How to manage Nivolumab (nivolumab)-induced fever?

Management of Nivolumab-Induced Fever

Nivolumab-induced fever should be promptly reported to healthcare providers, carefully monitored, and treated with antipyretics and corticosteroids if severe or persistent, as it can be an early sign of immune-related adverse events requiring immediate attention. 1

Clinical Presentation and Timing

• Nivolumab-induced fever typically occurs early in treatment, often within hours to days after administration, and should be considered an important immune-related adverse event (irAE) requiring monitoring 2, 3
• Fever may present as an isolated symptom or can be accompanied by other symptoms indicating potential organ inflammation 1
• Patients may develop fever as early as several hours after the first infusion, which can persist for several days 3, 4

Initial Assessment

• Evaluate for potential concurrent irAEs affecting other organ systems, as fever may be the first sign of a more serious immune-mediated reaction 1
• Rule out infection with appropriate laboratory tests (complete blood count, blood cultures, urinalysis) and imaging studies as needed 1
• Consider checking inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) to assess severity 3, 4
• Monitor vital signs and assess for signs of dehydration or hemodynamic instability 1

Management Algorithm

Grade 1 (Mild Fever <38.5°C)

• Continue nivolumab therapy with close monitoring 1
• Administer antipyretics such as acetaminophen as needed 1
• Ensure adequate hydration 1
• Educate patient to report worsening symptoms immediately 1

Grade 2 (Moderate Fever 38.5-40°C)

• Consider temporarily withholding nivolumab until fever resolves 1
• Administer antipyretics on a scheduled basis 1
• Monitor for signs of other emerging irAEs 1
• If fever persists >3 days despite antipyretics, consider low-dose corticosteroids (prednisone 0.5-1 mg/kg/day) 1

Grade 3-4 (Severe Fever >40°C or Fever with Complications)

• Immediately withhold nivolumab 1
• Initiate high-dose corticosteroids (prednisone 1-2 mg/kg/day or methylprednisolone equivalent) 1, 4
• Consider hospitalization for monitoring and supportive care 1
• Taper steroids slowly over at least 4-6 weeks once symptoms resolve 1
• Permanently discontinue nivolumab if fever is accompanied by life-threatening complications 1

Special Considerations

• Be vigilant for fever accompanied by specific organ-related symptoms that may indicate serious irAEs:

  • Respiratory: shortness of breath, cough (pneumonitis) 1
  • Gastrointestinal: diarrhea, abdominal pain (colitis) 1
  • Musculoskeletal: joint pain, morning stiffness (inflammatory arthritis, polymyalgia rheumatica) 5
  • Cardiac: chest pain, dyspnea (myocarditis, pericardial effusion) 6, 4
  • Renal: decreased urine output, edema (nephritis) 2
  • Hematologic: easy bruising, bleeding (thrombocytopenia) 3

• Fever with rash may indicate severe cutaneous adverse reactions requiring dermatology consultation 1

Monitoring and Follow-up

• After resolution of fever, closely monitor for recurrence when restarting nivolumab or tapering steroids 1
• Consider prophylactic antibiotics in patients requiring prolonged immunosuppression with corticosteroids 1
• If fever recurs upon rechallenge with nivolumab, consider permanent discontinuation 1
• Monitor for steroid-related side effects in patients requiring prolonged treatment 1

Patient Education

• Provide patients with an "Immunotherapy Patient Card" detailing potential side effects and when to seek medical attention 1
• Instruct patients to report any fever >38°C immediately, especially within the first weeks of treatment 1
• Emphasize that fever can occur at any time during treatment or even after discontinuation 1
• Advise against self-management of symptoms without consulting healthcare providers 1

Common Pitfalls and Caveats

• Do not assume fever is always due to infection; consider immune-related mechanisms 1
• Avoid delaying corticosteroid treatment in patients with persistent or high-grade fever, as early intervention is crucial 1
• Remember that fever may be the first manifestation of potentially life-threatening irAEs such as myocarditis, which can progress rapidly 6
• Be aware that fever can occur with combination immunotherapy (nivolumab plus ipilimumab) with higher frequency and severity 1
• Consider that patients with pre-existing autoimmune conditions may be at higher risk for developing fever and other irAEs 1