Scholarly article on topic 'Bacterial Foodborne Infections after Hematopoietic Cell Transplantation'

Bacterial Foodborne Infections after Hematopoietic Cell Transplantation Academic research paper on "Biological sciences"

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Abstract of research paper on Biological sciences, author of scientific article — Nicole M. Boyle, Sara Podczervinski, Kim Jordan, Zach Stednick, Susan Butler-Wu, et al.

Abstract Diarrhea, abdominal pain, and fever are common among patients undergoing hematopoietic cell transplantation (HCT), but such symptoms are also typical with foodborne infections. The burden of disease caused by foodborne infections in patients undergoing HCT is unknown. We sought to describe bacterial foodborne infection incidence after transplantation within a single-center population of HCT recipients. All HCT recipients who underwent transplantation from 2001 through 2011 at the Fred Hutchinson Cancer Research Center in Seattle, Washington were followed for 1 year after transplantation. Data were collected retrospectively using center databases, which include information from transplantation, on-site examinations, outside records, and collected laboratory data. Patients were considered to have a bacterial foodborne infection if Campylobacter jejuni/coli, Listeria monocytogenes, E. coli O157:H7, Salmonella species, Shigella species, Vibrio species, or Yersinia species were isolated in culture within 1 year after transplantation. Nonfoodborne infections with these agents and patients with pre-existing bacterial foodborne infection (within 30 days of transplantation) were excluded from analyses. A total of 12 of 4069 (.3%) patients developed a bacterial foodborne infection within 1 year after transplantation. Patients with infections had a median age at transplantation of 50.5 years (interquartile range [IQR], 35 to 57), and the majority were adults ≥18 years of age (9 of 12 [75%]), male gender (8 of 12 [67%]) and had allogeneic transplantation (8 of 12 [67%]). Infectious episodes occurred at an incidence rate of 1.0 per 100,000 patient-days (95% confidence interval, .5 to 1.7) and at a median of 50.5 days after transplantation (IQR, 26 to 58.5). The most frequent pathogen detected was C. jejuni/coli (5 of 12 [42%]) followed by Yersinia (3 of 12 [25%]), although Salmonella (2 of 12 [17%]) and Listeria (2 of 12 [17%]) showed equal frequencies; no cases of Shigella, Vibrio, or E. coli O157:H7 were detected. Most patients were diagnosed via stool (8 of 12 [67%]), fewer through blood (2 of 12 [17%]), 1 via both stool and blood simultaneously, and 1 through urine. Mortality due to bacterial foodborne infection was not observed during follow-up. Our large single-center study indicates that common bacterial foodborne infections were a rare complication after HCT, and the few cases that did occur resolved without complications. These data provide important baseline incidence for future studies evaluating dietary interventions for HCT patients.

Academic research paper on topic "Bacterial Foodborne Infections after Hematopoietic Cell Transplantation"

3. Fujimaki K, Maruta A, Yoshida M, et al. Severe cardiac toxicity in hematological stem cell transplantation: predictive value of reduced left ventricular ejection fraction. Bone Marrow Transplant. 2001;27:307-310.

4. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new toolfor risk assessment before allogeneic HCT. Blood. 2005;106:2912-2919.

5. Kasow KA, Krueger J, Srivastava DK, et al. Clinical utility of computed tomography screening of chest, abdomen, and sinuses before he-matopoietic stem cell transplantation: the St. Jude experience. Biol Blood Marrow Transplant. 2009;15:490-495.

6. Nieboer P, Roodenburg JL, van der Laan BF, et al. Screening for infectious foci in breast cancer patients prior to high-dose chemotherapy and stem cell transplantation. Anticancer Res. 2003;23:1779-1783.

7. Moeller CW, Martin J, Welch KC. Sinonasal evaluation preceding hematopoietic transplantation. Otolaryngol Head Neck Surg. 2011;144: 796-801.

8. Thompson AM, Couch M, Zahurak ML, et al. Risk factors for post-stem cell transplant sinusitis. Bone Marrow Transplant. 2002;29:257-261.

9. Billings KR, Lowe LH, Aquino VM, Biavati MJ. Screening sinus CT scans in pediatric bone marrow transplant patients. Int J Pediatr Oto-rhinolaryngol. 2000;52:253-260.

10. Toljanic JA, Bedard JF, Larson RA, Fox JP. A prospective pilot study to evaluate a new dental assessment and treatment paradigm for patients

scheduled to undergo intensive chemotherapy for cancer. Cancer. 1999;85:1843-1848.

11. Melkos AB, Massenkeil G, Arnold R, Reichart PA. Dental treatment prior to stem cell transplantation and its influence on the posttransplantation outcome. Clin Oral Invest. 2003;7:113-115.

12. Peters E, Monopoli M, Woo SB, Sonis S. Assessment of the need for treatment of postendodontic asymptomatic periapical radiolucencies in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol. 1993;76:45-48.

13. Niederhagen B, Wolff M, Appel T, et al. Location and sanitation of dental foci in liver transplantation. Transplant Int. 2003;16:173-178.

