Neutropenic Dietary Restrictions for Hematopoietic Stem Cell Patients: Time for a Change

In the 1960s and 1970s, eradication of host bacteria was thought to be achievable and beneficial for avoiding infection in the immunocompromised host. At that time, patients were fed autoclaved, sterile foods and kept in totally protected environments [1Preisler H.D. Goldstein I.M. Henderson E.S. Gastrointestinal "sterilization" in the treatment of patients with acute leukemia.Cancer. 1970; 26: 1076-1081Crossref PubMed Scopus (58) Google Scholar]. Over time, there became an obvious need to liberalize dietary options in these patients, because the sterile foods were not palatable and did not provide enough variety [1Preisler H.D. Goldstein I.M. Henderson E.S. Gastrointestinal "sterilization" in the treatment of patients with acute leukemia.Cancer. 1970; 26: 1076-1081Crossref PubMed Scopus (58) Google Scholar]. The neutropenic diet was developed to meet this need and essentially eliminates certain food groups, most commonly raw fruits and vegetables, which contain bacteria, in an effort to decrease bacterial content and potential pathogens from colonizing the gastrointestinal tract. This reduction in gastrointestinal flora and potential pathogens is hypothesized to reduce risk of bacterial translocation and subsequent bacteremia [2Moody K. Charlson M.E. Finlay J. The neutropenic diet: what's the evidence?.J Pediatr Hematol Oncol. 2002; 24: 717-721Crossref PubMed Scopus (63) Google Scholar]. Notably, the theoretical basis of this practice has never been proven in a clinical trial. Despite a lack of clinically relevant data, the neutropenic diet remains a very common recommendation among HSCT clinicians, justified by claims of "prudent practice" and "should not cause any harm" [3Somerville E.T. Special diets for neutropenic patients: do they make a difference?.Semin Oncol Nurs. 1986; 2: 55-58Crossref PubMed Scopus (8) Google Scholar]. However, several factors have led to a reevaluation of this practice, including increased interest by families and physicians in nutrition and its impact on medical and quality of life-related outcomes, substantial improvements in supportive care and anti-infection strategies, and emerging data on the role of the microbiome in health and disease [4Moody K.M. Baker R.A. Santizo R.O. et al.A randomized trial of the effectiveness of the neutropenic diet versus food safety guidelines on infection rate in pediatric oncology patients.Pediatr Blood Cancer. 2018; 65: e26711Crossref Scopus (36) Google Scholar]. Renewed interest in the rationale for use of the neutropenic diet has resulted in publication of survey data regarding practice patterns that show great variability within and across institutions and countries regarding the content and timing of the neutropenic diet recommendations [5Peric Z. Botti S. Stringer J. et al.Variability of nutritional practices in peritransplant period after allogeneic hematopoietic stem cell transplantation: a survey by the Complications and Quality of Life Working Party of the EBMT.Bone Marrow Transplant. 2018; 53: 1030-1037Crossref PubMed Scopus (19) Google Scholar]. These studies also show that the neutropenic diet is most often used in the hematopoietic stem cell transplantation (HSCT) setting [6Braun L.E. Chen H. Frangoul H. Significant inconsistency among pediatric oncologists in the use of the neutropenic diet.Pediatr Blood Cancer. 2014; 61: 1806-1810Crossref PubMed Scopus (15) Google Scholar]. Observational studies have also emerged showing no differences in infection rates between patients following a neutropenic diet versus those on a regular hospital diet [7DeMille D. Deming P. Lupinacci P. Jacobs L.A. The effect of the neutropenic diet in the outpatient setting: a pilot study.Oncol Nurs Forum. 2006; 33: 337-343Crossref PubMed Scopus (41) Google Scholar]. Finally, randomized controlled trials in neutropenic cancer patients confirmed that the neutropenic diet does not confer protection against infection or gut colonization [4Moody K.M. Baker R.A. Santizo R.O. et al.A randomized trial of the effectiveness of the neutropenic diet versus food safety guidelines on infection rate in pediatric oncology patients.Pediatr Blood Cancer. 2018; 65: e26711Crossref Scopus (36) Google Scholar, 8Gardner A. Mattiuzzi G. Faderl 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: 5684-5688Crossref PubMed Scopus (93) Google Scholar, 9van Tiel F. Harbers M.M. Terporten P.H. et al.Normal hospital and low-bacterial diet in patients with cytopenia after intensive chemotherapy for hematological malignancy: a study of safety.Ann Oncol. 