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Nutritional support practices in hematopoietic stem cell transplantation centers: A nationwide comparison
Nutrition 35 (2017) 43–50
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Nutrition journal homepage: www.nutritionjrnl.com
Applied nutritional investigation
Nutritional support practices in hematopoietic stem cell transplantation centers: A nationwide comparison Annic Baumgartner M.D. a, Mario Bargetzi M.D. b, Annika Bargetzi a, Noemi Zueger a, Micheal Medinger M.D. c, Jakob Passweg M.D. c, Urs Schanz M.D. d, Panagiotis Samaras M.D. d, Yves Chalandon M.D. e, Claude Pichard M.D. f, Alessandro Limonta M.D. f, Luciano Wannesson M.D. g, Thomas Pabst M.D. h, Michel A. Duchosal M.D. i, Urs Hess M.D. j, Zeno Stanga M.D. k, Beat Mueller M.D. a, Philipp Schuetz M.D. a, * a Medical University Department, Clinic for Endocrinology/Metabolism/Clinical Nutrition, Kantonsspital Aarau, Aarau and Medical Faculty of the University of Basel, Basel, Switzerland b Clinic for Hematology and Oncology, Kantonsspital Aarau, Aarau, Switzerland c Clinic for Hematology, University Hospital Basel, Basel, Switzerland d Clinic for Hematology and Clinic for Oncology, University Hospital Zürich, Zürich, Switzerland e Clinic for Hematology, University Hospital Geneva, Geneva, Switzerland f Nutrition Unit, Geneva University Hospital, Geneva, Switzerland g Instituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland h Clinic for Hematology and Oncology, University Hospital Bern, Bern, Switzerland i Service and Central Laboratory of Hematology, University Hospital of Lausanne, Lausanne, Switzerland j Clinic for Hematology and Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland k Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Bern University Hospital, and University of Bern, Bern, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history: Received 26 July 2016 Accepted 1 October 2016
Objective: In 2009, international nutritional societies published practice guidelines on screening and nutritional support for patients undergoing stem cell transplantation. Little is known about how these guidelines are implemented in clinical practice. We performed a nationwide survey with the aim of understanding current practice patterns, differences between clinical practice, and international recommendations as well as barriers to the use of nutritional therapy. Methods: We performed a qualitative survey including all centers across Switzerland offering allogeneic (n ¼ 3) or autologous (n ¼ 7) stem cell transplantation. We focused on in-house protocols pertaining to malnutrition screening, indications for nutritional support, types of nutritional therapy available and provided, and recommendations regarding neutropenic diets. Results: All centers offering allogeneic, and most of the centers offering autologous transplantation, had a malnutrition screening tool, mainly the nutritional risk score (NRS 2002) method. Only one center does not provide nutritional support. There is wide variation regarding start and stop of nutritional therapy as well as route of delivery, with five centers recommending parenteral nutrition and five centers recommending enteral nutrition as a first step. Although all centers offering allogeneic transplantation, and approximately every other autologous transplant center, used a neutropenic diet, specific recommendations regarding the type of food and food handling showed significant variation. Conclusion: This Swiss survey found wide variation in the use of nutritional therapy in patients undergoing stem cell transplantation, with low adherence overall to current practice guidelines.
Keywords: Nutrition Hematopoietic stem cell transplantation Survey Guidelines
We thank Prasad Kulkarni of Asclepius Medical Communications LLC, Ridgewood, NJ, USA for editorial review of the manuscript. Conflict of interest statement: PS and ZS received research grants from Nestle and Abbott. All other authors confirm that they do not have a conflict of interest associated with this manuscript. Funding: This study was supported in part by the Swiss National http://dx.doi.org/10.1016/j.nut.2016.10.007 0899-9007/Ó 2016 Elsevier Inc. All rights reserved.
Science Foundation (SNSF Professorship, PP00 P3_150531/1) and the Research Council of the Kantonsspital Aarau (1410.000.044). * Corresponding author. Tel.: 41 62 838 4141; fax: 41 62 838 4100. E-mail address: [email protected] (P. Schuetz).
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Understanding and reducing barriers to guideline implementation in clinical practice may improve clinical outcomes. Close collaboration of centers will facilitate future research needed to improve current practice and ensure high quality of treatment. Ó 2016 Elsevier Inc. All rights reserved.
Introduction Allogeneic and autologous hematopoietic stem cell transplantation (allo-HSCT/auto-HSCT) are the only potentially curative treatment options for specific hematological conditions [1,2]. Treatment protocols have undergone major changes over the last 40 y, specifically with improved conditioning regimens. Additionally, reduced-intensity conditioning (RIC) has been evaluated for elderly patients or patients with multiple comorbidities undergoing allo-HSCT [2]. A noteworthy feature of RIC is that it induces fewer toxic side effects such as mucositis and significantly shortens the duration of neutropenia [2, 3]. Changes in management of transplant patients have contributed to improved clinical outcomes and lead to an increasing number of patients undergoing HSCT. As a result, there are a growing number of long-term survivors [1]. However, HSCT, above all allo-HSCT, has considerable toxicity and induces an inflammatory response, metabolic changes (cachexia), gastrointestinal symptoms, and general constitutional effects, all of which lead to reduced oral intake and worsening nutritional status. This puts patients at increased risk for malnutrition, which might have a negative influence on clinical outcomes [4]. It is well known that malnutrition in patients undergoing allo-HSCT is associated with an increase in morbidity and mortality and that it puts them at higher risk for failure of the transplant [5–8]. Both the American Society for Parenteral and Enteral Nutrition (ASPEN) [9] and the European Society for Clinical Nutrition and Metabolism (ESPEN) [10] have published consensus guidelines on screening and nutritional support in patients undergoing HSCT. In brief, these guidelines recommend malnutrition screening and nutritional interventions if patients are unable to maintain their nutritional status on their own. It is recommended that enteral nutrition (EN) be used as a first step in all patients with a functioning gastrointestinal tract [9–11], and that parenteral nutrition (PN) be reserved for patients with severe mucositis (grade >3), ileus, or intractable vomiting [9,10]. A few guidelines also give weak recommendations for the use of a neutropenic diet (ND) [9,12], whereas others do not [10]. Currently, there is ongoing discussion on the extent of dietary restrictions needed to prevent food-borne infections [13–15]. Although these recommendations have been available for several years, little is known about the implementation of these international guidelines in routine clinical practice. We performed a nationwide survey that included all transplantation centers across Switzerland that offer either allo-HSCT or auto-HSCT. The aim of the study was to better understand current practice patterns, differences between clinical practice, and international recommendations as well as possible barriers to the use of nutritional therapy in patients undergoing HSCT. We speculate that the knowledge gained through this survey will contribute to the development of national practice guidelines in Switzerland and facilitate further research.
Methods Selection of study centers and study population In 2014, a total of 621 stem cell transplantations were performed in Switzerland (226 allogeneic, 395 autologous). Two centers in Switzerland offer allo-HSCT and auto-HSCT to patients: University Hospital Basel (USB) and University Hospital Zurich (USZ). One center only offers allo-HSCT, University Hospital Geneva (HUG), while five centers offer auto-HSCTs only: Kantonsspital Aarau (KSA); Istituto Oncologico della Svizzera Italiana (IOSI); Inselspital Bern (Insel); Centre Hospitalier Universitaire Vaudois (CHUV); and Kantonsspital St. Gallen (KSSG). We contacted the heads of the hematological departments or the transplant program directors of these Swiss centers and requested permission to further contact members of the medical team, dietitians, and the person(s) in charge of the nutritional team. No compensation was offered for their participation. Survey To evaluate clinical practices at all Swiss centers, we used a questionnaire focusing on general measures, such as the availability of a nutritional risk screening program, implementation of nutritional interventions, use of parenteral glutamine, dietary restrictions in terms of a neutropenic diet, and attitudes toward nutritional support in graft-versus-host disease (GvHD). The full questionnaire is presented in Appendix A and includes open-ended and close-ended questions. Centers offering allo-HSCT and auto-HSCT were asked to answer the questions for both procedures separately. The results are shown in Appendices B and C. Before sending the final questionnaire, a preliminary version of the questionnaire was developed through rounds of consensus conferences within the research team. Its content validity was established by getting it reviewed by independent physicians and dieticians and by testing it in a small pilot study within the University Hospital of Basel, Switzerland. After revision to incorporate their feedback, the questionnaire was translated into English and sent to all eight Swiss centers in either English or German. We contacted the person(s) in charge of the center if information was missing from the questionnaires. In addition, we collected individual guidelines and recommendations of the centers that focused on hygiene, food handling, and dietary advice. In case of uncertainty about specific questions, we individually contacted the centers until the issues were resolved. We decided to present data only qualitatively and did not perform a quantitative (statistical) analysis.