14. Zimmermann U, Mentzel HJ, Wolf J, et al. MRI screening before stem cell transplantation—necessary? Fortschr Geb Rontgenstr Nuklearmed. 2008;180:30-34.

15. Crawford SW, Fisher L. Predictive value of pulmonary function tests before marrow transplantation. Chest. 1992;101:1257-1264.

16. Chien JW, Madtes DK, Clark JG. Pulmonary function testing prior to hematopoietic stem cell transplantation. Bone Marrow Transplant. 2005;35:429-435.

17. Hildebrandt GC, Fazekas T, Lawitschka A, et al. Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GvHd. Bone Marrow Transplant. 2011;46: 1283-1295.

Bacterial Foodborne Infections after Hematopoietic Cell Transplantation

Nicole M. Boyle1, Sara Podczervinski2 Kim Jordan 2, Zach Stednick1, Susan Butler-Wu3, Kerry McMillen2, Steven A. Pergam1,2,4,*

1 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington

2 Seattle Cancer Care Alliance, Seattle, Washington

3 Laboratory Medicine, University of Washington, Seattle, Washington

4 Department of Medicine, University of Washington, Seattle, Washington

CrossMark

Article history: Received 25 April 2014 Accepted 27 June 2014

Key words:

Foodborne

Hematopoietic

Transplantation

Campylobacter Bacteria

ABSTRACT

Diarrhea, abdominal pain, and fever are common among patients undergoing hematopoietic cell transplantation (HCT), but such symptoms are also typical with foodborne infections. The burden of disease caused by foodborne infections in patients undergoing HCT is unknown. We sought to describe bacterial foodborne infection incidence after transplantation within a single-center population of HCT recipients. All HCT recipients who underwent transplantation from 2001 through 2011 at the Fred Hutchinson Cancer Research Center in Seattle, Washington were followed for 1 year after transplantation. Data were collected retrospectively using center databases, which include information from transplantation, on-site examinations, outside records, and collected laboratory data. Patients were considered to have a bacterial foodborne infection if Campylobacter jejuni/coli, Listeria monocytogenes, E. coli O157:H7, Salmonella species, Shigella species, Vibrio species, or Yersinia species were isolated in culture within 1 year after transplantation. Non-foodborne infections with these agents and patients with pre-existing bacterial foodborne infection (within 30 days of transplantation) were excluded from analyses. A total of 12 of 4069 (.3%) patients developed a bacterial foodborne infection within 1 year after transplantation. Patients with infections had a median age at transplantation of 50.5 years (interquartile range [IQR], 35 to 57), and the majority were adults >18 years of age (9 of 12 [75%]), male gender (8 of 12 [67%]) and had allogeneic transplantation (8 of 12 [67%]). Infectious episodes occurred at an incidence rate of 1.0 per 100,000 patient-days (95% confidence interval, .5 to 1.7) and at a median of 50.5 days after transplantation (IQR, 26 to 58.5). The most frequent pathogen detected was C. jejuni/coli (5 of 12 [42%]) followed by Yersinia (3 of 12 [25%]), although Salmonella (2 of 12 [17%]) and Listeria (2 of 12 [17%]) showed equal frequencies; no cases of Shigella, Vibrio, or E. coli O157:H7 were detected. Most patients were diagnosed via stool (8 of 12 [67%]), fewer through blood (2 of 12 [17%]), 1 via both stool and blood simultaneously, and 1 through urine. Mortality due to bacterial foodborne infection was not observed during follow-up. Our large single-center study indicates that common bacterial foodborne infections were a rare complication after HCT, and the few cases that did occur resolved without complications. These data provide important baseline incidence for future studies evaluating dietary interventions for HCT patients.

© 2014 American Society for Blood and Marrow Transplantation.

Financial disclosure: See Acknowledgments on page 1860.

* Correspondence and reprint requests: Steven A. Pergam, MD, MPH, Fred Hutchinson Cancer Center, 1100 Fairview Avenue North, E4-100, Seattle, WA 98109.

E-mail address: spergam@fhcrc.org (S.A. Pergam). 1083-8791/$ - see front matter © 2014 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2014.06.034

INTRODUCTION

Immunocompromised patients are known to be vulnerable to foodborne pathogens [1-6]. Hematopoietic cell transplantation (HCT) recipients have multiple factors that increase risk for foodborne infections, including profound deficits in innate and adaptive immunity and disruption of gastrointestinal mucosa from transplantation-associated

radiation therapy, chemotherapy, and graft-versus-host disease (GVHD). Although such alterations provide the ideal milieu for microbial invasion/dissemination, many patients have additional risk factors for bacterial infections, such as transfusion-associated iron overload, enteric acid suppression, and gastrointestinal microbiota perturbations from antibiotic use [7-10]. Furthermore, diagnosis and treatment may be delayed, as symptoms of foodborne infections, notably diarrhea and fever, are nearly universal amongst HCT recipients [11,12].

