AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Neutropenic enterocolitis is an acute life-threatening condition characterized by transmural inflammation of the small and large bowel in patients who are severely myelosuppressed and immunosuppressed.

The clinical presentation can be dramatic, and the outcome may be devastating. Mortality rates are high, and treatment is controversial, with options varying from conservative medical management to surgical intervention. Early recognition of the condition is paramount to a potentially good outcome.

Over the past 3 decades, this condition has increasingly been reported in adults with a variety of myeloproliferative disorders and solid malignant tumors and in adults who have had solid organ and bone marrow transplantation. Some cases in adults are due to the increasing use of myelotoxic chemotherapeutic regimens.

Pathophysiology

Although the exact etiology and progression are unknown, profound neutropenia appears to be the common denominator. Many factors have been described that may potentially play a role in the pathogenesis and include the following:

• Mucosal injury is caused by cytotoxic drugs. However, mucosal injury can occur in the absence of cytotoxic drug therapy, and neutropenia itself can cause mucosal ulcerations.
• Cecal distention, whether primary or secondary to vinca alkaloids, may compromise the blood supply, leading to further mucosal damage.
• The use of antibiotics and steroids may contribute to an altered enteric bacterial flora and overgrowth of fungi.
• Bacterial invasion of the impaired bowel wall may result in transmural inflammation, leading to perforation and peritonitis. Bacteremia, often recurrent, is a frequent complication.

The pathologic process appears to involve the cecum alone, or it may extend to the ileum, ascending colon, or both. It is felt that cecal distensibility and limited blood supply may predispose the cecum to injury more often than other areas.

Frequency

United States

The exact incidence and prevalence rates are unknown because many patients survive and are never diagnosed. An autopsy study in children reported a prevalence rate of 24%, while a cohort study in children treated for acute myelogenous leukemia reported a frequency rate of 33%. Data regarding neutropenic enterocolitis in adults are sparse. In one systematic review, a 5.3% pooled incidence rate has been reported in adults.

International

An even greater paucity of information regarding the international incidence and prevalence rates of neutropenic enterocolitis exists in the published literature. A recent study from India performed by Jain et al (2000) has reported a frequency rate of 6.1% in 180 children undergoing chemotherapy for acute lymphocytic leukemia. A retrospective study from Turkey performed by Buyukasik et al (1997) reported an incidence rate of 6.5% for neutropenic enterocolitis in acute myeloid leukemia and 4.6% for neutropenic enterocolitis in acute lymphoblastic leukemia in adults.

Mortality/Morbidity

• Mortality rates of 5-100% have been reported during conservative management, with an average of about 40-50%.
• In a collective review of 178 published cases, the mortality rate was reported at 48% for conservative management and 21% for surgical management; however, these numbers cannot be compared with each other because of selection bias.

Race

No predilection for any specific race is reported in the literature.

Sex

No sex predilection is reported in the literature.

Age

• No known frequency differences in age groups exist based on the published literature.
• Although neutropenic enterocolitis initially was described in children, it is increasingly reported in adults.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Most patients who are affected with neutropenic enterocolitis are receiving antineoplastic drugs and are profoundly neutropenic (ie, <1000 cells/mm³).

• Symptoms usually occur within 10-14 days after initiation of cytotoxic chemotherapy.
• The typical presentation mimics acute appendicitis.
• Symptoms include the following:
• • Right lower quadrant abdominal pain - May be cramping and intermittent or a continuous dull ache
  • Fever
  • Watery or bloody diarrhea - Occurs in about 25-45% of patients
  • Nausea
  • Vomiting
  • Abdominal distention
• Oral and pharyngeal mucositis may manifest prior to the onset of colonic symptoms.
• The time course and severity of the clinical presentation is variable.

Physical

Physical findings vary depending on the severity of the disease and the presence or absence of complications.

• Abdominal distention, absence of bowel sounds, and a tympanitic abdomen may suggest an ileus.
• The abdomen may be markedly tender, especially in the right lower quadrant.
• The cecum may be palpated as a boggy mass.
• Rebound tenderness may suggest colonic perforation.
• Sepsis may elicit shock.

Causes

Although cytotoxic chemotherapeutic agents account for most cases, other conditions that may predispose some patients to develop this condition exist.