Results Nutritional support practices in centers offering allogeneic transplantation Screening for malnutrition General screening for nutritional risk was performed at all centers (Table 1), mainly using the validated nutritional risk score (NRS 2002) as the preferred tool, which is also recommended by ESPEN [16]. In one center, screening was performed according to an individual hospital-developed guideline that incorporated additional parameters, such as indirect calorimetry and bioelectrical impedance analysis. Nutritionists were directly involved at all centers in the pre-transplant assessment of patients undergoing myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC). Supplementation and nutritional support Screening for vitamin or trace element deficiencies and supplementation (Table 2) is performed in one center while in the
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Table 1 Comparison of guideline recommendations on nutritional risk screening of HSCT patients and routine practices at Swiss transplant centers
Screening Screening parameters
Screening for vitamin or trace element deficiencies Routine use of a multivitamin
Recommendations by ASPEN
Recommendations by ESPEN
Practices at centers offering allo-HSCT (n ¼ 3)
Routine screening indicated No specific tools recommended
Routine screening indicated No specific tools recommended
Performed at all centers on admission
No recommendation
No recommendation
No recommendation
No recommendation
Practices at centers offering auto-HSCT (n ¼ 7)
3/7 screened on admission Other centers screen individually 5/7 centers use NRS 2/7 center do not screen
2/3 centers use NRS 1/3 centers use an individual algorithm (includes indirect calorimetry, bioelectrical impedance, height, weight, 24-h diet recall, physical activity in addition to other parameters) 1/3 centers performs screening Other centers do not screen
1/7 centers performs screening Other centers do not screen
2/3 routinely use multivitamin Other center does not
1/7 centers uses multivitamins Other centers do not
allo-HSCT, allogeneic hematopoietic stem cell transplantation; ASPEN, American Society for Parenteral and Enteral Nutrition; auto-HSCT, autologous hematopoietic stem cell transplantation; ESPEN, European Society for Clinical Nutrition and Metabolism; NRS, nutritional risk score
other centers it is not routinely done but may be performed on an individual patient level. Two centers routinely administer multivitamins to all patients. Other vitamins and trace elements are supplemented in all centers if quantitative deficits are detected.
All centers have recommendations in place for nutritional support (Table 2), although indications differ widely among the centers. Recommendations rely either on malnutrition risk based on the NRS 2002 or on clinical features such as the severity of
Table 2 Comparison of guideline recommendations on nutritional support for HSCT patients and routine practices at Swiss transplant centers Recommendations by ASPEN
Recommendations by ESPEN
Practices at centers offering allo-HSCT (n ¼ 3)
Primary nutritional support
EN
EN
2/3 PN 1/3 EN
Indication of primary nutritional support
Apparent malnutrition or anticipated insufficient oral intake for 7 to 14 d but functioning GIT and absence of neutropenia
Apparent malnutrition or insufficient oral intake (<60% or daily needs) and mucositis
3 different recommendations 1/3 NRS 1/3 oral intake 1/3 no quantitative parameter
Practices at centers offering auto-HSCT (n ¼ 7)
Criteria for discontinuation
Neutrophil engraftment and sufficient oral intake (no quantitative recommendation)
Tolerance of 50% daily needs orally
2/3 oral intake >60% of daily needs 1/3 oral intake >50% of daily needs
Dosage
Secondary nutritional support
No recommendation
PN if apparent malnutrition or anticipated insufficient oral intake for 7 to 14 d but nonfunctioning GIT or neutropenia/ thrombopenia
Kcal: 20 to 25/kg/d (bedridden) Kcal: 25 to 30/kg/d (ambulatory) Protein: 1 to 2 g/kg/d
PN if insufficient oral intake AND mucositis Grade 3 to 4, ileus, or intractable vomiting
2/3 estimate caloric requirements with HarrisBenedict formula (or adapted version BASAROT) 1/3 according to ESPEN guidelines 2/3 EN 1/3 PN if severe gut insufficiency
3/7 PN 3/7 EN 1/7 no nutritional support 7 different recommendations, 7 different parameters used 2/7 centers use oral intake to different extents 1/7 uses either NRS or weight loss (not quantified) 1/7 combination of NRS, weight loss and oral intake 1/7 combination of mucositis and weight loss (not quantified) 1/7 no quantitative parameters 1/7 no nutritional support 2/7 oral intake >60% of daily needs 2/7 oral intake >75% of daily needs 1/7 oral intake >25 to 50% of daily needs 1/7 recovery from mucositis 1/7 no nutritional support 2/7 Harris-Benedict formula 2/7 ESPEN guidelines 1/7 Kcal: 30 to 35/kg/d 1/7 individual decision 1/7 no nutritional support
3/7 PN if severe gut insufficiency and intolerance of EN 4/7 no further recommendations
allo-, allogeneic; ASPEN, American Society for Parenteral and Enteral Nutrition; auto-, autologous; ESPEN, European Society for Clinical Nutrition and Metabolism; GIT, gastrointestinal tract; HSCT, hematopoietic stem cell transplantation; NRS, nutritional risk score; PN, parenteral nutrition
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Table 3 Comparison of guideline recommendations on the use of glutamine, neutropenic diets, and nutritional support in patients with GvHD by international societies and routine practices at Swiss transplant centers
Use of glutamine parenterally Indication
Dosage
ND Indication Parameters for discontinuation
Restrictions for RIC-allo-HSCT
Recommendations by ASPEN
Recommendations by ESPEN
Indication given despite weak evidence No further recommendations
Indication given No further recommendations
1/3 if severe diarrhea 1/3 if no oral intake 1/3 centers does not use glutamine
No recommendations
0.6 g/kg/d
1/3 1.5 mL/kg/d 1/3 no information 1/3 centers does not use glutamine
Given despite weak evidence Neutrophil recovery
No recommendations No recommendations
No recommendations
No recommendations
Used in all centers 1/3 neutrophil recovery 1/3 discontinuation of amphotericin 1/3 clinical decision 1/3 alike MAC-allo-HSCT until neutrophil recovery 1/3 separate guidelines 1/3 alike MAC-allo-HSCT
Nutritional support in GvHD Indication Moderate to severe GvHD with insufficient oral intake or significant malabsorption Primary nutritional PN support
No recommendations
No recommendations
Centers offering allo-HSCT (n ¼ 3)
Centers offering auto-HSCT (n ¼ 7)
2/7 centers use glutamine 1/7 centers sees indication in severe diarrhea 1/7 centers no objective indication criteria 5/7 centers do not use glutamine 1/7 1.5 mL/kg/d 1/7 no further information 5/7 centers do not use glutamine
3/7 2/7 1/7 4/7
centers use ND neutrophil recovery clinical decision centers do not use ND
Not relevant
2/3 NRS >3 1/3 severe diarrhea (not quantified) PN in all centers
allo-HSCT, allogeneic hematopoietic stem cell transplantation; ASPEN, American Society for Parenteral and Enteral Nutrition; auto-HSCT, autologous hematopoietic stem cell transplantation; ESPEN, European Society for Clinical Nutrition and Metabolism; GvHD, graft-versus-host disease; MAC, myeloablative conditioning; ND, neutropenic diet; NRS, nutritional risk score; PN, parenteral nutrition; RIC, reduced-intensity conditioning
gastrointestinal mucositis and low oral intake according to the ESPEN guidelines [10]. In one center, however, no quantitative parameters have been defined, and the decision is left to the discretion of the team. The indication for PN is given explicitly by all centers in patients with severe mucositis, ileus, or intractable vomiting as recommended by the ESPEN guidelines [10]. Two centers recommend PN as the primary nutritional support intervention, with EN not being routinely used. A third center recommends EN as the first choice, with PN being indicated only in case of gastrointestinal failure. One center routinely uses parenteral immunonutrition (i.e., omega-3 fatty acids supplementation) to complement PN. Two centers estimate energy needs according to the original Harris-Benedict formula [17] or its corrected version (BASA-ROT by Valentini) [18]. One center complements these estimations with indirect calorimetry. A third center does not explicitly estimate energy expenditure, but calculates caloric needs according to a fixed formula [10]. Discontinuation of nutritional support is recommended in all centers if the oral intake is greater than 50% to 60% of daily requirements. Role of parenteral glutamine Two centers add parenterally administered products containing glutamine to nutritional support interventions if there is no oral intake or in cases of severe diarrhea (Table 3). One center does not utilize glutamine whatsoever. Neutropenic diet All centers have a neutropenic diet (ND) protocol in place for transplant recipients (Table 4) and provide detailed brochures on
peritransplant proceedings, covering recommendations for personal hygiene, food storage, handling of kitchen supplies, cooking in general, and preparation of raw foods if allowed. Two centers defined specific recommendations stratified for different subpopulations according to the extent of immunosuppression and acuity of GvHD or severity of the conditioning regime (MACallo-HSCT, RIC-allo-HSCT, or auto-HSCT). Criteria indicating when it is appropriate to safely discontinue neutropenic diets show important differences among the centers. Criteria used include discontinuation of immunosuppression, acuity of GvHD, smell of stool, and discontinuation of local amphotericin B therapy. One center did not provide objective criteria. The different centers do agree on most of the general recommendations concerning food hygiene, preparation of meals, and handling of convenience foods. There is heterogeneity regarding practices pertaining to safety of reheating and those related to consumption of freshly prepared meals or drinks. Table 5 gives an overview of areas where centers have disagreement or agreement on specific recommendations regarding ND. There is broad consensus regarding recommendations against the use of raw milk, raw milk products, probiotics, raw cereals, nuts, sprouts and seeds, as well as raw, smoked, dried, or salted meat and fish. There is also consensus against the use of unboiled tap water. Heterogeneity was found in recommendations regarding raw fruit and vegetables. Two centers allow raw fruit if correctly washed and peeled. A type of raw lettuce (Iceberg) is permitted by one center whereas the other centers strictly recommend avoiding consumption of raw fruits or vegetables that are unpeelable. Other points of disagreement concern dairy products