Most transplantation centers follow guidelines and implement specific dietary strategies to reduce the risk of exposure to foodborne pathogens. Particular emphasis has been placed on restricting the consumption of foods more likely to harbor high-risk bacteria by using various low-microbial diets [13]. However, these commonly applied guidelines have not been evaluated in randomized prospective clinical trials [13,14]. Credence for such recommendations is further stunted by a lack of studies addressing the burden of bacterial foodborne infections in HCT recipients [3,15]. More recent data suggest that restrictive nutritional strategies intended to prevent the consumption of pathogenic organisms may, in fact, increase the risk of infection [16].

We set out to determine the burden of common bacterial foodborne infections in a large comprehensive HCT center. Through retrospective chart review, we aimed to describe the incidence of bacterial foodborne pathogens within our HCT patient population during the first year after transplantation and to assess associated morbidity and mortality. These data are important for determining incidence of bacterial foodborne infections and providing a baseline for future studies evaluating nutritional strategies in this high-risk population.

MATERIALS AND METHODS Study Design/Participant Eligibility

All HCT recipients who underwent an autologous or allogeneic HCT at the Fred Hutchinson Cancer Research Center (FHCRC) in Seattle, Washington between January 1, 2001 and December 31, 2011 were eligible for inclusion in this retrospective cohort. Patients with evidence of bacterial foodborne infection 30 days before transplantation were excluded. All study activities were approved by the FHCRC institutional review board, and all participants provided written informed consent according to the principles of the Declaration of Helsinki.

Data Collection

Retrospective data were retrieved from a prospectively collected database of patients undergoing HCT at the FHCRC. Pre- and posttransplantation demographic and outcome data were available from clinical databases and medical records. Clinical and laboratory data after discharge from the center were also available in long-term follow-up databases.

Nutrition, Transplantation Procedures, and Infection Prophylaxis

Patients undergoing transplantation were encouraged to follow an "immunosuppressed patient" diet [13] until 3 months after transplantation (autologous recipients) or until cessation of immunosuppressive drugs (allogeneic recipients). Before transplantation, all patients and caregivers participated in a food safety training course that educated patients not only on what foods to avoid, but also on proper preparation, cleaning, and storage of foods and food products. Nutritional services were available for all patients to assist with questions regarding recommendations, to address posttransplantation dietary issues, and to assure and promote adequate nutrition.

HCT conditioning and GVHD prophylaxis/treatment were performed according to current standardization within the center [17]. Patients who were neutropenic received prophylactic antibacterial therapy with either oral levofloxacin or intravenous ceftazidime. Post-transplantation patients received antiviral prophylaxis with low-dose acyclovir [18] and all patients underwent cytomegalovirus screening and preemptive therapy [19,20]; fungal and Pneumocystis jirovercii prophylaxes were also routine. To prevent

late encapsulated bacterial infections in patients who developed chronic GVHD, long-term prophylaxis with trimethoprim-sulfamethoxazole, either daily or 3 times weekly, along with daily penicillin VK, was administered to those with previous splenectomies.

Bacterial cultures from blood, stool, and other sites were conducted at the discretion of the primary team, as center-based standard practice documents did not recommend routine testing for foodborne pathogens during initial episodes of diarrhea. All specimens submitted for stool culture were screened for the presence of Salmonella species (spp), Shigella spp, Campylobacter jejuni/coli, Yersinia spp, Escherichia coli O157:H7, Vibrio spp, Aeromonas spp and Plesiomonas. The following culture media were used: Hektoen Enteric (HE), blood (Trypticase soy agar with 5% sheep blood), MacConkey, MacConkey-Sorbitol, Yersinia selective and Campy CVA (cefo-perazone, vancomycin, and amphotericin B) agars. All specimens were also inoculated into selenite broth and subcultured to HE agar after 12 to 18 hours of incubation. Microbial identification of potential stool pathogens present was performed using a combination of microbiological methods, including biochemical identification methods (eg, VITEK 2 GN ID [Gramnegative identification] card [bioMérieux, Durham, NC]), as well as agglutinating sera for Salmonella and Shigella spp.

Definitions and Statistical Analysis

All patient events were reviewed up to 1 year after transplantation for bacterial foodborne infections. An infectious event was defined as detection of C. jejuni/coli, Listeria monocytogenes, E.coli O157:H7, Salmonella spp, Shigella spp, Vibrio spp, or Yersinia spp from any clinical site (excluding the lung) from day 1 to day 365 after transplantation. Site of detection for all bacterial foodborne infections was defined as the site of first positive culture. Cultures epidemiologically linked to a non-foodborne exposure (eg, zoonotic) and Campylobacter spp whose primary transmission is not epidemiologically established as foodborne, such as C. curvus and C. ureolyticus, were excluded from analyses [21]; nonspeciated cases were included and noted as such.

In this study, an attributable cause of death was defined when death was documented as a direct result of the bacterial foodborne infection. Infections in patients who survived beyond 30 days, without recurrence, were considered resolved. All bacterial, viral, and fungal infections were identified as concomitant if they were documented within ±7 days of foodborne event. The timing and severity of GVHD were reviewed and all episodes were graded according to standard criteria [22]. Neutropenia during bacterial foodborne infection was defined as an absolute neutrophil count of <500 mm cells/mm3 within ±2 days of infectious event.

