Typhlitis

Neutropenic enterocolitis refers to necrotizing inflammation of the small or large intestine that occurs in the setting of neutropenia. Typhlitis specifically refers to necrotizing inflammation of the cecum, the most commonly affected bowel segment. Typhlitis is an oncologic emergency because it may lead to bowel obstruction or perforation requiring surgical intervention.

Surgery team should be involved early, even if surgery is not anticipated. Surgery should be deferred until supportive therapy has failed or the following complications develop perforation, haemorrhage despite correction of thrombocytopenia and coagulopathies, obstruction, necrosis, abscess or peritonitis requiring drainage, fistula, toxic megacolon, or septic shock.

Pathogenesis

• unclear
• might be drug induced mucosal injury combined with inhibition of cellular replication followed by superinfection with colonic organisms.
• the caecum is particularly prone to involvement because of poor vascular supply.
• Pseudomonas, E coli, staph, strept, clostridium

Pathogenesis model of oral mucositis could also be applicable to the gut as a whole even though it is a more complex organ having a dynamic epithelial border with different functions and unique interactions with immune system and luminal microflora. Mucosal barrier injury occurs in four phases. The first phase is the inflammatory/vascular phase and is characterized by the induction of pro-inflammatory cytokines IL-1, TNF-alpha and IFN-gamma by cytotoxic drugs and irradiation while the epithelial cells are still intact. The second phase is the epithelial phase when cells cease dividing and die. This coincides with neutropenia. The third phase is when necrosis and ulceration occur and is when the resident microbial flora and their products, e.g. endotoxin translocate into the bloodstream. Moreover, impaired local defences and lower levels of secretory IgA may allow local infection to develop. The final phase is when healing takes place and involves the action of naturally occurring substances including trefoils, EGF and TGF. The events that take place in the gut are almost certainly more complicated than those occurring in the oral cavity since the gastrointestinal tract is intrinsically more complex in terms of its function, it possesses the specialized gastrointestinal-associated lymphoid tissue (GALT) system, and its resident microflora are more numerous and varied.

Diagnosis

Imaging studies may aid in the diagnosis of typhlitis:

• Radiograph of the abdomen may reveal pneumatosis intestinalis, free air in the peritoneum or bowel wall thickening.
• Ultrasonography may reveal thickening of the bowel wall in the region of the cecum and is becoming a more commonly used non-radiation modality to image for typhlitis.
• CT scan is the definitive imaging study and may demonstrate diffuse thickening of the caecal wall.

Management of Typhlitis

The management strategy should prioritize aggressive hydration therapy, correction of electrolyte imbalances, cessation of oral intake to rest the gastrointestinal tract, abdominal decompression, and administration of broad-spectrum antimicrobials. Addressing thrombocytopenia and coagulopathies may necessitate the transfusion of blood products.

An improvement in leukocyte count post-intervention is associated with enhanced patient prognoses. The administration of Granulocyte-colony stimulating factors (G-CSF) has been explored in this context, albeit in the absence of randomized controlled trials specific to typhlitis. Nevertheless, clinical guidelines for G-CSF application exist, suggesting its use under conditions including significant neutropenia (absolute neutrophil count < 100/mL), unmanaged primary disease, presence of pneumonia, hypotension, multi-organ failure, and severe fungal infections.

Antibiotic regimens must provide extensive coverage against enteric pathogens, notably Gram-negative and anaerobic bacteria, alongside Gram-positive enterococcal species. Initial empirical therapy might include monotherapy with piperacillin-tazobactam or imipenem-cilastatin, or combination therapy using ceftazidime or cefepime with metronidazole, effectively covering for neutropenic enterocolitis. Metronidazole is typically favoured for anaerobic coverage due to its efficacy in conditions clinically resembling typhlitis, like Clostridium difficile-associated pseudo-membranous enterocolitis. Vancomycin may be added to the regimen in cases where Clostridium difficile infection cannot be ruled out.

Surgical intervention may be warranted in instances of perforation, generalized peritonitis, persistent haemorrhage despite correction of thrombocytopenia and coagulopathy, or the need for vasopressor support indicative of uncontrolled sepsis secondary to intestinal infarction.

References

• Philip A. Pizzo, David G. Poplack (2021). Principles and Practice of Pediatric Oncology. 8th Edition. Lippincott Williams & Wilkins
• Arul GS, Spicer RD (2008) Gastrointestinal complications. In: Carachi R, Grosfeld JL, Azmy AF (eds) The surgery of childhood tumors, 2nd edn. Springer, New York
• McCarville MB, Adelman CS, Li C et al (2005) Typhlitis in childhood cancer. Cancer 104:380–387
• Sundell N, Boström H, Edenholm M et al (2012) Management of neutropenic enterocolitis in children with cancer. Acta Paediatr 101:308–312
• Cloutier RL (2010) Neutropenic enterocolitis. Hematol Oncol Clin North Am 24:577–584
• Blijlevens NM. Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview. Bone Marrow Transplant June 2000.
• Rodrigues FG, Dasilva G, Wexner SD. Neutropenic enterocolitis. World J Gastroenterol. 2017;23(1):42–47. doi:10.3748/wjg.v23.i1.42