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Table 4 Comparison of adherence to general recommendations on neutropenic diets among Swiss transplant centers offering allo-HSCT General recommendations Type of recommendation
Differentiation between populations and recommendations
Recommendations on food hygiene
Center 1
General food consumption
Convenience food Return to normal nutrition
Center 2
For in-patients For out-patients For nursery staff According to extent of immunosuppression and acuity of GvHD According to conditioning regime Inpatients and ambulatory patients Very detailed description for outhospital patients (personal hygiene, storage, kitchen supplies, temperatures for cooking, washing raw products) Routine consultation by nutritionist before discharge Reheating not recommended Allowed if heated > 70 C Consume tea within 24 h No recommendation on cooled food No recommendation on prepared fruit Only small packages Consume within 24 h If no immunosuppression or no active GvHD
For in-patients For out-patients For nursery staff According to conditioning regime Inpatients and ambulatory patients
Detailed description for outhospital patient (personal hygiene, storage, kitchen supplies, temperatures for cooking, washing raw products) Routine consultation by nutritionist before discharge Reheating not recommended Allowed if heated up “properly” Consume warm tea within 12 h Consume cooled food within 6 h Consume prepared fruit (peeled and sliced) within 2 h Only small packages Consume within 24 h After recontamination (¼ discontinuation of Ampho-Moronal) No later than Dþ100
Center 3 For out-hospital patients
None
Detailed description for patients (personal hygiene, storage, kitchen supplies, temperatures for cooking)
out-
No reheating No refreezing Consume self-prepared meals <24 h No recommendation on cooled food No raw fruit consumption allowed Only small packages Consume within 24 h According to individual decision
allo-HSCT, allogeneic hematopoietic stem cell transplantation; GvHD, graft-versus-host disease
such as cheese and yogurt, as well as grains, especially couscous, quinoa, and semolina. Neutropenic diet in reduced-intensity conditioning Two centers use a neutropenic diet during protective isolation of patients undergoing RIC-allo-HSCT. One center treats patients according to the protocol for MAC-allo-HSCT, whereas the other center shortens the duration of restrictions to include only the phase of neutropenia. The third center does have specific guidelines for patients undergoing RIC in terms of neutropenic diet, including fewer restrictions than for MAC-alloHSCT. Specifically, there are fewer restrictions regarding dairy products other than probiotics as well as raw fruits and vegetables. Raw meat, fish, sausages, and eggs are not recommended at this center. Nutritional support in patients with GvHD The indication for nutritional support in patients with GvHD at two centers is based on NRS 2002 in accordance with ESPEN guidelines (Table 3) [10]. The third center uses severity of diarrhea as the determining criterion. If criteria for imminent or apparent malnutrition are met, all centers prefer PN to EN for inpatients with a high likelihood of gastrointestinal malabsorption. All centers increase outpatient counseling in nutritional as well as hematological consultations to reduce and avoid rehospitalization. Nutritional support practices in centers offering autologous transplantation Screening for malnutrition Only half of the centers have a standard malnutrition screening protocol (Table 1) that is performed on admission by nutritionists, mainly using the validated NRS 2002 score. Three centers involve nutritionists only if suspicion of malnutrition
occurs during a hospital stay. With the exception of one center, no biochemical screening for deficiencies of vitamins or trace elements is performed routinely. Nutritional support There is heterogeneity among centers concerning the indication for nutritional support (Table 2). Low oral intake, heightened malnutrition risk, weight loss, and mucositis are parameters frequently used to recommend nutritional therapy. There is no preference of EN (3/7) or PN (3/7) in patients with a functioning gastrointestinal tract. Criteria for gastrointestinal failure that would make PN necessary include weight loss, mucositis, malabsorption, and diarrhea. These criteria are not quantitatively defined in any of the centers. Discontinuation of nutritional support is based on recovery of oral intake, but quantitative measures of recovery range between 25% and 75% of daily energy needs. Centers that primarily use PN frequently abstain completely from using EN. One center administers neither EN nor PN. Parenteral glutamine This is part of nutritional support interventions in a minority of the centers (2/7). Neutropenic diet Three of seven centers use a ND. As in the case of centers offering allo-HSCT, there is significant heterogeneity in recommendations with regard to the use of neutropenic diets. Differences in protocols between centers are similar to differences seen between centers offering allo-HSCT (Table 3). Discussion In 2009 and 2012, professional European and US nutritionists’ societies as well as the European Society for Blood and Marrow
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Table 5 Comparison of specific food recommendations in neutropenic diets among Swiss transplant centers offering allo-HSCT Food category Dairy products
Eggs Meat/Fish
Cereals Fruit, Nuts, Vegetables
Miscellaneous
Consensus
Disagreement (recommendation for and against product)
No raw milk or milk products No probiotics No fresh whipped cream Allowed: Soft/processed cheese in single servings Pasteurized, cooked hard cheese No raw, fried, or soft boiled (3 min) eggs Allowed: Scrambled eggs No raw, dried, smoked, or salted meat or fish No cooked meat eaten cold (ham, sausages) No poultry with bones Allowed: Cooked meat, seafood and sausages No raw cereals No bread containing nuts, dried fruit or seeds No raw and unpeeled fruit No dried fruit No uncooked nuts, no seeds, no sprouts No raw and unpeeled vegetables No fresh and uncooked herbs No fresh pepper No grapefruit juice Unpasteurized fruit juice No tap water or ice cubes from tap water No mineral water or soda with gas in >0.5 L quantities No filter coffee Allowed: Potato chips “natural” (with no preservatives) Allowed: Cake and cookies individually wrapped
Yoghurt Cheese Non-cooked hard cheese Cooked hard cheese
Couscous, quinoa, semolina Raw thin-peeled fruit Raw stone fruit Washed raw lettuce (“Eisberg” variety specifically)
Tap water boiled for 1 min Still mineral water Alcohol
allo-HSCT, allogeneic hematopoietic stem cell transplantation
Transplantation (EBMT) published guidelines on nutritional support for patients undergoing stem cell transplantation. However, little is known about how and to what extent these guidelines are implemented in current clinical practice. This knowledge is important to understand existing barriers to optimal nutritional support and to identify areas and topics for future quality work. We conducted a Swiss nationwide survey that included all centers offering either allo-HSCT or auto-HSCT. Particularly for the auto-HSCT centers, we found wide variation regarding indications, types, and routes of nutritional interventions as well as recommendations regarding neutropenic diets in patients undergoing HSCT, with rather low adherence to current practice guidelines being evident overall. Our survey is in line with a similar earlier survey that also demonstrated significant variation in nutritional therapy practices during the care of patients undergoing HSCT, as well as disregard of international guidelines. A recently published survey focusing on Italian transplant centers offering auto-HSCT and allo-HSCT showed important differences between guideline recommendations and routine clinical practices [19]. Notably, 42% of the centers did not have formal protocols to assess nutritional status. Screening for malnutrition risk was performed according to different guidelines and in a minority of the surveyed centers. The first choice for route of administration used by the majority (90%) of centers was PN. Protocols for neutropenic diets were found to be in place in 79% of the centers [19]. Patients undergoing MAC-allo-HSCT are at elevated risk for malnutrition during the course of treatment [20,21]. Malnutrition is negatively associated with overall survival, transplant-related mortality, and relapse rates [5,6]. In contrast to other factors influencing clinical outcome such as genetics or donor source [8], malnutrition is considered to be a partly modifiable risk factor. Screening for malnutrition is therefore recommended [9–11]. However, there is controversy whether
nutritional status is a mirror of more severe disease (confounding factor) or whether it is linked causally [22–24]. Evidence demonstrating that nutritional therapy is effective in reducing malnutrition-associated adverse outcomes is weak at best [25–27]. However, according to the ASPEN guidelines, there is consensus that HSCT alone justifies screening for malnutrition [9]. Despite this, disagreement persists on the ideal screening tool to use or the nutritional parameters that best define malnutrition [28–31]. Recent recommendations predominantly focus on patients’ body weight [29]. Whether malnutrition risk in patients undergoing auto-HSCT or RIC-allo-HSCT is as high as for MAC-allo-HSCT recipients needs further evaluation in sufficiently powered trials. Mainly for practical reasons, the majority of Swiss centers are currently using the validated NRS 2002 score as their screening tool following recommendations by the ESPEN [16]. The current recommendation for nutritional support still relies largely on one randomized trial performed by Weisdorf and published in 1987 [25], which found a decrease in mortality following provision of parenteral nutrition [9]. Several trials published in this patient population since then have not been able to replicate these findings and did not demonstrate that nutritional therapy improves survival [25–27]. The current guideline recommendations that favor EN over PN are mainly based on pathophysiological considerations and evidence from smaller studies arguing that PN is associated with higher risk for infectious and metabolic complications [4,27]. Recent research also shows better survival, lower infection rates, and lower rates of acute GvHD in patients provided nutritional therapy through EN [4]. Additionally, feasibility and safety of EN has been successfully proven in several small studies [4,32–34]. However, despite this paradigm shift toward the early use of EN, most allo-HSCT and about half of all auto-HSCT centers in Switzerland continue to use PN as a first option. Moreover, there is a lack of criteria in place for the use of PN in most centers starting with
