole concentration, inadequate tissue drug concentration, immune reconstitution inflammatory syndrome, or infection with voriconazole-resistant Aspergillus [62]. Proven/probable IA patients reportedly have a low culture-positive rate (17.7%) [63]. To determine the azole-resistance rate of Aspergillus clinical isolates in Korea, culture-positive cases should undergo susceptibility testing.

PNEUMOCYSTIS JIROVECII PNEUMONIA

The major symptoms of Pneumocystis jirovecii pneumonia (PCP) are fever, difficulty breathing, and dry cough rather than purulent sputum. Typical radiologic findings are bilateral diffuse infiltrates originating from the periphery of both lungs, but may be normal at the beginning. PCP can present as segmental consolidation in the upper lobe, or subtle ground glass opacities and pneumothorax. It usually occurs within 6 months after transplantation but also after 6 months of immunosuppressive therapy for chronic GVHD [3,4]. The known risk factors for PCP in hematologic patients are acute lymphoblastic leukemia, allogeneic HSCT recipients, alemtuzumab, fludarabine, cyclophosphamide, rituximab, and steroid use (> 20 mg/day prednisone for 4 weeks) [64].

If PCP is clinically suspected, CT, bronchoscopy, and BAL should be performed as early as possible. In a retrospective study of bronchial washings or BAL fluid from non-human immunodeficiency virus (HIV)-infected patients suspected of respiratory infection, among the 169 polymerase chain reaction (PCR)-positive patients, 63.3% were classified as PCP and 46.7% as non-PCP. The majority of patients (84%) in the non-PCP group recovered without treatment for PCP [65]. In two recent meta-analyses, the sensitivity and specificity of quantitative PCR (qPCR) assays were superior to those of non-qPCR assays [66,67]. The serum β-D-glucan test result has a high negative-predictive value but is not useful for the follow-up of PCP [68]. The prognosis is worse in the presence of concomitant infectious diseases, particularly CMV, Aspergillus, and so on. Steroids can be used as an adjunctive therapy in patients with hypoxia (PaO2 ≤ 70 mmHg or PAO2-PaO2 ≥ 35 mmHg).

The incidence of PCP has been significantly reduced by trimethoprim/sulfamethoxazole prophylaxis in highrisk patients. High-risk patients who do not take prophylaxis or who show poor compliance with the drug regimen are the main populations at risk of PCP. In a systematic review and meta-analysis of non-HIV immunocompromised hosts (patients with acute leukemia and recipients of HSCT and solid organ transplant), the incidence of PCP was reduced by 91% (relative risk [RR], 0.09) in trimethoprim/sulfamethoxazole prophylaxis group compared with placebo [69,70]. In addition, PCP-related mortality was significantly reduced by 83% (RR, 0.17). However, trimethoprim/sulfamethoxazole prophylaxis did not markedly reduce all-cause mortality in a hematology population [70]. Mortality rates remain very high in hematology patients (30% to 59%), particularly in HSCT recipients (48% to 70%), compared with 17% to 30% in patients with HIV infection [71]. Nevertheless, given the more severe course of PCP and the higher PCP-related mortality rates, trimethoprim/sulfamethoxazole prophylaxis can likely save lives in other immunocompromised groups as well. PCP should be prevented for at least 6 months or until the immunosuppressant is discontinued in allogeneic HSCT recipients [13,48,71]. Although the optimum duration of PCP prophylaxis is controversial, it is suggested to be continued for a period of time after the immunosuppressant is discontinued. In the setting of corticosteroid-containing regimens, prophylaxis should be continued while steroids are being weaned and/or for 6 weeks after their cessation [72]. With some chemotherapy regimens (i.e., alemtuzumab) consideration should be given to extended PCP prophylaxis for up to 12 months because of the high rate of late-onset PCP [73]. Table 4 summarizes the methods of preventing PCP after HSCT.

PCP prophylaxis after HSCT

CYTOMEGALOVIRUS

CMV infection can occur after HSCT and can be fatal. CMV can be reactivated or the patient can be reinfected after transplantation. The spectrum of CMV infection is extensive, from CMV reactivation without organ involvement (presenting mainly as asymptomatic antigenemia or DNAemia) to CMV disease such as esophagitis, gastritis, colitis, hepatitis, pneumonia, retinitis, and encephalitis. In addition to direct organ involvement, CMV reactivation can exert indirect effects—such as graft failure or immunosuppression—that may result in the development of concurrent bacterial and/or fungal infections [74]. CMV disease, especially CMV pneumonia or encephalitis, can be fatal despite aggressive anti-CMV therapy [75,76].

A 10-year retrospective single-center study performed in Korea reported that CMV disease occurred in 2.9% of allogeneic HSCT recipients and 0.5% of autologous HSCT recipients. Pneumonia (38.6%), retinitis (36.4%), and enteritis (15.9%) frequently developed in patients with CMV infection. The average time of onset of CMV disease was 90 days after transplantation, ranging from 12 to 936 days [77]. Another study in the same institution reported that CMV DNAemia developed in about 51% of HSCT recipients [78]. CMV reactivation can be associated with a higher non-relapse mortality rate (RR, 1.61 to 1.95) [79]. In another report, 70% of HSCT recipients had experienced any level of CMV antigenemia, of whom 41% had received ganciclovir therapy for significant CMV reactivation and 4% had CMV diseases. However, this incidence could be underestimated because disease prevalence was not evaluated in all patients undergoing pre-emptive therapy [80].

Because the diagnosis of CMV disease is based on the pathology findings, the diagnosis might be limited depending on the patient’s condition. Particularly for the diagnosis of CMV pneumonia, obtaining lung tissue from critically ill patients by transbronchial lung biopsy is problematic. One study aimed to measure the CMV level in bronchial washing fluid and suggest a cut-off for pneumonia diagnosis. CMV DNAemia of > 18,900 copies/mL (137,970 IU/mL) may be associated with CMV pneumonia in post-HSCT patients, as determined by the receiver operating characteristics curve [81]. However, further data are needed because it is difficult to distinguish whether the viral DNA in alveolar hemorrhage reflects viremia rather than lung tissue involvement, or whether CMV is detected as a bystander in bronchial washing fluid.

Management of CMV is categorized into prevention, pre-emptive treatment, and definitive treatment. Pre-emptive therapy is anti-CMV treatment even in the absence of clinical symptoms in cases with CMV infection (reinfection or reactivation). Most transplantation centers introduce pre-emptive therapy rather than routine universal prevention because of insurance coverage, cost-benefit ratio, and adverse drug reactions. Studies of monitoring strategies and early detection have resulted in the use of CMV pp65 antigenemia testing and real-time qPCR for the surveillance and identification of patients suitable for pre-emptive therapy [82,83]. However, in HSCT, the relationship between CMV viral load and CMV disease is different from that in solid organ transplantation. CMV gastrointestinal disease can develop without preceding CMV antigenemia or DNAemia, while > 75,000 copies/mL of CMV DNAemia is reportedly associated with an increased risk of CMV retinitis after HSCT [78,84]. However, the correlations were moderate, and antigenemia or DNAemia does not necessarily precede or accompany CMV disease. Therefore, it is important to identify the at-risk groups and clinical features of the various CMV diseases to facilitate early diagnosis and treatment.

A recent prospective double-blind trial evaluated letermovir prophylaxis for preventing CMV in HSCT recipients. A total of 565 patients underwent randomization and received letermovir or placebo through week 14 after transplantation. The incidence of clinically significant CMV infection was lower in the letermovir group than in the placebo group by week 24 after transplantation (122 of 325 patients [37.5%] vs. 103 of 170 patients [60.6%], p < 0.001). Letermovir prophylaxis resulted in a significantly lower risk of clinically significant CMV infection than placebo. Adverse events with letermovir were mainly of low grade [85]. As a result, the U.S. Food and Drug Administration has approved letermovir for the prevention of CMV infection and diseases in adult CMV-seropositive patients undergoing allogeneic HSCT.

