Annals of Oncology Advance Access originally published online on October 5, 2006
Annals of Oncology 2007 18(1):183-189; doi:10.1093/annonc/mdl337
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© 2006 European Society for Medical Oncology
supportive care |
Diarrhea in neutropenic patients: a prospective cohort study with emphasis on neutropenic enterocolitis
1 Department of Medicine
2 Section of Infectious Diseases, Department of Medicine
3 Department of Microbiology and Clinical Microbiology, Faculty of Medicine, Hacettepe University, Sihhiye, Ankara 06100, Turkey
4 Department of Radiology, University of Texas, Medical Branch at Galveston, Galveston, Texas
5 Department of Radiology
6 Department of Preventive Oncology, Institute of Oncology
7 Department of General Surgery, Faculty of Medicine, Hacettepe University, Sihhiye, Ankara 06100, Turkey
* Correspondence to: Dr M. D. Tanriover, Department of Medicine, Section of General Internal Medicine, Faculty of Medicine, Hacettepe University, Sihhiye, Ankara 06100, Turkey. Tel: +90 312 305 30 29; Fax: +90 312 310 41 79; E-mail: mdurusu{at}hacettepe.edu.tr
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Background: Although diarrhea is a frequent complication in neutropenic patients, its true incidence, risk factors and clinical course have not been investigated prospectively.
Patients and methods: The study was carried out at Hacettepe University Hospital for Adults and involved patients over 16 years of age. Patients with malignant diseases who were neutropenic on admission or who became neutropenic during their stay in the wards between January 2001 and February 2003 were included. They were monitored daily until discharge, exitus, or recovery from neutropenia—whichever occurred earlier—to monitor the presence of diarrhea and other infections.
Results: A total of 317 neutropenic episodes in 215 patients were followed. Diarrhea was observed in 18.6% episodes, and the incidence of NEC was 3.5%. The etiology in 27% episodes of diarrhea could not be identified. The use of anthracyclines and mitoxantrone increased the incidence of diarrhea. Prior use of penicillin derivatives plus beta-lactam inhibitors and N-imidazoline derivatives was associated with decreased incidence of diarrhea.
Conclusions: Diarrhea is a common complication in neutropenic patients. Not only specific conditions like NEC, but also nonspecific diseases like parasitosis may be the cause of diarrhea in this patient population.
Key words: cancer, diarrhea, leukemia, neutropenia, neutropenic enterocolitis
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Although diarrhea is a frequent complication of cytotoxic chemotherapy, its true incidence, risk factors and clinical course have not been investigated prospectively. It may be caused by several factors, including conventional gastrointestinal (GI) pathogens (i.e. Shigella serovars, Salmonella serovars, Yersinia enterocolitica, Campylobacter species (sp.), Entamoeba histolytica, Giardia intestinalis), suppression of normal intestinal flora and overgrowth of certain organisms (i.e. Clostridium difficile) as well as noninfectious causes such as mucositis and bowel ischemia. Therefore, diagnostic work-up of diarrhea may be exhaustive.
Neutropenic enterocolitis is a specific disease entity, usually manifesting itself with diarrhea. It is thought to be associated with chemotherapy-induced mucosal injury, followed by a superinfection usually by Gram-negative bacteria and may lead to bacteremia [1]. However, others such as fungi and viral pathogens can also be identified. Neutropenic enterocolitis may be seen in patients with solid tumors, aplastic anemia and neutropenia due to some other causes, but most cases are reported in those with acute leukemia [2]. An association between neutropenic enterocolitis and the use of certain antineoplastic drugs (5-fluorouracil, vinca alkaloids, anthracyclins, cyclophosphamide, cytarabine, taxanes) has been described [3–9].
Epidemiological data about neutropenic enterocolitis are conflicting because of the heterogeneity of the patient populations studied, diagnostic criteria used and the duration of patient follow-up in the studies. In adults, incidence rates between 0.8% and 26% have been reported [10, 11], with mortality rates up to 63% [3]. Studies in pediatric patient populations demonstrate incidence rates of 0.35%–6.1% [12, 13] and mortality rates up to 71% [12]. These results, although variable in different patient populations, underscore the importance of neutropenic enterocolitis as a clinical problem.