• The cytotoxic chemotherapeutic agents include cytosine arabinoside, vinca alkaloids, and doxorubicin.
• Other drugs that have been implicated anecdotally include paclitaxel, docetaxel, procainamide, sulfasalazine, 5-fluorouracil, vinorelbine, carboplatin, cisplatin, gemcitabine, and leucovorin.
• Other predisposing conditions include the following:
• • Myelodysplastic syndromes, multiple myeloma, and aplastic anemia
  • Solid organ and bone marrow transplantation
  • AIDS
  • Cyclic neutropenia
  • Solid malignant tumors
  • Lymphomas

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Ischemic colitis
Intussusception
Small bowel obstruction
Leukemic or lymphomatous infiltration of the bowel wall

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Complete blood count is used to confirm neutropenia.
• Stool studies are obtained for the following:
• • Clostridium difficile toxin to rule out pseudomembranous colitis
  • Culture for enteric pathogens to rule out infectious causes of enterocolitis
• Blood cultures are obtained for aerobic/anaerobic bacteria and fungus to rule out bacterial and fungal sepsis.

Imaging Studies

• Plain abdominal radiographs rarely help in the diagnosis of neutropenic enterocolitis. Radiographic findings usually are nonspecific and may even be normal. Nonspecific findings may include the following:
• • Right-sided colonic and small bowel dilatation
  • Thumbprinting of the right colon
  • Paucity of air in the right colon due to a fluid-filled colon
  • Intramural air or pneumatosis
  • Soft tissue mass displacing the small bowel
• Barium enema usually is contraindicated, especially if a potential for perforation exists. Water-soluble contrast may demonstrate rigidity and thickening of the cecum.
• Abdominal ultrasonography
• • Abdominal ultrasound is one of the most important diagnostic studies and is preferable to contrast enemas. This may be useful as a follow-up tool to assess the gradual decrease in bowel wall thickening.
  • Findings include thickening of the bowel wall that produces a target or halo sign. However, this is a nonspecific finding and may be observed in other conditions listed under the differential diagnosis (see Differentials).
  • Recently, bowel wall thickening (BWT) has been suggested as a significant prognostic factor as to the patient outcome. A retrospective study using ultrasonography showed that a BWT of greater than 5 mm was associated with a higher mortality (29% vs 0%). If one takes a cutoff of greater than 10 mm, the mortality was 60% vs 4.2%.
• CT scan of the abdomen is the diagnostic procedure of choice because it has a lower false-negative rate (15%) compared to ultrasound (23%) or plain abdominal radiographs (48%). Findings include the following:
• • Symmetrical thickening of the cecum
  • Fluid-filled cecum
  • Pericecal inflammation
  • Free air if an underlying perforation exists

Procedures

• Endoscopic procedures include colonoscopy or flexible sigmoidoscopy.
• • These procedures are relatively contraindicated due to an increased risk of complications, especially in the setting of underlying neutropenia and thrombocytopenia.
  • Usually, these procedures are unnecessary, except in rare circumstances in which a gentle sigmoidoscopy may aid in the diagnosis of pseudomembranous colitis.

Histologic Findings

Gross and microscopic findings include diffuse bowel wall thickening with mucosal and intramural edema and necrosis, mucosal ulcerations, and intramural or intraluminal hemorrhage. The bowel wall specimens obtained during colectomy or at autopsy demonstrate an abundance of bacteria, a striking lack of lymphoid inflammatory cells, and a virtual absence of neutrophils.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

No published randomized control trials comparing conservative medical therapy with surgical intervention exist; however, advocates for both types of therapy exist. The outcome appears to reflect the state of the underlying disease and other comorbidities at the time of clinical presentation rather than the treatment modality. Therefore, a uniform management strategy cannot be recommended. Individualize the approach to each patient. Early recognition of this condition in a patient who is neutropenic is paramount to a good outcome.

• Conservative management includes the following:
• • Bowel rest and nasogastric suction
  • Close monitoring of patients using serial abdominal examinations in an intensive care setting
  • Intravenous fluids, blood, and platelet transfusions as necessary
  • Parenteral broad-spectrum antibiotics: Antibiotics should include agents covering enteric gram-negative and anaerobic organisms, including Clostridium species. Metronidazole also may be considered if pseudomembranous colitis cannot immediately be excluded.
  • Cultures: Obtain blood cultures for fungus and consider antifungal agents if patients do not respond to antibiotics.
  • Avoidance of certain medications: Anticholinergic agents, antidiarrheal drugs, and narcotics may worsen the condition or further confuse the clinical picture.

