Clinical Significance of Serum Hepcidin Levels on Early Infectious Complications in Allogeneic Hematopoietic Stem Cell Transplantation

Article Outline

• Abstract
• Introduction
• Patients and Methods
  • Study Population
  • Serum Analysis
  • Prophylaxis, Monitoring, and Diagnosis of Infection
  • Statistical Analysis
• Results
  • Characteristics of Patients and Transplants
  • Documented Bacterial Infections
  • Other Transplant-Related Complications and Mortality
• Discussion
• Acknowledgments
• References
• Copyright

Abstract 

The association of iron overload with complications of allogeneic hematopoietic stem cell transplantation (HSCT) has been suggested in previous studies. Because hepcidin plays a central role in the regulation of iron homeostasis, we analyzed the association between pretransplant serum hepcidin-25 levels and early infectious complications after allogeneic HSCT. We studied 55 consecutive adult patients with a median age of 47 years (range: 20–64 years) who underwent allogeneic HSCT for hematologic malignancies at our institution. Thirty-two patients had myelogenous malignancies; the remaining 23 had lymphogenous malignancies. The median pretransplant serum hepcidin level of patients in the study was 21.6 ng/mL (range: 1.4–371 ng/mL), which was comparable to that of healthy volunteers (median: 19.1 ng/mL [range: 2.3–37 ng/mL]; n=17). When cumulative incidences of documented bacterial and cytomegalovirus (CMV) infections at day 100 were compared according to pretransplant hepcidin-25 levels, the incidence of bacterial, but not CMV, infection, was significantly higher in the high-hepcidin group (≥50 ng/mL; n=17) than in the low-hepcidin group (<50 ng/mL; n=38) (65% [95% confidence interval, 38%–82%] versus 11% [3%–23%]; P < .001). This finding was confirmed by multivariate Cox analysis adjusted for confounders, including pretransplant ferritin and C-reactive protein (CRP) levels. No fungal infection was documented in either group. These results suggest that the pretransplant serum hepcidin-25 level may be a useful marker for predicting the risk of early bacterial complications after allogeneic HSCT. Larger prospective studies are, however, warranted to confirm our findings.

Key Words: Hepcidin, Bacterial infection, Allogeneic stem cell transplantation

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Introduction 

Allogeneic hematopoietic stem cell transplantation (HSCT) has been widely performed as a potentially curative treatment for intractable hematologic malignancies with conventional chemotherapy. However, despite recent advances in the treatment of infectious diseases and conditioning regimens for transplantation, treatment-related complications remain a major problem. Therefore, it is particularly important to identify a good biomarker that can predict treatment-related complications before transplantation. A recently accumulated body of evidence suggests that iron overload is associated with adverse clinical outcomes in HSCT 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. Armand et al. [2] showed that a high pretransplant serum ferritin level was strongly associated with lower overall and disease-free survival (OS, DFS) in patients with allogeneic HSCT that was performed as a treatment for acute leukemia and myelodysplastic syndrome (MDS). Other studies have shown that pretransplant iron overload in autologous or allogeneic HSCT was a risk factor associated with posttransplant complications, such as mucositis, bacterial, and fungal infection, and hepatic veno-occlusive disease (VOD) 3, 4, 5, 6, 8, 9, 10, 11.

Hepcidin, first identified in human blood and urine as an antimicrobial small peptide 12, 13, is now considered to be a central molecule that regulates iron metabolism. Hepcidin decreases iron absorption from the intestine and blocks its release from iron stores by downregulating the expression of the cellular iron exporter, ferroportin 14, 15. Hepatic expression of hepcidin can be upregulated by iron loading 16, 17 as well as by inflammatory stimuli such as interleukin-6 (IL-6) [18]. Therefore, we hypothesized that serum hepcidin level could be a useful predictor of iron overload and inflammatory condition prior to HSCT. Here, we performed a single-center retrospective study at our institution to evaluate the significance of serum hepcidin levels as a predictor of early treatment-related complications after allogeneic HSCT with special reference to infectious complications.

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Patients and Methods 

Study Population 

The study population comprised 66 consecutive adult patients who underwent allogeneic HSCT for the treatment of hematologic malignancies at Kyoto University Hospital from July 2006 to September 2008. A total of 55 patients, excluding those who had received prior transplantations within 1 year or who had any active infections before the current transplantation, were included in the analysis. This study was approved by the Ethics Committee of Kyoto University Graduate School and the Faculty of Medicine. Written informed consent was obtained from all patients.