Although the classical triad of neutropenic enterocolitis—fever, abdominal pain and diarrhea—has been used as diagnostic criteria for many years, there is considerable overlap between neutropenic enterocolitis and other causes of diarrhea. Mucositis-related diarrhea, C. difficile-associated colitis, ischemic colitis, bacterial and viral colitides, parasitosis and surgical pathologies should be differentiated from neutropenic enterocolitis. With the advent of imaging techniques, computed tomography (CT) and ultrasonography have become the cornerstones for diagnosis. Imaging is necessary to rule out other intra-abdominal conditions, since neutropenic enterocolitis is usually a diagnosis of exclusion. However, controversies still exist about the specificity of certain findings. Bowel wall thickening has been indicated to be specific for neutropenic enterocolitis in some series [14, 15], but has also been reported in C. difficile-associated enterocolitis and bowel ischemia [16].
Current data on diarrhea in neutropenic patients and neutropenic enterocolitis are limited to case reports, retrospective series or autopsy series. Few prospective studies have either investigated neutropenic enterocolitis among neutropenic patients with acute leukemia or those undergoing bone marrow transplantation [1, 17, 18] or focused on all GI or infectious complications [10, 14, 19]. We conducted a prospective study to determine the incidence, risk factors and causes of diarrhea in neutropenic patients with cancer at Hacettepe University Hospital for adults—an 800-bed tertiary care hospital with active hematology and oncology units in Ankara, Turkey.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The study was carried out at Hacettepe University Hospital for adults and involved patients over 16 years of age. Patients with malignant diseases who were neutropenic [absolute neutrophil count (ANC) <1000 per mm3] on admission or who became neutropenic during their stay in the wards between January 2001 and February 2003 were included in the study regardless of their underlying malignancy, treatment modality (including prophylactic antibiotic use in stem-cell transplant recipients) and the cause of neutropenia. Neutropenia due to other diseases rather than malignancy (drug induced, idiopathic, etc.) was an exclusion criterion. The study was approved by the ethics committee of Hacettepe University Faculty of Medicine, and consent was obtained from all patients. All the eligible patients consented at the beginning of the study; however, two patients with diarrhea withdrew their consent at the time of imaging studies and two were discharged at their own will. Data of all patients except for those four patients were included in the final analysis.
Patients were monitored daily until discharge, exitus or recovery from neutropenia—whichever occurred earlier—to monitor the presence of diarrhea and other infections. Data regarding demographic characteristics (age, gender, underlying disease and the status of the disease) and potential risk factors for diarrhea were recorded.
The symptoms, vital signs and physical examination findings were monitored daily in patients who developed diarrhea. Abdominal imaging and surgical consultation were ordered in addition to detailed laboratory examination and microbiological studies to identify different etiologies of diarrhea. Patients with diarrhea were followed by a team consisting of an internist, an infectious disease specialist, a radiologist, a general surgeon and an infectious disease nurse.
microbiological evaluation
On the first day of diarrhea, complete blood count, blood cultures if the patient was febrile, stool microscopy for red and white blood cells, parasitic cysts and ova examination and stool cultures for specific pathogens (Salmonella, Shigella serovars, Campylobacter sp, EHEC O157:H7, C. difficile, Clostridium perfringens) and other possible causes including Aeromonas, Plesiomonas, Pseudomonas, Klebsiella, Edwardsiella, Candida sp., Staphylococcus aureus were carried out. Enzyme immunoassay for C. difficile Toxin A/B tests was requested. All microbiological tests were repeated on the following day.
Stool samples were inoculated onto 5% sheep blood-added Blood Agar Base, Eosin Methylene Blue, Salmonella–Shigella, Sorbitol MacConkey agars (Oxoid Limited, Hampshire, UK) and incubated at 37°C for 18–24 h, and streaked into Butzler medium (Oxoid) with antibiotic (SR 0085, Oxoid) and growth supplements (SR 0084, Oxoid) for Campylobacter jejuni and incubated at 42°C in the candle jar for 48 h. Colonies were identified by conventional biochemical tests and if necessary by API20E (BioMerieux, Marcy l'Etoile, France) for Enterobacteriaceae. Monovalent and polyvalent antisera (Difco, Detroit, MI) were available for serotyping Salmonella, Shigella and EHEC O157:H7 by slide-agglutination test. For anaerobic pathogens C. difficile and C. perfringens, stool samples were also cultured on cycloserine-cefoxitin-fructose AGAR (CCFA, Oxoid) prepared in house and Perfringens agar (Oxoid). Supplements of cycloserin and cefoxitin (SR 0096E, Oxoid) for CCFA; kanamycin, polymyxin B (SR 0093E, Oxoid) and egg yolk enrichment 50% (Difco) for Perfringens agar were used. The inoculated plates were incubated in an anaerobic jar for 48 h at 37°C. C. difficile indicated by typical colony morphology, distinctive odor and Gram stain were confirmed by latex agglutination (Fresenius Diagnostik, Bad Hamburg, Germany) test. C. perfringens strains were identified by typical black colonies, Gram stain and BBL CRYSTAL Anaerobe ID panel (Becton Dickinson Franklin Lakes, NJ, USA).