Surgical Care

• Immediate surgery has been proposed by Shamberger et al (1986) in patients with the following indications:
• • Free intra-abdominal perforation
  • Clinical deterioration during conservative medical therapy
  • Differentiation from other acute abdominal conditions for which surgery is indicated
  • Unrelenting intra-abdominal sepsis or abscess formation
  • Continued hemorrhage with a platelet count and coagulation parameters within the reference range
• Tailor the surgical procedure to the operative findings.
• Choice of surgical procedures includes the following:
  • Cecostomy and drainage
  • A 2-stage right hemicolectomy or total abdominal colectomy, with or without a primary anastomosis
  • Defunctioning of the colon with a loop ileostomy
• Normal-appearing serosal surfaces may conceal mucosal breakdown and necrosis. Therefore, resection should be extensive to assure removal of the diseased bowel.
• Consider elective right hemicolectomy in patients who have required repeated courses of chemotherapy and have responded to initial conservative medical therapy. Recurrent episodes of typhlitis have been reported in such patients.

Consultations

Joint management between medical and surgical teams is extremely important for a good outcome.

Diet

Because the patient is fasting and on bowel rest, consider parenteral nutrition.

Activity

These patients usually are extremely ill and are in the intensive care setting on complete bed rest.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Because these patients have received numerous courses of antibiotics previously for other indications, a specific agent or regimen cannot be recommended, and the decision must be made on an individual basis. However, a few possible choices of antibiotics and antifungals are listed below. The author favors a combination of amikacin plus imipenem or cefepime/ceftazidime plus metronidazole in addition to vancomycin.

Consider adding antifungal agents if clinical improvement does not occur with antibiotics.

Drug Category: Antibiotics

Empiric broad-spectrum antibiotics are recommended to cover potential primary or secondary infectious causes of neutropenic enterocolitis and to control sepsis. The antibiotics should cover aerobic and anaerobic enteric organisms, including Clostridium species because anecdotal reports reveal an association between Clostridium septicum and neutropenic enterocolitis.

Drug Category: Antifungal agents

Consider adding antifungal agents if no clinical improvement occurs with broad-spectrum antibiotics. Amphotericin B is the preferred agent because nonalbicans candidemia is more likely to be present and usually is fluconazole resistant. Consider liposomal amphotericin B if the infection is refractory to conventional amphotericin or in patients with renal failure.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• The patient must be monitored in an intensive care setting with serial abdominal examinations.
• Using recombinant granulocyte colony-stimulating factor (GCSF) may be considered in individual patients depending on the clinical progression. Controlled trials using GCSF in this specific entity are lacking, although several case reports of a successful outcome have been reported in the literature. Moreover, a better understanding and definition of specific subsets of patients that may benefit from treatment or prevention of neutropenic enterocolitis is needed.

Deterrence/Prevention

• Withhold further chemotherapy until complete recovery.
• Consider an elective right hemicolectomy in patients who have successfully recovered and may require repeated courses of chemotherapy in the near future.

Complications

• Bowel perforation and peritonitis
• Gastrointestinal bleeding
• Gastrointestinal obstruction
• Intra-abdominal abscess
• Sepsis
• Death