Serum Analysis 

Before the administration of conditioning regimens, serum samples were obtained at around 8:00 am, allocated in tubes, and stored at –80°C until analysis. The levels of serum hepcidin-25 (the main form of active hepcidin peptide) were quantified using a liquid chromatography-tandem mass spectrometry-based assay system following the method described by Murao et al. [19]. Other serum parameters were measured using standard laboratory techniques.

Prophylaxis, Monitoring, and Diagnosis of Infection 

The patients were isolated in a single room equipped with a high-efficiency particulate air filter (HEPA) system from 1 day before transplantation until at least 4 weeks after transplantation. No bacterial prophylaxis was prescribed for the patients according to our institutional protocols [20]. Trimethoprim-sulfamethoxazole (160mg/day [trimethoprim], 3 times a week) was administered as prophylactic therapy for Pneumocystis jirovecii pneumonia from the day of admission until the day of transplantation and restarted after the day of neutrophil engraftment. All patients received fluconazole (200 or 400mg/day) and acyclovir (1000mg/day) prophylaxis from the period of conditioning until 30 days after transplantation. After the first 30 days, the patients received fluconazole at a dose of 100mg/day until at least 100 days after transplantation. The administration of acyclovir (400mg/day) was continued when patients received steroid therapy for acute graft-versus-host disease (aGVHD). For each febrile episode, 1 or 2 sets of blood samples were cultured, and the cultures of specimens other than blood and imaging examinations were performed according to clinical judgment. The occurrence of cytomegalovirus (CMV) infection was closely monitored by CMV pp65 antigenemia testing with C10/C11 monoclonal antibodies (mAbs) from the day after neutrophil engraftment until at least 100 days after transplantation. Documented bacterial infection included any incidence of bloodstream infection or any other bacterial infection. Bloodstream infection was diagnosed if at least 1 of the following criteria was met: (1) blood culture obtained during a febrile episode was positive, at least once, for bacterial organisms not considered to be common skin contaminants; (2) blood culture obtained during a febrile episode was positive for the same common skin contaminant on separate occasions within 72hours; (3) blood culture was positive, at least once, for a common skin contaminant, and the patient was diagnosed with septicemia, including hypotension (systolic blood pressure, <90 mmHg) and abnormal coagulopathy. Infections other than bloodstream infection were diagnosed if the following criteria were met: (1) bacterial organisms were observed from specimens such as sputum, urine, and stool at least on 2 occasions, and (2) the patient showed symptoms of infection corresponding to those specimens. Clositridium difficile enterocolitis was excluded from the analysis, because this disease is toxin-mediated, and cannot be prevented by administration of common bacterial prophylactic agents such as fluoroquinolones, even if patients with a high risk of bacterial infection can be identified by using a putative biomarker. CMV infection was defined as positive if either C10 or C11 antigenemia assay showed at least 2 positive cells per 150,000 leukocytes. Invasive fungal infection was diagnosed according to the criteria of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group [21].

Statistical Analysis 

Endpoints included cumulative incidences of documented bacterial infection, fungal infection, CMV infection, and infection-related mortality, and OS within 100 days post transplantation. Patient and transplant characteristics between 2 groups were compared using the Mann-Whitney U-test or χ² analysis, as appropriate. The day of neutrophil engraftment was defined as the first of 3 consecutive days when the absolute neutrophil count (ANC) exceeded 500/μL. The day of neutrophil engraftment between 2 groups was compared by using the Mann-Whitney U-test. To eliminate the effect of competing risk, the cumulative incidences were assessed using methods described elsewhere [22]. The competing event in the cumulative incidence analyses was defined as death without an event of interest within 100 days post transplantation. OS was estimated using Kaplan-Meier methods. Infection-related death was defined as death associated with any infection within 100 days after transplantation. Standard risk disease was defined as complete remission (CR) in cases of acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), adult T cell leukemia/lymphoma (ATL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and untreated or CR in MDS and myeloproliferative disorder (MPD). High-risk disease was defined as statuses other than CR in AML, ALL, ATL, HL, and NHL and in MDS and MPD after treatment. The Cox proportional-hazard model was applied to assess the effect of factors that potentially affected the study endpoints. The following items were added as confounders: recipient's sex (male or female), recipient's age (<50 or ≥50 years), diagnosis (myelogenous or lymphogenous malignancies), risk of disease (standard or high risk), conditioning regimen (reduced or myeloablative intensity [RIC, MA]), type of donor (related or unrelated donor), reticulocyte count (<60×10⁹ or ≥60×10⁹/L), ferritin level (<1000 or ≥1000mg/dL), and C-reactive protein (CRP) level (<0.3 or ≥0.3 μg/dL). The cutoff points for reticulocyte count and the ferritin and CRP levels were chosen such that we could make optimal use of the information with a proviso that the smaller group contained at least 30% of patients. P values of < .05 were considered statistically significant. All analyses were conducted using STATA software version 10 (STATA Corp., College Station, TX).