Quantitative cultures were carried out for Candida sp.; 0.1 ml of the 1/10 diluted stool sample was inoculated into Sabouraud Dextrose agar (Oxoid) and incubated at room temperature for 24–48 h. Candida growth on culture was considered significant if the culture yielded 
105 colonies [20].
For the immunological detection of C. difficile Toxin A and B, RIDASCREEN C. difficile Toxin A/B (R-Biopharm AG, Darmstadt, Germany) and ProSpect II C. difficile Toxin A (Alexon-Trend, Ramsey, MN) were used. Enzyme-linked immunosorbent assay was carried out according to the manufacturer's instructions.
radiological studies
Abdominal CT scans were carried out within 3 days of the onset of diarrhea. Intravenous contrast was withheld if the patient's creatinine was >2.0 mg/dl. Water-soluble iodinated contrast was used as oral contrast in all of these patients. The presence and extent of the bowel wall thickening, mesenteric fat stranding, presence of fluid collection, free air and dilatation of the bowel segments were noted. CT evidence for neutropenic enterocolitis was accepted as the presence of concentric thickening of >3 mm of the bowel wall.
Abdominal ultrasonographic studies were carried out by a radiologist specialized in ultrasonography. Abdominal visceral organs were evaluated for the presence of bowel wall thickening, free fluid and dilatation of the bowel loops. Patients who had bowel wall thickening of >3 mm and thick-walled small bowel loops in the pelvis were accepted to have the ultrasonographic criteria for neutropenic enterocolitis.
definitions
A neutropenic episode was defined as starting from the first day of neutropenia (ANC <1000 per mm3) until two successive ANCs >1000 per mm3. Diarrhea was defined as the passage of soft or liquid stool t.i.d. or more, or an increase of at least twice the number of baseline bowel movements if the patient had the habit of passing soft stool o.d. or more, or the passage of unformed stool at least b.i.d. associated with at least one GI symptom such as abdominal cramps in the absence of laxative use.
Neutropenic enterocolitis was diagnosed if the patient fulfilled the following criteria: fever (axillary temperature >38.0°C); diarrhea with or without other abdominal symptoms (abdominal pain, tenderness, rebound tenderness, etc.) and bowel wall thickening on imaging.
C. difficile-associated diarrhea was diagnosed if diarrhea began at least 72 h after admission and stool specimens were positive for C. difficile Toxin A, or demonstrated C. difficile growth in culture [21].
Mucositis was defined as oral pain, erythema and/or ulceration, and was classified according to World Health Organization mucositis scale [22].
All statistical analyses were carried out using software (SPSS, version 10.0, SPSS; Chicago, IL). Parametric data were displayed in frequency tables; for nonparametric data, median values and interquartile range were calculated. Mann–Whitney U test was used to compare nonparametric variables. Differences between the qualitative variables in two groups were analyzed by chi-square test with continuity correction or Fisher's exact test where appropriate. A P value <0.05 was considered to be significant. Variables that were found to be significant in univariate analysis were included in a binary logistic regression model.
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results |
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A total of 317 neutropenic episodes in 215 patients were followed. The underlying disease was a hematological malignancy in most (83.7%) of the cases (Table 1). Diarrhea was observed in 59 (18.6%) episodes. Antimetabolites (55.8%) and alkylating agents (40.1%) were the most common cytotoxic chemotherapeutic agents administered. Fourteen patients (4.4%) did not receive any chemotherapeutic agent, but were neutropenic at the time of enrollment due to their underlying malignancies, among whom only one developed diarrhea.
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All the patients who developed diarrhea received antimicrobial therapy before the onset of diarrhea (Table 2). The longest time duration from the first dose of antimicrobial therapy to the onset of diarrhea was 35 days. In the remaining 258 neutropenic episodes without diarrhea, 17 did not receive any antimicrobials. Prophylactic antimicrobial use was reported in 35 of the 54 episodes undergoing autologous stem-cell transplantation and in all of the three episodes undergoing allogeneic stem-cell transplantation.
