Gastrointestinal immune-related adverse events (GI irAEs) are common manifestations of immune checkpoint inhibitor (ICI) toxicity. We present a comprehensive systematic review of the incidence, management, and clinical course of irAEs across the entire GI system, including the luminal GI tract, liver, and pancreas. MEDLINE, Embase, Web of Science Core Collection, and Cochrane Library were used to conduct this review. All studies pertaining to GI irAEs were included. Both abstracts and full manuscripts were eligible if they included human subjects and were written in the English language. Articles not available in English, animal studies, or research not specific to GI toxicity of immunotherapy were excluded. We excluded certain article types depending on whether stronger evidence was available in the literature for a specific toxicity, for example, if prospective studies were available on a topic, retrospective studies and case reports were excluded. We extracted a final 166 articles for our review and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for data reporting. Risk of bias tools were not used to evaluate the extracted studies given the narrative nature of this manuscript, but each study was critically appraised by the manuscript writer. We detail the incidence, presentation, evaluation, management, and outcomes of the various GI toxicities that may arise with ICI therapy. Specifically, we discuss the characteristics of upper GI toxicity (esophagitis and gastroenteritis), lower GI toxicity (colitis), hepatobiliary inflammation, pancreatitis, and rarer forms of GI toxicity. We hope this review serves as a useful and accessible clinical tool that helps physicians familiarize themselves with the nuances of gastrointestinal/hepatic/pancreatic ICI toxicity diagnosis and management.

Background Immune checkpoint inhibitors (ICPIs), used to treat different advanced malignancies, are associated with a wide range of immune-related adverse reactions (irAEs) that deserve close monitoring of patients. Gastrointestinal reactions and hepatotoxicity may occur, which warrant careful evaluation to confirm the etiology and attribution to ICPIs as these events could affect future management. Case presentation We describe a case of a patient with prostate adenocarcinoma, treated with dual ICPIs comprised of ipilimumab and nivolumab, who developed elevated liver enzymes in the context of infliximab therapy prescribed to treat gastrointestinal irAE from his ICPIs. The patient’s grade 3 colitis became steroid-refractory, requiring a one-time infusion of infliximab, a biologic agent used commonly in inflammatory bowel disease, as a rescue therapy, to which he responded. The patient subsequently developed liver injury. This presented a diagnostic dilemma involving differential diagnoses of hepatotoxicity due to ICPI or infliximab exposure. A careful review of the clinical history, evaluation of the chronology of events, and exclusion of other causes of acute hepatitis were employed to make the final diagnosis of this event as infliximab-associated hepatotoxicity. Conclusion ICPIs such as CTLA-4 and PD-1 inhibitors have the potential to cause both gastrointestinal reactions and hepatotoxicity. An additional confounding factor in our patient’s case was the exposure to infliximab used to manage an established irAE that developed after the last exposure to ICPIs. The clinical history and data supported infliximab-associated hepatotoxicity, rather than an irAE. With the increasing application of ICPIs for different cancers, in conjunction with potential risks for irAE, the liver profile should be closely monitored during treatment with ICPI as well as with anti-TNF-α agents in this patient population.

Hepatitis E virus (HEV) infection in immunocompetent patients can lead to chronic hepatitis and liver failure. However, the burden of HEV infection in cancer patients is largely unknown. We studied the characteristics of HEV infection in patients at a tertiary care cancer center in the United States. This retrospective study included adult cancer patients with HEV infection diagnosed between September 2011 to September 2021. A total of 405 patients were tested for HEV, and 63 (16%) had detectable HEV IgG. Thirty-three patients (52%) were male, 43 were born in America (68%), 46 (73%) were screened for HEV because of pre-existing liver conditions, and 22 (35%) had hematological malignancies. Only 2 patients had detectable HEV RNA. The first patient had myelodysplastic syndrome and underwent allogeneic stem cell transplantation (HSCT). He developed elevated liver enzymes with HEV RNA 14,000 IU/mL (4.2 log IU/mL) 13 months after HSCT. After reducing immunosuppression, his HEV viremia resolved. The second patient had diffuse large B-cell lymphoma and underwent anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. She had elevated liver enzymes with HEV RNA 4,560,000 IU/mL (6.7 log IU/mL) 12 months after CAR T-cell therapy. She developed chronic HEV infection, and ribavirin treatment failed. Now she is being considered for salvage treatment with peginterferon alfa-2a and ribavirin. This study is the first report of chronic HEV infection in patients who received CAR T-cell therapy. HEV infection in cancer patients appears to be at least as common as in the general population. Cancer patients with hematologic malignancies may be at risk for HEV viremia and chronic infection refractory to antiviral treatment.