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Results 

Characteristics of Patients and Transplants 

Characteristics of patients and transplants are shown in Table 1. The median age of patients was 47 years (range: 20–64 years). The primary disease in these patients was as follows: AML in 23, MDS/MPD in 9, ALL in 8, NHL in 9, HL in 1, and ATL in 5. The risk of diseases was standard in 27 and high in 28 patients. Nearly half of the patients (n=26) received a RIC regimen. The stem cell sources used were bone marrow (BM) in 39, peripheral blood (PB) in 1, and cord blood (CB) in 15 patients. The median pretransplant serum hepcidin level was 21.6 ng/mL (range: 1.4–371 ng/mL), which was comparable to that of healthy volunteers (median: 19.1 ng/mL [range: 2.3–37 ng/mL]; n=17) [23]. Because the lower hepcidin level of the third tertile among the patients in this study was 49.1 ng/mL, we set a cutoff hepcidin level of 50 ng/mL for practical use to divide the patients into low- and high-hepcidin groups (n=17 and 38, respectively). There was no difference in patient and transplant characteristics between the low- and high-hepcidin groups, except for serum ferritin levels (P < .001).

Table 1. Characteristics of Patients and Transplants

Variables	Hepcidin, Low (<50 ng/mL) n=38	Hepcidin, High (≥50 ng/mL) n=17	P Value
Age at transplant
Median age (range)	47.5 (23–64)	47 (20–63)	.750
Sex			.171
Male	21 (55%)	6 (35%)
Female	17 (45%)	11 (65%)
Disease			.612
Myeloid malignancies	23 (61%)	9 (53%)
AML	15	8
MDS/MPD	8	1
Lymphoid malignancies	15 (39%)	8 (47%)
ALL	4	4
ATL	4	1
HL	1	0
NHL	6	3
Risk of disease			.051
Standard	22 (58%)	5 (29%)
High	16 (42%)	12 (71%)
Conditioning regimen			.545
Myeloablative intensity	19 (50%)	10 (59%)
Reduced intensity	19 (50%)	7 (41%)
Prophylaxis against GVHD			.663
Cyclosporine-based	5 (13%)	3 (18%)
Tacrolimus-based	33 (87%)	14 (82%)
Type of donor			.181
Related donor
HLA∗-matched	10 (26%)	3 (18%)
HLA-mismatched	3 (8%)	1 (6%)
Unrelated donor
HLA-matched	18 (47%)	5 (29%)
HLA-mismatched	7 (18%)	8 (47%)
Source of stem cells			.259
Bone marrow	29 (76%)	10 (59%)
Peripheral blood	1 (3%)	0 (0%)
Cord blood	8 (21%)	7 (41%)
Serum ferritin (μg/dL)
mean (±SD)	664 (±796)	1551 (±993)	<.001
CRP (mg/dL)
mean (±SD)	0.36 (±0.68)	0.70 (±1.63)	.176
Reticulocyte (×109/L)
mean (±SD)	63.7 (±40.2)	64.0 (±42.2)	.979

AML indicates acute myelogenous leukemia; MDS/MPD, myelodysplastic syndrome and myeloproliferative disorders; ALL, acute lymphoblastic leukemia; ATL, acute T cell leukemia/lymphoma; HL, Hodgkin lymphoma; NHL, non-Hodgkin lymphoma; GVHD, graft-versus-host disease; Cyclosporine-based, cyclosporine with or without other agents; Tacrolimus-based, tacrolimus with or without other agents; HLA, human leukocyte antigen; CRP, C-reactive protein.

