Restriction of Fresh Fruits and Vegetables

STUDY PURPOSE: To evaluate the evidence to determine if a neutropenic diet decreases infection and the mortality rates of patients with cancer at risk for neutropenia

TYPE OF STUDY: Meta-analysis and systematic review

• DATABASES USED: MEDLINE, EMBASE, COCHRANE CENTRAL
• INCLUSION CRITERIA: Randomized, controlled trials and comparative observational studies. A neutropenic diet was any diet that excluded fresh fruits and vegetables, raw meats, and other types of food like soft cheese.
• EXCLUSION CRITERIA: Not specified

• TOTAL REFERENCES RETRIEVED: 537
• EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Cochrane risk of bias tool and the Newcastle Ottawa Scale for observational studies. Risk of bias found was related to lack of blinding, which is not always possible in such studies.

• FINAL NUMBER STUDIES INCLUDED = 4 
• TOTAL PATIENTS INCLUDED IN REVIEW = 918
• SAMPLE RANGE ACROSS STUDIES: 19–363 patients
• KEY SAMPLE CHARACTERISTICS: Multiple tumor types, one study of 19 pediatric patients

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Pediatrics

No differences in major infection rates were observed between those on regular diets and those on neutropenic diets. The risk of infection was higher in the neutropenic diet group (risk ratio [RR] = 1.18, p = 0.007), based upon inclusion of a large observational study. When removed, no differences existed between groups. No differences in mortality rates were observed.

The use of a neutropenic diet is not shown to reduce infection or mortality rates among patients with cancer at risk for neutropenia.

• Limited search
• Limited number of studies included

Questions have been raised regarding whether diet restrictions in neutropenic patients should be recommended or whether the focus should be on patient food choices and relaxing diet restrictions to improve nutritional intake and associated quality of life. Larger randomized controlled trials are needed to provide strong evidence in this area.

To determine the efficacy of a low bacterial diet (LBD) versus a control diet in preventing the occurrence of infection and reducing related mortality in patients with cancer receiving immunosuppressive chemotherapy.

Databases searched were the Cochrane Central Register (CENTRAL), DARE, PubMed, EMBASE, and CINAHL, as were conference proceedings from multiple professional groups.

Included in the study were patients with cancer receiving chemotherapy causing episodes of neutropenia, use of an LBD versus a control diet, with an LBD defined as any diet intended to reduce the ingestion of bacterial and fungal contaminants by exclusion of uncooked fruits and vegetables, cold cuts, undercooked eggs and meat, unsterilized water, unpasteurized milk products, and soft cheeses. The control diet was any other diet.

Children younger than 1 year were excluded from the study.
 

Six hundred nineteen total references were retrieved.

Risk of study bias was evaluated using the Cochrane Handbook for Systematic Reviews of Interventions.

• After exclusion, the final number of studies examined was three.
• The sample range across studies was 19 to 153.
• Samples included patients treated with remission induction chemotherapy for acute myeloid leukemia, high-risk myelodysplastic disease, or acute lymphoblastic leukemia.
• One study had a pediatric population.

• Patients were undergoing the active antitumor treatment phase of care.
• The study has clinical applicability for pediatrics.

Included studies had different definitions of infection rate and different outcomes measured and defined. Blinding and selection bias were problems in the study design, and only one study provided explicit data on the use of empirical antibiotics and antimycotics. Data could not be pooled for meta-analysis. In all three studies, there was no significant difference in outcomes between groups.

There is currently no strong evidence demonstrating the need or effectiveness of LBDs, and due to differing outcome measures, diets used and cointerventions for prophylaxis pooling of results was not possible. No firm conclusions can be drawn, and no recommendations for clinical practice are made.

• Small number of studies
• Various study design limitations and risks of study bias

The results suggest that no firm conclusions can be made about the usefulness of an LBD and that there is no strong evidence to show the effect. Additional well-designed research in this area would be helpful.