2007; 18: 1080-1084Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar]. Concurrently, in 2000, the Centers for Disease Control and Prevention, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation cosponsored official guidelines for food safety among HSCT recipients [10Centers for Disease Control and PreventionGuidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients.MMWR Recomm Rep. 2000; 49: 1-125Google Scholar]. In these guidelines, HSCT recipients were recommended to follow food safety practices appropriate for all persons to decrease the risk of foodborne infections. These food safety practices were created based on data collected during foodborne infectious disease outbreaks. They include guidance for food shopping, storage, cooking, and handling to reduce risk of foodborne infection (eg, cook meats well done). A low-microbial diet was also included in the recommendations for HSCT recipients; however, raw fruits and vegetables were not totally excluded from the diet. Instead, only fruits deemed difficult to clean due to their rough surface (eg, raspberries) and raw vegetable sprouts were to be avoided. Notably, other washed fruits and vegetables were acceptable. A short list of specific foods were still recommended to be eaten cooked: tofu, nuts, grains, and yeast. This low-microbial diet was only minimally changed in the 2009 published updates [11Tomblyn M. Chiller T. Einsele H. et al.Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective.Preface. Bone Marrow Transplant. 2009; 44: 453-455Crossref PubMed Scopus (266) Google Scholar] (Table 1). The consumption of fast foods is also allowed according to these guidelines with some associated prudent advice, such as "ask that food be freshly prepared." Interestingly, in 2009 the authors reported that "concern arising from the detection of potential pathogens in food has not been supported by documented evidence of such organisms as the source of opportunistic infections in immunocompromised persons. The potential benefit of food safety recommendations directed specifically toward HSCT recipients must be weighed against the uncertain value of such recommendations…and their potential to adversely affect patients' nutritional intake and/or quality of life."Table 1HSCT Recipient Low-Microbial Diet Endorsed by the Centers for Disease Control and Prevention, Infectious Disease Society of America, and American Society of Blood and Marrow Transplantation 11Tomblyn M. Chiller T. Einsele H. et al.Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective.Preface. Bone Marrow Transplant. 2009; 44: 453-455Crossref PubMed Scopus (266) Google ScholarDo Not EatMay EatRaw and undercooked eggs and foods containing them (eg, French toast, omelets, salad dressings, eggnog, puddings)Pasteurized or hard-boiled eggsUnpasteurized dairy products (eg, milk, cheese, cream, butter, and yogurt)Pasteurized dairy productsFresh-squeezed, unpasteurized fruit and vegetable juicesPasteurized juicesUnpasteurized cheeses or cheeses containing moldsPasteurized, commercially packaged cheeses; cooked soft cheesesUndercooked or raw poultry, meats, fish, and seafoodCooked poultry, well-done meats, cooked fish, and seafoodRaw or lightly cooked vegetable sprouts (eg, alfalfa, bean, other seed sprouts)Sprouts should be washed and well-cookedBerries, rawCooked or canned berriesUnwashed, raw, fruitsShould be washed under running water, peeled, cooked, or driedUnwashed raw vegetablesShould be washed under running water, peeled, or cooked; avoid fresh salsa and nonpasteurized preprepared items containing raw fruit in the grocery refrigerator (eg, salsa)Undercooked or raw tofuCooked tofu: avoid misoRaw or unpasteurized honeyShould be avoided; use pasteurized honey for children age >1 yrUncooked hot dogs and food from deli slicersShould be avoided unless further cooked until steaming, or use commercially packaged luncheon meatsRaw, uncooked grain productsCooked grain products including bread, cooked, and ready-to-eat cold cereal, pretzels, popcorn, potato chips, corn chips, tortilla chips, cooked pasta, and riceMaté teaShould be avoidedAll moldy and outdated food productsShould be avoidedUnpasteurized beer (eg, homebrews and certain microbrewery brews)Pasteurized beer (eg, retail bottled or canned, or draft beer that has been pasteurized after fermentation)Raw, uncooked brewer's yeastShould be avoided; HSCT recipients should avoid any contact with raw yeast (eg, should not make bread products themselves)Unroasted raw nutsCooked nutsRoasted nuts in the shellCanned or bottled roasted nuts or nuts in baked