Febrile Neutropenic Infection Occurred in Cancer Patients Undergoing Autologous Peripheral Blood Stem Cell Transplantation W.-X. Zhanga,b, Q.-Y. Zhaoa,c,*, and H.-Q. Huanga,d a State Key Laboratory of Oncology in South China, cDepartment of Infection Control, dDepartment of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; and bIntensive Care Unit, Henan Provincial People’s Hospital, Zhengzhou, China

ABSTRACT Objective. The objective of this study was to investigate the incidence, risk factors, and clinical and prognostic characteristics of febrile infection that occurred during the neutropenic period in cancer patients who underwent autologous peripheral blood stem cell transplantation (APBSCT). Methods. Clinical data of all the APBSCT cases from 2007 to 2009 in Sun Yat-sen University Cancer Center were collected and retrospectively analyzed. Results. Eighty-nine APBSCT subjects were investigated. Neutropenia usually occurred on the 4th day (range, 0e15) after transplantation and lasted 6 (range, 3e27) days. Febrile neutropenia occurred in 78.7% patients and lasted around 3 (range, 1e20) days and no infection-related deaths were observed. For febrile episodes, 12 patients (17.1%) were diagnosed as having microbiologically documented infections (MDI). Initial empirical antimicrobial therapy was given to all cases of post-APBSCT febrile neutropenia, of which 44 cases (62.9%) were effective. Febrile neutropenia occurred in 25/34 (73.5%) patients who were given antifungal drugs for prophylaxis. Conclusions. Neutropenic infection is still the major complication in APBSCT patients and duration of neutropenia is one of the major risk factors. Prophylactic administration of antifungal drugs seems to be invalid to reduce post-APBSCT infection. Sufficient doses of broad-spectrum antibiotics at the early stage lead to better results of initial antimicrobial treatment.

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INCE the early 1990s, autologous peripheral blood stem cell transplantation (APBSCT) has progressively replaced bone marrow transplantation (BMT) as the major therapy in hematologic malignancies, solid tumor, and autoimmune diseases. The current preference for the use of APBSCT over bone marrow stem cells can be mainly attributed to the faster hematologic and immunologic recovery observed following APBSCT, ease of collection of high numbers of CD34þ cells after chemotherapy followed by growth factor administration, as well as lower mortality and morbidity [1]. Post-transplantation infection is one of the major risk factors influencing the outcome of transplantation. Although lots of research has been made on infectious complications, few studies have focused on infections after APBSCT. Also, these studies enrolled relatively few patients and some have included patients treated with allogeneic PBSCT or autologous BMT [2]. ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

Transplantation Proceedings, 47, 523e527 (2015)

We have retrospectively studied 89 consecutive patients undergoing high-dose chemotherapy and APBSCT at a single institution between 2007 and 2009. Because most infections in APBSCT occurred during neutropenia, we aimed to ascertain the incidence and characteristics of infectious complications during the neutropenia phase, as well as to analyze possible risk factors. PATIENTS AND METHODS Patient Characteristics Between March 2007 and December 2009, 91 patients with hematologic malignancies and solid tumors underwent APBSCT at Sun *Address correspondence to Qing-Yu Zhao, MD, Department of Infection Control, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China. E-mail: [email protected] 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.01.013

523

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ZHANG, ZHAO, AND HUANG Table 1. Patient Characteristics Median (Range)

Patients enrolled Age Gender Male Female PS (WHO) 0 1 Diagnosis NHL HD MM Solid tumor Previous chemotherapy courses Previous radiotherapy Yes No Previous surgery Yes No Disease status at transplantation CR Other

No. of Patients (%)

89 (100) 36 (6e77) 59 (66.3) 30 (33.7) 77 (86.5) 12 (13.5) 64 10 3 12

(71.9) (11.2) (3.4) (13.5)

steroids to minimize the effects of dimethylsulfoxide-mediated histamine release.