Time at risk for bacterial foodborne infection was considered from the first day after transplantation until the bacterial foodborne event or occurrence of any of the following censoring events: lost to follow-up, death, retransplantation, or 365 days. For patients with multiple transplantation events, the at-risk period was considered only after the first transplantation; the at-risk period of patients who underwent a planned tandem transplantation began after the second transplantation.

Incidence rates of bacterial foodborne infection were estimated by dividing the number of incident cases developed in cohort subjects by the number of post-transplantation at risk patient-days contributed by the overall cohort; 95% confidence intervals (CI) were estimated based on a Poisson distribution. Incidence rates were also stratified by age (pediatric/ adult), with those <18 years of age considered pediatric HCT recipients.

RESULTS

Of the 4074 patients who underwent HCT at the FHCRC during the 2001 to 2011 study period, 5 were excluded from the primary analysis because of a pre-existing foodborne event (3 Yersinia spp,1 C. jejuni, and 1 Salmonella spp). Among the remaining HCT recipients, a total of 12 of 4069 (.3%) of patients developed a post-transplantation bacterial food-borne infection; none experienced multiple events. Patients with these infections had a median age at transplantation of 50.5 years (interquartile range [IQR], 35 to 57) and were primarily adults (9 of 12 [75%]) and male gender (8 of 12 [67%]) (Table 1 ). The majority of infections also occurred after allogeneic (8 of 12 [67%]) rather than autologous transplantation, although cumulative incidence estimates were similar between the 2 transplantation types (8 of 2540 [.3%] among allogeneic versus 4 of 1529 [.3%] among autologous). Clinical circumstances surrounding the foodborne infectious event can be found in Table 1.

Table 1

Case Demographics and Clinical Characteristics (n = 12)

Patient Demographics

Foodborne Illness Clinical Characteristics

Case No. Gender/Age* Disease/HCT Type Conditioning Regimen GVHD Prophylaxis Organism Primary Site/Days after HCT Hospitalizedy Gut GVHD Concomitant Infections* Neutropenic5 Antibacterial Regimen at Time of Diagnosis'

1 M/35 MM/Auto Melphalan None Yersinia, NOS Feces/4 No No None Yes None

2 M/67 MM/Auto Melphalan None C. jejuni/coli Feces/6 No No None Yes Levofloxacin1

3 F/46 AML/Allo BU, CY CSP, MTX Yersinia, NOS Urine/15 No No None Yes Levofloxacin

4 M/57 ML/Auto CY, etoposide, 1-131 None Yersinia, NOS Feces/15 Yes No CoNS; C difficile No Clindamycin

Vancomycin

Imipenem#

5 M/60 RA/Allo TREO, FLU, TBI (200 Gy) MTX, TAC C. jejuni/coli Feces/19 Yes Yes RSV/Rhinovirus No None

6 F/55 AMM/Allo BU, CY, ATG CSP, MTX, TAC Listeria monocytogenes Blood/46 No Yes None No Dapsone

7 F/4 CIMMDIS/Allo FLU, TBI (400 Gy) CSP, MMF C. jejuni Feces/55 Yes Yes Parainfluenza 3; No TMP-S

Rhinovirus; C. difficile

8 M/68 MDS/Allo FLU, TBI (300 Gy) CSP, MMF C. jejuni Feces/71 Yes No None No Dapsone, TMP-S**

9 M/55 MYLFI/Allo BU, CY MTX, TAC Campylobacter, NOS Feces/74 No No None No TMP-S

10 M/45 RAEB/Allo BU, CY MTX, TAC Listeria monocytogenes Blood/135 Yes Yes None Yesyt Dapsone

11 F/17 CML/Allo BU, CY CSP, MTX Salmonella, NOS Feces/175 Yes Yes C. difficile No Dapsone, cephalexin

12 M/3 NBL/Auto Melphalan, etoposide, CARBO None Salmonella, NOS Blood & Feces / 351 Yes No None Unk TMP-S

M indicates male; MM, multiple myeloma; Auto, autologous transplantation; NOS, not otherwise specified; F, female; AML, acute myeloid leukemia; Allo, allogeneic transplantation; BU, busulfan; CY, cyclophosphamide; CSP, cyclosporine; MTX, methotrexate; ML, malignant lymphoma, follicular, NOS; 1-131, monoclonal antibody 1-131 infusion; CoNS, coagulase negative Staphyloccocus; RA, refractory anemia, NOS; TREO, treosulfan; FLU, fludarabine; TBI, total body irradiation; TAC, tacrolimus; RSV, respiratory syncytial virus; AMM, agnogenic myeloid metaplasia; ATG, antithymocyte globulin; CML, chronic myeloid leukemia; CIMMDIS, immune deficiency disorder; MDS, myelodysplastic syndrome; MMF, mycophenolate mofetil; TMP-S, trimethoprim-sulfamethoxazole; MYLFI, myelofibrosis; RAEB, refractory anemia with excess blasts; NBL, neuroblastoma; CARBO, carboplatin; Unk, unknown.