In Korea, which has a high CMV-seropositive rate (95% to 100%) in adults, most donors and recipients are seropositive (D+/R+) and the frequency of CMV infection after transplantation is up to 50% [76]. In addition, owing to active CMV monitoring and pre-emptive therapy, there has been a decrease in the incidence of CMV infection immediately after transplantation. However, late CMV infection (> 3 months after transplantation) is increasing, especially if CMV-specific T-cell function has not been restored due to chronic GVHD. Therefore, immune monitoring is required in patients with high-risk of CMV disease. CMV-specific immune recovery has been studied in kidney transplantation (KT) and HSCT recipients [86-91]. CMV-specific cytotoxic T lymphocytes (CTLs) play an important role in the reconstitution of CMV-specific immunity in immunocompromised patients. The methods used to evaluate CMV-specific immunity include tetramer assay, intracellular cytokine analysis by flow cytometry, measurement of interferon-γ secretion by CMV-specific CD8 T-cells, and enzyme‑linked immunospot assay using IE-1 and pp65 peptide pools [92]. Quantification of CMV‑specific T-cell immunity after HSCT facilitates the identification of patients at risk of CMV‑related complications [87,88].

Currently available anti-CMV agents in Korea are ganciclovir, valganciclovir, foscarnet, and cidofovir. Since February 2018, the use of valganciclovir in HSCT patients with CMV infection has increased due to changes in the reimbursement rules. Regarding adverse events, attention should be paid to bone marrow suppression, and in patients with renal insufficiency. GVHD or the use of monoclonal antibodies (i.e., alemtuzumab) can increase the incidence of CMV infections. Such infections may not be distinguishable from GVHD, or may coexist with GVHD, and may not respond to antiviral drugs if diagnosis is delayed [93]. If there is persistent infection despite anti-CMV therapy, CMV refractoriness can be considered if a > 1 log10 decrease in CMV DNA level in blood or plasma is not achieved after ≥ 2 weeks of treatment. In CMV-refractory cases, resistance should also be suspected. Although CMV resistance remains uncommon in HSCT recipients from HLA-matched donors (0% to 7.9%), in high-risk patients, the incidence of CMV resistance is up to 14.5% [94-96]. The gold standard of CMV resistance testing is an increase in the IC50 (half maximal inhibitory concentration) value by plaque reduction assay. However, CMV resistance can be defined when one or more genetic mutations associated with ganciclovir, valganciclovir, foscarnet, and cidofocir are identified with clinical refractoriness. Therefore, in recent years, mutations in UL97 and UL54 can be tested. Predisposing factors for CMV resistance include prolonged use of anti-CMV agents, recurrent CMV infections, inadequate antiviral absorption, subtherapeutic antiviral level, haploidentical transplantation, or T-cell depletion [97]. If resistance is confirmed, a drug to which resistance has not been identified, or combination of drugs, may be used, but treatment is currently limited. Clinician’s experience is important in such complicated cases.

HERPES ZOSTER

Herpes zoster is caused by the reactivation of virus latent in the posterior ganglia after primary infection with varicella zoster virus (VZV). In Korea, VZV is transmitted by natural infection in most cases and its seroprevalence in adults is > 90%; previous VZV infection is a prerequisite for herpes zoster [98-100]. The clinical features of herpes zoster include abnormal sensation or pain through skin segments 2 to 3 days before skin lesions develop, erythematous spots with irritation, and rapid formation of blisters. The blisters burst and form ulcers, which scar and become dry. Pain and postherpetic neuralgia are major problems. In most cases, one or two dermatomes are involved unilaterally, but dissemination to several other dermatomes or systemically can occur and is associated with visceral or central nervous system involvement [101]. Treatment consists of antiviral administration and adjuvant therapy to reduce the acute pain and postherpetic neuralgia. It is not clear whether antiviral treatment is effective 72 hours after the onset of rash. However, immunocompromised patients with persistent or new vesicular rash, eye involvement, and/or neurologic complications should receive antiviral treatment even > 72 hours after the onset [1].

The risk of varicella is highest in the first 24 months after HCST, or during immunosuppressive therapy for GVHD [101]. In a Korean transplantation center, 34.3% of patients who underwent allogeneic HSCT in 2004 to 2005 experienced herpes zoster. The cumulative incidence was 22% at 1 year post-transplant, and 30.8%, 38.6%, and 41.2% at 2, 3, and 4 years (Fig. 1). Chest dermatomes were most commonly involved (43.8%), and 11.4% of cases were disseminated. There was no herpes-zoster-related mortality.

Figure 1.

Cumulative incidence of herpes zoster in allogeneic hematopoietic stem cell transplantation with myeloablative (MAC) or reduced intensity conditioning (RIC) regimens without long-term prophylaxis (log-rank test, p = 0.492).

A live attenuated zoster vaccine is available but cannot be used for HSCT recipients. Acyclovir prophylaxis can reduce the incidence of herpes simplex virus (HSV) and VZV infections not only before engraftment but also in the long term until the immunosuppressant is stopped [102]. It is recommended that acyclovir be maintained for at least 1 year after allogeneic HSCT and for 6 to 12 months after autologous HSCT [3,48]. Antiviral prophylaxis can prevent herpes zoster after allogeneic or autologous HSCT. The pooled RR was 0.29 (range, 0.24 to 0.36) in allogeneic HSCT recipients, and 0.36 (range, 0.25 to 0.54) in autologous HSCT recipients [103].

EPSTEIN-BARR VIRUS AND OTHER HERPESVIRUS INFECTIONS

EBV reactivation can occur 3 to 6 months after transplantation, typically in patients with chronic GVHD. However, progression to disease is relatively rare. Fever and neutropenia may occur as a result of EBV symptoms, which are similar to those of infectious mononucleosis. Most EBV reactivations are subclinical and require no therapy [101]. In addition, aplastic anemia, oral hairy leukoplakia, and post-transplant lymphoproliferative disease (PTLD) can occur. PTLD occurs less frequently after HSCT than after transplantation of other solid organs. EBV-related PTLD occurs in cases of unrelated donor transplantation, T-cell-depleted transplantation, GVHD, and use of an anti-lymphocyte antibody to prevent GVHD [104]. The diagnosis of EBV-associated PTLD can be established by tissue biopsy for histopathology and detection of EBV [105]. Among other herpesviruses, human herpes virus 6 (HHV6) may be responsible for meningitis and hemorrhagic cystitis [106].

HEMORRHAGIC CYSTITIS

Hemorrhagic cystitis in HSCT recipients can be classified according to the onset time (before vs. after engraftment), and cases occurring within 7 days after transplantation are usually non‑infectious. Non-infectious causes include radiotherapy and chemotherapy (e.g., cyclophosphamide, ifosfamide, busulfan, and etoposide), while post-engraftment hemorrhagic cystitis can be caused by virus. Viral reactivation can be accompanied by bladder urothelial damage due to the conditioning regimen. Viral hemorrhagic cystitis can be caused by polyomaviruses (BK and JC viruses), adenovirus, CMV, HSV, and HHV6 [107,108].

Of these viruses, BK virus (BKV) is the most common; 80% to 90% of adults are BKV seropositive [109-111]. BKV-associated hemorrhagic cystitis is predominant in allogeneic HSCT patients, and BKV-associated nephropathy in KT patients. Why BKV reactivation manifests as these two major forms in KT and HSCT patients is unclear [112]. The diagnostic criteria defined by the European Conference on Infections in Leukemia (ECIL)-6 comprise the following triad: viral replication (urine BKV > 107 copies/mL), symptoms of cystitis, and hematuria of grade II or higher. A blood BKV DNA level of > 103–4 copies/mL is reportedly associated with significant viruria. However, a negative plasma viral load does not rule out BKV-associated hemorrhagic cystitis [113-115].

The risk factors for hemorrhagic cystitis are myeloablative conditioning regimen, ATG, and GVHD. The incidence is higher in allogeneic than in autologous HSCT patients, and in adults than in pediatric cases. Treatment for virus-associated hemorrhagic cystitis should be initiated by minimizing immunosuppressants. Cidofovir might be effective for adenovirus, CMV, and BKV, and can be considered if there is ≥ grade III hematuria (gross hematuria with blood clots) and no response to conservative treatment [113].