Anti-Infectious Prophylaxis Patients received a low-germ diet and were treated with intensified hygiene measures on a separate transplantation ward in single rooms with high-efficiency particulate air filters. Anti-infectious prophylaxis commenced immediately after admission to the transplantation unit. Prophylactic antibiotics included norfloxacin (400 mg every 12 hours orally) and sulfamethoxazole-trimethoprim (200 mg every 12 hours orally) until neutrophil recovery or intravenous administration of antimicrobial therapy due to infection. Oral acyclovir (400 mg twice daily) was also routinely administered to prevent varicella zoster virus infection.

Definition Criteria

10 (4e31) 23 (25.8) 66 (74.2) 18 (20.2) 71 (79.8) 48 (53.9) 41 (46.1)

Yat-sen University Cancer Center. All patients were retrospectively analyzed except 2 patients who suffered from fever before neutropenia. There were 59 males and 30 females being studied, with a median age of 36 years (range, 6e77). Diagnoses were non-Hodgkin’s lymphoma (NHL; n ¼ 64), Hodgkin’s disease (HD; n ¼ 10), multiple myeloma (MM; n ¼ 3), and solid tumor (n ¼ 12). Fortyeight patients (53.9%) were in first complete remission (CR). The performance status (PS; World Health Organization [WHO] score) of 77 patients (86.5%) was 0, and that of the remaining 12 patients (13.5%) was 1. Patient characteristics are summarized in Table 1.

Transplantation Procedures Peripheral blood stem cells (PBSCs) were mobilized during the hematopoietic recovery following the first postremission consolidation therapy, stimulated by administration of granulocyte colonystimulating factor (G-CSF) 10 mg/kg/d. A minimum of 2  106 CD34þ cells/kg were collected by repeated leukaphereses, which started after an increase of leukocytes to >0.8/nL and more than 0.5% CD34þ cells in the peripheral blood. The collected PBSCs were frozen using a controlled-rate freezer and stored in liquid nitrogen at 196 C until use. Before APBSCT, conditioning regimens were chosen according to the underlying disease: bis-chloroethylnitrosourea 300 mg/m2, etoposide 1200 mg/m2, cytarabine 1600 mg/m2, and melphalan 140 mg/m2 (BEAM) in 71 patients with lymphoma and 2 patients with solid tumor; busulfan 40 mg/kg and cyclophosphamide 120 mg/kg (BUCY) in 3 patients with lymphoma; and high-dose melphalan alone in 3 patients with MM. Other conditioning regimens were also used occasionally. Harvested stem cells were infused 24 hours after the discontinuation of chemotherapy, and G-CSF 5 mg/kg/d was administered subcutaneously until leukocytes recovered to >10  109/L. After completion of the conditioning regimen, cryopreserved stem cells were thawed at 37 C in a water bath and infused through a Hickman catheter using a standard blood administration set without a filter. Patients were premedicated with antihistamines and

According to 2002 Guidelines for neutropenic patients with cancer [3], neutropenia was defined as an absolute neutrophil count (ANC) 38 C (axillary temperature) in the absence of an obvious noninfectious cause of fever such as blood products transfusion, cytotoxic drugs administration, or tumor fever. Multiple fever episodes were separated by at least 3 days of normal body temperature. Blood cultures were taken from peripheral blood and central venous catheter (CVC), and cultures from suspected sites were also taken.

