Abstract Learning Objectives - Differentiate ICI-related respiratory muscle failure from pneumonitis. - Recognize physiologic markers—declining NIF, rising PaCO2, elevated CK/troponin—as early warning sign - Apply coordinated pulmonary-critical-care and multidisciplinary management for fulminant ICI overlap syndromes. Background Immune checkpoint inhibitors (ICIs) have transformed oncology but can trigger severe immune-related adverse events (irAEs). While pneumonitis is the prototypical pulmonary manifestation, respiratory failure may also arise from immune-mediated injury of the diaphragm and intercostal muscles. The overlap of myocarditis, myositis, and myasthenia (“Triple-M syndrome”) represents the most fulminant form, often leading to hypercapnic respiratory failure despite normal lungs. Case Report An 84-year-old man with BAP-1-deficient epithelioid mesothelioma (PD-L1 positive) received dual ICI therapy with ipilimumab and nivolumab. Three weeks later, he developed fatigue, myalgia, transaminitis, and elevated troponin (1,456 ng/L) without obstructive coronary disease, suggesting ICI myocarditis and myositis (CK 2,404 U/L). He was started on IV methylprednisolone (1 g daily) for suspected myocarditis. When he failed to improve, abatacept and tofacitinib were added. Weakness progressed, with worsening NIF and vital capacity leading to hypercarbia and ventilatory failure requiring intubation. At that point, myocarditis-myositis-myasthenia (MMM) overlap was suspected, and IVIG (2 g/kg over 5 days) plus pyridostigmine was initiated. Despite all measures, he failed to improve. Chest CT showed clear lungs without pneumonitis. Telemetry revealed complete heart block requiring pacing. AChR binding antibody 0.49 nmol/L confirmed autoimmune neuromuscular junction involvement. Despite maximal immunosuppression and CRRT for acute kidney injury, he remained ventilator-dependent and transitioned to comfort care. Discussion This case illustrates a non-pneumonitic mechanism of respiratory failure from immune-mediated paralysis of respiratory musculature in ICI-induced Triple-M overlap. Synchronous injury to myocardium, skeletal, and diaphragmatic muscle reflects shared antigenic cross-reactivity and T-cell-mediated cytotoxicity, forming a continuum of immune myotoxicity rather than isolated irAEs. In our patient, centrally originating weakness, declining NIF, and rising PaCO2 marked early diaphragmatic compromise preceding respiratory collapse despite normal imaging. This mirrors emerging data describing MMM overlap as an aggressive, often irreversible syndrome even with multimodal immunosuppression. ICI-related respiratory failure may masquerade as pulmonary disease while originating from immune myotoxicity of the ventilatory pump. Early recognition of physiologic decline and coordinated, multi-agent immunosuppression within a critical-care framework are essential to prevent irreversible paralysis. Conclusion Triple-M overlap is a catastrophic irAE where respiratory failure results from immune-mediated respiratory muscle paralysis rather than lung inflammation. Prospective monitoring of respiratory mechanics (NIF, VC, PaCO2) after ICI initiation may allow earlier detection before irreversible compromise. This abstract is funded by: none
Kumar et al. (Fri,) studied this question.