In eight retrospective and two prospective studies, the use of cidofovir with or without probenecid (either 3 to 5 mg/kg with probenecid or 0.5 to 1.5 mg/kg without probenecid) was investigated. A reduction in the urine and blood BKV load reportedly occurs in 38% to 62% and 67% to 84% of patients, respectively [116-122]. A retrospective study did not recommend levofloxacin because of insufficient data and the low level of evidence [113]. In addition, retrospective data are available for vidarabine, leflunomide, hyaluronic acid, and mesenchymal cells, but these are not recommended by the guidelines [113]. Brincidofovir markedly reduces BKV replication in vitro [123]. In cases of persistent hematuria, renal function can be impaired by blood clots and related post-renal obstructions. Conservative care such as intravenous hydration and removal of obstructions is also important.

COMMON RESPIRATORY VIRUSES

Epidemiology and risk factors for progression to lower respiratory infections

Common respiratory virus (CRV) infections are frequent causes of upper respiratory tract infection (URTI) and lower respiratory tract infection (LRTI) in HSCT patients. CRV infections can also occur during neutropenia and show significant morbidity and mortality. The epidemiology of CRV infection in HSCT patients is likely to reflect that in the community, with seasonal variations. Influenza and respiratory syncytial virus (RSV) infections usually occur in winter, parainfluenza virus (PIV) infections in summer, and rhinovirus throughout the year. In HSCT recipients, CRV infection is not limited to URTIs and is more likely to progress to LRTIs [124,125]. Respiratory virus multiplex PCR enables rapid diagnosis of CRV infections in clinical practice [126].

There are little data on CRV infection in HSCT patients in Korea. In a 4-year retrospective study in the authors’ HSCT center from 2007 to 2011, 67 of 1,038 HSCT patients (6.5%) had 71 cases of CRV-LRTI. RSV (43.6%) was the most common pathogen of CRV-LRTI, followed by PIV (26.8%), influenza virus (19.7%), and rhinovirus (9.9%) [127]. The overall mortality rate at day 30 after CRV-LRTI was 32.8%, and high-dose steroid usage (> 1 mg/kg/day), severe immunodeficiency, and lymphopenia (absolute lymphocyte count < 200 cells/mm3) were significantly associated with mortality [127]. These findings are similar to the prevalence, mortality rate, and mortality-related risk factors of CRV-LRTI in Europe and the United States.

The average mortality rate of RSV-LRTI is 32% (range, 0% to 70%) in international studies, and the major risk factors for progression to LRTI are lymphopenia, old age, mismatched/unrelated donor, and neutropenia [128,129]. In cases of PIV-LRTI, the overall mortality rate is 10% to 30%, and high-level corticosteroid exposure, neutropenia, lymphopenia, and early onset after HSCT are the major risk factors for LRTI [129-131]. The rate of progression of influenza to LRTI is 25% to 28% and the overall mortality rate is 25% to 58% [132-134]. The risk factors for progression to influenza-LRTI are early onset after HSCT, lymphopenia, old age, neutropenia, and delayed antiviral administration [132-134]. In cases of rhinovirus, most infections are asymptomatic, less than 10% of patients progress to definite pneumonia, and the mortality rate is < 10% [135,136]. In addition, human metapneumovirus, adenovirus, coronavirus, and bocavirus can cause URTIs and LRTIs in HSCT patients [129,137].

Treatment

Management of CRV infection in HSCT patients can be classified into four categories: prevention (infection control), selective therapy for URTI, antiviral therapy, and supportive care. Currently, a commercialized vaccine is available only for influenza, and so preventive strategies to stop the spread of CRV infections—such as hand hygiene, wearing gloves and mask, and isolation of symptomatic patients—have been emphasized [129,134,137,138]. It is recommended that healthcare workers and family members of patients be vaccinated against influenza, as well as undergo post-exposure prophylaxis (in the Korea influenza guidelines, oseltamivir can be administered prophylactically for 10 days if an immunocompromised patient comes into contact with a patient with confirmed influenza or influenza-like illness) [134,137-139].

Because some CRV-URTIs do not progress to LRTI and therapeutic agents are limited, it is important to identify CRV‑URTI patients at increased risk of LRTI [129,137,140]. Treatment of RSV-URTI with aerosolized ribavirin significantly reduces the frequency of progression to LRTI (25% vs. 47%) [128]. In addition, the following immunodeficiency scoring index has been proposed: neutropenia (< 500 cells/mm3, 3 points), lymphopenia (< 200 cells/mm3, 3 points), age ≥ 40 years (2 points), myeloablative conditioning (1 point), GVHD (acute/chronic, 1 point), corticosteroids (1 point), and pre-engraftment or within 30 days of transplant (1 point). A score of > 7 is associated with a significantly increased risk of progression to LRTI, suggesting the necessity of criteria for identifying high-risk groups [141]. Palivizumab, a humanized anti-RSV monoclonal antibody, does not reduce the progression to LRTI in HSCT patients and is currently recommended only for prophylactic usage in high-risk children [142]. The risk factors for progression to LRTI have been discussed for PIV, human metapneumovirus, and rhinovirus URTIs, but treatment is not recommended because of a lack of evidence [129,137,140].

Oseltamivir, zanamivir, and peramivir can be used to treat influenza URTIs and LRTIs and should be administered within 48 hours of symptom onset [134,139]. Delayed administration is also beneficial, so these agents should be administered even after 48 hours [134,139]. Although there is no definitive evidence, most guidelines recommend that antiviral treatment be extended beyond the usual duration in cases of severe influenza LRTI [134,139,143]. Aerosolized ribavirin and intravenous immunoglobulin (IVIG) combination treatment significantly reduces RSV-LRTI-related mortality and is thus recommended by most guidelines [129,137,140,141]. Although evidence is lacking, if aerosolized ribavirin cannot be used, oral ribavirin or intravenous ribavirin may be considered [129,137,140,141]. A recent double-blind, placebo‑controlled study of GS-5806 (presatovir), an oral RSV-entry inhibitor, involved 54 RSV-infected healthy adult volunteers who received RSV challenge intranasally. GS-5806 reduced the viral load and the severity of clinical disease [143]. Proven PIV-LRTI should be treated with aerosolized ribavirin and IVIG in combination [129,137,140]. Unfortunately, aerosolized ribavirin is costly and available only through the Korea Orphan & Essential Drug Center in Korea, so its use is limited. No antiviral is available to treat CRV, rhinovirus, human metapneumovirus, and bocavirus LRTIs, so supportive care is the mainstay.

HSCT patients with CRV infection are often susceptible to other pathogens, and so work-up for co-existent pathogens is required [129,137,140]. S. aureus and S. pneumoniae infections are commonly followed by influenza infection. Therefore, patients with influenza LRTIs should be administered antibiotics to which these bacteria are susceptible [144]. As it is not possible to distinguish these bacteria from other co-pathogens (i.e., PCP, CMV, or fungi, etc.) using only imaging tests and clinical symptoms, examinations such as bronchoscopy are required [129,137,140].

TUBERCULOSIS

Tuberculosis (TB) is an important opportunistic infection among HSCT recipients, in whom its incidence is 2- to 40-fold higher than that in the general population; however, this is lower than in solid-organ-transplant patients [145-147]. HSCT recipients are immunosuppressed as a result of their hematologic disease, chemotherapy, radiotherapy, immunosuppressive agents, and GVHD [146]. Several risk factors for the development of TB after HSCT have been reported, including acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, busulfan, cyclophosphamide, TBI, corticosteroid therapy, HLA-mismatched transplant, GVHD, or a history of TB infection [148]. Of HSCT patients who develop TB, 80% and 20% had undergone allogeneic and autologous transplant, respectively.

A single-center study performed in Korea reported that 2.5% of allogeneic HSCT recipients were diagnosed with TB after HSCT. The median time to development of TB was 386 days after transplantation (range, 49 to 886). The standardized incidence ratio of TB, compared with that in the general population, was 9.10 (95% CI, 5.59 to 14.79). Extensive chronic GVHD was associated with the development of TB (p = 0.003) (Fig. 2) [146]. Another center in Korea reported that HSCT patients with TBI-based conditioning are likely to have TB disease [149]. Extrapulmonary TB comprises 42% of post-HSCT TB cases, which is higher than that in the general population (15% to 20%) [146].