* Age at time of HCT.

y Hospitalized during the course of foodborne infection. z Documented within ±7 days of foodborne infection diagnosis.

5 Absolute neutrophil count <500 mm cells/mm3 within ±2 days of foodborne infection diagnosis. 11 Antibiotics at time of diagnosis, not those used for treatment. { Levofloxacin started 12 hours before diagnosis.

# Multiple antibiotics changed throughout presentation.

** On low-dose trimethoprim-sulfamethoxazole during desensitization protocol at time of diagnosis. yt Presented with neutropenia during acute episode.

Figure 1. Frequency of common bacterial foodborne infections among HCT patients per year of infection (n = 12).

Documented infections were noted throughout the entire study period at a median of 50.5 days after transplantation (IQR, 26 to 58.5). The incidence rate of bacterial foodborne infection was 1.0 per 100,000 patient-days (95% CI, .5 to 1.7) for all patients, .8 (95% CI, .4 to 1.5) for adults, and 2.2 (95% CI, .5 to 6.4) for pediatric patients. There were no apparent associations between incidence and calendar year of transplantation (Figure 1 ). The most frequently detected pathogen was C. jejuni/coli (5 of 12 [42%]), followed by Yersinia spp (3 of 12 [25%]) and equal distributions of Salmonella and Listeria spp (2 of 12 [17%], respectively); no Shigella spp, Vibrio spp, or E. coli O157:H7 were detected. Diagnoses were made in most patients through stool culture (8 of 12 [67%]), whereas a smaller proportion were first positive through blood cultures (2 of 12 [17%]); 1 patient was positive simultaneously at both sites (blood and stool), and another was first positive in the urine (Table 1 ).

Four cases had 1 or more concomitant infectious event, including the following: Clostridium difficile infection (3 of 12 [25%]), rhinovirus upper respiratory infection (2 of 12 [17%]), and single events of parainfluenza (type 3) upper respiratory infection and coagulase-negative Staphylococcus bacteremia. Of the 8 cases in allogeneic HCT recipients, 5 (62%) were diagnosed with gut GVHD; 4 had GVHD onset before the bacterial foodborne infection diagnosis and 1 after. Among the 11 cases with absolute neutrophil counts within ±2 days of infection, 4 (36%) were found to be neutropenic. Nearly one half (5 of 12 [42%]) of cases were admitted for treatment of their infection and/or for symptom management. No death was found to be attributable or associated with bacterial foodborne infection during follow-up, and no patients developed septic shock or required admission to intensive care.

DISCUSSION

In this retrospective cohort study, we sought to describe the incidence of bacterial foodborne pathogens after HCT. Incidence rates in the first year after transplantation were very low, with just 12 cases identified over an 11-year period. Overall, Campylobacter spp were the most frequently identified pathogens, followed by Yersinia spp, Salmonella spp, and L. monocytogenes. No events, even those with documented bacteremia, were associated with major complications or mortality in this high-risk population.

Foodborne illness remains an important cause of morbidity and mortality in the United States. The Centers for Disease Control and Prevention estimates that 1 in 6 Americans will develop a foodborne infection each year [23] and the most common of these microbial agents are expected to cause greater than 9 million illnesses and over 50,000 hospitalizations in the United States annually [24]. Given underreporting, limitations to current diagnostic methods, and emerging pathogens, rates are likely an underestimate of the true burden of these infections [24,25].

Bacterial foodborne events in our HCT cohort were infrequent, with approximately 1 event per 100,000 patient-days. Comparing rates observed in our cohort with other populations is difficult, particularly when considering the multiple risks associated with transplantation, including immunosuppression, mucosal injury, and the higher frequency of testing and health care engagement. Estimating the general population's rate of those foodborne illnesses described in this study using the Foodborne Diseases Active Surveillance Network data from 2001 to 2012 [26] and extrapolating incidence rates to 100,000 patient-days suggests that our HCT recipients experienced a rate approximately 10-fold that of the general population (1.0 in HCT versus .1 in the general population). However, it should be noted that these rough estimates do not account for significant underreporting in the general population [24], and may, therefore, overestimate rate differences.

These data must also be taken in context, particularly when considering factors known to modify infection risk in our patient population, such as the routine use of prophylactic antibiotics, which would be expected to provide a level of protection against foodborne pathogens during the posttransplantation period. Alterations in oral intake that occur after HCT may further limit exposure, particularly among those who receive total parenteral or peripheral nutrition [27]. Because unregulated foodborne exposures in outpatient environments likely make up the majority of foodborne risk, and hospital-based bacterial foodborne infectious events are rarely observed [28,29], expanded inpatient time would also be expected to limit risk in these patients. Standardized food safety education and nutritional support are also likely to decrease exposure.

