Bilateral diaphragmatic palsy following Nivolumab–Ipilimumab therapy: A rare respiratory complication of immune checkpoint inhibitors

Dear Editor, Immune checkpoint inhibitors (ICIs), including programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) inhibitors, have significantly transformed cancer therapy. However, these agents are associated with immune-related adverse events (irAEs), which have been reported in approximately 10%–30% of patients undergoing treatment, depending on the specific agent and tumour type.[1] The most common pulmonary irAEs typically present as pneumonitis; nevertheless, neuromuscular complications, such as myositis, neuropathies, and overlap syndromes, are increasingly recognised and are associated with substantial morbidity and mortality.[2,3] Isolated bilateral diaphragmatic palsy remains exceedingly rare, with only sporadic cases documented in the literature.[4-7] A 69-year-old male with metastatic acral amelanotic melanoma of the left great toe, with skeletal and pulmonary metastases, was commenced on combination therapy with nivolumab and ipilimumab. Treatment was discontinued after three cycles due to grade III transaminasemia, with the final dose administered in July 2025. Approximately four weeks later, he developed rapidly progressive orthopnoea without exertional dyspnoea and became unable to lie in a supine position, thereby requiring hospital admission. Upon examination, the patient exhibited tachypnoea accompanied by the use of accessory muscles and demonstrated paradoxical inward movement of the abdomen during inspiration. The oxygen saturation was 97% on room air. Chest auscultation yielded normal findings, and the cardiovascular assessment revealed no abnormalities. Neurological evaluation showed no evidence of ptosis, bulbar weakness, limb weakness, or focal deficit. Arterial blood gas analysis demonstrated mild hypoxemia without hypercapnia. Chest radiography revealed bilateral elevation of the hemidiaphragms, reduced lung volumes, and no pulmonary infiltrates [Figure 1]. Bedside diaphragm ultrasound and fluoroscopic examination confirmed markedly reduced bilateral diaphragmatic excursion [Figure 2]. Spirometry revealed a restrictive ventilatory defect with a forced vital capacity of 45% predicted, although supine manoeuvres could not be performed due to severe orthopnoea. Laboratory evaluation showed elevated serum creatine kinase levels (1350 U/L) with normal troponin levels. Cerebrospinal fluid analysis demonstrated mild lymphocytic pleocytosis without features of inflammatory demyelinating neuropathy. Transthoracic echocardiography revealed preserved left ventricular systolic function, excluding myocarditis. Electrophysiological studies showed reduced phrenic nerve compound muscle action potentials, consistent with diaphragmatic myopathy. Contrast-enhanced computed tomography of the chest demonstrated pulmonary metastases with basal atelectasis attributable to impaired diaphragmatic motion [Figure 3].Figure 1: Chest radiograph showing bilateral elevation of the hemidiaphragms with reduced lung volumes and no pulmonary infiltrates or pleural effusionFigure 2: Fluoroscopy demonstrating reduced diaphragmatic excursion consistent with bilateral diaphragmatic palsyFigure 3: CT chest showing bilateral decreased lung volumes due to diaphragmatic palsyAlternative diagnoses, including pneumonia, mediastinal compression, heart failure, neuromuscular junction disorders, and inflammatory polyneuropathies, were excluded based on clinical, radiological, and laboratory findings. The temporal association with ICI therapy, elevated creatine kinase levels, and electrophysiological findings supported a diagnosis of immune-mediated bilateral diaphragmatic palsy. The patient was treated with high-dose intravenous methylprednisolone followed by oral corticosteroids, in accordance with current irAE management guidelines.[1] Noninvasive bilevel positive airway pressure support was instituted, providing symptomatic relief during sleep and when lying in bed. Due to an incomplete clinical response, intravenous immunoglobulin was administered. Despite aggressive immunosuppression, diaphragmatic weakness persisted, and the patient required long-term nocturnal ventilatory support. Neurological irAEs occur in fewer than 1% of patients receiving ICIs but are associated with disproportionately high mortality.[2] Diaphragmatic dysfunction is thought to result from immune-mediated myositis or phrenic neuropathy, with histopathological studies demonstrating CD8-positive lymphocytic infiltration and muscle fibre necrosis.[4,5] Prior case series have reported severe orthopnoea, paradoxical respiration, and prolonged ventilator dependence despite immunosuppressive therapy.[6-8] Early recognition is critical, as delayed diagnosis may lead to fatal hypercapnic respiratory failure. Bedside diaphragm ultrasound is a rapid, noninvasive diagnostic tool and should be considered in ICI-treated patients presenting with unexplained orthopnoea or respiratory failure.[9] Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.