Figure 2.

Cumulative incidence of tuberculosis (TB) in allogeneic hematopoietic stem cell transplantation (HSCT) recipients with and without chronic graft-versus-host disease (cGVHD) (p = 0.003).

Owing to the risk of reactivation or new infection, prophylaxis is recommended for HSCT recipients with a positive TB-specific interferon-γ release assay result [3]. Isoniazid is well tolerated in the post-HSCT period. However, concurrent itraconazole is not recommended due to drug interactions, and the impact of voriconazole or posaconazole is unclear. Isoniazid should be continued for at least 9 months until immunosuppression is reduced. Rifampin may undergo drug-drug interactions with immunosuppressants, which makes this option not practical. To determine the optimum timing and duration of isoniazide prophylaxis in HSCT patients, further studies are needed.

POST-HSCT VACCINATION

Post-HSCT vaccination is recommended regardless of the type of transplantation and source of stem cells. Guidelines recommend that both allogeneic and autologous HSCT recipients should be immunized as scheduled even during immunosuppressive therapy for chronic GVHD [150,151]. However, if > 0.5 mg/kg prednisolone is administered for GVHD, it may be temporarily delayed to increase the immune response until the dosage of immunosuppressants become decreased. The recommended schedules in Korea are presented in Table 5 [152].

Recommended vaccination for HSCT recipients

CONCLUSIONS

HSCT is performed to treat various hematologic malignancies and other disorders. Although survival rates have improved due to developments in transplantation techniques, infectious complications remain major causes of morbidity and mortality after HSCT. The severity of infectious complications varies according to the phase post-transplant, type of transplantation, GVHD, and the degree of immunosuppression or reconstitution. Further studies are required to improve the treatment of infectious diseases, and the outcomes of HSCT patients are expected to improve in future.

Notes

No potential conflict of interest relevant to this article was reported.