Empirical Antibiotic Therapy Febrile patients were immediately intravenously injected with empirical antibiotics. First-line treatment included a beta-lactam or piperacillin/tazobactam, and, in patients who did not respond, a glycopeptide was added in the 72nd hour if the patient had a catheter or a suspicion of Gram-positive infection. If fever continued after 5 days, itraconazole was added. If the etiology of infection was identified, antibiotic treatment would be adjusted to the most appropriate therapy. Response to antibiotic treatment was defined as body temperature 5  106/ kg CD34þ cells, and the average amount of neutrophil at the beginning of PBSCT was (2.36  1.60)  109/L. Primary graft failure occurred in 1 patients, and no patients died because of transplantation-related causes. All the patients suffered from

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Fig 1. Differences of ANC between febrile and nonfebrile patients.

neutropenia, which occurred 4 (range, 0e15) days after stem cell infusion, and lasted 6 (range, 3e27) days. The median duration of severe neutropenia was 4 (range, 1e8) days, and ANC valley was 0.020  109/L (0e0.09  109/L). The median duration of hospital stay was 26 (range, 17e60) days. Incidence and Characteristics of Infection

During neutropenia, 70 patients (78.7%) suffered 1 episode of fever, the median occurrence of which was on the second day (range, 0e8) from the onset of neutropenia. The median duration of fever was 3 (range, 1e20) days. There were no significant differences in age, gender, and median numbers of transplanted CD34þ cells per kg body weight between febrile and nonfebrile patients, whereas the differences in ANC and neutropenia duration between groups were significant (Fig 1 and Fig 2). In the study, 45 of the 55 patients not taking antifungal prophylaxis suffered from fever, whereas 25 of the 34 patients taking antifungal prophylaxis suffered from fever, and there was no significant difference in fever incidence between the 2 groups (P ¼ .354). Clinical characteristics in febrile and nonfebrile patients are summarized in Table 2. Among patients who had fever, 43 of 70 also had diarrhea, and microbiologically documented infections (MDI) accounted for 17.1% (12/70). Among MDI, 1 was diagnosed as bacteremia with extended-spectrum beta-lactamaseþ Escherichia coli, and another was diagnosed as pneumonia with Acinetobacter lwoffii. The rest were fungal enteritis. Outcome of Infections

No infection-related death occurred in this cohort study. Of the 70 febrile patients, 59 (84.3%) were treated with a single

first-line broad-spectrum antibiotic, 7 (10.0%) with an antibiotic regimen plus a glycopeptide or linezolid, and 4 with an antibiotic regimen plus an aminoglycoside. Response to firstline antibiotic therapy was noticed in 44 (62.9%) patients. The median antibiotic duration was 6 (range, 3e22) days. Empirical antifungal therapy was given to 17 (24.3%) patients. Risk Factors Analysis

Factors affecting infection development were investigated, including age, PS at transplantation, number of CD34þ cells infused, gammaglobuline, days on neutropenia >6, days on severe neutropenia >4, ANC valley, and antifungal prophylaxis by using logistic stepwise analysis. Univariate and multivariate analysis showed that days on neutropenia >6 was associated with a higher risk of early infection (Table 3). DISCUSSION

With the increasing use of high-dose therapy (HDT) followed by stem cell transplantation, various infectious complications have become the leading cause of morbidity and mortality due to prolonged neutropenia, profound immunosuppression, and interruption of mucocutaneous barriers [4]. Prolonged and profound neutropenia in the preengraftment period is accompanied by severe bacterial and fungal infections that endanger the BMT recipients’ lives highly. APBSCT and growth factors have drastically shortened the duration of neutropenia in comparison with BMT. The current study demonstrated that all the patients suffered from neutropenia, which lasted for a mean of 6 (range, 3e27) days, and the duration was remarkably

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ZHANG, ZHAO, AND HUANG

Fig 2. Differences of neutropenia duration between febrile and nonfebrile patients.

shortened compared with BMT [5]. Despite the superiority in neutrophil recovery, infectious complications occurred in 78.7% of the investigated patients. Likewise, the studies comparable with ours [6,7] similarly showed a high incidence of infection. The short period of neutropenia probably favors the rapid resolution of bacterial infections Table 2. Comparison of Clinical Characteristics Between Febrile and Nonfebrile Patients Febrile n ¼ 70

