Eosinophilic small bowel enteritis in response to folinic acid, fluorouracil, and oxaliplatin chemotherapy

Abstract

A 70-year-old woman being treated with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) therapy for relapsed colon cancer metastatic to the lung presented to the hospital with a 1-week history of abdominal pain, anorexia, a 1-day history of diarrhea, and a fever of 101°F. Neutropenia and a peripheral eosinophilia were present, and computed tomogram of the abdomen showed thickening of the wall of a segment of small bowel with luminal stenosis. Colonoscopy and double-balloon small bowel enteroscopy found a stenosis in the ileum that upon biopsy revealed small bowel eosinophilic enteritis. She improved rapidly with the administration of dexamethasone. A Medline search for reports of small bowel eosinophilic enteritis in response to any of the components of FOLFOX was unrevealing.

Small bowel eosinophilic enteritis is a rare and poorly described cause of diarrhea and abdominal pain. Here we describe a case of small bowel eosinophilic enteritis in a patient with relapsed metastatic colon cancer following chemotherapy.

CASE DESCRIPTION

A 70-year-old woman presented to the emergency department with a 1-week history of abdominal pain, anorexia, fatigue, a fever of 101°F, and severe diarrhea. She had recently completed her second round of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) therapy for metastatic colon cancer and was neutropenic. The colon cancer was diagnosed when she was 66 years old and was in complete remission after chemotherapy and operative resection until biopsy-proven colon cancer metastases to the lung were discovered at age 69. She had been diagnosed with asthma at age 67. She took nebulized budesonide and albuterol for her asthma in addition to ondansetron as needed for nausea and diphenoxylate/atropine as needed for diarrhea. She was allergic only to sulfa drugs.

On admission her temperature was 101°F; heart rate, 110 beats per minute; blood pressure, 166/69 mm Hg; and respiratory rate, 16 breaths per minute. She appeared ill with abdominal distention and tenderness to palpation with rebound tenderness. Her bowel sounds were normal. Initial white count was 1.9 K/uL with an absolute neutrophil count of 400/uL. Hemoglobin was 8.5 g/dL and platelet count, 80 K/uL. Eosinophils were 200/uL and rose to 500/uL over the next 5 days.

She was admitted with a diagnosis of neutropenic fever and given supportive care with broad-spectrum antibiotics (meropenem and vancomycin), intravenous fluid administration, and filgrastim. Her blood, urine, and stool were cultured. Her white blood cell count and fever resolved quickly, but her abdominal pain and diarrhea continued. An abdominal computed tomography (CT) scan showed a long segment of wall thickening in the small bowel without evidence of perforation or intra-abdominal fluid collection (Figure 1). Enteroscopy found normal-appearing colonic mucosa and normal-appearing terminal ileal mucosa distal to the stenosis (Figure 2). Biopsy of the stenotic portion of small bowel showed moderate to severe acute and chronic inflammatory infiltrates, mucosal edema, eosinophilic infiltrates, and epithelial apoptotic degeneration (Figure 3). There were no granulomas, evidence of vasculitis, or atypical lymphoid infiltrates.

Figure 1.

Coronal CT of the abdomen showing a stenotic segment of small bowel (arrows).

Figure 2.

The distal end of the portion of stenotic, edematous bowel and a closer view showing the erythematous, friable mucosa as viewed on endoscopy. The yellow material is corn from the patient's diet.

Figure 3.

Hematoxylin and eosin stain of a portion of small bowel mucosa showing inflammatory infiltrate consisting of mononuclear cells, lymphocytes, and eosinophils. The inset shows typical eosinophils (yellow arrows) with bilobed nuclei and eosinophilic granules.

Therapy was started with 10 mg of dexamethasone by mouth daily. She showed a rapid improvement in diarrheal symptoms and pain with radiographic resolution of the inflamed portion of bowel. Peripheral eosinophilia up to 500 cells/μL was noted during her hospital stay and had been trending down to 100 cells/μL prior to corticosteroid administration and resolved upon dexamethasone administration. She was discharged shortly thereafter.

COMMENTS

A PubMed search for small bowel eosinophilic enteritis in response to the components of FOLFOX chemotherapy found multiple reports for small bowel eosinophilic enteritis associated with a drug reaction (1–3) but none specifically for any of the components of FOLFOX. Case reports exist for idiopathic small bowel eosinophilic enteritis (3) and small bowel eosinophilic enteritis due to other conditions such as systemic lupus erythematosus (4, 5) or food allergy (3, 6). Eosinophilic enteritis may also mimic a partial small bowel obstruction (7), as in this case, or even an acute abdomen (8). The most common findings of small bowel eosinophilic enteritis are diarrhea and abdominal pain with peripheral eosinophilia on laboratory studies (3).

Diarrhea and abdominal pain are side effects of traditional chemotherapy regimens due to direct cytotoxic effects of the chemotherapeutic agents upon the lining of the gut. In this case the diarrhea presumably was due to an allergic reaction to one of the chemotherapy agents and differed from the typical diarrhea seen in chemotherapy patients in a few important ways. First, the diarrhea and abdominal pain did not improve with usual supportive care over the course of a week, prompting more invasive investigation. Second, the patient had a history of atopic disorder (asthma) and presented with a mild peripheral blood eosinophilia that resolved with treatment. Next, the CT scan of the abdomen showed small bowel transmural inflammation and edema confined to one segment of the ilium. Finally, colonoscopy and retrograde double-balloon small bowel enteroscopy showed normal colonic and terminal ileal mucosa until the scope reached the stenotic portion of the mid ileum without the pattern of ulceration seen in mucosal toxicity of chemotherapy. The histologic findings of cytotoxic chemotherapy–induced enteritis differ as well. Inflammatory cells invade the lamina propria, followed by loss of mucosal structure and denuding of the overlying epithelium, and finally a slower healing process as the mucosa reepithelializes. In contrast, this case had a significant inflammatory infiltrate including eosinophils, a lack of intraepithelial lymphocytosis, and little loss of surface epithelium.

It is not completely certain that the small bowel eosinophilic enteritis was secondary to FOLFOX therapy. The most obvious means of proving the connection would be to rechallenge the patient with leucovorin, fluorouracil, and oxaliplatin in sequence until symptoms redeveloped and, without this, coincidence cannot be completely ruled out.