References

1. Lee DG. Common infectious diseases in hematopoietic stem cell transplant recipients. Korean J Med 2013;84:158–167.
2. Wingard JR, Hsu J, Hiemenz JW. Hematopoietic stem cell transplantation: an overview of infection risks and epidemiology. Hematol Oncol Clin North Am 2011;25:101–116.
3. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant 2009;15:1143–1238.
4. Safdar A, Armstrong D. Infections in patients with hematologic neoplasms and hematopoietic stem cell transplantation: neutropenia, humoral, and splenic defects. Clin Infect Dis 2011;53:798–806.
5. Lee JW, Kim CC. The activity of hematopoietic stem cell transplantation in Korea. Bone Marrow Transplant 2008;42 Suppl 1:S92–S95.
6. Yoo JH, Lee DG, Choi SM, et al. Infectious complications and outcomes after allogeneic hematopoietic stem cell transplantation in Korea. Bone Marrow Transplant 2004;34:497–504.
7. Park SH, Choi SM, Lee DG, et al. Current trends of infectious complications following hematopoietic stem cell transplantation in a single center. J Korean Med Sci 2006;21:199–207.
8. Kim SH, Kee SY, Lee DG, et al. Infectious complications following allogeneic stem cell transplantation: reduced-intensity vs. myeloablative conditioning regimens. Transpl Infect Dis 2013;15:49–59.
9. Bosch M, Khan FM, Storek J. Immune reconstitution after hematopoietic cell transplantation. Curr Opin Hematol 2012;19:324–335.
10. Seggewiss R, Einsele H. Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update. Blood 2010;115:3861–3868.
11. Ogonek J, Kralj Juric M, Ghimire S, et al. Immune reconstitution after allogeneic hematopoietic stem cell transplantation. Front Immunol 2016;7:507.
12. Dropulic LK, Lederman HM. Overview of infections in the immunocompromised host. In : Hayden RT, Carroll KC, Tang YW, Wolk DM, eds. Diagnostic Microbiology of the Immunocompromised Host 1st edth ed. Washington, DC: ASM Press; 2009. p. 3–43.
13. Lee DG, Kim SH, Kim SY, et al. Evidence-based guidelines for empirical therapy of neutropenic fever in Korea. Korean J Intern Med 2011;26:220–252.
14. Sahin U, Toprak SK, Atilla PA, Atilla E, Demirer T. An overview of infectious complications after allogeneic hematopoietic stem cell transplantation. J Infect Chemother 2016;22:505–514.
15. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of America. Clin Infect Dis 2011;52:e56–e93.
16. EORTC International Antimicrobial Therapy Cooperative Group. Gram-positive bacteraemia in granulocytopenic cancer patients. Eur J Cancer 1990;26:569–574.
17. Klastersky J. Science and pragmatism in the treatment and prevention of neutropenic infection. J Antimicrob Chemother 1998;41 Suppl D:13–24.
18. Mikulska M, Viscoli C, Orasch C, et al. Aetiology and resistance in bacteraemias among adult and paediatric haematology and cancer patients. J Infect 2014;68:321–331.
19. Jun HX, Zhixiang S, Chun W, et al. Clinical guidelines for the management of cancer patients with neutropenia and unexplained fever. Int J Antimicrob Agents 2005;26 Suppl 2:S128–S132.
20. Choi SM, Lee DG, Park YH, et al. Infections in patients with acute leukemia: comparison of induction chemotherapy group and reinduction chemotherapy group. Infect Chemother 2003;35:78–85.
21. Kim HB, Park SW, Kim US, et al. Infections in patients with acute leukemia (1993-1996). Korean J Hematol 1999;34:359–365.
22. Kwon JC, Kim SH, Choi JK, et al. Epidemiology and clinical features of bloodstream infections in hematology wards: one year experience at the catholic blood and marrow transplantation center. Infect Chemother 2013;45:51–61.
23. Hammarstrom V, Pauksen K, Svensson H, et al. Serum immunoglobulin levels in relation to levels of specific antibodies in allogeneic and autologous bone marrow transplant recipients. Transplantation 2000;69:1582–1586.
24. Gustinetti G, Mikulska M. Bloodstream infections in neutropenic cancer patients: a practical update. Virulence 2016;7:280–297.
25. Gudiol C, Bodro M, Simonetti A, et al. Changing aetiology, clinical features, antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer patients. Clin Microbiol Infect 2013;19:474–479.
26. Kim SH, Kwon JC, Choi SM, et al. Escherichia coli and Klebsiella pneumoniaei bacteremia in patients with neutropenic fever: factors associated with extended-spectrum β-lactamase production and its impact on outcome. Ann Hematol 2013;92:533–541.
27. Prabhash K, Medhekar A, Ghadyalpatil N, et al. Blood stream infections in cancer patients: a single center experience of isolates and sensitivity pattern. Indian J Cancer 2010;47:184–188.
28. Girmenia C, Rossolini GM, Piciocchi A, et al. Infections by carbapenem-resistant Klebsiella pneumoniaei in SCT recipients: a nationwide retrospective survey from Italy. Bone Marrow Transplant 2015;50:282–288.
29. Gedik H, Simsek F, Kanturk A, et al. Bloodstream infections in patients with hematological malignancies: which is more fatal. Cancer or resistant pathogens? Ther Clin Risk Manag 2014;10:743–752.
30. Giannella M, Trecarichi EM, De Rosa FG, et al. Risk factors for carbapenem-resistant Klebsiella pneumoniaei bloodstream infection among rectal carriers: a prospective observational multicentre study. Clin Microbiol Infect 2014;20:1357–1362.
31. Kim SB, Min YH, Cheong JW, et al. Incidence and risk factors for carbapenem- and multidrug-resistant Acinetobacter baumannii bacteremia in hematopoietic stem cell transplantation recipients. Scand J Infect Dis 2014;46:81–88.
32. Cho SY, Lee DG, Choi SM, et al. Impact of vancomycin resistance on mortality in neutropenic patients with enterococcal bloodstream infection: a retrospective study. BMC Infect Dis 2013;13:504.
33. Bow EJ. Fluoroquinolones, antimicrobial resistance and neutropenic cancer patients. Curr Opin Infect Dis 2011;24:545–553.
34. Cullen M, Baijal S. Prevention of febrile neutropenia: use of prophylactic antibiotics. Br J Cancer 2009;101 Suppl 1:S11–S14.
35. Neumann S, Krause SW, Maschmeyer G, et al. Primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumonia in patients with hematological malignancies and solid tumors: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 2013;92:433–442.
36. Kanafani ZA, Mehio-Sibai A, Araj GF, Kanaan M, Kanj SS. Epidemiology and risk factors for extended-spectrum beta-lactamase-producing organisms: a case control study at a tertiary care center in Lebanon. Am J Infect Control 2005;33:326–332.
37. Lautenbach E, Patel JB, Bilker WB, Edelstein PH, Fishman NO. Extended-spectrum beta-lactamase-producing Escherichia coli and Pseudomonas aeruginosa: risk factors for infection and impact of resistance on outcomes. Clin Infect Dis 2001;32:1162–1171.
38. Colodner R, Rock W, Chazan B, et al. Risk factors for the development of extended-spectrum beta-lactamase-producing bacteria in nonhospitalized patients. Eur J Clin Microbiol Infect Dis 2004;23:163–167.
39. Craig M, Cumpston AD, Hobbs GR, Devetten MP, Sarwari AR, Ericson SG. The clinical impact of antibacterial prophylaxis and cycling antibiotics for febrile neutropenia in a hematological malignancy and transplantation unit. Bone Marrow Transplant 2007;39:477–482.
40. Cumpston A, Craig M, Hamadani M, Abraham J, Hobbs GR, Sarwari AR. Extended follow-up of an antibiotic cycling program for the management of febrile neutropenia in a hematologic malignancy and hematopoietic cell transplantation unit. Transpl Infect Dis 2013;15:142–149.
41. von Baum H, Sigge A, Bommer M, et al. Moxifloxacin prophylaxis in neutropenic patients. J Antimicrob Chemother 2006;58:891–894.
42. Mikulska M, Averbuch D, Tissot F, et al. Fluoroquinolone prophylaxis in haematological cancer patients with neutropenia: ECIL critical appraisal of previous guidelines. J Infect 2018;76:20–37.
43. Gea-Banacloche J. Evidence-based approach to treatment of febrile neutropenia in hematologic malignancies. Hematology Am Soc Hematol Educ Program 2013;2013:414–422.
44. Averbuch D, Orasch C, Cordonnier C, et al. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia. Haematologica 2013;98:1826–1835.
45. Kurosawa M, Yonezumi M, Hashino S, et al. Epidemiology and treatment outcome of invasive fungal infections in patients with hematological malignancies. Int J Hematol 2012;96:748–757.
46. Pagano L, Caira M, Nosari A, et al. Fungal infections in recipients of hematopoietic stem cell transplants: results of the SEIFEM B-2004 study. Sorveglianza Epidemiologica Infezioni Fungine Nelle Emopatie Maligne. Clin Infect Dis 2007;45:1161–1170.
47. Choi JK, Cho SY, Yoon SS, et al. Epidemiology and risk factors for invasive fungal diseases among allogeneic hematopoietic stem cell transplant recipients in Korea: results of "RISK" Study. Biol Blood Marrow Transplant 2017;23:1773–1779.
48. National Comprehensive Cancer Network. National Comprehensive Cancer Network clinical practice guidelines in oncology: prevention and treatment of cancer-related infections. Version 1. 2018 [Internet]. Fort Washington (PA): NCCN; c2018. [cited 2018 Feb 12]. Available from: https://www.nccn.org/professionals/physician_gls/recently_updated.aspx.
49. Leventakos K, Lewis RE, Kontoyiannis DP. Fungal infections in leukemia patients: how do we prevent and treat them? Clin Infect Dis 2010;50:405–415.
50. Kullberg BJ, Arendrup MC. Invasive candidiasis. N Engl J Med 2015;373:1445–1456.
51. Pappas PG, Kauffman CA, Andes DR, et al. clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016;62:e1–e50.
52. Wingard JR, Hsu J, Hiemenz JW. Hematopoietic stem cell transplantation: an overview of infection risks and epidemiology. Infect Dis Clin North Am 2010;24:257–272.