Age (median, range) 36.5 (6e77) Gender (male/female) 45/25 Weight (kg) 60.25 (18e82) Height (cm) 163.5 (119e181) Body surface area (m2) 1.66 (0.76e1.98) Hospital stay (d) 26 (19e60) ANC at stem 2.00 (0.06e8.40) cell infusion (109/L) Neutropenia (d) 6 (4e27) Severe neutropenia (d) 4 (1e8) ANC valley (109/L) 0.019 (0e0.090) CD34þcell 4.34 (1.01e25.58) transplanted (106/kg) Gammaglobuline (g/L) 19.6 (13.0e30.3) Previous 10 (4e31) chemotherapy courses CR/other 35/35 Diarrhea (%) 43 (61.4%) Antifungal 25/45 prophylaxis (yes/no) *P < .05.

Nonfebrile n ¼ 19

P

36 (13e65) 14/5 65 (43e82) 164 (151e181) 1.7 (1.4e1.98) 24 (17e43) 2.70 (1.04e6.90)

.916 .442 .108 .281 .110 .101 .031*

5 4 0.020 4.46

(3e8) (1e6) (0e0.870) (2.04e11.99)

21.0 (14.2e38.5) 11 (6e18)

13/6 10 (52.6%) 9/10

.015* .142 .606 .896 .411 .644

.153 .480 .354

because the patients experienced only 1 febrile episode, of which the median duration was 3 (range, 1e20) days, and most patients responded effectively to empirical antibiotics. No early infection-related deaths occurred in this cohort of 89 patients. The current study indicated that the reduced duration of neutropenia seen with APBSCT remains a significant risk factor for early infections. In contrast, there’s also a report showing that the duration of neutropenia does not affect the rate of febrile episodes [2]. However, this result does not represent the situation among APBSCT patients. This study was undertaken by comparing neutropenia infections between patients after conventional chemotherapy, allogeneic PBSCT, or APBSCT. Because all the patients included went through APBSCT, our study has superiority in homogeneity, and, therefore, could display the characteristics of febrile neutropenia among APBSCT patients more precisely. Scheid et al showed that infusion with CD34þ cell >5  106/kg could decrease the incidence of infectious complications of graft recipients [8]. However, in our study, there were no significant differences on the duration of neutropenia and severe neutropenia between patients infused with CD34þ cell >5  106/kg and patients with CD34þ cell 5  106/kg. Meanwhile, the difference on the incidence of fever, duration of fever, and days on antibiotics was not remarkable (P ¼ .597, P ¼ .333, and P ¼ .195, respectively). Logistic analysis showed that number of CD34þ cells was not associated with febrile neutropenia (P ¼ .598), which corresponded with the study by Offidani et al [7]. The prophylactic administration of 200 mg twice a day fluconazole has been shown to be useful in preventing fungal infections to BMT recipients [9]. Offidani et al suggested that

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Table 3. Univariate and Multivariate Analysis of Risk Factors Affecting Infection Development Univariate

Age Performance status Status at transplant (CR or not) ANC at stem cell infusion Days on neutropenia >6 Days on severe neutropenia >4 ANC valley Gammaglobulin CD34þ >5  106/kg Diarrhea Antifungal prophylaxis

Multivariate

P

OR

P

.915 .075 .159 .053 .022* .110 .259 .077 .598 .490 .356

1.002 0.311 0.462 0.739 6.012 2.497 0 0.912 1.364 1.433 0.617

.844 .152 .068 .504 .034* .881 .892 .121 .297 .803 .650

OR

5.385

*P < .05.