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EN. Cultural and logistic issues as well as the paucity of strong trial data may explain these differences. There is a large ongoing trial in France [35] comparing EN with PN in this vulnerable patient population which may help to further shed light on this issue and have a profound influence on the use of EN in routine clinical practice. The significance of neutropenic diets for patients undergoing HSCT continues to be debated, with no strong guideline recommendations [36,37]. Our survey found that different Swiss centers had relevant heterogeneity with respect to restriction and handling of food. Most centers offering auto-HSCT did not use any type of neutropenic diet, while those offering allo-HSCT used neutropenic diets but had noticeable differences in the types of foods that were not permitted. Historically, the neutropenic diet emerged based more on pathophysiological considerations than on clinical trial data [36]. Since the beginning of transplantation in the 1970s, there was a mind shift from very strict to less strict diets, mainly due to the lack of evidence in favor of such rigid measures [13,36–38]. The current focus lies less on direct restrictions but emphasizes safe food-handling, particularly of raw fruit and vegetables [14,15,37,39]. Thus, keeping in place restrictions for certain raw meat or dairy products as well as those with apparent fungal components, such as mold cheese, but allowing raw fruit and vegetables if properly washed and/or peeled seems adequate and appropriate [13–15]. Several authors as well as health organizations, such as the US Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA), proposed replacing neutropenic diets with safe food handling guidelines [13]. The focus on safe food handling guidelines would be on protecting food from contamination and instructing patients on the proper cleaning, separation, cooking, and refrigeration of food were deemed to be appropriate [13]. The US Department of Agriculture (USDA) [13] has already issued these recommendations. In line with these considerations and in agreement with a large study performed by Trifilio et al. [14], two of the Swiss centers offering allo-HSCT reported that they currently integrate raw fruit and vegetables into their neutropenic diet plans. Nutrition is one of the few supportive treatments for HSCT in which patients can actively participate. To assist as much as possible in their treatment many patients actively exchange knowledge and experiences over the Internet. Differences between recommendations among transplant centers as well as differences between international guidelines and clinical practice in transplant centers might cause insecurity for patients and diminishes credibility of the centers and caregivers. Therefore, it seems important to ensure that differences between clinical practices among transplant centers and international guidelines are minimized. In order to better understand the effect of nutritional support on outcomes within this high-risk patient population, larger-size randomized trials as well as larger comparative outcome research initiatives are crucial. For these research efforts, it would be helpful to have more common practice guidelines in place to understand “usual care” across centers to which new interventions are being compared. Particularly for small countries such as Switzerland, centers should put more efforts into common national guidelines and bundle their resources for common research initiatives. Our survey has limitations. First, it is based on a questionnaire rather than on clinical observation, and there may be differences between the guideline recommendations and routine clinical practices that may not be fully uncovered by a questionnaire. Additionally, our questionnaire was not a validated tool but
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developed for the purpose of this study. Thus, the true extent to which guidelines are assiduously followed in actual clinical practice is likely to remain weak. Although we included all centers performing HSCT in Switzerland, the sample was still small. Secondly, we did not further investigate barriers to the implementation of guidelines and the reasons for nonadherence within the different centers. Knowledge of such factors may help to optimize the practical implementation of guideline recommendations in the future. Conclusion Our survey revealed significant heterogeneity with regard to nutritional support practices among the centers performing allo- or auto-HSCT. Adherence to guidelines issued by the ASPEN and the ESPEN was low. Understanding and reducing barriers to guideline implementation in clinical practice may improve clinical outcomes. An important factor for low adherence to guidelines might be the lack of strong trial data supporting guidelines recommendations. Close collaboration of centers will facilitate future research needed to improve guidelines and ensure high quality of treatment. Furthermore, homogeneity of recommendations will improve patient confidence and enhance the credibility of caregiver recommendations. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.nut.2016.10.007. References [1] Passweg JR, Baldomero H, Bregni M, Cesaro S, Dreger P, Duarte RF, et al. Hematopoietic SCT in Europe: Data and trends in 2011. Bone Marrow Transplant 2013;48:1161–7. [2] Ljungman P, Bregni M, Brune M, Cornelissen J, de Witte T, Dini G, et al. Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: Current practice in Europe 2009. Bone Marrow Transplant 2010;45:219–34. [3] Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P, et al. Hematopoietic stem cell transplantation in Europe 2014: More than 40 000 transplantations annually. Bone Marrow Transplant 2016;51:786–92. [4] Seguy D, Duhamel A, Rejeb MB, Gomez E, Buhi ND, Bruno B, et al. Better outcome of patients undergoing enteral tube feeding after myeloablative conditioning for allogeneic stem cell transplantation. Transplantation 2012;94:287–94. [5] Fuji S, Takano K, Mori T, Eto T, Taniguchi S, Ohashi K, et al. Impact of pretransplant body mass index on the clinical outcome after allogeneic hematopoietic SCT. Bone Marrow Transplant 2014;49:1505–12. [6] Navarro WH, Agovi MA, Logan BR, Ballen K, Bolwell BJ, Fangoul H, et al. Obesity does not preclude safe and effective myeloablative hematopoietic cell transplantation (HCT) for acute myelogenous leukemia (AML) in adults. Biol Blood Marrow Transplant 2010;16:1442–50. [7] Le Blanc K, Ringden O, Remberger M. A low body mass index is correlated with poor survival after allogeneic stem cell transplantation. Haematologica 2003;88:1044–52. [8] Deeg HJ, Seidel K, Bruemmer B, Pepe MS, Applebaum FR. Impact of patient weight on non-relapse mortality after marrow transplantation. Bone Marrow Transplant 1995;15:461–8. [9] Bozzetti F. A.S.P.E.N. clinical guidelines: Nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. JPEN J Parenter Enteral Nutr 2010;34:455. [10] Bozzetti F, Arends J, Lundholm K, Mickelwright A, Zurcher G, Muscaritoli M, et al. ESPEN Guidelines on parenteral nutrition: Non-surgical oncology. Clin Nutr 2009;28:445–54. [11] Mank A. Chapter 10-Supportive care. EBMT-ESH Handb; 2012. [12] Mensa J. Chapter 12-Infections after HSCT. EBMT-ESH Handb; 2012. [13] Fox N, Freifeld A. The neutropenic diet reviewed: Moving toward a safe food handling approach. Oncology 2012;26:572–5. [14] Trifilio S, Helenowski I, Giel M, Gobel B, Pi J, Greenberg D, et al. Questioning the role of a neutropenic diet following hematopoetic stem cell transplantation. Biol Blood Marrow Transplant 2012;18:1385–90.
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[15] Gardner A, Mattiuzzi G, Faderl S, Borthakur G, Garcia-Manero G, Pierce S, et al. Randomized comparison of cooked and noncooked diets in patients undergoing remission induction therapy for acute myeloid leukemia. J Clin Oncol 2008;26:5684–8. [16] Kondrup J, Allison SP, Elia M, Vellas B, Plauth M, Educational and Clinical Practice Committee, European Society of Parenteral and Enteral Nutrition. ESPEN guidelines for nutrition screening 2002. Clin Nutr 2003;22:415–21. [17] Harris JA, Benedict FG. A biometric study of human basal metabolism. Proc Natl Acad Sci U S A 1918;4:370–3. [18] Valentini L, Roth E, Jadrna K, Postrach E, Schulzke JD. The BASA-ROT table: An arithmetic-hypothetical concept for easy BMI-, age-, and sex-adjusted bedside estimation of energy expenditure. Nutrition 2012;28:773–8. [19] Botti S, Liptrott SJ, Gargiulo G, Orlando L. Nutritional support in patients undergoing haematopoietic stem cell transplantation: A multicenter survey of the Gruppo Italiano Trapianto Midollo Osseo (GITMO) tansplant programmes. Ecancermedicalscience 2015;9:545. [20] Fuji S, Mori T, Khattry N, Cheng J, Do YR, Yakushijin K, et al. Severe weight loss in 3 months after allogeneic hematopoietic SCT was associated with an increased risk of subsequent non-relapse mortality. Bone Marrow Transplant 2014;50:100–5. [21] Kiss N, Seymour JG, Prince HM, Dutu G. Challenges and outcomes of a randomized study of early nutrition support during autologous stem-cell transplantation. Curr Oncol 2014;21:334–9. [22] Schuetz P. “Eat your lunch!” - controversies in the nutrition of the acutely, non-critically ill medical inpatient. Swiss Med Wkly 2015;145:w14132. [23] Bally MR, Blaser Yildirim PZ, Bounoure L, Gloy VL, Mueller B, Briel M, et al. Nutritional support and outcomes in malnourished medical inpatients: A systematic review and meta-analysis. JAMA Intern Med 2016;176:43–53. [24] Schuetz P, Bally M, Stanga Z, Keller U. Loss of appetite in acutely ill medical inpatients: Physiological response or therapeutic target? Swiss Med Wkly 2014;144:w13957. [25] Weisdorf SA, Lysne J, Wind D, Haake RJ, Sharp HL, Goldman A, et al. Positive effect of prophylactic total parenteral nutrition on long-term outcome of bone marrow transplantation. Transplantation 1987;43:833–8. [26] Murray SM, Pindoria S. Nutrition support for bone marrow transplant patients. Cochrane Database Syst Rev; 2009:CD002920. [27] Sheean P, Freels SA, Helton WS, Braunschweig CA. Adverse clinical consequences of hyperglycemia from total parenteral nutrition exposure during hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2006;12:656–64.
