Novel Systematic Review Ideas: Biologics and Cytokine Release Syndrome
High-Priority Research Gaps
1. Comparative Effectiveness of IL-6 Antagonists in CRS Management
Conduct a systematic review and network meta-analysis comparing tocilizumab, siltuximab, and clazakizumab for CRS treatment across different etiologies (CAR T-cell therapy, bispecific antibodies, COVID-19). Current guidelines acknowledge that no direct comparative studies exist between available IL-6 antagonists 1. This represents a critical knowledge gap, as tocilizumab is the only FDA-approved agent for CRS 2, yet alternatives are used when tocilizumab is unavailable or refractory 1, 3. The review should stratify by CRS grade (using ASTCT consensus criteria), underlying disease, and timing of intervention to determine if specific IL-6 antagonists demonstrate superior efficacy in particular clinical contexts 1.
2. Predictive Biomarker Algorithms for CRS Severity Stratification
Develop and validate a systematic review of combinatorial biomarker models that predict severe CRS before clinical deterioration. While individual biomarkers (IL-6, IFN-γ, ferritin, CRP) are elevated in CRS 1, 4, combinatorial algorithms show superior predictive accuracy 4. A systematic review synthesizing existing biomarker data across CAR T-cell products, bispecific antibodies, and other immune therapies could identify optimal biomarker panels for early intervention 4, 5. This is particularly urgent given that extremely elevated IL-6 levels (>2000 pg/mL) indicate severe inflammatory states with high mortality risk 3, yet current management relies primarily on clinical grading rather than laboratory thresholds 1.
3. Optimal Timing and Sequencing of Immunosuppression in CRS
Systematically review the impact of early versus delayed tocilizumab and corticosteroid administration on CRS outcomes and underlying disease response. Current guidelines recommend tocilizumab for grade 2-4 CRS with corticosteroids added for grade 3-4 or refractory cases 1, 3, but the optimal timing remains unclear. Early aggressive immunosuppression could limit therapeutic efficacy of the underlying immunotherapy 6, while delayed treatment increases mortality risk 3. A systematic review examining time-to-treatment intervals, CRS resolution rates, and long-term disease outcomes would inform evidence-based treatment algorithms 1.
4. Biologic Therapy Selection in Chronic Rhinosinusitis: Comparative Effectiveness
Compare efficacy, safety, and cost-effectiveness of available biologics (dupilumab, omalizumab, mepolizumab) for CRSwNP versus aspirin desensitization. The EPOS 2020 guidelines explicitly identify the need to "establish whether aspirin desensitization or biologics has better efficacy in patients with N-ERD" 1. Current evidence shows biologics improve endoscopic polyp scores and symptoms in CRSwNP 7, but head-to-head comparisons are lacking 1. This review should also address the critical question of whether biological treatment is lifelong and how to choose between different biological treatments 1.
5. Differentiation of CRS from Sepsis in Immunotherapy Recipients
Systematically review diagnostic criteria and biomarker profiles that distinguish CRS from sepsis in critically ill patients receiving immune effector cell therapies. Patients receiving CAR T-cell therapy face dual risks of CRS and sepsis 5, yet clinical presentations overlap significantly 1. