Triple M overlap syndrome in the intensive care unit: differential diagnosis and management

Immune checkpoint inhibitors (ICIs) are increasingly used as first-line therapy for various malignancies and are associated with a growing spectrum of immune-related adverse events. While many toxicities are managed in the outpatient setting, a clinically significant subset progresses to life-threatening multisystem disease requiring intensive care. Among these, the Triple M overlap syndrome, characterized by concurrent myasthenia gravis-like disease, inflammatory myositis, and myocarditis, represents the most severe and lethal phenotype encountered in critical care.

Triple M overlap syndrome presents unique diagnostic and management challenges in critically ill patients. Clinical features frequently overlap with sepsis, pneumonia, thromboembolism, and cardiopulmonary disease, creating significant diagnostic uncertainty. In addition, traditional diagnostic tools such as myasthenia gravis antibody testing and early cardiac imaging may be normal or nondiagnostic early in the disease course. This review focuses on the recognition and management of Triple M overlap syndrome in the intensive care unit. We highlight key diagnostic pitfalls, including the frequent under-recognition of occult myocarditis and the limitations of electrophysiologic and serologic testing. A structured ICU-oriented approach is proposed, emphasizing early multisystem evaluation with creatine kinase, serial troponins, electrocardiography, and cardiac imaging, alongside concurrent assessment for infection. Management strategies include prompt discontinuation of ICIs, early initiation of corticosteroids, and escalation to intravenous immunoglobulin or plasma exchange for severe neuromuscular involvement. Cardiac complications require close monitoring and early immunosuppression. Targeted therapies such as abatacept are discussed in the context of myocarditis, with current evidence limited primarily to cardiac involvement. This review emphasizes a practical ICU-oriented framework incorporating parallel evaluation for immune-mediated toxicity and infection in critically ill patients.

Triple M overlap syndrome represents a high-risk and often underrecognized manifestation of ICI toxicity in critically ill patients. Early recognition, parallel evaluation for infection and immune-mediated disease, and coordinated multisystem management are essential to improving outcomes. Greater awareness and structured diagnostic approaches may reduce delays in treatment and associated mortality.