Neutropenic enterocolitis

Marta L. Davila

Purpose of review This review will cover the recent literature pertaining to the pathogenesis, diagnosis, and management of patients with neutropenic enterocolitis. Recent ndings Neutropenic enterocolitis, also referred to as typhlitis, is a life-threatening gastrointestinal complication of chemotherapy, most often associated with leukemia or lymphoma. Recently, a larger number of reports have been published of individuals presenting with this syndrome after being treated with newer chemotherapeutic agents for solid tumors such as non-small cell lung, ovarian, and peritoneal cancer, as well as following autologous stem cell transplantation. Recent studies have also better characterized computed tomographic and ultrasonographic features of this entity that can help differentiate neutropenic enterocolitis from other gastrointestinal complications. A newly published systematic analysis of the literature, which included 145 articles, denes appropriate diagnostic criteria and treatment recommendations. Summary Neutropenic enterocolitis is a serious, potentially lethal complication of anticancer therapy. The studies discussed in this review will help the practitioner make an appropriate, early diagnosis and implement a therapeutic program that would improve the outcome of these patients. Keywords acute leukemia, gastrointestinal complications during chemotherapy, necrotizing enterocolitis, neutropenic enterocolitis, typhlitis
Curr Opin Gastroenterol 22:4447. 2006 Lippincott Williams & Wilkins. Department of Gastrointestinal Medicine and Nutrition, University of Texas MD Anderson Cancer Center, Houston, Texas, USA Correspondence to Marta L. Davila, MD, Associate Professor, Department of Gastrointestinal Medicine and Nutrition, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard Unit 436, Houston, TX 77030-4009, USA Tel: +1 713 563 8906; fax: +1 713 563 4398; e-mail: mdavila@mdanderson.org Current Opinion in Gastroenterology 2006, 22:4447 Abbreviations BWT CT bowel-wall thickening computed tomography

Introduction
Neutropenic enterocolitis or typhlitis (from the Greek word typhlon) is a clinical syndrome in neutropenic patients characterized by fever and abdominal pain. This entity has received various names including neutropenic colitis, necrotizing enterocolitis, ileocecal syndrome and cecitis [1,2]. Neutropenic enterocolitis was originally described in children following induction chemotherapy for acute leukemia [3]. It has subsequently been reported in adults with acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, aplastic anemia, myelodysplastic syndromes, granulocytopenias from other causes, AIDS, and following immunosuppressive therapy for solid malignancies and transplants [4,5]. This review will discuss recent reports on newer chemotherapeutic agents implicated in the development of this syndrome, as well as on imaging criteria that can be useful in making a diagnosis. The review will also cover comprehensive clinical diagnostic criteria and management recommendations based on a recent systematic analysis of the literature.

Pathogenesis
The pathogenesis of this syndrome is poorly understood. The disease appears to be the result of a combination of factors including mucosal injury by cytotoxic drugs, neutropenia, and impaired host defense to intestinal organisms [5]. It has been postulated that the intact colonic mucosa cannot be maintained due to either leukemic inltration or direct cytotoxic effect of chemotherapy. Bacterial invasion of the bowel wall ensues, facilitated by a decreased defense due to neutropenia. This is followed by production of bacterial endotoxins, with subsequent bacteremia, necrosis, and hemorrhage. The cecum is almost always affected but the disease can often extend into the terminal ileum, other parts of the small bowel, and right and left colon [4]. The predilection for the cecum may be related to its distensibility and limited blood supply. Pathology may reveal edema of the mucosa or entire intestinal wall, mucosal ulcerations, focal hemorrhage, and mucosal or transmural necrosis [4]. Rarely are leukemic or acute inammatory inltrates identied [5]. Various organisms, alone or in combination, have been identied in surgical specimens and peritoneal uid, including Gram-negative rods, Gram-positive cocci, enterococci, Clostridium septicum, Candida, and cytomegalovirus [3,4]. Clostridium difcile toxin is occasionally detected in the stools [3]. Bacteremia and fungemia are frequently reported [6].

