Durvalumab is a monoclonal antibody immune checkpoint inhibitor (ICI) that targets the transmembrane protein programmed death ligand 1 (PD-L1), which normally suppresses T-cell proliferation and limits adaptive immunity. By blocking this inhibitory pathway, durvalumab enhances T-cell activation and proliferation, thereby potentiating antineoplastic immune responses. Durvalumab has emerged as an effective immunomodulatory therapy for the treatment of multiple malignancies, including non–small cell lung cancer (NSCLC) [1]. Although enhanced T-cell activation underlies its antineoplastic efficacy, disruption of peripheral immune tolerance confers a substantial risk of autoimmunity. This immune dysregulation may result in a broad spectrum of immune-mediated adverse effects (imAEs). Commonly discussed as “-itis” complications during outpatient oncology visits, imAEs may have systemic and potentially severe consequences. Pneumonitis is among the most feared imAEs; however, several nonpneumonitis imAEs have been described in case reports and retrospective analyses [2]. Endocrine imAEs are increasingly recognized. New-onset type 1 diabetes mellitus (T1DM) has been reported in patients treated with durvalumab and typically develops early in the treatment course. This complication may initially present as diabetic ketoacidosis (DKA) and can result in significant morbidity, hospitalization, and death [3]. Gastrointestinal adverse effects are among the most commonly observed complications of ICIs. Colitis and asymptomatic pneumatosis intestinalis have been reported in this population and are hypothesized to result from immune-mediated inflammation of the enteric vasculature, rather than the bowel wall alone [4]. Severe, catastrophic nonpneumonitis imAEs remain rare. We present the case of a 66-year-old man who developed fatal immune-mediated complications following durvalumab therapy for lung cancer, presenting with DKA due to new-onset T1DM and progressive acute mesenteric ischemia, ultimately resulting in death.

Institutional review board approval was not required for this report according to institutional policy. Attempts were made to obtain consent from the patient’s next of kin; however, consent for publication could not be obtained. All identifying information has been removed to protect patient privacy.

A 66-year-old man with a 96-pack-year smoking history and a medical history significant for hypertension, hypothyroidism, chronic obstructive pulmonary disease (COPD), right upper lobe carcinoid tumor, and left-sided NSCLC status post chemoradiation, currently receiving immunotherapy, presented to the emergency department (ED) in mid-May 2024 after approximately 24 hours of intractable vomiting, progressive weakness, altered mental status, and shortness of breath. His weakness had progressed to the point that he was unable to stand from a seated position, prompting family concern and hospital presentation. On arrival, he was tachycardic, hypertensive, and required a high-flow nasal cannula for hypoxemia. He denied abdominal pain and had a benign abdominal examination. Following his lung cancer diagnosis the preceding December, he completed chemoradiation in February and initiated durvalumab therapy approximately one month before ED presentation. He reported no adverse effects at his first posttreatment oncology follow-up and received his second durvalumab infusion 13 days before presentation.

ED evaluation demonstrated profound hyperglycemia (blood glucose, 1,134 mg/dL), leukocytosis (white blood cell count, 16,000/µL), metabolic acidosis (pH, 7.02), and an elevated lactate level of 3.5 mmol/L. He was diagnosed with DKA due to new-onset T1DM and initiated on an insulin infusion. Computed tomography pulmonary embolism protocol imaging demonstrated findings concerning for post-immunotherapy pneumonitis versus left (perihilar, apical, and lower) lobe pneumonia, and broad-spectrum antibiotics were initiated. Additional computed tomography imaging of the abdomen and pelvis revealed incidental pneumatosis intestinalis involving the entire jejunum with extensive portal venous gas (Fig. 1). Given his history of COPD, absence of abdominal pain, and benign abdominal examination, interpretation of the pneumatosis was initially uncertain; however, an acute care surgery consultation was obtained. He was evaluated by surgery shortly before intubation in the intensive care unit (ICU) for worsening respiratory distress and fatigue. Despite increasing confusion, he again denied abdominal pain, and serial abdominal examinations remained benign. Notably, new bilateral lower-extremity mottling developed, although his skin remained warm and pedal pulses were intact.

The patient was taken emergently to the operating room for diagnostic laparoscopy. Upon abdominal entry, necrotic small bowel was immediately visualized, prompting conversion to exploratory laparotomy. Approximately 360 cm of frankly necrotic small bowel was resected (Fig. 2). Given the questionable viability of the remaining bowel, temporary abdominal closure was performed using negative pressure wound therapy (NPWT; Abthera, 3M Co). Given concern for a thrombotic or embolic etiology, computed tomography angiography was obtained and demonstrated widely patent visceral abdominal arteries. Vascular surgery was consulted, and an empiric heparin infusion was initiated in an effort to limit further progression of mesenteric ischemia. The patient returned to the operating room later that day. Threatened antimesenteric small bowel both proximal and distal to the previously resected segment was observed, although the colon appeared viable. The NPWT system was replaced without additional resection, as no further areas of frank necrosis were identified.

After resuscitation in the ICU, the patient returned to the operating room on postoperative day 2 for a planned second-look laparotomy. A frankly necrotic segment of small bowel approximately 7 cm distal to the ligament of Treitz was identified and resected. The descending colon newly appeared grossly necrotic, necessitating left hemicolectomy. Patchy areas of questionable viability were noted within the remaining 150 cm of small bowel. Intraoperative assessment of mesenteric perfusion using indocyanine-green fluorescence angiography demonstrated preserved perfusion. Temporary abdominal closure with NPWT was again performed, and the patient returned to the ICU. Two days later, at a subsequent operation, further progression of mesenteric ischemia was observed, with less than 10 cm of viable bowel remaining. This extent of bowel loss was deemed incompatible with survival. The patient was transitioned to comfort-focused care and died shortly thereafter. Postmortem testing for anticardiolipin antibodies and β2 glycoprotein 1 immunoglobulin G and M antibodies was negative, with no evidence of acute immune-mediated vasculitis.

Shortly after initiating durvalumab therapy for lung cancer, the patient developed fulminant multisystem immune-mediated adverse effects, including new-onset T1DM with DKA and near-total acute mesenteric ischemia, leaving fewer than 10 cm of viable bowel. Given the futility of further operative intervention, care was transitioned to comfort measures, and he died on hospital day 5.

This case underscores the need for improved understanding of the inflammatory sequelae associated with nonpneumonitis immune-mediated adverse effects of ICIs, their potential contribution to the development of an acute surgical abdomen, and the optimal approach to operative management in this context. Additional studies are needed to identify patients at increased risk for severe imAEs and to determine whether the antineoplastic survival benefit outweighs the risk of potentially fatal complications. Development of validated risk stratification profiles may help prevent administration of ICIs to patients at unacceptably high risk of life-threatening imAEs, such as those observed in this case. Further investigation into the role of immunomodulatory therapies, including infliximab, in mitigating immune toxicity that may ultimately result in severe imAEs is also warranted.

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