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Acute leukemias (acute myeloblastic, acute lymphoblastic and biphenotypic leukemias) were more common in patients with neutropenic enterocolitis (P = 0.011) (Table 1). Anthracyclines and mitoxantrone were more frequently used in patients with diarrhea. Administration of anthracyclines was also more frequent in patients who developed neutropenic enterocolitis when compared with those who had no neutropenic enterocolitis, but diarrhea only (Table 2). The median duration of neutropenia was longer in episodes with diarrhea and with neutropenic enterocolitis compared with the group without diarrhea (P < 0.001) (Table 1). There was no statistically significant difference among mortality rates in the three patient subgroups.
Abdominal pain was present in 72.7% of patients with neutropenic enterocolitis (Table 3). However, only 22.2% of the patients with neutropenic enterocolitis had pain localized to the right lower quadrant. There were no significant differences in vital signs and laboratory measurements between episodes with or without neutropenic enterocolitis.
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Ascaris lumbricoides infestation and C. difficile Toxin A were detected in the stool samples of one patient diagnosed with neutropenic enterocolitis, and there was concomitant Klebsiella and Candida overgrowth in the stool culture of another one. Microbiological evaluation of the stool cultures is summarized in Table 4. No surgical pathology was identified in any of the diarrheal episodes.
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Neither ultrasonography nor CT could be carried out in 10 episodes. In 20 episodes, both ultrasonography and CT were carried out, 12 revealed similar findings on both imaging studies (Table 3). CT findings were consistent with neutropenic enterocolitis in five episodes with negative ultrasound. There were five cases of bowel wall thickening detected by ultrasonography that did not fulfill the criteria for neutropenic enterocolitis. One was diagnosed with paralytic ileus, another had biliary tract disease and in the remaining three, CT was negative.
A multivariate analysis was carried out to evaluate the risk factors for diarrhea. Those variables, which turned out to be significant in univariate analysis, were introduced separately into a multivariate model. Aminoglycosides and cephalosporins were combined in the multivariate model because of their simultaneous use in the empirical treatment of febrile neutropenia in our hospital. Because duration of neutropenia was a surrogate marker of disease severity indirectly related to other factors, such as the intensity of the chemotherapeutic regimen, delayed recovery of the bone marrow and the resistance of the underlying disease, it was not introduced in the multivariate model. The use of anthracyclines [risk ratio 3.7, 95% confidence interval (CI) 1.6–8.5, P value = 0.002] and mitoxantrone (risk ratio 3.2, 95% CI 1.6–6.3, P value = 0.001) was associated with an increased occurence of diarrhea (Table 5). Prior use of penicillin derivatives plus ß-lactam inhibitors (piperacillin/tazobactam, ampicillin/sulbactam, amoxicillin/clavulanate) and N-imidazoline derivatives (metronidazole, ornidazole) was associated with decreased incidence of diarrhea (risk ratio 2.6, 95% CI 1.2–5.7, P value = 0.015 and risk ratio 2.9, 95% CI 1.0–8.1, P value = 0.049, respectively).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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To our knowledge, this is the largest prospective study to date, which evaluates the incidence, etiology and risk factors of diarrhea in neutropenic patients. The data in the literature mainly rely on case reports, case series and retrospective studies as excellently reviewed in a recent systemic analysis by Gorschlüter et al. [23].
We observed diarrhea in 18.6% of 317 neutropenic episodes, and the incidence of neutropenic enterocolitis was 3.5%. A retrospective study from our institution reported an incidence of 6.5% in patients with acute leukemia [24]. The reported incidences of neutropenic enterocolitis in the literature vary considerably from 0.8% to 26% on the basis of the patient population studied, definitions and diagnostic criteria [10, 11]. Most of the earlier reports have focused on typhlitis, which may be regarded as a localized form of neutropenic enterocolitis limited to caecal inflammation [25]. Pooled analysis of 21 studies involving 5058 patients/neutropenic episodes revealed a 5.3% incidence for neutropenic enterocolitis in adults [23].
Abdominal imaging studies in neutropenic patients are sometimes challenging; CT cannot always be carried out due to the critical condition of the illness of these patients and confounding factors such as renal failure. Ultrasonography may be a valuable option; however, it is not as accurate as CT in demonstrating the intra-abdominal pathologies. In a study of 1720 patients who received intensive chemotherapy for high-risk hematological malignancies, intestinal wall thickening was detected in 50% of patients with neutropenic enterocolitis; however, this study was limited because of its retrospective manner, lack of comparison with CT and, finally, diagnosis of neutropenic enterocolitis on clinical grounds only [15]. In our study, we demonstrated a lower yield with ultrasonography, indicating the use of CT as the imaging modality in neutropenic patients with diarrhea.