Concerns for increased susceptibility for infection have led most programs to limit exposure to foodborne pathogens through use of a low-microbial diet, which aims to prevent consumption of these organisms by restricting certain higher-risk foods. Despite implementation of low-microbial diets across US transplantation centers [13], empirical evidence supporting such recommendations is lacking [30]. Although this study cannot directly address the value of our center's "immunosuppressed" diet, the safety and efficacy of such low-microbial diets during HCT have been questioned by other studies [31,32], with 1 transplantation center even noting an increased risk of infection with the use of their neutropenic diet [32]. Further evaluation of low-microbial diets in HCT is complicated by the variety of dietary restrictions and decisions regarding timing of diet implementation across centers [30,33].

While the small number of documented events could be interpreted as evidence of our "immunosuppressed patient" diet's effectiveness, it is also important to note that bacterial foodborne illnesses did occur in this cohort, regardless of our center's dietary restrictions. Infectious events occurred even during periods of neutropenia. Case reports in similar populations and 1 cohort study of nontyphoidal Salmonella spp

from a large transplantation center [2,3,34,35] also suggest that these findings are not likely isolated to our center.

The foodborne bacteria evaluated in this study are not considered normal flora and have been epidemiological^ defined as foodborne pathogens, and as such, can serve as a proxy for assessing risk of foodborne exposures in future studies. It is important to note that although HCT dietary recommendations are organized to prevent exposure to these foodborne pathogens, such recommendations also aim to prevent exposure to other organisms that might occur through improper processing or food preparation practices [36,37]. Any studies addressing dietary recommendations in this population will need to evaluate how these changes affect C. difficile, E. coli (non-0157:H7), Staphylococcus aureus, and other infections that are not exclusively foodborne.

As with all retrospective studies, our data were limited by available records and reporting. Dietary compliance was not evaluated in this study, so it is unknown if the observed events resulted from failures of dietary guidelines or from nonadherence. Stool cultures were not standardized and were dependent on the clinician directing care, so it is possible that we underestimated the true incidence. Direct associations with specific foods or exposures could not be addressed in this study, and these infections may not have been acquired through foodborne pathways. Finally, this is a single-center study, which may limit the generalizability to other centers. Regardless, this study is the largest to date that addresses the incidence of these pathogens in this population.

In conclusion, common bacterial foodborne infections were infrequently observed after HCTat our center, and these pathogens were not associated with significant morbidity or mortality. These results raise additional questions about low-microbial dietary recommendations in HCT and indicate a need for additional studies to determine the value of such practices. These data provide important baseline incidence for future studies addressing dietary interventions among HCT recipients.

ACKNOWLEDGMENTS

Data from this manuscript have been presented in part at the ASBMT/CIBMTR Tandem Meeting in Salt Lake City, Utah in February 2013.

Financial Disclosure: This research was supported by NIH grants CA-18029 and CA-15704. S.A.P is supported by NIH grant K23HL096831 and an ASBMT/Viropharma new investigator award. S.A.P. has received research support from Chimerix and Merck, and has been a consultant from Merck and Optimer/Cubist Pharmaceuticals.

REFERENCES

1. Allerberger F, Wagner M. Listeriosis: a resurgent foodborne infection. Clin Microbiol Infect. 2010;16:16-23.

2. Barton JC, Ratard RC. Vibrio vulnificus bacteremia associated with chronic lymphocytic leukemia, hypogammaglobulinemia, and hepatic cirrhosis: relation to host and exposure factors in 252 V. vulnificus infections reported in Louisiana. Am J Med Sci. 2006;332:216-220.

3. Dadwal SS, Tegtmeier B, Nakamura R, et al. Nontyphoidal Salmonella infection among recipients of hematopoietic SCT. Bone Marrow Transplant. 2011;46:880-883.

4. Fernandez-Cruz A, Munoz P, Mohedano R, et al. Campylobacter bacteremia: clinical characteristics, incidence, and outcome over 23 years. Medicine. 2010;89:319-330.

5. Lund BM, O'Brien SJ. The occurrence and prevention of foodborne disease in vulnerable people. Foodborne Pathog Dis. 2011;8:961-973.

6. Schwartz S, Vergoulidou M, Schreier E, et al. Norovirus gastroenteritis causes severe and lethal complications after chemotherapy

and hematopoietic stem cell transplantation. Blood. 2011;117: 5850-5856.

7. Hammer MJ, Casper C, Gooley TA, et al. The contribution of malglyce-mia to mortality among allogeneic hematopoietic cell transplant recipients. Biol Blood Marrow Transplant. 2009;15:344-351.

8. Meyer SC, O'Meara A, Buser AS, et al. Prognostic impact of posttransplantation iron overload after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19:440-444.

9. Murphy S, Nguyen VH. Role of gut microbiota in graft-versus-host disease. Leuk Lymphoma. 2011;52:1844-1856.

10. Ubeda C, Taur Y, Jenq RR, et al. Vancomycin-resistant Enterococcus domination of intestinal microbiota is enabled by antibiotic treatment in mice and precedes bloodstream invasion in humans. J Clin Invest. 2010;120:4332-4341.

11. Barker CC, Anderson RA, Sauve RS, Butzner JD. GI complications in pediatric patients post-BMT. Bone Marrow Transplant. 2005;36:51-58.

