MON-070 - Immune Checkpoint Inhibitor-Induced Multisystem Endocrinopathies with Recurrent Septic Shock-Like Presentations: Diagnostic and Therapeutic Challenges

Immune checkpoint inhibitors (ICIs), including CTLA-4 and PD-1 inhibitors are associated with immune-related endocrinopathies that may involve multiple endocrine axes. While hypophysitis with central adrenal insufficiency (CAI) is well recognized, concurrent multisystem endocrine toxicities remain underappreciated. Adrenal crisis may present with fever, hypotension, and encephalopathy, closely mimicking septic shock leading to recurrent hospitalizations when unrecognized.

A 64-year-old man with recurrent mucosal melanoma treated with combination ipilimumab and nivolumab presented shortly after his fourth cycle with fever, confusion, and profound weakness. Evaluation revealed hypopituitarism with central hypothyroidism [TSH 0.196 mIU/mL (n = 0.3- 5 mIU/mL), free T4 0.6 (n = 0.7- 1.9 ng/mL)], secondary adrenal insufficiency [random cortisol 2 µg/dL (n = 4- 19 µg/dL), ACTH < 5 (n = 7.2- 63 pg/mL)], hypogonadotropic hypogonadism [total testosterone 8 ( n =221- 796 ng/dL), FSH 1.9 (n = 1- 12 mIU/ mL), LH < 1 (n = 0.5- 12.1 mIU/mL), and hyponatremia [sodium 126 (n= 136- 145 mmol/L)] . He was treated with intravenous glucocorticoids followed by physiologic hydrocortisone replacement and levothyroxine.

Within weeks, he developed ICI–associated type 1 diabetes mellitus with positive GAD65 antibodies. Over subsequent months, he experienced multiple recurrent hospitalizations labeled as sepsis or septic shock, often with hypotension, and encephalopathy. Infectious evaluations were repeatedly unrevealing. Each episode demonstrated rapid clinical improvement following stress-dose glucocorticoids, while antimicrobial therapy yielded no clear sustained benefit. The recurrent pattern of shock physiology with brisk steroid responsiveness suggested adrenal crisis rather than true sepsis. His outpatient glucocorticoid regimen was transitioned from hydrocortisone to once-daily prednisone to improve coverage given hydrocortisone’s short half-life and concern for insufficient dosing during intercurrent illness. Following this change, no further hospitalizations for recurrent shock-like episodes occurred.

This case highlights the potential for ICIs to cause concurrent, multisystem endocrine toxicities, including hypophysitis, autoimmune diabetes, and recurrent adrenal crisis masquerading as septic shock. Recognition of stereotyped presentations, negative infectious evaluations, and rapid responsiveness to glucocorticoids is critical. Interindividual variability in glucocorticoid pharmacokinetics, and adherence challenges with multiple daily dosing, may predispose patients to recurrent decompensation despite apparently adequate replacement. In high-risk patients with ICI–induced CAI, individualized glucocorticoid selection, including consideration of longer-acting agents, may reduce life-threatening presentations.

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