STUDY PURPOSE: To determine the efficacy of a low bacterial diet (LBD) versus a control diet in preventing infection and in decreasing infection-related mortality in adult and pediatric patients with cancer receiving chemotherapy that causes episodes of neutropenia

TYPE OF STUDY: Meta-analysis and systematic review

DATABASES USED: CENTRAL (2015, Issue 4), DARE (2015, Issue 4), PubMed (from 1946 to May 2015), EMBASE (from 1980 to May 2015), CINAHL (from 1981 to May 2015), reference lists of relevant articles and conference proceedings of the American Society of Hematology (ASH) (from 2000 to 2015), European Bone Marrow Transplantation (EBMT) (from 2000 to 2015), Oncology Nursing Society (ONS) (from 2000 to 2015), International Society for Paediatric Oncology (SIOP) (from 2000 to 2014), Multinational Association of Supportive Care in Cancer (MASCC) (from 2000 to 2015), ASCO (from 2000 to 2015), ICAAC (from 2000 to 2015), European Society for Clinical Nutrition and Metabolism (ESPEN) (from 2000 to 2015), American Society for Parenteral and Enteral Nutrition (ASPEN) (from 2000 to 2015), European Hematology Association (EHA) (from 2000 to 2015), National Institutes of Health Register via clinicaltrials.gov (May 2016), International Standard Randomized Controlled Trial Number (ISRCTN) Register

INCLUSION CRITERIA: Randomized, controlled trials (RCTs) comparing the use of an LBD versus a control diet in regard to infection rate

EXCLUSION CRITERIA: None stated

• FINAL NUMBER STUDIES INCLUDED = 3
• TOTAL PATIENTS INCLUDED IN REVIEW = 192 patients
• KEY SAMPLE CHARACTERISTICS: Adult and pediatric patients undergoing chemotherapy who experienced neutropenia

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Pediatrics, elder care

No evidence suggests that a LBD decreases the incidence of infection in patients undergoing chemotherapy who experience neutropenia. However, the evidence was not robust enough for the authors to conclude that no benefit existed, so the possibility of benefit/no benefit was inconclusive.

• Limited search
• Mostly low quality/high risk of bias studies

A LBD is not recommended for patients undergoing chemotherapy who experience episodes of neutropenia. Further research is indicated to conclude that no benefit exists.

The study examined adherence to neutropenic diet and whether differences existed in rates of hospital admissions for febrile episodes and positive blood cultures between patients who adhered to the neutropenic diet and those who did not.

Data collected at 6 and 12 weeks.

• The study started with 28 participants; 23 completed the study.
• Participants' age range was 33–67 years.
• Patients had a wide range of diagnoses (except acute leukemia and HIV). Patients with acute leukemia and HIV were excluded.
• Adult patients were eligible to be included if they were to receive chemotherapy associated with a high degree of neutropenia and were not being treated with colony-stimulating factors (CSFs).

Outpatient cancer center

• Rates of hospital admissions for febrile episode
• Rates of positive blood culture

Questionnaires were developed to document demographic and medical variables as well as baseline knowledge of food safety and the neutropenic diet. Adherence to restrictions of the neutropenic diet was measured via self-report based on “yes” or “no” questions and a food-use questionnaire. The 6- and 12-week evaluations measured dietary adherence as a self-reported subjective statement with “yes” or “no” responses.

Adherence was verified via eight questions targeting specific points of the food safety aspects and diet restrictions covered in the instruction. Patients’ degree of difficulty in following the diet was assessed using Likert scales with four response choices. Patients were questioned regarding hospital admissions; however, the researchers verified all admission information via chart review. The instrument designed to collect information was developed specifically for this study to assess the major aspects of the neutropenic diet for food safety and the diet instructions as given to patients. Content validity was established by review of the tool by a multidisciplinary team.

A chart review was conducted post-treatment to validate self-reported medical information and verify neutropenia (i.e., absolute neutrophil count [ANC] less than 1,000/mm³). The chart review was reviewed by a multidisciplinary team for content validity.

Fisher’s exact test was used to analyze proportions between the groups.

30% of patients were noncompliant with the neutropenic diet.