Data are counts of individuals unless specified otherwise.

Documented Bacterial Infections 

There was no significant difference between the days of neutrophil engraftment of the low- and high-hepcidin groups (median day: 21 [range: 14–99] and median day: 22.5 [range: 12–53], respectively, P=.54). A total of 16 episodes of bacterial infections were documented; these included 15 episodes of bloodstream infections and 1 episode of pneumonia. No patient experienced more than 1 episode of bacterial infection within 100 days after transplantation. The documented bacterial organisms are listed in Table 2. The main organisms were Gram-negative bacilli in both the low- and high-hepcidin groups. In the antimicrobial-susceptibility tests, 12 of the 13 Gram-negative isolates were sensitive to fluoroquinolone. We documented 2 bacterial infections in the late period of transplantation; 1 patient showed infection at day 89 after transplantation, which was attributed to delayed neutrophil engraftment, and another patient showed infection at day 68, when the neutrophil counts had temporarily decreased. The cumulative incidences of the documented bacterial infection in the low- and high-hepcidin groups were 11% (95% confidence interval [CI], 3%–23%) and 65% (95% CI, 38%–82%), respectively (Figure 1A). In the low-hepcidin group, the cumulative incidence of bacterial infection was lower in patients with a hepcidin level of <25 ng/mL than in those with a hepcidin level ranging from ≥25 to <50 ng/mL (10% [95% CI, 2%–23%] versus 17%, [95% CI, 1%–52%]). Univariate analysis of various potential confounders showed that high hepcidin level was the only factor that affected the cumulative incidence of documented bacterial infection (hazard ratio [HR], 8.98; 95% CI, 2.82–28.57; P < .001) (Table 3). To exclude the effect of other confounders, the significance of high hepcidin level was assessed in the stratified category of each confounder (eg, in either the high- or low-ferritin group); we noted consistently high HRs in the high-hepcidin group in each stratified category (data not shown). We also found that hepcidin had a significant impact on the patients, excluding the patients in other specific categories, such as those who received a CB transplant or those who underwent a transplant from an unrelated HLA-mismatched donor (data not shown). Furthermore, the significant effect of hepcidin persisted even after the adjustment for confounders in multivariate analysis (HR, 28.46; 95% CI, 2.51–323.34; P=.007) (Table 3). Even when the variables were treated as continuous instead of categoric, the significant effect of hepcidin persisted (HR, 1.01; 95% CI, 1.00-1.01; P=.001).

Table 2. Documented Bacterial Organisms within 100 Days after Stem Cell Transplantations

Category	Hepcidin, Low (<50 ng/mL) n=38	Hepcidin, High (≥50 ng/mL) n=17
Gram-positive cocci (n)	Staphylococcus epidermidis (1)	Enterococcus faecium (2)
Gram-negative bacilli (n)	Klebsiella pneumoniae (2)	Klebsiella pneumoniae (3)
	Enterobacter cloacae (1)	Escherichia coli (3)
	Prevotella intermedia (1)	Pseudomonas aeruginosa (2)
		Klebsiella oxytoca (1)

P. intermedia was detected in the sputum of 1 patient with pneumonia. Other organisms were detected in blood culture bottles.

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• Figure 1 

  The cumulative incidences of documented bacterial infection (A) and cytomegalovirus (CMV) infection (B) at 100 days after stem cell transplantation. Solid black line, the low-hepcidin group (<50 ng/mL); solid gray line, the high-hepcidin group (≥50 ng/mL); CI, confidence interval. CMV infection was not assessable in 2 patients because of early death before neutrophil engraftment.

Table 3. Univariate and Multivariate Analyses of Documented Bacterial Infection, CMV Infection, and Overall Survival at 100 Days after Stem Cell Transplantations

	Number	Univariate Analysis		Multivariate Analysis
		HR (95% CI)	P Value	HR (95% CI)	P Value
1) Documented bacterial infection
Hepcidin, low (<50 ng/mL)	5/38	1	–	1	–
Hepcidin, high (≥50 ng/mL)	11/17	8.98 (2.82–28.57)	<.001	28.46 (2.51–323.34)	.007
2) CMV antigenemia (C10 or C11 ≥2)
Hepcidin, low (<50 ng/mL)	18/37	1	–	1	–
Hepcidin, high (≥50 ng/mL)	7/16	0.97 (0.40–2.32)	.939	0.63 (0.16–2.49)	.511
3) Overall survival
Hepcidin, low (<50 ng/mL)	36/38	1	–	–	–
Hepcidin, high (≥50 ng/mL)	14/17	3.60 (0.60–21.56)	.161	–	–

CMV indicates cytomegalovirus; CI, confidence interval.