[28] Urbain P, Birlinger J, Ihorst G, Biesalsi HK, Finke J, Bertz H. Body mass index and bioelectrical impedance phase angle as potentially modifiable nutritional markers are independent risk factors for outcome in allogeneic hematopoietic cell transplantation. Ann Hematol 2013;92:111–9. [29] Cederholm T, Bosaeus I, Barazzoni R, Bauer J, Van Gossum A, Klek S, et al. Diagnostic criteria for malnutrition - an ESPEN consensus statement. Clin Nutr 2015;34:335–40. [30] Rzepecki P, Barzal J, Sarosiek T, Oborska S, Szczylik C. Which parameters of nutritional status should we choose for nutritional assessment during hematopoietic stem cell transplantation? Transplant Proc 2007;39:2902–4. [31] Kyle UG, Chalandon Y, Miralbell R, Karsegard VL, Hans D, Trombetti A, et al. Longitudinal follow-up of body composition in hematopoietic stem cell transplant patients. Bone Marrow Transplant 2005;35:1171–7. ze R, Lemal R, Cabrespine A, Hermet E, Tournilhac O, Combal C, et al. [32] Guie Enteral versus parenteral nutritional support in allogeneic haematopoietic stem-cell transplantation. Clin Nutr 2014;33:533–8. [33] Azarnoush S, Bruno B, Beghin L, Guimber D, Nelken B, Yakoyb-Agha I, et al. Enteral nutrition: A first option for nutritional support of children following allo-SCT? Bone Marrow Transplant 2012;47:1191–5. [34] Bicakli DH, Yilmaz MC, Aksoylar S, Kantar M, Cetingul N, Kansoy S. Enteral nutrition is feasible in pediatric stem cell transplantation patients. Pediatr Blood Cancer 2012;59:1327–9. [35] Lemal R, Cabrespine A, Pereira B, Combal C, Ravinet A, Hermet E, et al. Could enteral nutrition improve the outcome of patients with haematological malignancies undergoing allogeneic haematopoietic stem cell transplantation? A study protocol for a randomized controlled trial (the NEPHA study). Trials 2015;16:136. [36] French M, Levy-Milne R, Zibrik D. A survey of the use of low microbial diets in pediatric transplant programs. J Am Diet Assoc 2001;101:1194–8. [37] Jubelirer SJ. The benefit of the neutropenic diet: Fact or fiction? Oncologist 2011;16:704–7. [38] Moody K, Finlay J, Mancuso C, Charlson M. Feasibility and safety of a pilot randomized trial of infection rate: Neutropenic diet versus standard food safety guidelines. J Pediatr Hematol Oncol 2006;28:126–33. [39] Galati PC, Lataro RC, Souza VM, de Martinis EC, Chiarello PG. Microbiological profile and nutritional quality of raw foods for neutropenic patients under hospital care. Rev Bras Hematol Hemoter 2013;35:94–8. [40] ESPEN guidelines on enteral nutrition: non-surgical patients. Clinical nutrition 2006;25:245-259
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Nutrition journal homepage: www.nutritionjrnl.com
Applied nutritional investigation
Nutritional support practices in hematopoietic stem cell transplantation centers: A nationwide comparison Annic Baumgartner M.D. a, Mario Bargetzi M.D. b, Annika Bargetzi a, Noemi Zueger a, Micheal Medinger M.D. c, Jakob Passweg M.D. c, Urs Schanz M.D. d, Panagiotis Samaras M.D. d, Yves Chalandon M.D. e, Claude Pichard M.D. f, Alessandro Limonta M.D. f, Luciano Wannesson M.D. g, Thomas Pabst M.D. h, Michel A. Duchosal M.D. i, Urs Hess M.D. j, Zeno Stanga M.D. k, Beat Mueller M.D. a, Philipp Schuetz M.D. a, * a Medical University Department, Clinic for Endocrinology/Metabolism/Clinical Nutrition, Kantonsspital Aarau, Aarau and Medical Faculty of the University of Basel, Basel, Switzerland b Clinic for Hematology and Oncology, Kantonsspital Aarau, Aarau, Switzerland c Clinic for Hematology, University Hospital Basel, Basel, Switzerland d Clinic for Hematology and Clinic for Oncology, University Hospital Zürich, Zürich, Switzerland e Clinic for Hematology, University Hospital Geneva, Geneva, Switzerland f Nutrition Unit, Geneva University Hospital, Geneva, Switzerland g Instituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland h Clinic for Hematology and Oncology, University Hospital Bern, Bern, Switzerland i Service and Central Laboratory of Hematology, University Hospital of Lausanne, Lausanne, Switzerland j Clinic for Hematology and Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland k Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Bern University Hospital, and University of Bern, Bern, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history: Received 26 July 2016 Accepted 1 October 2016
Objective: In 2009, international nutritional societies published practice guidelines on screening and nutritional support for patients undergoing stem cell transplantation. Little is known about how these guidelines are implemented in clinical practice. We performed a nationwide survey with the aim of understanding current practice patterns, differences between clinical practice, and international recommendations as well as barriers to the use of nutritional therapy. Methods: We performed a qualitative survey including all centers across Switzerland offering allogeneic (n ¼ 3) or autologous (n ¼ 7) stem cell transplantation. We focused on in-house protocols pertaining to malnutrition screening, indications for nutritional support, types of nutritional therapy available and provided, and recommendations regarding neutropenic diets. Results: All centers offering allogeneic, and most of the centers offering autologous transplantation, had a malnutrition screening tool, mainly the nutritional risk score (NRS 2002) method. Only one center does not provide nutritional support. There is wide variation regarding start and stop of nutritional therapy as well as route of delivery, with five centers recommending parenteral nutrition and five centers recommending enteral nutrition as a first step. Although all centers offering allogeneic transplantation, and approximately every other autologous transplant center, used a neutropenic diet, specific recommendations regarding the type of food and food handling showed significant variation. Conclusion: This Swiss survey found wide variation in the use of nutritional therapy in patients undergoing stem cell transplantation, with low adherence overall to current practice guidelines.
Keywords: Nutrition Hematopoietic stem cell transplantation Survey Guidelines
We thank Prasad Kulkarni of Asclepius Medical Communications LLC, Ridgewood, NJ, USA for editorial review of the manuscript. Conflict of interest statement: PS and ZS received research grants from Nestle and Abbott. All other authors confirm that they do not have a conflict of interest associated with this manuscript. Funding: This study was supported in part by the Swiss National http://dx.doi.org/10.1016/j.nut.2016.10.007 0899-9007/Ó 2016 Elsevier Inc. All rights reserved.
Science Foundation (SNSF Professorship, PP00 P3_150531/1) and the Research Council of the Kantonsspital Aarau (1410.000.044). * Corresponding author. Tel.: 41 62 838 4141; fax: 41 62 838 4100. E-mail address: [email protected] (P. Schuetz).
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Understanding and reducing barriers to guideline implementation in clinical practice may improve clinical outcomes. Close collaboration of centers will facilitate future research needed to improve current practice and ensure high quality of treatment. Ó 2016 Elsevier Inc. All rights reserved.
Introduction Allogeneic and autologous hematopoietic stem cell transplantation (allo-HSCT/auto-HSCT) are the only potentially curative treatment options for specific hematological conditions [1,2]. Treatment protocols have undergone major changes over the last 40 y, specifically with improved conditioning regimens. Additionally, reduced-intensity conditioning (RIC) has been evaluated for elderly patients or patients with multiple comorbidities undergoing allo-HSCT [2]. A noteworthy feature of RIC is that it induces fewer toxic side effects such as mucositis and significantly shortens the duration of neutropenia [2, 3]. Changes in management of transplant patients have contributed to improved clinical outcomes and lead to an increasing number of patients undergoing HSCT. As a result, there are a growing number of long-term survivors [1]. However, HSCT, above all allo-HSCT, has considerable toxicity and induces an inflammatory response, metabolic changes (cachexia), gastrointestinal symptoms, and general constitutional effects, all of which lead to reduced oral intake and worsening nutritional status. This puts patients at increased risk for malnutrition, which might have a negative influence on clinical outcomes [4]. It is well known that malnutrition in patients undergoing allo-HSCT is associated with an increase in morbidity and mortality and that it puts them at higher risk for failure of the transplant [5–8]. Both the American Society for Parenteral and Enteral Nutrition (ASPEN) [9] and the European Society for Clinical Nutrition and Metabolism (ESPEN) [10] have published consensus guidelines on screening and nutritional support in patients undergoing HSCT. In brief, these guidelines recommend malnutrition screening and nutritional interventions if patients are unable to maintain their nutritional status on their own. It is recommended that enteral nutrition (EN) be used as a first step in all patients with a functioning gastrointestinal tract [9–11], and that parenteral nutrition (PN) be reserved for patients with severe mucositis (grade >3), ileus, or intractable vomiting [9,10]. A few guidelines also give weak recommendations for the use of a neutropenic diet (ND) [9,12], whereas others do not [10]. Currently, there is ongoing discussion on the extent of dietary restrictions needed to prevent food-borne infections [13–15]. Although these recommendations have been available for several years, little is known about the implementation of these international guidelines in routine clinical practice. We performed a nationwide survey that included all transplantation centers across Switzerland that offer either allo-HSCT or auto-HSCT. The aim of the study was to better understand current practice patterns, differences between clinical practice, and international recommendations as well as possible barriers to the use of nutritional therapy in patients undergoing HSCT. We speculate that the knowledge gained through this survey will contribute to the development of national practice guidelines in Switzerland and facilitate further research.
