Severe Cytokine Release Syndrome and Immune Effector Cell-associated Neurotoxicity Syndrome in a Man Receiving Immune Checkpoint Inhibitors for Lung Cancer

Abstract

A 55-year-old man with stage IV lung adenocarcinoma was treated with cisplatin, pemetrexed, nivolumab, and ipilimumab. Approximately 100 days after treatment initiation, he became disoriented and presented to the emergency department with a high fever. Blood tests revealed liver and kidney dysfunctions. Subsequently, the patient developed generalized convulsions that required intensive care. He was clinically diagnosed with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Organ damage was gradually controlled with immunosuppressive drugs, including steroids, and the patient was discharged. Successful treatment is rare in patients with CRS, including ICANS, during immune checkpoint inhibitor treatment for solid tumors.

Keywords: cytokine release syndrome; immune checkpoint inhibitor; immune effector cell-associated neurotoxicity syndrome; ipilimumab; nivolumab.

Figure 1.

Computed tomography findings at the time of the lung cancer diagnosis. The nodular shadow in the right lower lobe of the lung (yellow arrows) is thought to be the primary tumor. The peripheral shadow (red arrows) is thought to be a pleural metastasis. Fluorodeoxyglucose-positron emission tomography (FDG-PET) shows a nodular shadow in the liver (red arrowheads).

Figure 2.

Computed tomography findings at the time of admission. The nodular shadow in the right lower lobe of the lung (yellow arrows), thought to be the primary tumor, was smaller than in the previous image. The kidneys are markedly enlarged (red circles), but there are no signs of obstructive hydronephrosis.

Figure 3.

Magnetic resonance imaging on admission. The cerebral sulcus is narrowed (yellow arrows), reflecting brain swelling.

Figure 4.

Timeline of the patient’s clinical course and laboratory values. The patient developed a skin rash and fever after the fifth nivolumab dose. Sepsis or some form of immune-related adverse event (irAE) was suspected on the day of the emergency room visit based on laboratory abnormalities. Blood cultures were obtained, and treatment with meropenem and 1 g of methylprednisolone was initiated. On the day of admission, the patient’s consciousness was clouded, and he developed generalized convulsions; therefore, he was intubated, and mechanical ventilation was initiated. He was also hypotensive; therefore, he was treated with vasopressors; within one day, his blood pressure recovered to within the normal range. However, his renal function was poor; therefore, continuous hemodiafiltration (CHDF) was continued until his renal function recovered. We attempted to decrease the prednisone dose, but his temperature remained elevated; therefore, we increased the steroid dose from 1 to 2 mg/kg and administered daptomycin in combination with cyclophosphamide and intravenous immunoglobulin. With multidisciplinary treatment, the patient’s liver and kidney functions slowly improved, and he was weaned off dialysis. The patient was discharged 47 days after admission and continued to receive prednisone (1 mg/kg/day) after discharge.