Novel application of infliximab for diversion colitis

Abstract

Diversion colitis (DC) that was refractory to standard treatments was successfully treated with infliximab. A 24-year-old man with a transverse colostomy suffered from severe DC. Topical steroids, 5-aminosalicylic acid (5-ASA) enemas and synbiotics were initially effective, and the colostomy was successfully closed with a covering ileostomy to minimise the risk of anastomotic leakage owing to the damaged colon. DC subsequently relapsed in the entire colon and was refractory to the previous protocol and autologous faecal transplantation. Intravenous methylprednisolone and oral 5-ASA were discontinued owing to possible adverse effects. Infliximab with intravenous prednisolone was introduced, and the protocol was so effective in suppressing the acute colitis that total colectomy was avoided. The stoma was subsequently closed, and the patient is currently symptom-free. Infliximab is used for ulcerative colitis but could also be effective against severe DC.

Background

Diversion colitis (DC) defines non-specific colonic inflammation occurring in the colon distal to the diversion ileostomy or colostomy.¹ DC occurs secondary to disruption of the normal intestinal flora by the discontinuation of the faecal stream; therefore, curative management involves surgically re-establishing total bowel continuity to enhance recovery of the colonic flora.² Medical management consisting of 5-aminosalicylic acid (5-ASA), glucocorticoids and synbiotics is implemented if surgically re-establishing bowel continuity cannot be performed initially because of a risk of anastomotic leakage owing to the severely inflamed bowel mucosa. Furthermore, removing the affected bowel and creating a permanent colostomy or ileostomy are required if medical management fails to suppress the colitis and there is concern regarding further complications, such as bowel perforation, bleeding or systemic sepsis.³ In this report, we present a case of DC in which infliximab suppressed acute inflammation that was refractory to standard medical management and which successfully avoided total colonic resection. Re-establishing bowel continuity was performed subsequently.

Case presentation

A 24-year-old man with a transverse loop colostomy was referred for intermittent hematochezia with abdominal pain that gradually worsened over 3 years. His medical history included Kasai portoenterostomy at 94 days of age for biliary atresia and living donor liver transplantation (LDLT) at 14 years of age for end-stage liver failure. The initial transplantation resulted in graft failure, and a second LDLT was performed 1 year after the initial transplantation. At the second LDLT, colonic perforation occurred during difficult adhesiolysis, and a transverse colostomy was created.

Total colonoscopy for the hematochezia revealed moderate to severe mucosal inflammation in the colorectal segment distal to the transverse colostomy (figure 1A). A biopsy showed non-specific inflamation with leucocyte infiltration and cryptitis. The colon proximal to the colostomy exhibited subtle inflammation, but the degree of inflammation was far less compared with that in the distal segment (figure 1B). There were no abnormal extraintestinal findings. Based on these findings, DC, rather than inflammatory bowel disease (IBD), was suspected in the current case. Surgically re-establishing the faecal stream, which is the best treatment for DC, could not be performed owing to the severe mucosal damage in the affected bowel. Therefore, medical management comprising synbiotics, 5-ASA and steroid enemas was performed and improved the inflammation, which was confirmed endoscopically 4 weeks after beginning the treatment. The transverse colostomy was closed 4 months later at another hospital, and a temporary ileostomy was placed to minimise the risk of anastomotic leakage owing to the previous severe mucosal damage. Unfortunately, DC relapsed in the entire length of the colon soon after the procedure. Colonoscopy revealed severe mucosal inflammation (figure 2A, B). Medical management was reinitiated but failed to suppress the inflammation, and autologous faecal transplantation failed owing to severe tenesmus. Intravenous methylprednisolone and oral 5-ASA caused fever and chest pain for unknown reasons and were abandoned. Owing to these treatment failures, infliximab was introduced with daily intravenous prednisolone as a last resort to avoid removing the affected colon. This therapy dramatically improved the colonic inflammation and alleviated the patient’s symptoms. Colonoscopy performed 4 weeks after initiating infliximab and prednisolone showed significant improvement in the colitis, and the ileostomy was subsequently closed successfully.

Figure 1.

Colonoscopic images of the affected bowel distal (A) and proximal (B) to the diversion colostomy at the first episode of colonic inflammation. (A) Colonoscopy showing severely inflamed mucosa with haemorrhage in the sigmoid colon distal to the transverse colostomy. (B) Colonoscopic findings in the ascending colon to the cecum, which was proximal to the colostomy. Inflammation is visible, but it is milder than that in the sigmoid colon.

Figure 2.

Colonoscopic findings in the sigmoid colon (A) and ascending colon to the cecum (B) at the second episode of diversion colitis. (A) The sigmoid colon exhibits significant mucosal inflammation. (B) The ascending colon and the cecum show similar degrees of inflammation to that in the sigmoid colon.

