Background: Cytokine Release Syndrome (CRS) is an acute inflammatory response syndrome marked by fever and/or multiorgan dysfunction and increased inflammatory cytokine release. CRS is generally observed in patients receiving CAR-T cell therapy, bispecific T cell engager therapy, or haploidentical hematopoietic cell transplantation. We present an intriguing case of Grade-3 CRS in a patient who recently contracted COVID-19 and was taking pembrolizumab.

Case Presentation: A 67-year-old man presented to the hospital with complaints of nausea, vomiting, diarrhea, and fever for two weeks. His family reported intermittent confusion, anorexia, and weight loss before hospital admission. Medical history was significant for metastatic renal cell carcinoma on pembrolizumab with axitinib for one year, CKD stage 3A, hypertension, left-sided nephrectomy, and recent COVID-19 infection four weeks ago. Physical examination revealed fever, tachycardia, tachypnea, and delirium. He was initially treated for severe sepsis with broad-spectrum antibiotic therapy but subsequently transferred to ICU for hypotension, and worsening delirium. Workup showed negative blood culture, urine culture, fungal culture, CSF culture, MRI brain, autoimmune connective tissue cascade, and paraneoplastic panel, albeit CRP was elevated to 239.3 mg/L. Due to worsening delirium, hypotension, and recent immunotherapy, there was clinical suspicion of CRS. Interleukin-6 level testing was ordered, and an elevated level of 1088 pg/mL was confirmed. He was given IV methyl prednisone 1 mg/kg on Day 7 of hospital admission, which improved his hypotension and minimal improvement in delirium. On Day 11, a one-time dose of tocilizumab was administered, and rapid resolution of delirium along with significant clinical improvement. After discharge, the oncology team discontinued pembrolizumab and started second-line therapy with cabozantinib.

Discussion: CRS is a frequently observed phenomenon in patients receiving CAR T-cell therapy and bispecific antibody therapies, often presenting with high fever, multiorgan failure, and elevated serum IL6 levels. Pembrolizumab is an immune checkpoint inhibitor (CPI), and several cases of CRS are reported in patients receiving this treatment. COVID-19 vaccination in patients receiving CPI therapy has been attributed to causing CRS-like symptoms in several reports. We observed a unique phenomenon in our patient who was receiving pembrolizumab for one year without side effects and presented with acute CRS after COVID-19 infection. Our literature review identified one other case of a patient presenting with acute COVID-19 infection, CRS symptoms, and colitis while receiving nivolumab/ipilimumab therapy. However, our patient had a delayed onset of CRS. Incidence of CRS is rare but has high mortality and requires prompt identification and treatment.