products Open table in a new tab Another concern relevant to this discussion is the emerging science regarding the role of the human microbiome in transplantation-related complications, including infection, graft-versus-host disease (GVHD), and mortality. Interventions that restore a healthy and biodiverse microbiome may lead to improvements in these adverse HSCT outcomes. In fact, some ongoing studies are looking at interventions to support the microbiome in this population including dietary changes (adding back raw fruits and vegetables), prebiotics, probiotics and fecal microbial transplants [12Andermann T.M. Peled J.U. Ho C. et al.The microbiome and hematopoietic cell transplantation: past, present, and future.Biol Blood Marrow Transplant. 2018; 24: 1322-1340Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar]. So then, why is it, in the face of expert recommendations informed by best evidence, and a lack of relevant rationale, do we clinicians continue to recommend the broad elimination of raw fruits and vegetables, and other foods, in HSCT recipients' diets? Perhaps it can be attributed to habit, coupled with a historical lack of clinical studies in HSCT. In this issue of Biology and Bone Marrow Transplant, Taggart et al [13Taggart C, Neumann N, Alonso PB, et al. Comparing a neutropenic diet to a food safety-based diet in pediatric patients undergoing hematopoietic stem cell transplantation [e-pub ahead of print]. Biol Blood Marrow Transplant. doi: 10.1016/j.bbmt.2019.03.017, Accessed June 1, 2019.Google Scholar] contribute to the state of the science, by reporting on a controlled before-and-after study comparing a neutropenic diet with a food safety-based diet in 102 pediatric patients undergoing HSCT. Notably the food safety diet used in this study allows for consumption of all fresh fruits and vegetables, if washed under running water and free from visible damage; it also allows freshly prepared fast food, and packaged lunch meats. Similar to previous studies in neutropenic, non-HSCT populations, they found no difference in bloodstream infections between the 2 groups. Furthermore, Taggert at al [13Taggart C, Neumann N, Alonso PB, et al. Comparing a neutropenic diet to a food safety-based diet in pediatric patients undergoing hematopoietic stem cell transplantation [e-pub ahead of print]. Biol Blood Marrow Transplant. doi: 10.1016/j.bbmt.2019.03.017, Accessed June 1, 2019.Google Scholar] found no significant between-group differences in the rates of viral infections, GVHD, total parenteral nutrition use, and death in the first 100 days. That study, the first published study of the neutropenic diet in children undergoing HSCT, provides valuable evidence that the neutropenic diet does not reduce infection rate in this population. This finding is consistent with the studies in adult HSCT recipients [14Lassiter M. Schneider S.M. A pilot study comparing the neutropenic diet to a non-neutropenic diet in the allogeneic hematopoietic stem cell transplantation population.Clin J Oncol Nurs. 2015; 19: 273-278Crossref PubMed Scopus (23) Google Scholar, 15Trifilio S. Helenowski I. Giel M. et al.Questioning the role of a neutropenic diet following hematopoetic stem cell transplantation.Biol Blood Marrow Transplant. 2012; 18: 1385-1390Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar]. Although the evidence in HSCT is limited to nonrandomized studies and a small randomized controlled trial, the findings also match those obtained from every other clinical trial in neutropenic cancer patients, as shown in 3 recent meta-analyses [16Ball S. Brown T.J. Das A. Khera R. Khanna S. Gupta A. Effect of neutropenic diet on infection rates in cancer patients with neutropenia: a meta-analysis of randomized controlled trials.Am J Clin Oncol. 2019; 42: 270-274Crossref PubMed Scopus (16) Google Scholar, 17Sonbol M.B. Firwana B. Diab M. Zarzour A. Witzig T.E. The effect of a neutropenic diet on infection and mortality rates in cancer patients: a meta-analysis.Nutr Cancer. 2015; 67: 1230-1238Crossref PubMed Scopus (33) Google Scholar, 18Sonbol MB, Jain T, Firwana B, et al. Neutropenic diets to prevent cancer infections: updated systematic review and meta-analysis [e-pub ahead of print]. BMJ Support Palliat Care. doi: 10.1136/bmjspcare-2018-001742, Accessed June 1, 2019.Google Scholar]. The time has come to stop eliminating raw, washed fruits and vegetables from the diets of HSCT patients and start implementing food safety guidelines to prevent foodborne infection while we aim to further understand the diverse microbiome, how to support it, and how it supports health.