53. Marchetti O, Lamoth F, Mikulska M, et al. ECIL recommendations for the use of biological markers for the diagnosis of invasive fungal diseases in leukemic patients and hematopoietic SCT recipients. Bone Marrow Transplant 2012;47:846–854.
54. Hsu LY, Lee DG, Yeh SP, et al. Epidemiology of invasive fungal diseases among patients with haematological disorders in the Asia-Pacific: a prospective observational study. Clin Microbiol Infect 2015;21:594.
55. Bergeron A, Porcher R, Sulahian A, et al. The strategy for the diagnosis of invasive pulmonary aspergillosis should depend on both the underlying condition and the leukocyte count of patients with hematologic malignancies. Blood 2012;119:1831–1837.
56. Kim SH, Lee DG, Kwon JC, et al. Clinical impact of cytochrome P450 2C19 genotype on the treatment of invasive aspergillosis under routine therapeutic drug monitoring of voriconazole in a Korean population. Infect Chemother 2013;45:406–414.
57. Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet 2016;387:760–769.
58. Tissot F, Agrawal S, Pagano L, et al. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica 2017;102:433–444.
59. Michallet M, Ito JI. Approaches to the management of invasive fungal infections in hematologic malignancy and hematopoietic cell transplantation. J Clin Oncol 2009;27:3398–3409.
60. Maertens J, Marchetti O, Herbrecht R, et al. European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3. 2009 update. Bone Marrow Transplant 2011;46:709–718.
61. Kim SB, Cho SY, Lee DG, et al. Breakthrough invasive fungal diseases during voriconazole treatment for aspergillosis: a 5-year retrospective cohort study. Med Mycol 2017;55:237–245.
62. Park SY, Yoon JA, Kim SH. Voriconazole-refractory invasive aspergillosis. Korean J Intern Med 2017;32:805–812.
63. Cho SY, Lee DG, Choi JK, et al. Characteristics of culture-positive invasive pulmonary aspergillosis in patients with hematologic diseases: comparison between Aspergillus fumigatus and non-fumigatus Aspergillus species. Medicine (Baltimore) 2017;96e8841.
64. Maertens J, Cesaro S, Maschmeyer G, et al. ECIL guidelines for preventing Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients. J Antimicrob Chemother 2016;71:2397–2404.
65. Lee HY, Kang HS, Lee HY, et al. Clinical significance of positive Pneumocystis jirovecii polymerase chain reaction in non-human immunodeficiency virus immunocompromised patients in a real practice. Korean J Intern Med 2017;32:478–485.
66. Fan LC, Lu HW, Cheng KB, Li HP, Xu JF. Evaluation of PCR in bronchoalveolar lavage fluid for diagnosis of Pneumocystis jirovecii pneumonia: a bivariate meta-analysis and systematic review. PLoS One 2013;8e73099.
67. Lu Y, Ling G, Qiang C, et al. PCR diagnosis of Pneumocystis pneumonia: a bivariate meta-analysis. J Clin Microbiol 2011;49:4361–4363.
68. Alanio A, Hauser PM, Lagrou K, et al. ECIL guidelines for the diagnosis of Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients. J Antimicrob Chemother 2016;71:2386–2396.
69. Green H, Paul M, Vidal L, Leibovici L. Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials. Mayo Clin Proc 2007;82:1052–1059.
70. Green H, Paul M, Vidal L, Leibovici L. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev 2007;(3)CD005590.
71. Cordonnier C, Cesaro S, Maschmeyer G, et al. Pneumocystis jirovecii pneumonia: still a concern in patients with haematological malignancies and stem cell transplant recipients. J Antimicrob Chemother 2016;71:2379–2385.
72. Cooley L, Dendle C, Wolf J, et al. Consensus guidelines for diagnosis, prophylaxis and management of Pneumocystis jirovecii pneumonia in patients with haematological and solid malignancies, 2014. Intern Med J 2014;44:1350–1363.
73. Thursky KA, Worth LJ, Seymour JF, Miles Prince H, Slavin MA. Spectrum of infection, risk and recommendations for prophylaxis and screening among patients with lymphoproliferative disorders treated with alemtuzumab. Br J Haematol 2006;132:3–12.
74. Boeckh M, Geballe AP. Cytomegalovirus: pathogen, paradigm, and puzzle. J Clin Invest 2011;121:1673–1680.
75. Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 2002;34:1094–1097.
76. Ljungman P, Reusser P, de la Camara R, et al. Management of CMV infections: recommendations from the infectious diseases working party of the EBMT. Bone Marrow Transplant 2004;33:1075–1081.
77. Choi SM, Lee DG, Park SH, et al. Characteristics of cytomegalovirus diseases among hematopoietic stem cell transplant recipients: a 10-year experience at an university hospital in Korea. Infect Chemother 2009;41:9–19.
78. Jeon S, Lee WK, Lee Y, Lee DG, Lee JW. Risk factors for cytomegalovirus retinitis in patients with cytomegalovirus viremia after hematopoietic stem cell transplantation. Ophthalmology 2012;119:1892–1898.
79. Teira P, Battiwalla M, Ramanathan M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood 2016;127:2427–2438.
80. Kim T, Lee YM, Lee SO, et al. Differences of cytomegalovirus diseases between kidney and hematopoietic stem cell transplant recipients during preemptive therapy. Korean J Intern Med 2016;31:961–970.
81. Lee HY, Rhee CK, Choi JY, Lee HY, Lee JW, Lee DG. Diagnosis of cytomegalovirus pneumonia by quantitative polymerase chain reaction using bronchial washing fluid from patients with hematologic malignancies. Oncotarget 2017;8:39736–39745.
82. Choi SM, Lee DG, Lim J, et al. Comparison of quantitative cytomegalovirus real-time PCR in whole blood and pp65 antigenemia assay: clinical utility of CMV real-time PCR in hematopoietic stem cell transplant recipients. J Korean Med Sci 2009;24:571–578.
83. Choi SM, Lee DG, Choi JH, et al. Risk-adapted preemptive therapy for cytomegalovirus disease after allogeneic stem cell transplantation: a single-center experience in Korea. Int J Hematol 2005;81:69–74.
84. Cho BS, Yahng SA, Kim JH, et al. Impact of cytomegalovirus gastrointestinal disease on the clinical outcomes in patients with gastrointestinal graft-versus-host disease in the era of preemptive therapy. Ann Hematol 2013;92:497–504.
85. Marty FM, Ljungman P, Chemaly RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med 2017;377:2433–2444.
86. Khanna R. Immune monitoring of infectious complications in transplant patients: an important step towards improved clinical management. J Clin Microbiol 2018 Jan 17 [Epub]. https://doi.org/10.1128/JCM.02009-17.
87. Yong MK, Cameron PU, Slavin M, et al. Identifying cytomegalovirus complications using the quantiferon-CMV assay after allogeneic hematopoietic stem cell transplantation. J Infect Dis 2017;215:1684–1694.
88. Jung J, Lee HJ, Kim SM, et al. Diagnostic usefulness of dynamic changes of CMV-specific T-cell responses in predicting CMV infections in HCT recipients. J Clin Virol 2017;87:5–11.
89. Kim SH, Lee HS, Lee HJ, et al. Clinical applications of interferon-γ releasing assays for cytomegalovirus to differentiate cytomegalovirus disease from bystander activation: a pilot proof-of-concept study. Korean J Intern Med 2017;32:900–909.
90. Kim SH, Lee HJ, Kim SM, et al. Diagnostic usefulness of cytomegalovirus (CMV)-specific T cell immunity in predicting CMV infection after kidney transplantation: a pilot proof-of-concept study. Infect Chemother 2015;47:105–110.
91. Lee H, Park KH, Ryu JH, et al. Cytomegalovirus (CMV) immune monitoring with ELISPOT and QuantiFERON-CMV assay in seropositive kidney transplant recipients. PLoS One 2017;12e0189488.
92. Han SH. Immunological prediction of cytomegalovirus (CMV) replication risk in solid organ transplantation recipients: approaches for regulating the targeted anti-CMV prevention strategies. Infect Chemother 2017;49:161–175.
93. Park SH, Choi SM, Lee DG, et al. Infectious complications associated with alemtuzumab use for allogeneic hematopoietic stem cell transplantation: comparison with anti-thymocyte globulin. Transpl Infect Dis 2009;11:413–423.
94. Gilbert C, Roy J, Belanger R, et al. Lack of emergence of cytomegalovirus UL97 mutations conferring ganciclovir (GCV) resistance following preemptive GCV therapy in allogeneic stem cell transplant recipients. Antimicrob Agents Chemother 2001;45:3669–3671.
95. Hantz S, Garnier-Geoffroy F, Mazeron MC, et al. Drug-resistant cytomegalovirus in transplant recipients: a French cohort study. J Antimicrob Chemother 2010;65:2628–2640.
96. Shmueli E, Or R, Shapira MY, et al. High rate of cytomegalovirus drug resistance among patients receiving preemptive antiviral treatment after haploidentical stem cell transplantation. J Infect Dis 2014;209:557–561.
97. El Chaer F, Shah DP, Chemaly RF. How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients. Blood 2016;128:2624–2636.
98. Kang CI, Choi CM, Park TS, Lee DJ, Oh MD, Choe KW. Incidence of herpes zoster and seroprevalence of varicella-zoster virus in young adults of South Korea. Int J Infect Dis 2008;12:245–247.
99. Kim YH, Hwang JY, Lee KM, et al. Seroepidemiologic survey of varicella-zoster virus in Korean adults using glycoprotein enzyme immunoassay and fluorescent antibody to membrane antigen test. Ann Dermatol 2011;23:39–43.
100. Choi WS, Noh JY, Huh JY, et al. Seroprevalence of varicella-zoster virus in Korea. J Med Virol 2010;82:2123–2126.
101. Styczynski J, Reusser P, Einsele H, et al. Management of HSV, VZV and EBV infections in patients with hematological malignancies and after SCT: guidelines from the Second European Conference on Infections in Leukemia. Bone Marrow Transplant 2009;43:757–770.
102. Kim DH, Kumar D, Messner HA, et al. Clinical efficacy of prophylactic strategy of long-term low-dose acyclovir for Varicella-Zoster virus infection after allogeneic peripheral blood stem cell transplantation. Clin Transplant 2008;22:770–779.
