In a patient with fever, tachycardia, hypotension and organ dysfunction of unclear cause, when should I order a serum interleukin‑6 (IL‑6) level, what values are considered elevated, and how should the result guide management?

When to Order Serum IL-6 in Critically Ill Patients

Serum IL-6 should NOT be routinely ordered in patients with fever, tachycardia, hypotension, and organ dysfunction of unclear cause, as it lacks validated diagnostic thresholds and does not guide management in general sepsis or critical illness. 1

Clinical Contexts Where IL-6 Testing May Be Appropriate

CAR T-Cell Therapy-Related Cytokine Release Syndrome (CRS)

• Order IL-6 levels in patients who have recently received CAR T-cell therapy (typically within 2-15 days post-infusion) presenting with fever ≥38°C, hypotension, or hypoxia. 1
• IL-6 is a central mediator of CRS, though cytokine levels should not dictate treatment choices and are not required to determine treatment plans. 1
• Extremely elevated IL-6 levels (>2000 pg/mL) indicate severe inflammatory state requiring immediate tocilizumab 8 mg/kg IV. 2
• CRS grading and treatment decisions are based on clinical parameters (fever, hypotension requiring vasopressors, hypoxia requiring oxygen support), not IL-6 values. 1

Multisystem Inflammatory Syndrome in Children (MIS-C)

• In pediatric patients with persistent fever, mucocutaneous lesions, cardiac involvement, and recent SARS-CoV-2 exposure, IL-6 may be measured as part of a cytokine panel, but is not required for diagnosis or treatment decisions. 1
• IL-6 levels are often increased in MIS-C alongside IL-10 and TNF, but elevated levels do not distinguish MIS-C from other inflammatory conditions. 1
• Priority testing includes troponin, BNP/NT-proBNP, echocardiography, and SARS-CoV-2 PCR plus serology. 1, 3

Acute Coronary Syndrome (ACS)

• IL-6 has been studied for risk stratification in ACS, but no validated cut-off values exist (reported ranges from 12 to 2760 pg/mL across studies). 1
• IL-6 should not be used as a routine biomarker in ACS, as evidence is conflicting and clinical utility remains uncertain. 1

IL-6 Values and Interpretation

"Normal" vs. "Elevated" Ranges

• There is no universally accepted reference range for serum IL-6 due to marked assay-dependent variability and high biological variability even in healthy individuals. 4
• ELISA assays show moderate stability (correlation coefficients r = 0.318 to r = 0.707), and different platforms yield different absolute values. 4
• Fasting status, time of day, and acute stressors can transiently elevate IL-6 in healthy individuals. 4

Clinically Significant Elevations

• In COVID-19, IL-6 levels are elevated but typically 10-40 fold less than in pre-pandemic ARDS. 4
• IL-6 >2000 pg/mL in the context of CAR T-cell therapy indicates severe CRS requiring immediate anti-IL-6 therapy. 2
• In intra-abdominal sepsis, studies have used cut-offs ranging from 12 to 2760 pg/mL with inconsistent predictive value. 1

How IL-6 Results Should (and Should Not) Guide Management

When IL-6 Results Matter

• In CAR T-cell therapy patients with Grade 2-4 CRS: Administer tocilizumab 8 mg/kg IV regardless of IL-6 level; repeat in 8 hours if no improvement (maximum 3 doses in 24 hours, 4 total). 1, 2
• For Grade 3-4 CRS or refractory Grade 2: Add dexamethasone 10 mg IV every 6-12 hours in addition to tocilizumab. 1, 2
• If tocilizumab is unavailable, consider siltuximab (direct IL-6 antagonist) or JAK inhibitors (baricitinib) for patients with contraindications. 2

When IL-6 Results Do NOT Guide Management

• In general sepsis or intra-abdominal infections: IL-6 measurement requires further controlled studies before guiding clinical care. 1
• Procalcitonin and C-reactive protein are more established biomarkers for infection monitoring than IL-6. 1
• In MIS-C, treatment with IVIG and corticosteroids is based on clinical criteria, not cytokine levels. 1

Critical Pitfalls to Avoid

Diagnostic Pitfalls

• Do not delay treatment in severe CRS waiting for IL-6 results; early tocilizumab improves outcomes. 2
• Do not use IL-6 as a standalone marker to diagnose sepsis or predict mortality in general critical illness. 1
• Do not interpret a single IL-6 value without clinical context, as levels vary by assay, timing, and patient factors. 4

Treatment Pitfalls

• Do not administer tocilizumab in patients with active, untreated infections. 2
• In COVID-19 patients, do not give tocilizumab without concurrent corticosteroids (dexamethasone). 2
• Do not use IL-6 levels to withhold tocilizumab in clinically severe CRS; treat based on hemodynamic and respiratory status. 1

Monitoring Pitfalls

• Monitor for tocilizumab adverse effects: serious infections, liver enzyme elevations, and gastrointestinal perforations (rare but serious). 2
• Reassess clinical response (fever resolution, hemodynamic stability) rather than repeat IL-6 levels to guide ongoing therapy. 2

Practical Algorithm for IL-6 Testing

Step 1: Identify the clinical context

• Recent CAR T-cell therapy (within 2-15 days)? → Consider IL-6 if CRS suspected
• Pediatric patient with fever, rash, cardiac involvement, recent COVID-19? → IL-6 optional as part of MIS-C workup
• General sepsis/critical illness? → Do not order IL-6

Step 2: If ordering IL-6, order simultaneously:

• For CRS: CBC, CMP, CRP, ferritin, LDH, procalcitonin, troponin, BNP 1
• For MIS-C: Troponin, BNP, echocardiogram, SARS-CoV-2 PCR + serology 1, 3

Step 3: Treat based on clinical severity, not IL-6 value

• CRS Grade 2-4: Tocilizumab ± dexamethasone 1, 2
• MIS-C: IVIG + corticosteroids per ACR guidelines 1

Step 4: Monitor clinical response, not serial IL-6 levels 2