12. Holmberg L, Kikuchi K, Gooley TA, et al. Gastrointestinal graft-versus-host disease in recipients of autologous hematopoietic stem cells: incidence, risk factors, and outcome. Biol Blood Marrow Transplant. 2006;12:226-234.

13. 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.

14. Boeckh M. Neutropenic diet—good practice or myth? Biol Blood Marrow Transplant. 2012;18:1318-1319.

15. Kamboj M, Mihu CN, Sepkowitz K, et al. Work-up for infectious diarrhea after allogeneic hematopoietic stem cell transplantation: single specimen testing results in cost savings without compromising diagnostic yield. Transplant Infect Dis. 2007;9:265-269.

16. Trifilio S, Helenowski I, Giel M, et al. Questioning the role of a neu-tropenic diet following hematopoetic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18:1385-1390.

17. Nakamae H, Kirby KA, Sandmaier BM, et al. Effect of conditioning regimen intensity on CMV infection in allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2009;15:694-703.

18. Erard V, Guthrie KA, Varley C, et al. One-year acyclovir prophylaxis for preventing varicella-zoster virus disease after hematopoietic cell transplantation: no evidence of rebound varicella-zoster virus disease after drug discontinuation. Blood. 2007;110:3071-3077.

19. Green ML, Leisenring W, Stachel D, et al. Efficacy of a viral load-based, risk-adapted, preemptive treatment strategy for prevention of cyto-megalovirus disease after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2012;18:1687-1699.

20. Milano F, Pergam SA, Xie H, et al. Intensive strategy to prevent CMV disease in seropositive umbilical cord blood transplant recipients. Blood. 2011;118:5689-5696.

21. Man SM. The clinical importance of emerging Campylobacter species. Nat Rev Gastroenterol Hepatol. 2011;8:669-685.

22. Thomas ED, Storb R, Clift RA, et al. Bone-marrow transplantation (second of two parts). N Eng J Med. 1975;292:895-902.

23. Centers for Disease Control and Prevention. CDC Estimates of Food-borne Illness in the United States. Available at: http://www.cdc.gov/ foodborneburden/estimates-overview.html; 2013.

24. Scallan E, Hoekstra RM, Angulo FJ, et al. Foodborne illness acquired in the United States—major pathogens. Emerg Infect Dis. 2011;17:7-15.

25. Morris JG Jr. How safe is our food? Emerg Infect Dis. 2011;17:126-128.

26. Centers for Disease Control and Prevention. Table 2a FoodNet— Number of Laboratory—Confirmed Infections by Year 2012. Available at:http://www.cdc.gov/foodnet/data/trends/tables/2012/table2a-b.html# table-2b, ; 2013.

27. Rzepecki P, Barzal J, Sarosiek T, et al. Which parameters of nutritional status should we choose for nutritional assessment during hematopoietic stem cell transplantation? Transplant Proc. 2007;39: 2902-2904.

28. Gaul LK, Farag NH, Shim T, et al. Hospital-acquired listeriosis outbreak caused by contaminated diced celery—Texas, 2010. Clin Infect Dis. 2013;56:20-26.

29. Lee MB, Greig JD. A review of nosocomial Salmonella outbreaks: infection control interventions found effective. Public Health. 2013;127: 199-206.

30. Fox N, Freifeld AG. The neutropenic diet reviewed: moving toward a safe food handling approach. Oncology. 2012;26:572-575. 580, 582 passim.

31. Galati PC, Lataro RC, Souza VM, et al. Microbiological profile and nutritional quality of raw foods for neutropenic patients under hospital care. Rev Bras Hematol Hemoter. 2013;35:94-98.

32. Trifilio SM, Pi J, Mehta J. Changing epidemiology of Clostridium difficile-associated disease during stem cell transplantation. Biol Blood Marrow Transplant. 2013;19:405-409.

33. Rasheed W, Ghavamzadeh A, Hamladji R, et al. Hematopoietic stem cell transplantation practice variation among centers in the Eastern Mediterranean Region (EMRO): Eastern Mediterranean Bone Marrow Transplantation (EMBMT) group survey. Hematol Oncol Stem Cell Ther. 2013;6:14-19.

34. Bousquet A, Demoures T, Malfuson JV, et al. Campylobacter jejuni cutaneous infection in a patient with graft versus host disease. Med Mal Infect. 2012;42:235-236.

35. Radice C, Munoz V, Castellares C, et al. Listeria monocytogenes meningitis in two allogeneic hematopoietic stem cell transplant recipients. Leuk Lymphoma. 2006;47:1701-1703.

36. Falomir MP, Rico H, Gozalbo D. Enterobacter and Klebsiella species isolated from fresh vegetables marketed in Valencia (Spain) and their clinically relevant resistances to chemotherapeutic agents. Foodborne Pathog Dis. 2013;10:1002-1007.

37. Jensen AN, Storm C, Forslund A, et al. Escherichia coli contamination of lettuce grown in soils amended with animal slurry. J Food Prot. 2013; 76:1137-1144.