103. Seo HM, Kim YS, Bang CH, et al. Antiviral prophylaxis for preventing herpes zoster in hematopoietic stem cell transplant recipients: a systematic review and meta-analysis. Antiviral Res 2017;140:106–115.
104. Park SH, Choi SM, Lee DG, et al. Clinical characteristics and outcomes of posttransplant lymphoproliferative disorders following allogeneic hematopoietic stem cell transplantation in Korea. J Korean Med Sci 2006;21:259–264.
105. Styczynski J, van der Velden W, Fox CP, et al. Management of Epstein-Barr virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines. Haematologica 2016;101:803–811.
106. Kim YJ, Kim DW, Lee DG, et al. Human herpesvirus-6 as a possible cause of encephalitis and hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation. Leukemia 2002;16:958–959.
107. Dropulic LK, Jones RJ. Polyomavirus BK infection in blood and marrow transplant recipients. Bone Marrow Transplant 2008;41:11–18.
108. Ison MG. Adenovirus infections in transplant recipients. Clin Infect Dis 2006;43:331–339.
109. Knowles WA, Pipkin P, Andrews N, et al. Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol 2003;71:115–123.
110. Kean JM, Rao S, Wang M, Garcea RL. Seroepidemiology of human polyomaviruses. PLoS Pathog 2009;5e1000363.
111. Egli A, Infanti L, Dumoulin A, et al. Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J Infect Dis 2009;199:837–846.
112. Rinaldo CH, Tylden GD, Sharma BN. The human polyomavirus BK (BKPyV): virological background and clinical implications. APMIS 2013;121:728–745.
113. Cesaro S, Dalianis T, Hanssen Rinaldo C, et al. ECIL guidelines for the prevention, diagnosis and treatment of BK polyomavirus-associated haemorrhagic cystitis in haematopoietic stem cell transplant recipients. J Antimicrob Chemother 2018;73:12–21.
114. Erard V, Kim HW, Corey L, et al. BK DNA viral load in plasma: evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients. Blood 2005;106:1130–1132.
115. Cesaro S, Tridello G, Pillon M, et al. A prospective study on the predictive value of plasma BK virus-DNA load for hemorrhagic cystitis in pediatric patients after stem cell transplantation. J Pediatric Infect Dis Soc 2015;4:134–142.
116. Gaziev J, Paba P, Miano R, et al. Late-onset hemorrhagic cystitis in children after hematopoietic stem cell transplantation for thalassemia and sickle cell anemia: a prospective evaluation of polyoma (BK) virus infection and treatment with cidofovir. Biol Blood Marrow Transplant 2010;16:662–671.
117. Koskenvuo M, Dumoulin A, Lautenschlager I, et al. BK polyomavirus-associated hemorrhagic cystitis among pediatric allogeneic bone marrow transplant recipients: treatment response and evidence for nosocomial transmission. J Clin Virol 2013;56:77–81.
118. Kwon HJ, Kang JH, Lee JW, Chung NG, Kim HK, Cho B. Treatment of BK virus-associated hemorrhagic cystitis in pediatric hematopoietic stem cell transplant recipients with cidofovir: a single-center experience. Transpl Infect Dis 2013;15:569–574.
119. Faraci M, Cuzzubbo D, Lanino E, et al. Low dosage cidofovir without probenecid as treatment for BK virus hamorrhagic cystitis after hemopoietic stem cell transplant. Pediatr Infect Dis J 2009;28:55–57.
120. Ganguly N, Clough LA, Dubois LK, et al. Low-dose cidofovir in the treatment of symptomatic BK virus infection in patients undergoing allogeneic hematopoietic stem cell transplantation: a retrospective analysis of an algorithmic approach. Transpl Infect Dis 2010;12:406–411.
121. Lee SS, Ahn JS, Jung SH, et al. Treatment of BK virus-associated hemorrhagic cystitis with low-dose intravenous cidofovir in patients undergoing allogeneic hematopoietic cell transplantation. Korean J Intern Med 2015;30:212–218.
122. Savona MR, Newton D, Frame D, Levine JE, Mineishi S, Kaul DR. Low-dose cidofovir treatment of BK virus-associated hemorrhagic cystitis in recipients of hematopoietic stem cell transplant. Bone Marrow Transplant 2007;39:783–787.
123. Tylden GD, Hirsch HH, Rinaldo CH. Brincidofovir (CMX001) inhibits BK polyomavirus replication in primary human urothelial cells. Antimicrob Agents Chemother 2015;59:3306–3316.
124. Weigt SS, Gregson AL, Deng JC, Lynch JP 3rd, Belperio JA. Respiratory viral infections in hematopoietic stem cell and solid organ transplant recipients. Semin Respir Crit Care Med 2011;32:471–493.
125. Kumar D, Humar A. Respiratory viral infections in transplant and oncology patients. Infect Dis Clin North Am 2010;24:395–412.
126. Ahn MY, Choi SH, Chung JW, Kim HR. Utilization of the respiratory virus multiplex reverse transcription-polymerase chain reaction test for adult patients at a Korean tertiary care center. Korean J Intern Med 2015;30:96–103.
127. Hong KW, Choi SM, Lee DG, et al. Lower respiratory tract diseases caused by common respiratory viruses among stem cell transplantation recipients: a single center experience in Korea. Yonsei Med J 2017;58:362–369.
128. Shah JN, Chemaly RF. Management of RSV infections in adult recipients of hematopoietic stem cell transplantation. Blood 2011;117:2755–2763.
129. Hirsch HH, Martino R, Ward KN, Boeckh M, Einsele H, Ljungman P. Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis and treatment of human respiratory syncytial virus, parainfluenza virus, metapneumovirus, rhinovirus, and coronavirus. Clin Infect Dis 2013;56:258–266.
130. Chemaly RF, Hanmod SS, Rathod DB, et al. The characteristics and outcomes of parainfluenza virus infections in 200 patients with leukemia or recipients of hematopoietic stem cell transplantation. Blood 2012;119:2738–2745.
131. Nichols WG, Corey L, Gooley T, Davis C, Boeckh M. Parainfluenza virus infections after hematopoietic stem cell transplantation: risk factors, response to antiviral therapy, and effect on transplant outcome. Blood 2001;98:573–578.
132. Ljungman P, de la Camara R, Perez-Bercoff L, et al. Outcome of pandemic H1N1 infections in hematopoietic stem cell transplant recipients. Haematologica 2011;96:1231–1235.
133. Schnell D, Mayaux J, de Bazelaire C, et al. Risk factors for pneumonia in immunocompromised patients with influenza. Respir Med 2010;104:1050–1056.
134. Engelhard D, Mohty B, de la Camara R, Cordonnier C, Ljungman P. European guidelines for prevention and management of influenza in hematopoietic stem cell transplantation and leukemia patients: summary of ECIL-4 (2011), on behalf of ECIL, a joint venture of EBMT, EORTC, ICHS, and ELN. Transpl Infect Dis 2013;15:219–232.
135. Parody R, Rabella N, Martino R, et al. Upper and lower respiratory tract infections by human enterovirus and rhinovirus in adult patients with hematological malignancies. Am J Hematol 2007;82:807–811.
136. Gutman JA, Peck AJ, Kuypers J, Boeckh M. Rhinovirus as a cause of fatal lower respiratory tract infection in adult stem cell transplantation patients: a report of two cases. Bone Marrow Transplant 2007;40:809–811.
137. Dignan FL, Clark A, Aitken C, et al. BCSH/BSBMT/UK clinical virology network guideline: diagnosis and management of common respiratory viral infections in patients undergoing treatment for haematological malignancies or stem cell transplantation. Br J Haematol 2016;173:380–393.
138. Baek JH, Seo YB, Choi WS, et al. Guideline on the prevention and control of seasonal influenza in healthcare setting. Korean J Intern Med 2014;29:265–280.
139. Choi WS, Lee J, Lee HY, et al. Clinical practice guideline for antiviral treatment and chemoprophylaxis of seasonal influenza. Infect Chemother 2012;44:233–249.
140. von Lilienfeld-Toal M, Berger A, Christopeit M, et al. Community acquired respiratory virus infections in cancer patients-guideline on diagnosis and management by the Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology. Eur J Cancer 2016;67:200–212.
141. Shah DP, Ghantoji SS, Ariza-Heredia EJ, et al. Immunodeficiency scoring index to predict poor outcomes in hematopoietic cell transplant recipients with RSV infections. Blood 2014;123:3263–3268.
142. de Fontbrune FS, Robin M, Porcher R, et al. Palivizumab treatment of respiratory syncytial virus infection after allogeneic hematopoietic stem cell transplantation. Clin Infect Dis 2007;45:1019–1024.
143. DeVincenzo JP, Whitley RJ, Mackman RL, et al. Oral GS-5806 activity in a respiratory syncytial virus challenge study. N Engl J Med 2014;371:711–722.
144. Choi WS, Baek JH, Seo YB, et al. Severe influenza treatment guideline. Korean J Intern Med 2014;29:132–147.
145. Bumbacea D, Arend SM, Eyuboglu F, et al. The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement. Eur Respir J 2012;40:990–1013.
146. Lee HJ, Lee DG, Choi SM, et al. The demanding attention of tuberculosis in allogeneic hematopoietic stem cell transplantation recipients: high incidence compared with general population. PLoS One 2017;12e0173250.
147. Fan WC, Liu CJ, Hong YC, et al. Long-term risk of tuberculosis in haematopoietic stem cell transplant recipients: a 10-year nationwide study. Int J Tuberc Lung Dis 2015;19:58–64.
148. Al-Anazi KA, Al-Jasser AM, Alsaleh K. Infections caused by mycobacterium tuberculosis in recipients of hematopoietic stem cell transplantation. Front Oncol 2014;4:231.
149. Lee J, Lee MH, Kim WS, et al. Tuberculosis in hematopoietic stem cell transplant recipients in Korea. Int J Hematol 2004;79:185–188.
150. Tsigrelis C, Ljungman P. Vaccinations in patients with hematological malignancies. Blood Rev 2016;30:139–147.
151. Chong PP, Avery RK. A comprehensive review of immunization practices in solid organ transplant and hematopoietic stem cell transplant recipients. Clin Ther 2017;39:1581–1598.
152. Lee DG. Vaccination of hematopoietic stem cell transplantation recipients: perspective in Korea. Infect Chemother 2013;45:272–282.