Differential diagnosis

Infectious colitis owing to viral or bacterial infection and IBD should be considered as a differential diagnosis in the current case. The patient in this case was immunosuppressed, post-LDLT; therefore, colitis due to Epstein-Barr virus or cytomegalovirus was initially suspected. However, there were no findings indicating the presence of these organisms on serological and microbiological examinations. The most difficult part of making a diagnosis in this case was differentiating DC from ulcerative colitis (UC) because DC presents with clinicopathological findings similar to UC regardless of the absence of pre-existing IBD.^{4 5} Furthermore, in the presence of Crohn’s disease and UC, the number of symptomatic patients with DC increases to 33% and 87%, respectively.⁶ The absence of extraintestinal findings and the significantly worse inflammatory response in the distal part of the diverted bowel were suggestive of DC rather than UC in this case; however, these findings were not a sole determinant in confirming the diagnosis. Hence, it should be mentioned that clinicopathologically, DC rather than UC was more suspected in the current case, but there was a chance that both conditions coexisted. Indeed, this limitation was one of the reasons we chose infliximab because we expected that this medication could effectively suppress inflammation regardless of the aetiology.

Treatment

The second episode of DC was treated successfully with intravenous infliximab with prednisolone. The infliximab dose was 5 mg/kg, and the dose was repeated 2 and 6 weeks after the initial dose. The patient’s body weight was 45 kg. The initial dose of intravenous prednisolone was 40 mg per body per day administered once per day then tapered by 5 mg each week. Total colonoscopy performed 4 weeks after initiating this protocol showed almost complete resolution of the inflammation.

Outcome and follow-up

Total colonoscopy performed 1 and 7 months after the ileostomy closure revealed no recurrence of inflamation, and prednisolone was gradually tapered and stopped. Infliximab infusion once every 6–8 weeks was continued. Currently, the patient has been symptom-free regarding the colitis for 8 months from closing the ileostomy.

Discussion

DC is characterised by non-specific bowel inflammation in the distal part of the diverted colon and occurs in nearly all patients who undergo defunctioning colostomy or ileostomy.^{1 2 7} This condition is presumed to arise from derangement of the colonic microflora, which is elicited by disruption of the faecal stream.⁸ Decreased amounts of nitrate-reducing bacteria lead to toxic levels of nitric oxide in the diverted colon. Furthermore, fewer normal colonic flora cannot provide sufficient amounts of short-chain fatty acids, which are important to maintain appropriate blood circulation in the affected bowel.^{9 10} Hence, the definitive management of DC is surgically re-establishing the faecal stream to recover the normal colonic microflora.² However, the treatment is sometimes difficult to choose, initially, owing to the severe mucosal inflammation from DC and the subsequent risk of anastomotic leakage. In such cases, medical management comprising 5-ASA, topical or systemic steroids and synbiotics is chosen. Autologous faecal transplantation is also promising.¹¹ In the majority of cases, these treatments are sufficient to suppress the acute inflammation in DC and allow patients to undergo definitive surgery. However, removing the affected bowel and creating an ileostomy or colostomy are advised in cases of severe DC refractory to medical management to prevent further complications, such as massive colonic bleeding, perforation or systemic sepsis.^{3 12} This decision should be made after in-depth discussion because of the significant patient morbidity.

Infliximab was used in our case to alleviate the bowel inflammation, which was not responsive to standard medical management. Infliximab is a monoclonal antibody against human tissue necrosis factor alfa (TNF-α) and has been used to treat moderate to severe UC.¹³ Moreover, infliximab’s effect in an experimental animal model of DC was recently reported, and Buanain et al suggested a positive effect of infliximab against DC, based on their experimental model.^14–16 Clinically, DC tends to occur in patients with pre-existing IBD, and the clinicopathological findings in both conditions can mimic each other.^4–6 Additionally, a similar pathogenesis, such as derangement of the colonic microbiota, has been presumed in both conditions.^17–19 Considering this information, we initiated infliximab in our case as a last resort to avoid removing the entire affected colon. Fortunately, the effect of infliximab was remarkable, and there were no adverse events causing further complications. Infliximab was quite beneficial for this patient. Importantly, the results in this case should be interpreted with caution because intravenous prednisolone was used with infliximab, and it is difficult to estimate the effect of sole therapy with infliximab. Additional reports and, ideally, controlled studies, are awaited to confirm the positive impact of infliximab on DC. Furthermore, infliximab had a fairly high drug-related complication rate of >80% in a meta-analysis; therefore, its benefit should be weighed carefully.²⁰ Despite the potential risk, we stress the positive results of infliximab against severe DC in this case. We believe it is worthwhile considering this medication in cases of severe DC refractory to standard treatment to avoid compelling bowel resection, which causes significant morbidity in patients with DC.

Learning points.

• Severe diversion colitis was successfully treated with infliximab.

• The entire large bowel was preserved for re-establishing bowel continuity after infliximab therapy.

• This is a single case report; however, infliximab may be beneficial for patients with DC who are refractory to standard management.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).