Methods Selection of study centers and study population In 2014, a total of 621 stem cell transplantations were performed in Switzerland (226 allogeneic, 395 autologous). Two centers in Switzerland offer allo-HSCT and auto-HSCT to patients: University Hospital Basel (USB) and University Hospital Zurich (USZ). One center only offers allo-HSCT, University Hospital Geneva (HUG), while five centers offer auto-HSCTs only: Kantonsspital Aarau (KSA); Istituto Oncologico della Svizzera Italiana (IOSI); Inselspital Bern (Insel); Centre Hospitalier Universitaire Vaudois (CHUV); and Kantonsspital St. Gallen (KSSG). We contacted the heads of the hematological departments or the transplant program directors of these Swiss centers and requested permission to further contact members of the medical team, dietitians, and the person(s) in charge of the nutritional team. No compensation was offered for their participation. Survey To evaluate clinical practices at all Swiss centers, we used a questionnaire focusing on general measures, such as the availability of a nutritional risk screening program, implementation of nutritional interventions, use of parenteral glutamine, dietary restrictions in terms of a neutropenic diet, and attitudes toward nutritional support in graft-versus-host disease (GvHD). The full questionnaire is presented in Appendix A and includes open-ended and close-ended questions. Centers offering allo-HSCT and auto-HSCT were asked to answer the questions for both procedures separately. The results are shown in Appendices B and C. Before sending the final questionnaire, a preliminary version of the questionnaire was developed through rounds of consensus conferences within the research team. Its content validity was established by getting it reviewed by independent physicians and dieticians and by testing it in a small pilot study within the University Hospital of Basel, Switzerland. After revision to incorporate their feedback, the questionnaire was translated into English and sent to all eight Swiss centers in either English or German. We contacted the person(s) in charge of the center if information was missing from the questionnaires. In addition, we collected individual guidelines and recommendations of the centers that focused on hygiene, food handling, and dietary advice. In case of uncertainty about specific questions, we individually contacted the centers until the issues were resolved. We decided to present data only qualitatively and did not perform a quantitative (statistical) analysis.
Results Nutritional support practices in centers offering allogeneic transplantation Screening for malnutrition General screening for nutritional risk was performed at all centers (Table 1), mainly using the validated nutritional risk score (NRS 2002) as the preferred tool, which is also recommended by ESPEN [16]. In one center, screening was performed according to an individual hospital-developed guideline that incorporated additional parameters, such as indirect calorimetry and bioelectrical impedance analysis. Nutritionists were directly involved at all centers in the pre-transplant assessment of patients undergoing myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC). Supplementation and nutritional support Screening for vitamin or trace element deficiencies and supplementation (Table 2) is performed in one center while in the
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Table 1 Comparison of guideline recommendations on nutritional risk screening of HSCT patients and routine practices at Swiss transplant centers
Screening Screening parameters
Screening for vitamin or trace element deficiencies Routine use of a multivitamin
Recommendations by ASPEN
Recommendations by ESPEN
Practices at centers offering allo-HSCT (n ¼ 3)
Routine screening indicated No specific tools recommended
Routine screening indicated No specific tools recommended
Performed at all centers on admission
No recommendation
No recommendation
No recommendation
No recommendation
Practices at centers offering auto-HSCT (n ¼ 7)
3/7 screened on admission Other centers screen individually 5/7 centers use NRS 2/7 center do not screen
2/3 centers use NRS 1/3 centers use an individual algorithm (includes indirect calorimetry, bioelectrical impedance, height, weight, 24-h diet recall, physical activity in addition to other parameters) 1/3 centers performs screening Other centers do not screen
1/7 centers performs screening Other centers do not screen
2/3 routinely use multivitamin Other center does not
1/7 centers uses multivitamins Other centers do not
allo-HSCT, allogeneic hematopoietic stem cell transplantation; ASPEN, American Society for Parenteral and Enteral Nutrition; auto-HSCT, autologous hematopoietic stem cell transplantation; ESPEN, European Society for Clinical Nutrition and Metabolism; NRS, nutritional risk score
other centers it is not routinely done but may be performed on an individual patient level. Two centers routinely administer multivitamins to all patients. Other vitamins and trace elements are supplemented in all centers if quantitative deficits are detected.
All centers have recommendations in place for nutritional support (Table 2), although indications differ widely among the centers. Recommendations rely either on malnutrition risk based on the NRS 2002 or on clinical features such as the severity of
Table 2 Comparison of guideline recommendations on nutritional support for HSCT patients and routine practices at Swiss transplant centers Recommendations by ASPEN
Recommendations by ESPEN
Practices at centers offering allo-HSCT (n ¼ 3)
Primary nutritional support
EN
EN
2/3 PN 1/3 EN
Indication of primary nutritional support
Apparent malnutrition or anticipated insufficient oral intake for 7 to 14 d but functioning GIT and absence of neutropenia
Apparent malnutrition or insufficient oral intake (<60% or daily needs) and mucositis
3 different recommendations 1/3 NRS 1/3 oral intake 1/3 no quantitative parameter
Practices at centers offering auto-HSCT (n ¼ 7)
Criteria for discontinuation
Neutrophil engraftment and sufficient oral intake (no quantitative recommendation)
Tolerance of 50% daily needs orally
2/3 oral intake >60% of daily needs 1/3 oral intake >50% of daily needs
Dosage
Secondary nutritional support
No recommendation
PN if apparent malnutrition or anticipated insufficient oral intake for 7 to 14 d but nonfunctioning GIT or neutropenia/ thrombopenia
Kcal: 20 to 25/kg/d (bedridden) Kcal: 25 to 30/kg/d (ambulatory) Protein: 1 to 2 g/kg/d
PN if insufficient oral intake AND mucositis Grade 3 to 4, ileus, or intractable vomiting
2/3 estimate caloric requirements with HarrisBenedict formula (or adapted version BASAROT) 1/3 according to ESPEN guidelines 2/3 EN 1/3 PN if severe gut insufficiency
3/7 PN 3/7 EN 1/7 no nutritional support 7 different recommendations, 7 different parameters used 2/7 centers use oral intake to different extents 1/7 uses either NRS or weight loss (not quantified) 1/7 combination of NRS, weight loss and oral intake 1/7 combination of mucositis and weight loss (not quantified) 1/7 no quantitative parameters 1/7 no nutritional support 2/7 oral intake >60% of daily needs 2/7 oral intake >75% of daily needs 1/7 oral intake >25 to 50% of daily needs 1/7 recovery from mucositis 1/7 no nutritional support 2/7 Harris-Benedict formula 2/7 ESPEN guidelines 1/7 Kcal: 30 to 35/kg/d 1/7 individual decision 1/7 no nutritional support
3/7 PN if severe gut insufficiency and intolerance of EN 4/7 no further recommendations
allo-, allogeneic; ASPEN, American Society for Parenteral and Enteral Nutrition; auto-, autologous; ESPEN, European Society for Clinical Nutrition and Metabolism; GIT, gastrointestinal tract; HSCT, hematopoietic stem cell transplantation; NRS, nutritional risk score; PN, parenteral nutrition
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Table 3 Comparison of guideline recommendations on the use of glutamine, neutropenic diets, and nutritional support in patients with GvHD by international societies and routine practices at Swiss transplant centers
Use of glutamine parenterally Indication
Dosage
ND Indication Parameters for discontinuation
Restrictions for RIC-allo-HSCT
Recommendations by ASPEN
Recommendations by ESPEN
Indication given despite weak evidence No further recommendations
Indication given No further recommendations
1/3 if severe diarrhea 1/3 if no oral intake 1/3 centers does not use glutamine
No recommendations
0.6 g/kg/d
1/3 1.5 mL/kg/d 1/3 no information 1/3 centers does not use glutamine
Given despite weak evidence Neutrophil recovery
No recommendations No recommendations
No recommendations
No recommendations
Used in all centers 1/3 neutrophil recovery 1/3 discontinuation of amphotericin 1/3 clinical decision 1/3 alike MAC-allo-HSCT until neutrophil recovery 1/3 separate guidelines 1/3 alike MAC-allo-HSCT
Nutritional support in GvHD Indication Moderate to severe GvHD with insufficient oral intake or significant malabsorption Primary nutritional PN support
No recommendations
No recommendations
Centers offering allo-HSCT (n ¼ 3)
Centers offering auto-HSCT (n ¼ 7)
2/7 centers use glutamine 1/7 centers sees indication in severe diarrhea 1/7 centers no objective indication criteria 5/7 centers do not use glutamine 1/7 1.5 mL/kg/d 1/7 no further information 5/7 centers do not use glutamine
3/7 2/7 1/7 4/7
centers use ND neutrophil recovery clinical decision centers do not use ND
Not relevant
2/3 NRS >3 1/3 severe diarrhea (not quantified) PN in all centers
allo-HSCT, allogeneic hematopoietic stem cell transplantation; ASPEN, American Society for Parenteral and Enteral Nutrition; auto-HSCT, autologous hematopoietic stem cell transplantation; ESPEN, European Society for Clinical Nutrition and Metabolism; GvHD, graft-versus-host disease; MAC, myeloablative conditioning; ND, neutropenic diet; NRS, nutritional risk score; PN, parenteral nutrition; RIC, reduced-intensity conditioning
