When Immunotherapy Meets COVID-19: A Perfect Storm for Adrenal Crisis

Introduction: Pembrolizumab, a PD-1 immune checkpoint inhibitor (ICI) used in immunotherapy, can cause rare but fatal immune-related adverse events such as adrenal insufficiency. This toxicity may manifest insidiously with nonspecific symptoms and can lead to life-threatening adrenal crisis if unrecognized. COVID-19 infection can also lead to injury to the adrenal axis, possibly potentiating adrenal insufficiency in patients on immunotherapy.


Description: We present an 83-year-old man with metastatic melanoma on pembrolizumab who presented with progressive weakness, hypotension, and electrolyte abnormalities (hyponatremia, hyperkalemia). Initial management addressed presumed dehydration and infection with intravenous fluids and broad-spectrum antibiotics. Despite transient improvement, his course was complicated by recurrent hypotension, respiratory failure necessitating intubation, and persistent hyponatremia. Workup revealed a concurrent COVID-19 infection with secondary pneumonia. On hospital day 21, worsening hypotension and hyponatremia (sodium 120 mmol/L) prompted evaluation for adrenal crisis. An ACTH stimulation test confirmed adrenal insufficiency. High-dose intravenous hydrocortisone administration resulted in fast recovery of blood pressure together with sodium levels.  The adrenal insufficiency was attributed to pembrolizumab-induced adrenalitis, likely exacerbated by ongoing COVID-19 infection.


Discussion: Immunotherapy agents can trigger autoimmune destruction of endocrine organs. Pembrolizumab-induced adrenal insufficiency typically arises weeks to months into therapy with nonspecific symptoms (fatigue, hypotension, hyponatremia) and can progress to adrenal crisis if untreated. The hypothalamic-pituitary-adrenal axis becomes further disrupted by COVID-19 through direct adrenal invasion, coagulopathy and cytokine storm worsening adrenal dysfunction. The case demonstrates why ICI-treated patients need regular endocrine monitoring and healthcare providers must strongly suspect adrenal insufficiency. The prompt administration of corticosteroids along with early diagnosis remains essential for preventing serious consequences. Artificial intelligence was utilized to support the drafting of the abstract in the preparation of this case report.