Gorschlüter et al. [23] have suggested that the presence of fever, abdominal pain and bowel wall thickening of >4 mm in a neutropenic patient should be accepted as diagnostic criteria for neutropenic enterocolitis. In our series, 27.3% of the patients with documented neutropenic enterocolitis did not have abdominal pain at all. Therefore, we believe that abdominal pain should not be an obligatory criterion for neutropenic enterocolitis—rather, a component of a spectrum of abdominal signs and symptoms observed in neutropenic enterocolitis.
C. difficile enterocolitis is one of the most frequent nosocomial etiology of diarrhea in neutropenic patients. In a retrospective study including 875 courses of chemotherapy in leukemic patients, C. difficile-associated diarrhea occurred in 7.0% of all cycles [26]. Differential diagnosis of C. difficile-associated diarrhea and neutropenic enterocolitis may sometimes be challenging, or they can co-exist. In a retrospective series of 76 neutropenic patients with radiological abnormalities on CT, Kirkpatrick and Greenberg [16] reported the greatest mean wall thickness in patients with C. difficile colitis (12 mm in C. difficile colitis versus 7 mm in neutropenic enterocolitis). We had one patient diagnosed with neutropenic enterocolitis whose stool sample was positive for C. difficile Toxin A. Whether this represents a coexistence of the two disease entities is not clear because of nonspecificity of diagnostic criteria for neutropenic enterocolitis.
Parasitic infestations should also be considered in the diagnostic work-up of diarrhea in certain settings; they were detected in four diarrheal episodes among our patients. There are no data on the causative role of members of the Enterobacteriaceae or Candida sp. in the pathogenesis of diarrhea in neutropenic patients with cancer. This may reflect heavy colonization, but several reports have emphasized their potential role in antibiotic-associated diarrhea [27]. We observed heavy growth of Klebsiella sp., C. perfringens and Candida sp. in several patients with diarrhea; however, they were not regarded as causative pathogens and no change in antimicrobial therapy was made. The etiology in 16 of 59 episodes of diarrhea (27%) could not be identified.
In our study, administration of mitoxantrone and anthracyclines was associated with an increased occurence of diarrhea. Mitoxantrone and anthracyclines, like all other cytotoxic drugs, have the potential to cause diarrhea and neutropenic enterocolitis [28, 29]. Diarrhea induced by cytotoxic compounds is most likely due to mucositis, but may also be due to the alteration of the bacterial flora of the gut [30].
Interestingly, we found that the use of penicillin derivatives plus ß-lactam inhibitors as well as N-imidazoline derivatives was associated with a decreased incidence of diarrhea in the multivariate analysis. Metronidazole and ornidazole may prevent overgrowth of certain pathogens such as C. difficile, but we could not explain the protective effect of the former antibiotic group, which are well known for their potential to cause antibiotic-associated diarrhea.
This study has several limitations. First, the tests for viral etiologies in the stool specimens were not available. Therefore, such diseases as cytomegalovirus enterocolitis, which may resemble neutropenic enterocolitis, may well be overlooked. In addition, we do not have data about the degree of bowel wall thickening, which seems to be a valuable index in determining the prognosis of neutropenic enterocolitis [15]. Finally, this study was designed to determine the incidence, risk factors and causes of diarrhea in neutropenic patients. Diarrhea is not uniformly present in patients with neutropenic enterocolitis [3, 24]. We might, thus, have underestimated the true incidence of neutropenic enterocolitis, especially of the more subtle forms.
In conclusion, diarrhea is a common complication in neutropenic patients. Not only specific conditions like neutropenic enterocolitis but also nonspecific diseases like parasitosis may be the cause of diarrhea in this patient population. In addition, diagnosing one etiology should not be a cause to give up further investigation. In spite of exhaustive work-up, differential diagnosis and identification of the underlying etiology of diarrhea sometimes may not be possible.
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This study was supported by a grant (No. 00-01-101-004) from Hacettepe University Medical Research Foundation. We are indebted to Research Nurse Nimet Simsek and Yildiz Yaykir for their assistance during data and specimen collection.
Received for publication March 27, 2006. Revision received April 26, 2006. Revision received June 29, 2006. Accepted for publication August 14, 2006.
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