in PBSCT recipients routine surveillance cultures and antifungal prophylaxis should be undertaken only in high-risk patients with prolonged severe neutropenia. In our study, 45 of the 55 patients not taking antifungal prophylaxis suffered from fever, whereas 25 of the 34 patients taking antifungal prophylaxis suffered from fever, and there was no significant difference between the 2 groups. In accordance with previous studies, we suggest that antifungal prophylaxis only be used in high-risk patients with prolonged severe neutropenia. Diarrhea is a major cause of morbidity during high-dose chemotherapy followed by APBSCT. It is generally attributed to the mucosal injury caused by high-dose chemotherapy and/or the effects of broad-spectrum antibiotic regimens for prophylaxis and treatment of neutropenic fever [4]. Accumulating evidence suggests that the dynamic balance between microbes, particularly commensal flora, and host defensive responses at the mucosal frontier has a pivotal role in the initiation and pathogenesis of chronic inflammatory bowel disease [10] and probiotic combinations benefit graft recipients [11]. In addition, it is also reported that diarrhea in this population is frequent, but only infrequently due to Clostridium difficile, and empiric therapy for C. difficile should be administered with caution in the consideration of the widespread emergence of vancomycinresistant Gram-positive bacteria [12]. In conclusion, infection is still the major complication arising after APBSCT, although it has the characteristics of reduced severity, lower incidence of pneumonia, and virtual absence of early and late fungal and other opportunistic

infections and, consequently, low mortality when compared with BMT. However, the reduced duration of neutropenia seen with APBSCT remains a significant risk factor for early infections, and isolation of immunocompromised patients from likely contamination may help to reduce infectious complications. In APBSCT recipients, antifungal prophylaxis should be used with caution. The incidence of diarrhea is high in APBSCT recipients, suggesting that prophylactic use of probiotics may be beneficial to patients against pathogenic bacteria. REFERENCES [1] Dettenkofer M, Ebner W, Bertz H, et al. Surveillance of nosocomial infections in adult recipients of allogeneic and autologous bone marrow and peripheral blood stem-cell transplantation. Bone Marrow Transplant 2003;31(9):795e801. [2] Celebi H, Akan H, Akcaglayan E, et al. Febrile neutropenia in allogeneic and autologous peripheral blood stem cell transplantation and conventional chemotherapy for malignancies. Bone Marrow Transplant 2000;26(2):211e4. [3] Hughes WT, Armstrong D, Bodey GP, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002;34(6):730e51. [4] Wingard JR, Hsu J, Hiemenz JW. Hematopoietic stem cell transplantation: an overview of infection risks and epidemiology. Infect Dis Clin North Am 2010;24(2):257e72. [5] Beyer J, Schwella N, Zingsem J, et al. Hematopoietic rescue after high-dose chemotherapy using autologous peripheral-blood progenitor cells or bone marrow: a randomized comparison. J Clin Oncol 1995;13(6):1328e35. [6] Kolbe K, Domkin D, Derigs HG, Bhakdi S, Huber C, Aulitzky WE. Infectious complications during neutropenia subsequent to peripheral blood stem cell transplantation. Bone Marrow Transplant 1997;19(2):143e7. [7] Offidani M, Corvatta L, Olivieri A, et al. Infectious complications after autologous peripheral blood progenitor cell transplantation followed by G-CSF. Bone Marrow Transplant 1999;24(10):1079e87. [8] Scheid C, Draube A, Reiser M, et al. Using at least 5x10(6)/ kg CD34þ cells for autologous stem cell transplantation significantly reduces febrile complications and use of antibiotics after transplantation. Bone Marrow Transplant 1999;23(11):1177e81. [9] Capizzi R. Amifostine: the preclinical basis for broadspectrum selective cytoprotection of normal tissues from cytotoxic therapies. Semin Oncol 1996;23(4 Suppl 8):2e17. [10] Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007;448(7152):427e34. [11] Macintyre A, Cymet TC. Probiotics: the benefits of bacterial cultures. Compr Ther 2005;31(3):181e5. [12] Avery R, Pohlman B, Adal K, et al. High prevalence of diarrhea but infrequency of documented Clostridium difficile in autologous peripheral blood progenitor cell transplant recipients. Bone Marrow Transplant 2000;25(1):67e9.