No differences were found in the rate of febrile hospital admissions (per patient report and confirmed by chart review) and positive blood cultures between those patients who adhered to the neutropenic diet and those who did not.

• Reports of whether patients adhered to a neutropenic diet were done by patients via a survey at 6- and 12-week intervals, which may have decreased the accuracy of self-reported data.
• No randomization of patients was done. The convenience sample compared patients who were compliant with a neutropenic diet with patients who were noncompliant.
• It was a small outpatient study in one setting; therefore, results cannot be generalized.
• Content validity of the tool was established at the institution. Reliability was not tested.

Of note, this study underscores the time spent for diet education, the question of appropriate content of diet education regarding food restrictions, and the difficulty adhering to diet requirements.

This study was an evaluation of whether a diet including fresh fruits and vegetables increased the risk of infection in adult patients with cancer who were receiving induction chemotherapy for either acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) in a protective environment.

Patients were randomized to either a “raw group” (n = 75) that was allowed a general diet including fresh fruits and vegetables or to a “cooked group” (n = 78) that was restricted to a low-microbial diet of all cooked food but no fresh fruit or vegetables. Patients remained in a protective environment from the initiation of induction chemotherapy until recovery of the absolute neutrophil count (ANC) over 500 mcl.  

Patients received routine antimicrobial prophylaxis with levofloxacin, valacyclovir, and an antifungal agent (itraconazole, voriconazole, or lipid amphotericin B).

Granulocyte–colony-stimulating factor was not used routinely.

Endpoints for the study were pneumonia, bacteremia, major infection, fever of unknown origin, and death.

• A total of 153 patients were in the study.
• Patients were all newly diagnosed with either AML or MDS and received induction chemotherapy in a protective environment (with a high-efficiency particulate air-filtered room).
• Median age of the patients in the raw group was 63 years.
• Median age of the patients in the cooked group was 64 years.
• The most frequent chemotherapy used was cytarabine.
• One-third of the new patients (n = 53) refused to participate in the study and were placed in a nonrandomized group. They stayed on the low-microbial diet and were given a separate consent for chart review.

A single institution

The statistical design was the Bayesian multiple outcome design of Thall and Sung. The X2 or Kruskal-Wallis test was used to compare various pretreatment characteristics.

There was no statistically significant difference in the rate of infection, pneumonia, fever of unknown origin, or overall survival between the raw and cooked groups. A significantly higher rate of bacteremia was found in the raw group; however, the authors noted that most of the organisms responsible for the baceteremia were not of enteric origin.

The median number of days with an ANC less than 500 mcl was 20 days in the cooked group and 21 days in the raw group.
The median number of days with an ANC less than 100 mcl was 15 in the cooked group and 16 in the raw group.

• Major infection rates: raw group: 35%; cooked group: 29% (p = 0.6)
• Pneumonia rates: raw group: 5%; cooked group: 15% (p = 0.06)
• Bacteremia or fungemia rates: raw group: 23%; cooked group: 9% (p = 0.03)
• Fever of unknown origin rates: raw group: 36%; cooked group: 51% (p = 0.07)
• Rate of infection or fever of unknown origin: raw group: 76%; cooked group: 87% (p = 0.09)
• No significant difference existed in the rate of enteric organisms cultured from blood in either group (p = 0.12).
• Survival rates: raw group: 61%; cooked group: 56%; non-randomized: 64%
• Survival in all three groups was as expected in older patients with newly diagnosed AML or MDS.

A diet that includes raw fruits and vegetables did not increase the risk of infection or death in patients with MDS or AML treated with remission induction chemotherapy in a protective environment when compared to a diet that restricted raw fruits and vegetables.

One strength of the study is that the sample was a population of high-risk patients who had an ANC less than 500 mcl for a median of 20 days. In comparison, patients with solid tumors treated with chemotherapy are at low risk for infection, and the patients that experience neutropenia generally have an ANC less than 500 mcl less than seven days. Because this study demonstrated an absence of efficacy of the low-microbial diet in high-risk patients; it is unlikely to be of benefit in low-risk patients with a much shorter duration of neutropenia. However, further research is warranted to confirm the findings in other populations of neutropenic patients.