gastrointestinal mucositis and low oral intake according to the ESPEN guidelines [10]. In one center, however, no quantitative parameters have been defined, and the decision is left to the discretion of the team. The indication for PN is given explicitly by all centers in patients with severe mucositis, ileus, or intractable vomiting as recommended by the ESPEN guidelines [10]. Two centers recommend PN as the primary nutritional support intervention, with EN not being routinely used. A third center recommends EN as the first choice, with PN being indicated only in case of gastrointestinal failure. One center routinely uses parenteral immunonutrition (i.e., omega-3 fatty acids supplementation) to complement PN. Two centers estimate energy needs according to the original Harris-Benedict formula [17] or its corrected version (BASA-ROT by Valentini) [18]. One center complements these estimations with indirect calorimetry. A third center does not explicitly estimate energy expenditure, but calculates caloric needs according to a fixed formula [10]. Discontinuation of nutritional support is recommended in all centers if the oral intake is greater than 50% to 60% of daily requirements. Role of parenteral glutamine Two centers add parenterally administered products containing glutamine to nutritional support interventions if there is no oral intake or in cases of severe diarrhea (Table 3). One center does not utilize glutamine whatsoever. Neutropenic diet All centers have a neutropenic diet (ND) protocol in place for transplant recipients (Table 4) and provide detailed brochures on
peritransplant proceedings, covering recommendations for personal hygiene, food storage, handling of kitchen supplies, cooking in general, and preparation of raw foods if allowed. Two centers defined specific recommendations stratified for different subpopulations according to the extent of immunosuppression and acuity of GvHD or severity of the conditioning regime (MACallo-HSCT, RIC-allo-HSCT, or auto-HSCT). Criteria indicating when it is appropriate to safely discontinue neutropenic diets show important differences among the centers. Criteria used include discontinuation of immunosuppression, acuity of GvHD, smell of stool, and discontinuation of local amphotericin B therapy. One center did not provide objective criteria. The different centers do agree on most of the general recommendations concerning food hygiene, preparation of meals, and handling of convenience foods. There is heterogeneity regarding practices pertaining to safety of reheating and those related to consumption of freshly prepared meals or drinks. Table 5 gives an overview of areas where centers have disagreement or agreement on specific recommendations regarding ND. There is broad consensus regarding recommendations against the use of raw milk, raw milk products, probiotics, raw cereals, nuts, sprouts and seeds, as well as raw, smoked, dried, or salted meat and fish. There is also consensus against the use of unboiled tap water. Heterogeneity was found in recommendations regarding raw fruit and vegetables. Two centers allow raw fruit if correctly washed and peeled. A type of raw lettuce (Iceberg) is permitted by one center whereas the other centers strictly recommend avoiding consumption of raw fruits or vegetables that are unpeelable. Other points of disagreement concern dairy products
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Table 4 Comparison of adherence to general recommendations on neutropenic diets among Swiss transplant centers offering allo-HSCT General recommendations Type of recommendation
Differentiation between populations and recommendations
Recommendations on food hygiene
Center 1
General food consumption
Convenience food Return to normal nutrition
Center 2
For in-patients For out-patients For nursery staff According to extent of immunosuppression and acuity of GvHD According to conditioning regime Inpatients and ambulatory patients Very detailed description for outhospital patients (personal hygiene, storage, kitchen supplies, temperatures for cooking, washing raw products) Routine consultation by nutritionist before discharge Reheating not recommended Allowed if heated > 70 C Consume tea within 24 h No recommendation on cooled food No recommendation on prepared fruit Only small packages Consume within 24 h If no immunosuppression or no active GvHD
For in-patients For out-patients For nursery staff According to conditioning regime Inpatients and ambulatory patients
Detailed description for outhospital patient (personal hygiene, storage, kitchen supplies, temperatures for cooking, washing raw products) Routine consultation by nutritionist before discharge Reheating not recommended Allowed if heated up “properly” Consume warm tea within 12 h Consume cooled food within 6 h Consume prepared fruit (peeled and sliced) within 2 h Only small packages Consume within 24 h After recontamination (¼ discontinuation of Ampho-Moronal) No later than Dþ100
Center 3 For out-hospital patients
None
Detailed description for patients (personal hygiene, storage, kitchen supplies, temperatures for cooking)
out-
No reheating No refreezing Consume self-prepared meals <24 h No recommendation on cooled food No raw fruit consumption allowed Only small packages Consume within 24 h According to individual decision
allo-HSCT, allogeneic hematopoietic stem cell transplantation; GvHD, graft-versus-host disease
such as cheese and yogurt, as well as grains, especially couscous, quinoa, and semolina. Neutropenic diet in reduced-intensity conditioning Two centers use a neutropenic diet during protective isolation of patients undergoing RIC-allo-HSCT. One center treats patients according to the protocol for MAC-allo-HSCT, whereas the other center shortens the duration of restrictions to include only the phase of neutropenia. The third center does have specific guidelines for patients undergoing RIC in terms of neutropenic diet, including fewer restrictions than for MAC-alloHSCT. Specifically, there are fewer restrictions regarding dairy products other than probiotics as well as raw fruits and vegetables. Raw meat, fish, sausages, and eggs are not recommended at this center. Nutritional support in patients with GvHD The indication for nutritional support in patients with GvHD at two centers is based on NRS 2002 in accordance with ESPEN guidelines (Table 3) [10]. The third center uses severity of diarrhea as the determining criterion. If criteria for imminent or apparent malnutrition are met, all centers prefer PN to EN for inpatients with a high likelihood of gastrointestinal malabsorption. All centers increase outpatient counseling in nutritional as well as hematological consultations to reduce and avoid rehospitalization. Nutritional support practices in centers offering autologous transplantation Screening for malnutrition Only half of the centers have a standard malnutrition screening protocol (Table 1) that is performed on admission by nutritionists, mainly using the validated NRS 2002 score. Three centers involve nutritionists only if suspicion of malnutrition
occurs during a hospital stay. With the exception of one center, no biochemical screening for deficiencies of vitamins or trace elements is performed routinely. Nutritional support There is heterogeneity among centers concerning the indication for nutritional support (Table 2). Low oral intake, heightened malnutrition risk, weight loss, and mucositis are parameters frequently used to recommend nutritional therapy. There is no preference of EN (3/7) or PN (3/7) in patients with a functioning gastrointestinal tract. Criteria for gastrointestinal failure that would make PN necessary include weight loss, mucositis, malabsorption, and diarrhea. These criteria are not quantitatively defined in any of the centers. Discontinuation of nutritional support is based on recovery of oral intake, but quantitative measures of recovery range between 25% and 75% of daily energy needs. Centers that primarily use PN frequently abstain completely from using EN. One center administers neither EN nor PN. Parenteral glutamine This is part of nutritional support interventions in a minority of the centers (2/7). Neutropenic diet Three of seven centers use a ND. As in the case of centers offering allo-HSCT, there is significant heterogeneity in recommendations with regard to the use of neutropenic diets. Differences in protocols between centers are similar to differences seen between centers offering allo-HSCT (Table 3). Discussion In 2009 and 2012, professional European and US nutritionists’ societies as well as the European Society for Blood and Marrow
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Table 5 Comparison of specific food recommendations in neutropenic diets among Swiss transplant centers offering allo-HSCT Food category Dairy products
Eggs Meat/Fish
Cereals Fruit, Nuts, Vegetables
Miscellaneous
Consensus
Disagreement (recommendation for and against product)
No raw milk or milk products No probiotics No fresh whipped cream Allowed: Soft/processed cheese in single servings Pasteurized, cooked hard cheese No raw, fried, or soft boiled (3 min) eggs Allowed: Scrambled eggs No raw, dried, smoked, or salted meat or fish No cooked meat eaten cold (ham, sausages) No poultry with bones Allowed: Cooked meat, seafood and sausages No raw cereals No bread containing nuts, dried fruit or seeds No raw and unpeeled fruit No dried fruit No uncooked nuts, no seeds, no sprouts No raw and unpeeled vegetables No fresh and uncooked herbs No fresh pepper No grapefruit juice Unpasteurized fruit juice No tap water or ice cubes from tap water No mineral water or soda with gas in >0.5 L quantities No filter coffee Allowed: Potato chips “natural” (with no preservatives) Allowed: Cake and cookies individually wrapped
Yoghurt Cheese Non-cooked hard cheese Cooked hard cheese
Couscous, quinoa, semolina Raw thin-peeled fruit Raw stone fruit Washed raw lettuce (“Eisberg” variety specifically)
Tap water boiled for 1 min Still mineral water Alcohol
allo-HSCT, allogeneic hematopoietic stem cell transplantation
Transplantation (EBMT) published guidelines on nutritional support for patients undergoing stem cell transplantation. However, little is known about how and to what extent these guidelines are implemented in current clinical practice. This knowledge is important to understand existing barriers to optimal nutritional support and to identify areas and topics for future quality work. We conducted a Swiss nationwide survey that included all centers offering either allo-HSCT or auto-HSCT. Particularly for the auto-HSCT centers, we found wide variation regarding indications, types, and routes of nutritional interventions as well as recommendations regarding neutropenic diets in patients undergoing HSCT, with rather low adherence to current practice guidelines being evident overall. Our survey is in line with a similar earlier survey that also demonstrated significant variation in nutritional therapy practices during the care of patients undergoing HSCT, as well as disregard of international guidelines. A recently published survey focusing on Italian transplant centers offering auto-HSCT and allo-HSCT showed important differences between guideline recommendations and routine clinical practices [19]. Notably, 42% of the centers did not have formal protocols to assess nutritional status. Screening for malnutrition risk was performed according to different guidelines and in a minority of the surveyed centers. The first choice for route of administration used by the majority (90%) of centers was PN. Protocols for neutropenic diets were found to be in place in 79% of the centers [19]. Patients undergoing MAC-allo-HSCT are at elevated risk for malnutrition during the course of treatment [20,21]. Malnutrition is negatively associated with overall survival, transplant-related mortality, and relapse rates [5,6]. In contrast to other factors influencing clinical outcome such as genetics or donor source [8], malnutrition is considered to be a partly modifiable risk factor. Screening for malnutrition is therefore recommended [9–11]. However, there is controversy whether