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Figure 1.

Figure 1.

Cumulative incidence of herpes zoster in allogeneic hematopoietic stem cell transplantation with myeloablative (MAC) or reduced intensity conditioning (RIC) regimens without long-term prophylaxis (log-rank test, p = 0.492).

Figure 2.

Figure 2.

Cumulative incidence of tuberculosis (TB) in allogeneic hematopoietic stem cell transplantation (HSCT) recipients with and without chronic graft-versus-host disease (cGVHD) (p = 0.003).

Table 1.

Common infectious diseases and risk factors according to the various time periods after hematopoietic stem cell transplantation

Pre-engraftment period (1st 2–4 week) Immediate post-engraftment period (2nd and 3rd month) Late post-engraftment period (after 2nd and 3rd month)
Risk factors Neutropenia, barrier breakdown (mucositis, central venous catheter) Acute GVHD Chronic GVHD
Organ dysfunction due to conditioning regimen Immune modulating viruses Hyposplenism, decrease in opsonization
Impaired cellular and humoral immunity; NK cells recover 1st, CD8 T-cell numbers increasing but restricted T-cell repertoire Impaired cellular and humoral immunity; B-cell and CD4 T-cell numbers recover slowly and repertoire diversifies
Bacteria Gram negative bacteria (especially enteric bacteria) Gram negative bacteria (especially enteric bacteria) Encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, etc.)
Gram positive cocci (mainly viridans group streptococci) Gram positive cocci Nocardia
Clostridium difficile
Fungi Candida Aspergillus and other non-Aspergillus molds Aspergillus and other non-Aspergillus molds
Aspergillus Pneumocystis jirovecii Pneumocystis jirovecii
Herpesviruses HSV EBV, CMV, HHV-6 EBV, CMV, VZV
Others Polyoma virus (BK, JC virus) Respiratory viruses with seasonal variations
Respiratory viruses with seasonal variations Tuberculosis, NTM

GVHD, graft-versus-host disease; NK, natural killer; HSV, herpes simplex virus; EBV, Epstein-Barr virus; CMV, cytomegalovirus; HHV-6, human herpes virus 6; VZV, varicella zoster virus; NTM, non-tuberculous mycobacteria.

Table 2.

Overall infection risk and needs for antimicrobial prophylaxis after HSCT

Risk Examples of therapy Antimicrobial prophylaxis
Intermediate Autologus HSCT Bacteria: consider fluoroquinolone prophylaxis during neutropeniaa
Anticipated neutropenia less than 7–10 days Fungus: consider prophylaxis during neutropenia and for anticipated mucositis, consider PCP prophylaxis
Virus: during neutropenia or longer depending on risks
High Allogenenic HSCT including unrelated or family mismatched donor Bacteria: consider fluoroquinolonea
Anticipated neutropenia more than 10 days Fungus: consider prophylaxis during neutropenia, consider PCP prophylaxis
Prolonged neutropenia Virus: during neutropenia or longer depending on risks
Secondary neutropenia after engraftment
Status of malignancy not in remission
GHVD with significant steroids treatment (> 20 mg/day of prednisolone equivalents)
Use of secondary immunosuppressive agents due to refractory GVHD (e.g., TNF-α inhibitor)

HSCT, hematopoietic stem cell transplantation; PCP, Pneumocystis jirovecii pneumonia; GVHD, graft-versus-host disease; TNF-α, tumor necrosis factor-α.

a

Recent data concern the correlation with fluoroquinolone prophylaxis and development of resistance or Clostridium difficile associated diarrhea.

Table 3.

Suggested anti-fungal prophylaxis after HSCT

Condition Drugsa Duration and comments
Autologous HSCTb Fluconazole During neutropenia
Micafungin During neutropenia
Allogeneic HSCT with neutropenia Fluconazole During neutropenia
Itraconazole syrup During neutropenia; consider less absorption and drug interactions with conditioning regimens
Micafungin During neutropenia
Voriconazole As secondary prophylaxis for prior invasive aspergillosis
Allogeneic HSCT with significant GVHD Fluconazole Until resolution of significant GVHD; consider no activity against mold infections, not for primary choice
Posaconazole Until resolution of significant GVHD; both oral suspension and gastro-resistant tablet can be used. Intravenous formulation is not available in Korea yet.
Voriconazole As secondary prophylaxis for prior invasive aspergillosis

HSCT, hematopoietic stem cell transplantation; GVHD, graft-versus-host disease.

a

The list of recommended drugs is alphabetical and does not reflect preference.

b

If no mucositis, consider no prophylaxis.

Table 4.

PCP prophylaxis after HSCT

Condition Duration Drugs Dose and Comments
Allogeneic HSCT From engraftment to at least ≥ 6 months and as long as receiving immunosuppressive therapy is ongoing Trimethoprim/sulfamethoxazole Primary choice for PCP prevention. Single-strength (80/400 mg) daily or double-strength (160/800 mg) daily or three times weekly; consider side effects including fever, drug sensitivity rash, headache, nausea, vomiting, neutropenia, pancytopenia, meningitis, nephrotoxicity, hepatitis, hypoglycemia, hyperkalemia, and anaphylaxis. Occasionally causes hemolytic anemia in patients with G6PD deficiency.
Pentamidine 300 mg once/month by inhalation, special equipment for aerosolization such as Respirgard II® (GE Healthcare) which produces particles with a mass mean aerodynamic diameter of < 1 μm is required. Should be administered in a separate room; consider side effects including coughing and wheezing.
Dapsone 50 mg twice daily; consider drug-related hemolytic anemia and methemoglobinemia and should not be given to patients with G6PD deficiency.
Atovaquone 1,500 mg/day with fatty food; common toxicities include rash, headache and gastrointestinal disturbances.
Autologous HSCT 3–6 Months after HSCT Same as allogeneic HSCT

PCP, Pneumocystis jirovecii pneumonia; HSCT, hematopoietic stem cell transplantation; G6PD, glucose-6-phosphate dehydrogenase.

Table 5.

Recommended vaccination for HSCT recipients

Vaccine Time post-HSCT to initiate vaccination, mon No. of doses
Inactivated vaccines
 Pneumococcal vaccination 3–6 3–4a
 Inactivated influenza 3–6 1, annually
 Tetanus-Diphtheria-acelluar pertussisb 6–12 3c
 Inactivated poliovirus 6–12 3
 Haemophilus influenzae type b 6–12 3
 Meningococcus 6–12 1–2
 Hepatitis A 6–12 2
 Hepatitis B 6–12 3
Live vaccines
 Measles-Mumps-Rubellad 24 1–2
 Chickenpoxd 24 1

HSCT, hematopoietic stem cell transplantation.

a

Following the three doses of 13-valent pneumococcal conjugate vaccine (PCV), a dose of 23-valent polysaccharide pneumococcal vaccine may be given to broaden the covered spectrum. In HSCT recipients with chronic graft-versus-host disease (GVHD) who are likely to respond poorly to polysaccharide vaccine, a fourth PCV should be considered at intervals of more than 6 months.

b

DTaP (diphtheria-tetanus-reduced acellular pertussis vaccine) is preferred over tetanus toxoid-reduced diphtheria toxoid-reduced acellular pertussis vaccine (Tdap). If only Tdap is available, it can be used.

c

Re-immunization with Td (tetanus toxoid-reduced diphtheria toxoid vaccine) or Tdap at least every 10 years.

d

Indicated ≥ 24 months after HSCT (if no GVHD or ongoing immunosuppression and patient is seronegative for each vaccine).