• The study was done at a single institution.
• The study was conducted with patients in a protective environment, and patients were treated routinely with prophylactic antimicrobial agents. Therefore, findings are not generalizable to outpatients, patients cared for in non-protective environments, or patients not treated with prophylactic antimicrobial agents.
• The rates of infection and death were the same between study groups; however, the rate of bacteremia was significantly higher in the raw group. Although the incidence of bacteremia was higher in the raw group, the authors reported that a substantial part of the difference reflected isolation of organisms not resident in the gut; the presence of such organisms would not be expected to be influenced by cooking of fruits and vegetables. In addition, the incidence of fever of unknown origin was higher in the cooked group, suggesting that some cases of bacteremia in the cooked group were not identified.

The purpose of the study is to demonstrate a safe and feasible methodology to evaluate the infection rate in pediatric patients with cancer randomized to the neutropenic diet or the U.S. Food and Drug Administration (FDA)-approved food safety guidelines.

Pediatric patients (aged 1–21 years) undergoing myelosuppressive chemotherapy were randomized to receive a neutropenic diet or a diet based on the FDA food safety guidelines (emphasis on safe handling and cooking). Patients were enrolled during one cycle of chemotherapy.

Primary outcome was febrile neutropenia.  
Secondary outcome was adherence and diet tolerability.

• The sample size was 19.
• The two groups of participants were matched on all variables except history of febrile neutropenia.

Two hospitals in New York

Prospective, randomized, controlled pilot study

• Infection was measured with hospital admission data for febrile neutropenia.  
• Localized infection (along with an ANC less than 500 cells/mm³) also was included.  
• Dietary adherence measured by 24-hour diet recall.
• Student t test measured differences between the groups.

No statistically significant differences in infection was found between the two groups.  
Four patients on each arm developed febrile neutropenia.  
Adherence rate was 94% for neutropenic diet and 100% for FDA-approved food safety guidelines.

• Small sample size.  
• Difficulty adhering to the neutropenic diet was reported.  
• Adherence measured by 24-hour diet recall.

To evaluate the impact of dietary and social restrictions on infections among children participating in a clinical trial

Data on infectious complications were abstracted from medical records at the institutions where the patients were treated. At the same time, an international survey was conducted regarding practices in restricting social contacts, pets at home, and food diets. Analysis was conducted by linking institutional survey results with associated patient infection–related outcome data.

• N = 339   
• AGE RANGE = 0–18 years, 30% were between 1–18 years
• MALES: 50%, FEMALES: 50%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: All had acute myeloid leukemia (AML)
• OTHER KEY SAMPLE CHARACTERISTICS: 59% were deemed high risk for neutropenia

• SITE: Multi-site   
• SETTING TYPE: Multiple settings    
• LOCATION: International

• PHASE OF CARE: Multiple phases of care
• APPLICATIONS: Pediatrics

• Cohort comparison, retrospective

Infection was defined as clinical signs and symptoms associated with the institution of antibiotics, an isolated pathogen, or an identified infection site though a physical exam or imaging study.

A wide variety of restrictions existed. Over 90% were restricted from attending kindergarten or school, and more than 80% were restricted from eating raw seafood or meat. Higher restriction of social contacts was associated with an increased incidence of bactermia (incidence rate ratio [IRR] = 1.21, p = 0.003). Higher restriction of pets at home was associated with a decreased incidence of pneumonia (IRR = 0.86, p = 0.05). No relationship was observed between food restriction and infections. When adjusted for age, risk stratification, and antibiotic prophylaxis, none of the restrictions used were associated with infections. Patients who were overweight (p = 0.002) or underweight (p = 0.028) had higher risks of infection.

The restriction of social contact, pets at home, and the use of dietary restrictions were not significantly associated with the decreased incidence of infections.

• Risk of bias (no control group)
• Risk of bias (no blinding)
• Risk of bias (no random assignment)
• Key sample group differences that could influence results

The findings suggest that strict neutropenic diets; restrictions of social contact, such as school attendance; and restriction of pets at home do not reduce infections in pediatric patients with neutropenia. These policies need to be questioned and evaluated further for their effects on overall clinical and quality-of-life outcomes.