nutritional status is a mirror of more severe disease (confounding factor) or whether it is linked causally [22–24]. Evidence demonstrating that nutritional therapy is effective in reducing malnutrition-associated adverse outcomes is weak at best [25–27]. However, according to the ASPEN guidelines, there is consensus that HSCT alone justifies screening for malnutrition [9]. Despite this, disagreement persists on the ideal screening tool to use or the nutritional parameters that best define malnutrition [28–31]. Recent recommendations predominantly focus on patients’ body weight [29]. Whether malnutrition risk in patients undergoing auto-HSCT or RIC-allo-HSCT is as high as for MAC-allo-HSCT recipients needs further evaluation in sufficiently powered trials. Mainly for practical reasons, the majority of Swiss centers are currently using the validated NRS 2002 score as their screening tool following recommendations by the ESPEN [16]. The current recommendation for nutritional support still relies largely on one randomized trial performed by Weisdorf and published in 1987 [25], which found a decrease in mortality following provision of parenteral nutrition [9]. Several trials published in this patient population since then have not been able to replicate these findings and did not demonstrate that nutritional therapy improves survival [25–27]. The current guideline recommendations that favor EN over PN are mainly based on pathophysiological considerations and evidence from smaller studies arguing that PN is associated with higher risk for infectious and metabolic complications [4,27]. Recent research also shows better survival, lower infection rates, and lower rates of acute GvHD in patients provided nutritional therapy through EN [4]. Additionally, feasibility and safety of EN has been successfully proven in several small studies [4,32–34]. However, despite this paradigm shift toward the early use of EN, most allo-HSCT and about half of all auto-HSCT centers in Switzerland continue to use PN as a first option. Moreover, there is a lack of criteria in place for the use of PN in most centers starting with
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EN. Cultural and logistic issues as well as the paucity of strong trial data may explain these differences. There is a large ongoing trial in France [35] comparing EN with PN in this vulnerable patient population which may help to further shed light on this issue and have a profound influence on the use of EN in routine clinical practice. The significance of neutropenic diets for patients undergoing HSCT continues to be debated, with no strong guideline recommendations [36,37]. Our survey found that different Swiss centers had relevant heterogeneity with respect to restriction and handling of food. Most centers offering auto-HSCT did not use any type of neutropenic diet, while those offering allo-HSCT used neutropenic diets but had noticeable differences in the types of foods that were not permitted. Historically, the neutropenic diet emerged based more on pathophysiological considerations than on clinical trial data [36]. Since the beginning of transplantation in the 1970s, there was a mind shift from very strict to less strict diets, mainly due to the lack of evidence in favor of such rigid measures [13,36–38]. The current focus lies less on direct restrictions but emphasizes safe food-handling, particularly of raw fruit and vegetables [14,15,37,39]. Thus, keeping in place restrictions for certain raw meat or dairy products as well as those with apparent fungal components, such as mold cheese, but allowing raw fruit and vegetables if properly washed and/or peeled seems adequate and appropriate [13–15]. Several authors as well as health organizations, such as the US Centers for Disease Control and Prevention (CDC) and the US Food and Drug Administration (FDA), proposed replacing neutropenic diets with safe food handling guidelines [13]. The focus on safe food handling guidelines would be on protecting food from contamination and instructing patients on the proper cleaning, separation, cooking, and refrigeration of food were deemed to be appropriate [13]. The US Department of Agriculture (USDA) [13] has already issued these recommendations. In line with these considerations and in agreement with a large study performed by Trifilio et al. [14], two of the Swiss centers offering allo-HSCT reported that they currently integrate raw fruit and vegetables into their neutropenic diet plans. Nutrition is one of the few supportive treatments for HSCT in which patients can actively participate. To assist as much as possible in their treatment many patients actively exchange knowledge and experiences over the Internet. Differences between recommendations among transplant centers as well as differences between international guidelines and clinical practice in transplant centers might cause insecurity for patients and diminishes credibility of the centers and caregivers. Therefore, it seems important to ensure that differences between clinical practices among transplant centers and international guidelines are minimized. In order to better understand the effect of nutritional support on outcomes within this high-risk patient population, larger-size randomized trials as well as larger comparative outcome research initiatives are crucial. For these research efforts, it would be helpful to have more common practice guidelines in place to understand “usual care” across centers to which new interventions are being compared. Particularly for small countries such as Switzerland, centers should put more efforts into common national guidelines and bundle their resources for common research initiatives. Our survey has limitations. First, it is based on a questionnaire rather than on clinical observation, and there may be differences between the guideline recommendations and routine clinical practices that may not be fully uncovered by a questionnaire. Additionally, our questionnaire was not a validated tool but
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developed for the purpose of this study. Thus, the true extent to which guidelines are assiduously followed in actual clinical practice is likely to remain weak. Although we included all centers performing HSCT in Switzerland, the sample was still small. Secondly, we did not further investigate barriers to the implementation of guidelines and the reasons for nonadherence within the different centers. Knowledge of such factors may help to optimize the practical implementation of guideline recommendations in the future. Conclusion Our survey revealed significant heterogeneity with regard to nutritional support practices among the centers performing allo- or auto-HSCT. Adherence to guidelines issued by the ASPEN and the ESPEN was low. Understanding and reducing barriers to guideline implementation in clinical practice may improve clinical outcomes. An important factor for low adherence to guidelines might be the lack of strong trial data supporting guidelines recommendations. Close collaboration of centers will facilitate future research needed to improve guidelines and ensure high quality of treatment. Furthermore, homogeneity of recommendations will improve patient confidence and enhance the credibility of caregiver recommendations. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.nut.2016.10.007. References [1] Passweg JR, Baldomero H, Bregni M, Cesaro S, Dreger P, Duarte RF, et al. Hematopoietic SCT in Europe: Data and trends in 2011. Bone Marrow Transplant 2013;48:1161–7. [2] Ljungman P, Bregni M, Brune M, Cornelissen J, de Witte T, Dini G, et al. Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: Current practice in Europe 2009. Bone Marrow Transplant 2010;45:219–34. [3] Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P, et al. Hematopoietic stem cell transplantation in Europe 2014: More than 40 000 transplantations annually. Bone Marrow Transplant 2016;51:786–92. [4] Seguy D, Duhamel A, Rejeb MB, Gomez E, Buhi ND, Bruno B, et al. Better outcome of patients undergoing enteral tube feeding after myeloablative conditioning for allogeneic stem cell transplantation. Transplantation 2012;94:287–94. [5] Fuji S, Takano K, Mori T, Eto T, Taniguchi S, Ohashi K, et al. Impact of pretransplant body mass index on the clinical outcome after allogeneic hematopoietic SCT. Bone Marrow Transplant 2014;49:1505–12. [6] Navarro WH, Agovi MA, Logan BR, Ballen K, Bolwell BJ, Fangoul H, et al. Obesity does not preclude safe and effective myeloablative hematopoietic cell transplantation (HCT) for acute myelogenous leukemia (AML) in adults. Biol Blood Marrow Transplant 2010;16:1442–50. [7] Le Blanc K, Ringden O, Remberger M. A low body mass index is correlated with poor survival after allogeneic stem cell transplantation. Haematologica 2003;88:1044–52. [8] Deeg HJ, Seidel K, Bruemmer B, Pepe MS, Applebaum FR. Impact of patient weight on non-relapse mortality after marrow transplantation. Bone Marrow Transplant 1995;15:461–8. [9] Bozzetti F. A.S.P.E.N. clinical guidelines: Nutrition support therapy during adult anticancer treatment and in hematopoietic cell transplantation. JPEN J Parenter Enteral Nutr 2010;34:455. [10] Bozzetti F, Arends J, Lundholm K, Mickelwright A, Zurcher G, Muscaritoli M, et al. ESPEN Guidelines on parenteral nutrition: Non-surgical oncology. Clin Nutr 2009;28:445–54. [11] Mank A. Chapter 10-Supportive care. EBMT-ESH Handb; 2012. [12] Mensa J. Chapter 12-Infections after HSCT. EBMT-ESH Handb; 2012. [13] Fox N, Freifeld A. The neutropenic diet reviewed: Moving toward a safe food handling approach. Oncology 2012;26:572–5. [14] Trifilio S, Helenowski I, Giel M, Gobel B, Pi J, Greenberg D, et al. Questioning the role of a neutropenic diet following hematopoetic stem cell transplantation. Biol Blood Marrow Transplant 2012;18:1385–90.
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