1. Typhlitis Medical versus Surgical Management Amanda E. Jacobson, MD
University of Virginia, Department of Pediatrics

2. What is Typhlitis?
Necrotizing enterocolitis in immunocompromised patients; a.k.a neutropenic enterocolitis
Causes: Cytotoxic drugs  Mucosal injury + impaired defenses  invasion by microorganisms  bowel wall necrosis
Cecum usually affected, often extends to the terminal ileum and ascending colon
Infection is usually polymicrobial: gram – rods, gram + cocci, anaerobes, fungi (Candida)
Occurs almost exclusively in patients undergoing chemotherapy, but can occur on occasion in patients with HIV/AIDS and cyclic or drug-induced neutropenia
First described in children undergoing chemotherapy for acute leukemia
First described by Wagner et at in 1970
Pathogenesis is not well understood, likely a combination of factors
Cecum thought to be most affected due to dispensability and diminished vascularization

3. Who is at risk?
Moran et al (2009): retrospective case-control study of 843 pediatric cancer patients over 10 year period found incidence of 5%
Of those, 76% were being treated for a hematologic malignancy
Incidence was highest in patients with Burkitt’s lymphoma (15%) and AML (12%)
Risk factors: SCT (OR: 58.9), mucositis (OR: 30.7) and chemotherapy in the previous 2 weeks (12.9)
SCT: stem cell transplantation
2 weeks post chemo: precipitous decline in ANC
Other data: 46% incidence on autopsy (Wagner et al, 1970); 3.5% (Wade et al, 1992); 0.35%: 30 year study at St. Jude’s, included BMT for patients without malignancy (Sloas et al, 1993); 2.6%: Study 10 years later from St. Jude’s, excluded BMT for non-malignancy

4. Presentation
Should be on Ddx in neutropenic patient (ANC < 500 microL) with fever and abdominal pain
Symptoms: fever, abdominal pain (usually RLQ), abdominal distention, n/v, watery or bloody diarrhea; peritoneal signs and shock may suggest perforation; stomatitis or widespread mucositis
Difficult to distinguish from acute appy due to location of pain
Should be on the differential diagnosis for any patient with profound neutropenia (ANC < 500microL)
Usually occurs days after cytotoxic chemotherapy, when neutropenia is most profound

5. Diagnosis CT is gold standard, but US may also be useful
Findings: presence of dilated, distended and fluid-filled cecum (all modalities); CT: cecal wall thickening, intramural edema/air/hemorrhage, perforation with free air or mass suggesting abscess formation
Blood and stool cultures + C. diff toxin assays
CT has lowest rate of false-negatives (15% vs 23% with US and 28% with XR)
One center found that high-resolution US was more useful as CT tended to overestimate bowel wall thickness, but US is operator dependent
CT is most useful in distinguishing between typhlitis and acute appendicitis or appendiceal abscess
Lower GI bleeding more common in typhlitis vs acute appendicitis
Barium enema and colonoscopy are contraindicated due to risk of perforation

6. Computed tomgraphic scan of the abdomen shows thickening of the hepatic flexure of the colon (arrowheads). Intraluminal contents (straight arrow) and surrounding inflammatory changes (curved arrow) which make accurate measurement of the bowel wall difficult.
Image from McCarville et al. “Typhlitis in childhood cancer.” Cancer. 2005; 104:

7. Courtesy of google images

8. Medical Management
Patients without peritonitis, perforation or severe bleeding
Broad-spectrum antibiotics: covering gram +/- organisms, anaerobes, fungi
Bowel rest: NPO, TPN, NG suction, IV fluids
Blood products as needed
Anti-diarrheal agents and laxative agents should be avoided
GCSF
Note: GCSF in patients with acute leukemia should only be considered in the face of severe typhlitis as GCSF is contraindicated in this population
Other treatments: selective decontamination of the GI tract

9. Surgical Management Indications:
Peritonitis
Free air
GI bleeding despite supportive management
Clinical deterioration
Gold standard: two stage right hemicolectomy
Hemicolectomy including ileostomy and mucous fistula
Failure to remove the necrotic focus in these severely immunocompromised patients is fatal
Diffuse mucosal necrosis may be present beneath unimpressive serosal inflammation
Delay of chemotherapy until recovery
Urbach et al, 1999

10. Treatment should be individualized but the algorithm above can be useful

11. Necrotic foci visible on cecal surface
Stanislaw et al. “Necrotizing Enterocolitis in Acute Lymphoblastic Leukemia Patients: Department Experience.” International Journal of Hematology. 2005;82:319-23

12. Summary
Typhlitis is a relatively uncommon but important complication in the treatment of pediatric malignancies
It can be difficult to differentiate from acute appendicitis
If recognized early, medical management is very effective
Overall mortality has decreased substantially, early numbers suggested 40-50%, now much improved

13. References
Wong Kee Song, LM; Marcon, NE. “Typhlitis (neutropenic enterocolitis).” UpToDate Online.
Mullassery, D; Bader, A; Battersby, A; Mohammad, Z; Jones, ELL; Parmar, C; Scott, R; Pizer, B; Baille, C. “Diagnosis, incidence, and outcomes of suspected typhlitis in oncology patients—experience in a tertiary pediatric surgery center in the United Kingdom.” Journal of Pediatric Surgery. 2009;44:381-5.
Moran, H; Yaniv, I; Ashkenazi, S; Schwartz, M; Fisher, S; Levy, I. “Risk Factors for Typhlitis in Pediatric Patients With Cancer.” Journal of Pediatric Hematology and Oncology ;31:630-4.
McCarville, B. “Evaluation of typhlitis in children: CT versus US.” Pediatric Radiology. 2006;36:890-1.
Fike, FB; Mortellaro, V; Juang, D; St. Peter, SD; Andrews, WS; Snyder, CL. “Neutropenic Colitis in Children.” Journal of Surgical Research. 2011;170:73-6.
McCarville et al. “Typhlitis in childhood cancer.” Cancer. 2005;104:
Moir, CR; Scudamore, CH; Benny, WB. “Typhlitis: Selective Surgical Management.” The American Journal of Surgery. 1986;151:
Stanislaw et al. “Necrotizing Enterocolitis in Acute Lymphoblastic Leukemia Patients: Department Experience.” International Journal of Hematology. 2005;82:319-23