Hazard ratios (HRs) in multivariate analysis were adjusted for recipient's sex (male or female), recipient's age (<50 or ≥50 years), diagnosis (myelogenous or lymphoid malignancies), risk of disease (standard or high risk), conditioning regimen (reduced or myeloablative intensity), type of donor (related or unrelated donor), reticulocyte count (<60 × 109 or ≥60 × 10⁹/L), ferritin level (<1000 or ≥1000 mg/dL), and C-reactive protein (CRP) level (<0.3 or ≥0.3 μg/dL). Overall survival was not analyzed in the multivariate model because of the low incidence of death.

Other Transplant-Related Complications and Mortality 

The cumulative incidences of CMV infection in the low- and high-hepcidin group were 49% (95% CI, 32%–64%) and 45% (95% CI, 20%–67%), respectively (Figure 1B); univariate and multivariate analyses showed no significant difference between the 2 groups (Table 3). All CMV infections were well treated by the administration of ganciclovir or foscarnet. No fungal infection was documented. Therefore, all infection-related deaths were attributed to bacterial infection. The cumulative incidence of infection-related mortality in the low-hepcidin group was 3% (95% CI, 0.2%–12%), whereas that in the high-hepcidin group was 6% (95% CI, 0.4%–24%), with no statistical difference between the 2 groups. OS at 100 days after transplantation in the low- and high-hepcidin groups was 95% (95% CI, 81%–99%) and 82% (95% CI, 55%–94%), respectively (Figure 2). No significant difference in OS was observed (Table 3).

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• Figure 2 

  Kaplan-Meier estimate of OS at 100 days after stem cell transplantation. Solid black line, the low-hepcidin group (<50 ng/mL); solid gray line, the high-hepcidin group (≥50 ng/mL); CI, confidence interval.

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Discussion 

In our cohort of patients who underwent allogeneic HSCT for hematologic malignancies, we found a significant association between the pretransplant serum hepcidin levels and the cumulative incidence of documented bacterial infection. To our knowledge, this is the first study that has evaluated the clinical significance of serum hepcidin levels in predicting transplant-related complications; the findings suggest that the pretransplant serum hepcidin level can be used as a good pretransplant biomarker to predict bacterial infection in a patient scheduled for HSCT.

Hepcidin production is regulated by at least 3 factors: iron load 16, 17, inflammation [18], and unknown erythropoietic signals 23, 24, 25. Therefore, the good predictive value of hepcidin with respect to the incidence of documented bacterial infection can be partly explained by the cumulative effect of at least these 3 factors on bacterial infection. Iron overload increases the level of circulating non-transferrin-bound iron, which is known to amplify free-radical reactions in inflammatory or ischemia-related conditions 7, 26. Such reactions could enhance tissue damage such as mucositis during the conditioning regimen, thereby allowing bacterial translocation through the damaged mucosa [27]. In addition, iron is a necessary nutrient for bacteria and fungus [28]. The association between hemochromatosis, 1 of the iron overload disorders, and infection with certain organisms has already been described [29]. Therefore, the high hepcidin levels might reflect iron overload status, which has an adverse effect on bacterial infections. Second, a high hepcidin level may indicate inflammation because of a latent bacterial infection that was undetectable before HSCT, but may surface in posttransplant neutropenic status. Last, a high hepcidin level could reflect suppressed erythropoiesis, probably because of the short duration from the last chemotherapy to the start of the conditioning regimen for transplantation. Repeated cytotoxic chemotherapy in a short period may exacerbate tissue damage and increase the risk of bacterial infection.