Prognostic Biomarkers for Acute Graft-versus-Host Disease Risk after Cyclophosphamide-Fludarabine Nonmyeloablative Allotransplantation

Robert P. Nelson Jr.1,2, Muhammad Rizwan Khawaja1, Susan M. Perkins3, Lindsey Elmore2, Christen L. Mumaw2, Christie Orschell1, Sophie Paczesny1,2,*

1 Division of Hematology/Oncology, Indiana University School of Medicine and the Melvin and Bren Simon Cancer Center, Indianapolis, Indiana

2 Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana

3 Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana

CrossMark

Article history: Received 1 May 2014 Accepted 30 June 2014

Key Words:

Acute graft-versus-host-disease Nonmyeloablative allotransplantation Biomarkers

ABSTRACT

Five candidate plasma biomarkers (suppression of tumorogenesis 2 [ST2], regenerating islet-derived-3a [REG3a], elafin, tumor necrosis factor receptor 1 [TNFR1], and soluble IL-2 receptor-alpha [sIL2Ra]) were measured at specific time points aftercyclophosphamide/fludarabine-based nonmyeloablative allotransplantation (NMAT) in patients who did or did not develop acute graft-versus-host disease (aGVHD). Plasma samples from 34 patients were analyzed at days +7, +14, +21, and +30. At a median follow-up of 358 days, 17 patients had experienced aGVHD with a median time to onset at day +36. Risk of aGVHD was associated with elevated plasma ST2 concentrations at day +7 (c-statistic = .72, P = .03), day +14(c-statistic = .74, P = .02), and day +21 (c-statistic = .75, P = .02); elevated plasma REG3a concentrations at day +14 (c-statistic = .73, P = .03), day +21 (c-statistic = .76, P = .01), and day +30 (c-statistic = .73, P = .03); and elevated elafin at day +14 (c-statistic = .71, P = .04). Plasma concentrations of TNFR1 and sIL2Ra were not associated with aGVHD risk at any of the time points studied. This study identified ST2, REG3a, and elafin as prognostic biomarkers to evaluate risk of aGVHD after cyclophosphamide/fludarabine-based NMAT. These results need to be confirmed in an independent validation cohort.

© 2014 American Society for Blood and Marrow Transplantation.

INTRODUCTION

Acute graft-versus-host disease (aGVHD) continues to be a major contributor to early transplant-related mortality after allogeneic hematopoietic cell transplantation. There is no reliable way to determine before the onset of symptoms who will suffer complications. To date, the choice of candidate biomarkers for aGVHD has been guided by studies performed in groups of patients who received myeloablative full or reduced-intensity conditioning. We previously demonstrated that a biomarker panel consisting of IL-2 receptor-alpha (IL2Ra), tumor necrosis factor receptor-1 (TNFR1), IL-8, and hepatocyte growth factor correlated with clinical diagnosis of aGVHD as well as survival, independent of clinical grade severity. A panel of 6 biomarkers predicted treatment response and survival after aGVHD [1,2]. Recently, the suppression of tumorogenesis 2 (ST2) was identified as a novel marker useful in predicting glucocorticoid-resistant aGVHD and nonrelapse mortality (NRM) [3].

Financial disclosure: See Acknowledgments on page 1864.

* Correspondence and reprint requests: Sophie Paczesny, MD, PhD, Department of Pediatrics, Bone Marrow and Stem Cell Transplantation Program, Indiana University Melvin and Bren Simon Cancer Center and Wells Center for Pediatric Research, 1044 W Walnut Street, Rm 425, Indianapolis, IN 46202.

E-mail address: sophpacz@iu.edu (S. Paczesny). 1083-8791/$ - see front matter © 2014 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2014.06.039

Nonmyeloablative allotransplantation (NMAT) conditioning extends allotransplant options to older individuals who may be at higher risk for aGVHD on the basis of age; NMAT, a minimally intense RIC is associated with low incidences of early transplant-related complications and mortality. Cyclophosphamide (Cy) and fludarabine (Flu) based NMAT enables engraftment in recipients of related and unrelated HLA-matched grafts without mucositis and/or sinusoidal obstructive syndrome [4,5]. The validation of biomarkers across a variety of settings is critical before attempting to integrate their use in clinical practice. We conducted a study to test the ability of plasma levels of 5 individual biomarkers at specific time points to serve as prognostic markers for aGVHD among patients undergoing Cy/Flu-based NMAT.

METHODS Patient Population

Thirty-four patients with hematological malignancies who underwent Cy/Flu-based NMAT at Indiana University between 2008 and 2012 were included in the study, which was approved by the Indiana University institutional review board. Disease status at transplant was categorized according to the American Society of Blood and Marrow Transplantation criteria [6].

Patients received mobilized peripheral blood hematopoietic cells from matched related or matched unrelated donors. GVHD prophylaxis for matched unrelated donor recipients consisted of cyclosporine A ± mycophenolate mofetil or basiliximab (NCT00975975) or a combination of tacrolimus and sirolimus. Matched related recipients received a combination of cyclosporine A ± mycophenolate mofetil or basiliximab. Patients were followed prospectively until death or for a median of 358 days (range, 182 to 1381 days) and