Prognosis

• The prognosis generally is poor, with mortality rates varying from 5-100% and averaging about 40-50%.
• The prognosis depends highly on the rapidity of restoration of the white blood cell count.
• The potential for recovery may be improved by aggressive and meticulous medical and supportive therapy.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Consider the possibility of neutropenic enterocolitis in all patients who are immunosuppressed and have right lower quadrant pain.
• Early recognition of this condition is paramount to reducing mortality rates and achieving a potentially good outcome.
• Monitor the patient in an intensive care setting with frequent serial abdominal examinations.
• Joint management by the medical and surgical teams is essential for optimal management.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Alt B, Glass NR, Sollinger H. Neutropenic enterocolitis in adults. Review of the literature and assessment of surgical intervention. Am J Surg. Mar 1985;149(3):405-8. [Medline].
• Avigan D, Richardson P, Elias A. Neutropenic enterocolitis as a complication of high dose chemotherapy with stem cell rescue in patients with solid tumors: a case series with a review of the literature. Cancer. Aug 1 1998;83(3):409-14. [Medline].
• Buyukasik Y, Ozcebe OI, Haznedaroglu IC. Neutropenic enterocolitis in adult leukemias. Int J Hematol. Jul 1997;66(1):47-55. [Medline].
• Cantoni C, Dragoni F, Micozzi A. Neutropenic enterocolitis in patients with acute leukemia: prognostic significance of bowel wall thickening detected by ultrasonography. J Clin Oncol. 2001;19:756-61.
• Crosby WH, Haubrich WS. The death of Walter Reed. JAMA. Sep 17 1982;248(11):1342-5. [Medline].
• Cunningham SC, Fakhry K, Bass BL. Neutropenic enterocolitis in adults: case series and review of the literature. Dig Dis Sci. Feb 2005;50(2):215-20. [Medline].
• Davila AD, Willenbucher RF. Neutropenic typhlitis. In: Feldman M, Sleisenger BF, et al, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management. 6th ed. Philadelphia, Pa:. Saunders;1998:1998-2000.
• Davila ML. Neutropenic enterocolitis. Curr Opin Gastroenterol. Jan 2006;22(1):44-7.
• Ettinghausen SE. Collagenous colitis, eosinophilic colitis, and neutropenic colitis. Surg Clin North Am. Oct 1993;73(5):993-1016. [Medline].
• Gomez L, Martino R, Rolston KV. Neutropenic enterocolitis: spectrum of the disease and comparison of definite and possible cases. Clin Infect Dis. Oct 1998;27(4):695-9. [Medline].
• Gorbach SL. Neutropenic enterocolitis. Clin Infect Dis. Oct 1998;27(4):700-1. [Medline].
• GorschlĂĽter M, Mey U, Strehl J. Neutropenic enterocolitis in adults: systematic analysis of evidence quality. Eur J Haematol. Jul 2005;75(1):1-13.
• Hanada T, Ono I, Hirano C. Successful treatment of neutropenic enterocolitis with recombinant granulocyte colony stimulating factor in a child with acute lymphocytic leukaemia. Eur J Pediatr. Aug 1990;149(11):811-2. [Medline].
• Hoelzer D. Hematopoietic growth factors--not whether, but when and where. N Engl J Med. Jun 19 1997;336(25):1822-4. [Medline].
• Horton KM, Corl FM, Fishman EK. CT evaluation of the colon: inflammatory disease. Radiographics. Mar-Apr 2000;20(2):399-418. [Medline].
• Jain Y, Arya LS, Kataria R. Neutropenic enterocolitis in children with acute lymphoblastic leukemia. Pediatr Hematol Oncol. Jan-Feb 2000;17(1):99-103. [Medline].
• Katz JA, Wagner ML, Gresik MV. Typhlitis. An 18-year experience and postmortem review. Cancer. Feb 15 1990;65(4):1041-7. [Medline].
• Keidan RD, Fanning J, Gatenby RA. Recurrent typhlitis. A disease resulting from aggressive chemotherapy. Dis Colon Rectum. Mar 1989;32(3):206-9. [Medline].
• Kirkpatrick ID, Greenberg HM. Gastrointestinal complications in the neutropenic patient: characterization and differentiation with abdominal CT. Radiology. Mar 2003;226(3):668-74. [Medline].
• Kulaylat M, Doerr R, Ambrus J. A case presentation and review of neutropenic enterocolitis. J Med. 1997;28(1-2):1-19. [Medline].
• Lev R, Sweeney KG. Neutropenic enterocolitis. Two unusual cases with review of the literature. Arch Pathol Lab Med. May 1993;117(5):524-7. [Medline].
• Mulholland MW, Delaney JP. Neutropenic colitis and aplastic anemia: a new association. Ann Surg. Jan 1983;197(1):84-90. [Medline].
• Nagler A, Pavel L, Naparstek E. Typhlitis occurring in autologous bone marrow transplantation. Bone Marrow Transplant. Jan 1992;9(1):63-4. [Medline].
• Or R, Mehta J, Nagler A. Neutropenic enterocolitis associated with autologous bone marrow transplantation. Bone Marrow Transplant. May 1992;9(5):383-5. [Medline].
• Shaked A, Shinar E, Freund H. Neutropenic typhlitis. A plea for conservatism. Dis Colon Rectum. May 1983;26(5):351-2. [Medline].
• Shamberger RC, Weinstein HJ, Delorey MJ. The medical and surgical management of typhlitis in children with acute nonlymphocytic (myelogenous) leukemia. Cancer. Feb 1 1986;57(3):603-9. [Medline].
• Sloas MM, Flynn PM, Kaste SC. Typhlitis in children with cancer: a 30-year experience. Clin Infect Dis. Sep 1993;17(3):484-90. [Medline].
• Urbach DR, Rotstein OD. Typhlitis. Can J Surg. Dec 1999;42(6):415-9. [Medline].
• Wade DS, Nava HR, Douglass HO. Neutropenic enterocolitis. Clinical diagnosis and treatment. Cancer. Jan 1 1992;69(1):17-23. [Medline].
• Wagner ML, Rosenberg HS, Fernbach DJ. Typhlitis: a complication of leukemia in childhood. Am J Roentgenol Radium Ther Nucl Med. Jun 1970;109(2):341-50. [Medline].
• Weinberger M, Hollingsworth H, Feuerstein IM. Successful surgical management of neutropenic enterocolitis in two patients with severe aplastic anemia. Case reports and review of the literature. Arch Intern Med. Jan 11 1993;153(1):107-13. [Medline].

Article Last Updated: Dec 8, 2006