THE BOTTOM LINE
Neutropenic Diet – Good Practice or Myth?
Michael Boeckh
Hematopoietic cell transplant (HCT) is one of
the most complex procedures in medicine. Since its
inception several decades ago, it has been continu-
ously refined and is now a standard procedure for
many hematologic malignancies and some nonmalig-
nant diseases. However, despite these advances, re-
lapse of the underlying disease, graft-versus-host
disease (GVHD), organ toxicities, and infectious
complications continue to be major obstacles to suc-
cess. Inherent to the HCT procedure is a profound
posttransplantation immunodeficiency, which in-
creases the risk of serious and often fatal infectious
complications. Infections can originate from exoge-
nous acquisition of pathogens or reactivation from
latency. Once infected, the patient may develop pro-
gressive and often fatal disease. Infections have also
been implicated in the development of GVHD. To
minimize exposure from food-borne pathogens,
most cancer centers recommend a restricted diet.
This diet, also referred to as the ‘‘neutropenic diet’’,
is usually recommended throughout the period of im-
munosuppression with the goal to minimize invasive
infections originating from food-derived pathogens
and, in the allogeneic transplantation setting, also to
potentially minimize GVHD. The practice to recom-
mend this diet is endorsed by evidence-based guide-
lines; however, the quality of the evidence is
generally weak - mostly category III (ie, based on ex-
pert opinion) [1,2]. In fact, although there are
theoretical arguments as well as preclinical non-
human studies and clinical results from the early
days of HCT [3] to support the concept, the strategy
as a whole has never been evaluated and proven to be
From the Vaccine and Infectious Disease and Clinical Research
Divisions, Fred Hutchinson Cancer Research Center,
Department of Medicine, University of Washington, Seattle,
Washington.
Financial disclosure: See Acknowledgments on page 1319.
Correspondence and reprint requests: Michael Boeckh, MD, Fred
Hutchinson Cancer Research Center, 1100 Fairview Avenue
North, Seattle, WA 98109 (e-mail: mboeckh@fhcrc.org).
Received July 6, 2012; accepted July 6, 2012
Ó 2012 American Society for Blood and Marrow Transplantation
1083-8791/$36.00
http://dx.doi.org/10.1016/j.bbmt.2012.07.006
1318
beneficial in a properly powered randomized trial in
patients undergoing HCT with current transplanta-
tion practices.
In this issue of Biology of Blood and Marrow Trans-
plantation, Trifilio et al. [4] report the results of a ret-
rospective analysis of outcomes in a cohort study of
363 mainly autograft recipients who did not receive
a strict neutropenic diet but rather a general hospital
diet that mandated safe food handling practices but
permitted black pepper and well-washed fresh fruits
and vegetables (raw tomatoes, seeds, and grains
were excluded and other restrictions also remained
in place). Outcomes were compared with a well-
matched historical cohort of the same size that re-
ceived a standard strict neutropenic diet. The study
showed a higher rate of microbiologically confirmed
infections after resolution of neutropenia in patients
who received the strict neutropenic diet and similar
rates of diarrhea, gastrointestinal GVHD, days of
hospitalization, and overall mortality. Although these
results are intriguing, the study has notable limita-
tions, including the primarily autologous transplan-
tation population (which limits the ability to study
the effects on GVHD), the lack of accounting for
the degree of gut toxicity of the conditioning regi-
mens, the low incidence of some infections (eg,
molds), the single-center experience, the lack of sta-
tistical power for specific infections, and, most im-
portantly, the nonrandomized nature of the study.
However, the results are provocative and should
give us pause. Recent discoveries of the impact of
the gut microbiota on the immune system [5], bacte-
rial invasion [6,7], and GVHD [8] have provided new
insight into the pathogenesis and interrelationship of
gut pathogens, translocation, and inflammation and
suggest a far more complicated relationship between
pathogens, the immune system, and clinical out-
comes than previously assumed. We now have the
tools to study these interactions of gut pathogens
in the context of diet after HCT. Not only was the
neutropenic diet not beneficial in the analysis by
Trifilio et al. [4], there was also a suggestion that
it could potentially be harmful. In addition, the re-
strictions that go with neutropenic diet are often dis-
liked by patients. Indeed, the authors report a clear
Biol Blood Marrow Transplant 18:1318-1321, 2012
preference for the less restrictive diet among patients
who experienced both forms of diet during the tran-
sition period at their center. Although this was not
a formal quality of life analysis, these preferences
are plausible and future studies should include a -
formal analysis of how diet affects quality of life after
HCT.
Where should we go from here? The article by
Trifilio et al. [4], the generally weak or lacking clinical
evidence supporting current practices of recommend-
ing strict neutropenic diets [1], and the results of re-
cent randomized and nonrandomized pilot trials in
patients with hematologic cancer [9,10] all call for
a renewed systematic look at the neutropenic diet in
HCT recipients. It would not be the first time that
an intervention strategy made good theoretical sense,
but ultimately was ineffective when put to the test.
Prospective cohort studies aimed at examining
the impact of adherence to the neutropenic diet
on the gut microbiome, the immune system,
infectious complications, the development of
GVHD, quality of life, and overall clinical outcome
are needed to understand the biologic effects of the
neutropenic diet and its effect on clinical endpoints.
The results from these studies will inform the design
of randomized trials, which should ultimately be
performed. Two randomized trials in patients
with cancer who are undergoing chemotherapy
are presently ongoing according to the www.
clinicaltrials.gov database (NCT00726934, NC-
T00947648). The autologous transplantation setting
is an obvious first target for randomized trials and
one might argue that the data now available are
sufficient to propose such study provided appropriate
stopping rules are included in the design. In the
allogeneic setting, a more cautious approach seems
prudent due to the higher risk of serious invasive
infectious and the possible adverse effects on
GVHD. Such trials are costly but are needed in
order to replace expert opinion with actual data and,
ultimately, improve outcomes and quality of life.
Clinical trial organizations such as the Blood and
Marrow Transplant Clinical Trials Network could
The Bottom Line 1319
be platforms to conduct such trials and funding
agencies should make it a priority to fund research
of the biologic effects of diet on outcomes in
transplantation recipients and patients with cancer.
ACKNOWLEDGMENTS
Financial disclosure: The author has no conflict of
interest to declare that is relevant to this topic.
Grant support: National Institutes of Health
HL093294.
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