Guideline Recommendations for Serum IL‑6 Testing in Critically Ill Patients

1. General Critical Illness and Sepsis

Routine measurement of serum IL‑6 in patients with fever, tachycardia, hypotension, and organ dysfunction of unclear cause is not recommended because validated diagnostic thresholds are lacking and the result does not alter management of sepsis or general critical illness. [@1]
IL‑6 should not be used as a standalone biomarker to diagnose sepsis or predict mortality; procalcitonin and C‑reactive protein remain the more established infection markers. [@1]
Current evidence indicates that IL‑6 measurement in intra‑abdominal sepsis or other infections requires further controlled studies before it can guide clinical decisions. [@1]

In patients who have received CAR T‑cell therapy within 2–15 days and present with fever ≥ 38 °C, hypotension, or hypoxia, serum IL‑6 may be ordered as part of the CRS work‑up. [@2][@3]
IL‑6 is a central mediator of CRS, but treatment decisions should be based on clinical severity (fever, vasopressor requirement, oxygen support) rather than IL‑6 levels. [@2][@3]
An IL‑6 concentration > 2000 pg/mL signals a severe inflammatory state and warrants immediate administration of tocilizumab 8 mg/kg IV. [@5]
For Grade 2–4 CRS, give tocilizumab 8 mg/kg IV regardless of IL‑6 value; repeat after 8 h if no improvement (maximum 3 doses in 24 h, up to 4 total). [@2][@3][@5]
For Grade 3–4 CRS or refractory Grade 2, add dexamethasone 10 mg IV every 6–12 h in addition to tocilizumab. [@2][@3][@5]
If tocilizumab is unavailable, consider alternative IL‑6 pathway inhibitors such as siltuximab or JAK inhibitors (e.g., baricitinib) for patients with contraindications to tocilizumab. [@5]
Do not delay anti‑IL‑6 therapy while awaiting IL‑6 results; early tocilizumab improves outcomes. [@5]
Do not withhold tocilizumab in clinically severe CRS based on IL‑6 values; treat according to hemodynamic and respiratory status. [@2][@3]
Contraindication: Avoid tocilizumab in patients with active, untreated infections. [@5]

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 broader cytokine panel, but it is not required for diagnosis or therapeutic decisions. [@4]
Elevated IL‑6 (often alongside IL‑10 and TNF) does not differentiate MIS‑C from other inflammatory conditions. [@4]
Priority diagnostic tests for MIS‑C include troponin, BNP/NT‑proBNP, echocardiography, and SARS‑CoV‑2 PCR + serology. [@4]
Treatment (IVIG ± corticosteroids) is guided by clinical criteria per the American College of Rheumatology, not by cytokine levels. [@4]

Studies of IL‑6 for risk stratification in ACS report a wide range of concentrations (12–2760 pg/mL) with no validated cut‑off; therefore, IL‑6 should not be used routinely as a biomarker in ACS. [@1]
The evidence regarding IL‑6’s prognostic utility in ACS is conflicting and uncertain, precluding its incorporation into standard care pathways. [@7]

No universally accepted reference range exists for serum IL‑6 because of assay‑dependent variability and high biological variability even among healthy individuals. [@8]
ELISA platforms demonstrate moderate analytical stability (correlation coefficients r ≈ 0.3–0.7); different assay kits can yield disparate absolute values. [@8]
Factors such as fasting status, circadian timing, and acute stress can transiently raise IL‑6 in otherwise healthy persons. [@8]
In COVID‑19, IL‑6 elevations are typically 10–40 fold lower than those observed in pre‑pandemic ARDS. [@8]

After tocilizumab administration, monitor for serious infections, hepatic enzyme elevations, and rare gastrointestinal perforations. [@5]
Clinical response (resolution of fever, hemodynamic stability) should be used to guide ongoing therapy; repeat IL‑6 measurements are not required for monitoring. [@5]

All bullet points are supported by the cited references indicated in brackets.