2006 Lippincott Williams & Wilkins 0267-1379

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Initial reports commented on the association of this entity with particular chemotherapeutic agents used in the treatment of leukemias and lymphomas, especially cytosine arabinoside (Ara-C), vincristine, doxorubicin, methotrexate, cyclophosphamide, etoposide (VP-16), daunomycin, and prednisone [3,4,7]. More recently, other agents have been implicated in the treatment of ovarian, peritoneal, non-small-cell lung, squamous cell carcinoma of the lung, colorectal, and breast cancer, including vinorelbine, docetaxel, paclitaxel, carboplatin, cisplatin, gemcitabine, and 5-uorouracil [815]. There are also an increased number of reports of neutropenic enterocolitis after high-dose chemotherapy and autologous stem cell transplantation for solid tumors [16].

Figure 1 Computed tomography scan of a patient with neutropenic enterocolitis showing thickening of the cecum, ascending colon, and sigmoid colon

Epidemiology
The true incidence of neutropenic enterocolitis is unknown. In the only published systematic review on the subject, which involved 145 published articles, the authors report a 5.3% pooled incidence rate (266/5058; 95% condence interval, 4.75.9%) in adult patients hospitalized for the treatment of hematological malignancies, high-dose chemotherapy in solid tumors, or aplastic anemia [17]. In the subgroup of patients with acute leukemias treated with chemotherapy (except for those undergoing transplantation), a similar pooled incidence rate was reported at 5.6% (84/1489; 95% condence interval, 4.66.9%). The mortality rate varies from 50 to 100% [1,7], with most deaths due to bowel perforation and sepsis. More recently, early recognition and progress in management probably have reduced mortality; however, no large series have ever been published on the subject.

noses. Abnormal ndings on CT imaging and ultrasonography include bowel-wall thickening (BWT), a uidlled, dilated cecum, a right lower-quadrant inammatory mass, and pericecal uid or inammatory changes in the pericecal soft tissues [3] (Fig. 1). Plain lms of the abdomen may be non-specic but, occasionally, a distended cecum with dilated adjacent small-bowel loops, thumbprinting, or localized pneumatosis intestinalis is seen [7]. Barium enema and colonoscopy can be hazardous and may be contraindicated as they can precipitate perforation. In the only prospective study using ultrasonography to evaluate leukemic patients after chemotherapy, signicant BWT (> 4 mm) was seen only in those patients who fullled symptom criteria for neutropenic enterocolitis, and not in those patients with mucositis alone, those with documented bacterial infectious colitis, or in those who remained asymptomatic [18]. Recently, BWT has been shown to be a valuable prognostic factor that may help determine patient outcome. In a retrospective study by Cartoni et al. [19], ultrasonography was used to evaluate BWT in neutropenic patients with fever, diarrhea, and abdominal pain. A thickness of > 5 mm was considered abnormal and diagnostic of neutropenic enterocolitis. The study revealed that the mean duration of symptoms was signicantly longer among patients with sonographically detected BWT (7.9 days) than among patients without mural thickening (3.8 days), and the related mortality rate was higher (29.5 versus 0%). Furthermore, the degree of BWT signicantly correlated with the outcome of patients with neutropenic enterocolitis. In particular, 60% of patients with BWT > 10 mm died from this

Clinical presentation
Neutropenic enterocolitis should be suspected in any neutropenic patient (absolute neutrophil count < 500/ ml) presenting with fever and abdominal pain, particularly in the right lower quadrant, with or without rebound tenderness. Other presenting symptoms include abdominal distension, nausea, vomiting, and watery or bloody diarrhea. Peritoneal signs and shock can be present with bowel perforation. Symptoms often occur 1014 days after initiation of cytotoxic chemotherapy [7]. Given that the clinical ndings may be subtle and non-specic, one must consider other entities in the differential diagnosis, including pseudomembranous colitis, colonic pseudoobstruction, acute appendicitis, ischemic colitis, inammatory bowel disease, and infectious colitis.

Diagnosis
Imaging studies can be useful in supporting a diagnosis of neutropenic enterocolitis. Computed tomography (CT) may be the preferred diagnostic modality over ultrasound and plain abdominal lms [3], particularly because it helps differentiate this entity from other potential diag-

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complication, compared with only 4.2% of those with mural thickness 10 mm. Despite the encouraging results of ultrasonography in the recognition of this disease, there have been other studies reporting signicant overlap in BWT measurements among neutropenic patients with a variety of gastrointestinal disorders. In a retrospective study comparing CT ndings in patients with neutropenic enterocolitis, C. difcile colitis, graft-versus-host disease, cytomegalovirus colitis, and ischemic colitis, BWT was signicantly more prominent in patients with C. difcile colitis compared to the other groups [20]. Pneumatosis intestinalis was a much more specic nding, seen only in those with neutropenic enterocolitis and ischemia. The location of the abnormalities was also helpful, with combined involvement of the small and large bowel pointing more towards the diagnosis of neutropenic enterocolitis. In summary, the value of BWT in the diagnosis of neutropenic enterocolitis remains a matter of debate. A systematic study validating the sensitivity and specicity of radiologically detected BWT is lacking. Nevertheless, some authors argue that the diagnostic accuracy for neutropenic enterocolitis can be increased when radiologic ndings are added to symptoms and physical signs. It is for this reason that some have recommended the following criteria for the diagnosis of neutropenic enterocolitis: fever, abdominal pain, and demonstration of BWT of more than 4 mm in any segment by ultrasound or CT scanning [17]. These criteria await validation by well-designed, prospective studies.

cytopenias and coagulopathy, for those with free intraabdominal perforation or clinical deterioration during medical therapy, and to differentiate from other acute abdominal diseases for which surgery is indicated [7,22]. The standard surgical approach is a two-stage right hemicolectomy [7]. Some authors have reported signicant complications when primary bowel anastomoses have been attempted in the face of ongoing leucopenia [23, 24]. A surgeon must exert caution when dealing with edematous bowel without apparent gangrene, since mucosal necrosis may be present below very unimpressive serosal inammation. Incomplete removal of all necrotic tissue may lead to death [5]. Patients who develop neutropenic enterocolitis during chemotherapy are at risk from developing this complication during subsequent treatment. Patients should be allowed to heal completely and recover from enterocolitis before chemotherapy is again administered.

Conclusion
In summary, recent studies have reported a wider spectrum of chemotherapeutic agents associated with the development of neutropenic enterocolitis. Newer diagnostic criteria are being recommended to include three basic elements: fever, abdominal pain, and BWT of > 4 mm by ultrasound or CT. Most patients can be managed conservatively with bowel rest, total parenteral nutrition, intravenous antibiotics, and recombinant granulocyte colony-stimulating factor. Surgery should be reserved for those with signicant clinical deterioration, massive bleeding, and perforation. Better-designed, prospective, multicenter studies are needed to evaluate the suggested diagnostic criteria and treatment.

Management
There have been no prospective randomized trials or high-quality retrospective studies on the treatment of neutropenic enterocolitis. Therefore, a uniform management strategy cannot be recommended. The best strategy should be an individualized approach to each case given the wide spectrum of presentation. In those patients presenting without signicant complications such as peritonitis, perforation, or bleeding, non-surgical management may be a reasonable initial approach. Conservative management consists of bowel rest, nasogastric suction, total parenteral nutrition, and broad-spectrum antibiotic therapy [3,17,21]. Antibiotic coverage for C. difcile infection should be added if pseudomembranous colitis has not been excluded. Cytopenias and coagulopathy should be corrected. Recombinant granulocyte colony-stimulating factor has been used to hasten recovery, since normalization of the leukocyte count may allow containment and healing of bowel lesions [7,15,17]. Surgery has been recommended for patients with gastrointestinal bleeding that persists despite correction of

References and recommended reading

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