Although serum ferritin levels do not necessarily correlate with the amount of iron load in patients with inflammation or specific diseases 1, 30, 31, it is frequently used and regarded as a indicator of iron overloading, and several studies have demonstrated the association between high ferritin levels and treatment-related mortality (TRM) 3, 11. In this cohort, an elevation of serum ferritin level was not found to be a significant risk factor for bacterial infection, whereas an elevated hepcidin level was a strong risk factor even after adjustment for other potential confounders. Furthermore, we observed consistent association of high hepcidin levels with high risk for developing bacterial infection when analyses were confined to either the low- or high-ferritin subgroups. These findings collectively suggest that hepcidin can be used as a better predictor of documented bacterial infections than serum ferritin levels. Moreover, various new techniques to quantify hepcidin-25, such as a competitive enzyme-linked immunoassay as well as mass spectrometry-based methods, have been recently developed 19, 25, 32, 33. Standardization of those methods will make it possible to use the serum hepcidin level as a biomarker in routine clinical practice.

Hepcidin was first isolated and characterized as an antimicrobial peptide in human blood [12]. In radial diffusion assays, synthetic hepcidin suppressed the growth of several strains of Gram-positive bacteria and some strains of Gram-negative bacteria, but not of Escherichia coli or Pseudomonas fluorescens. Our findings pertaining to the adverse association of high hepcidin levels with bacterial infection indicated that the bactericidal effect of hepcidin was either considerably limited in neutropenic settings such as HSCT or was ineffective on the bacterial organisms observed in our cohort. Moreover, we observed a significant adverse effect of hepcidin even after the adjustment for potential confounders, suggesting that hepcidin itself may play an unknown biologic role in susceptibility to bacterial infection, or it may represent an unknown surrogate marker for predicting bacterial infection. To answer this issue, the significance of pretransplant serum hepcidin levels needs to be evaluated in a more homogeneous group of patients having the same level of confounders.

We did not detect any adverse effect of high hepcidin levels on infection-related mortality or OS at 100 days after transplantation, although there was a marked difference in the incidence of bacterial infection. One possible explanation for this observation is that bacterial infection of the blood was well managed by prompt and appropriate treatment with antibiotics in our transplant centers. However, because the incidence of early death after HSCT is considerably low, the effect of bacterial infection on early mortality should be evaluated in larger cohort studies to gain enough statistical power for comparison. Alternatively, selective prophylactic administration of oral antibiotics such as fluoroquinolones to patients with a high risk of bacterial infection may be an effective approach; however, this approach will be effective only if most of the bacterial isolates at the transplant center are sufficiently sensitive to these prophylactic antibiotics. With regard to other endpoints, there was no association between high hepcidin levels and the incidence of CMV infection. The effect of hepcidin level on the incidence of fungal infection could not be evaluated because of the very low incidences of these conditions in our cohorts. These effects should also be evaluated in studies with a larger cohort in the future.

The present study, however, has some limitations. We cannot exclude the possibility of a pseudonegative result for bloodstream infection, because broad-spectrum antibiotics were administered to all neutropenic patients at the time of blood culture, regardless of the results of blood culture. In addition, the retrospective study design and heterogeneous background of diseases and transplantation procedures could also bias the results. Particularly, in the small cohort of 55 patients, the adjustment of HRs by confounders may be incomplete. In particular, the higher proportion of CB transplants and the high risk of diseases in the high-hepcidin group may cause bias, although we found consistently high HRs in the high-hepcidin group in various stratified categories. Therefore, larger studies are necessary to confirm our results.

In conclusion, our study revealed that the pretransplant serum hepcidin level was significantly associated with bacterial infection, particularly bloodstream infection, suggesting that quantification of serum hepcidin levels could be useful for predicting early bacterial complications. Prophylactic antibiotic therapy based on the local sensitivities of common bacterial isolates can be considered in the patients with high hepcidin levels who are undergoing allogeneic HSCT. Larger prospective studies are, however, warranted to confirm our findings.

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Acknowledgments 

Financial disclosure: This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports, and Culture of Japan; a grant from the Takeda Science Foundation; and a grant for Project Research from the High-Technology Center of Kanazawa Medical University (H2007-2). The authors are grateful to Rie Goi and Mika Kobayashi, for their expert data management and secretarial assistance, and all the transplant teams for their dedicated care of the patients and donors.

Conflict of interest: N.T. declares that he is the President of Medical Care Proteomics Biotechnology Co. Ltd. (Ishikawa-ken, Japan), a startup company, the stock of which is not publicly traded. The other authors declare that they have no conflicts of interest relevant to this paper.

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