To evaluate the effects of a general hospital diet (GD) and a neutropenic diet (ND) on the incidence of microbiologically confirmed infections in hematopoietic stem cell transplantation (HSCT) recipients.

In 2006, the organization replaced its ND with a GD that retained restrictions for undercooked meat, fish, and some unpasteurized dairy products but allowed fresh fruits and vegetables. Data were obtained from electronic medical records of consecutive hospitalized HSCT recipients who received the GD or the ND during neutropenia.  All patients were receiving standard antibiotic, antifungal, and antiviral prophylaxis.  The ND excluded all fresh fruits and vegetables, black pepper, raw and undercooked meats and cheeses, cold smoked fish, raw or unpasteurized dairy products, raw miso and grain products, and brewer’s yeast. The GD permitted black pepper and well-washed fresh fruits and vegetables but excluded raw tomatoes, seeds, and grains. Other diet restrictions remained in place.  All patients were placed on these particular diets around the time of neutropenia and reverted back to a GD once neutropenia resolved.

• In total, 726 patients (58.6% male, 41.4% female) were included. 
• Mean age was 57 (range 18–78).
• All patients were HSCT recipients. 
• The majority of patients had myeloma, non-Hodgkin lymphoma, or acute myeloid leukemia.
• Sixty to seventy percent of patients developed neutropenic fever.

• Single site
• Inpatient 
• Chicago

Patients were undergoing the active antitumor treatment phase of care.

This was a retrospective descriptive study.

• Neutropenic fever (defined as a temperature of >101°F or two temperatures >100.5°F with an absolute neutrophil count of <500/mm³)
• All positive microbial cultures from onset of neutropenia until hospital discharge
   

There were significantly fewer confirmed infections in the GD group (p < 0.0272). Diarrhea (p < 0.095) and urinary tract infection (p < 0.003) were more common in the ND group. Overall mortality and hospital length of stay was similar between the groups.  The ND group had a higher rate of infection after resolution of neutropenia, with more frequent Clostridium difficile and vancomycin-resistant enterococci infections (p < 0.07).

Maintaining an ND that restriced fresh fruits and vegetables did not reduce infection and was associated with an increased risk of infection after resolution of neutropenia.

• Risk of bias (no control group, no blinding, no random assignment) 
• Retrospective descriptive study design

The study findings provide further evidence that restricting fresh fruits and vegetables from the diet of patients who are neutropenic is not beneficial.  These findings suggest that such restrictions may have a negative impact.

Adult patients with acute leukemia receiving remission-induction chemotherapy.
Patients received either antibacterial prophylaxis (AP) and low-microbial diet (LBD) or AP and normal hospital diet (NHD) to prevent infections.

Patients were randomized into two groups.

• Patients receiving antibiotic prophylaxis (AP) and low-bacterial diet (LBD)
• Patients receiving AP and normal hospital diet (NHD).  

AP included ciprofloxacin 500 mg every 12 hours and oral fluconazole 50 mg every 24 hours and was started before initiation of chemotherapy and discontinued when leukocyte counts recovered to 1,000/mm³ or higher.

• The total sample size was 20 (15 men and 5 women).
• All were patients with acute leukemia undergoing remission-induction chemotherapy.

Randomized, controlled pilot study

• Infection was measured by gastrointestinal tract colonization with yeast or gram-negative bacilli or fever higher than 38ºC.
• Stool was measured daily for bacterial colonization.  
• A Student's t test compared degree of colonization between the two groups. Differences at cycle-specific points in time were evaluated with a multivariate analysis of variance (MANOVA). Differences in temperature were measured by the Fisher’s exact test.

No statistically significant differences were found between the two groups for rates of infection.

• The small pilot study and sample size were inadequate to observe significant differences between the study groups.
• The study did not measure whether patients were adherent to their assigned diets.  
• Randomization could not create two equal groups.  
• Patients received AP.
• Results cannot be generalized because of the small sample size.