1. Clinical Manifestations of CRS

CRS presents acutely after CAR-T or bispecific antibody infusion with fever, hemodynamic instability, hypoxia, and evolving organ dysfunction. Early recognition of these patterns is critical to prompt intervention.

A. Fever Patterns & Constitutional Symptoms

• Hallmark: Temperature ≥ 38 °C, typically with an onset 1–7 days post-infusion.
• Patterns: Can be intermittent or sustained with spiking fevers; often precedes the onset of hypotension and hypoxia.
• Constitutional Symptoms: Rigors, malaise, anorexia, and myalgias are common, mimicking a severe infection, but the tempo is linked to cellular therapy kinetics.

B. Hemodynamic Changes: The Hypotension Spectrum

• Grade 2 CRS: Characterized by fluid-responsive hypotension, where a mean arterial pressure (MAP) ≥ 65 mm Hg can be maintained with ≤ 2 L of crystalloid bolus.
• Grade 3–4 CRS: Defined by vasoplegia requiring vasopressor support. Norepinephrine is the first-line agent, with vasopressin considered as an add-on for refractory vasodilation.
• Fluid Strategy: Judicious use of balanced crystalloids is key. The goal is to restore perfusion without exacerbating fluid overload in the context of capillary leak.

C. Respiratory Involvement: Hypoxia & ARDS-like Features

• Grade 2: Requires low-flow oxygen via nasal cannula (NC) at ≤ 6 L/min.
• Grade 3: Escalation to high-flow nasal cannula (HFNC) or noninvasive ventilation (NIV) is required.
• Grade 4: Defined by the need for mechanical ventilation. Lung-protective settings (tidal volumes of 4–6 mL/kg ideal body weight and appropriate PEEP titration) are crucial.

D. Multi-Organ Dysfunction

• Hepatic: Transaminitis (AST/ALT elevations 5–10× the upper limit of normal), hyperbilirubinemia, and coagulopathy are common.
• Renal: Acute kidney injury (AKI) per KDIGO criteria can develop. Early consideration of continuous renal replacement therapy (CRRT) can aid in volume control and potential cytokine clearance.
• Neurologic: Mild encephalopathy may occur and can overlap with Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Close monitoring of the ICE score and mental status is essential.

Case Vignette: A 62-year-old patient, post CAR-T infusion, develops an AST of 450 U/L, creatinine of 2.1 mg/dL, and has an episode of transient hypotension responsive to fluids. This clinical picture warrants initiation of the Grade 3 CRS pathway, including consideration of early CRRT for progressive organ injury.

2. Laboratory & Biomarker Assessment

Laboratory assays are crucial for supporting the diagnosis of CRS and stratifying its severity. However, clinicians must be aware of their limitations, including turnaround time, specificity, and availability.

A. Cytokine Assays (IL-6, IL-10, IFN-γ)

• Interleukin-6 (IL-6): Levels typically peak 2–3 days post-infusion and correlate with CRS severity. However, a 24–48 hour turnaround time limits its utility for real-time decision-making.
• IL-10 & IFN-γ: These are complementary markers, but they share similar cost and turnaround time limitations as IL-6.
• Point-of-Care (POC): Emerging POC platforms for cytokine measurement are currently under validation and not yet standard of care.

B. Acute Phase Reactants (CRP, Ferritin)

• C-Reactive Protein (CRP): Levels begin to rise 12–24 hours after CRS onset, closely paralleling the kinetics of IL-6.
• Ferritin: Can exceed 10,000 ng/mL in severe CRS, but this finding is nonspecific and can be seen in other hyperinflammatory states.
• Monitoring: The trend of these markers over time is more informative for tracking disease activity and response to therapy than any single absolute value.

C. Organ Function Panels

• Chemistry: Serial monitoring of AST, ALT, bilirubin, creatinine, and BUN is essential.
• Coagulation: INR, aPTT, fibrinogen, and D-dimer should be checked to screen for disseminated intravascular coagulation (DIC).
• Frequency: Daily monitoring in patients with Grade 3–4 CRS is critical to uncover early organ injury and guide supportive care measures.

D. Emerging Biomarkers & POC Testing

Soluble CD25 (sCD25), angiopoietin-2, and microfluidic cytokine assays show promise in research settings but currently lack the multicenter validation needed for routine clinical use.

3. Classification Systems for CRS

Standardized grading systems are essential for harmonizing clinical trial reporting, facilitating clear communication between providers, and guiding the urgency of management. The American Society for Transplantation and Cellular Therapy (ASTCT) criteria are the current gold standard.

A. ASTCT Consensus Grading (2019)

The single required feature for grading is a fever ≥ 38 °C. Grading is then determined by the severity of hypotension and/or hypoxia.

Note: Pediatric oxygen and fluid thresholds are typically lower. Always check institutional protocols for age-based adjustments.

B. Alternative Grading Scales

While ASTCT is the standard, other systems exist. The Lee et al. (2014) system was an early five-grade scale that incorporated organ dysfunction beyond just hypotension and hypoxia. Frameworks from SITC and in the EU also exist, often adding specific hepatic and renal criteria, but the core differences are minor.

C. Impact on Management

• Grade 1–2: Management is primarily supportive (antipyretics, fluids).
• Persistent Grade 2 or Grade 3: Warrants early administration of tocilizumab. Corticosteroids should be added for refractory symptoms.
• Grade 4: Requires aggressive, combined therapy with IL-6 blockade (tocilizumab) and high-dose corticosteroids in an ICU setting.

4. Differential Diagnosis

It is critical to distinguish CRS from its clinical mimics. The differential diagnosis is guided by the timing of symptom onset relative to infusion, specific laboratory profiles, and the overall clinical context.

A. Sepsis / Systemic Inflammatory Response Syndrome (SIRS)

• Clinical Overlap: Fever, hypotension, tachycardia, and organ dysfunction are common to both.
• Key Differentiators: CRS onset is temporally linked to cell infusion, often in the absence of a clear infectious source. The cytokine profile, if available, is distinct.
• Initial Workup: Always includes blood cultures, procalcitonin, and lactate measurement. Empirical antibiotics should be administered until infection is reasonably excluded.

B. Hemophagocytic Lymphohistiocytosis (HLH) / Macrophage Activation Syndrome (MAS)

C. Tumor Lysis Syndrome (TLS) & Other Mimics

5. Clinical Decision Algorithms

Algorithmic approaches that integrate clinical signs and biomarkers are being developed to improve risk stratification and optimize the timing of immunomodulatory interventions.

A. Integrated Scoring Systems

Predictive models, such as the one developed by Komanduri et al., assign points based on early clinical and laboratory data to generate a risk score. This approach aims to identify high-risk patients before they clinically deteriorate.

B. Early vs. Delayed Classification

A key challenge is determining the optimal time to formally grade CRS. Early classification may lead to overtreatment of transient symptoms, while delayed classification risks life-threatening progression. Currently, no consensus exists on the optimal timing beyond the initial onset of fever.

C. Biomarkers in Clinical Workflows

The integration of biomarkers into real-time clinical workflows remains largely investigational. Some centers are piloting EHR-based alerts that combine vital sign changes with laboratory trends to prompt clinicians to perform a formal CRS grading. However, clinical grading remains the standard of care, as real-time cytokine monitoring has not yet been proven to improve outcomes.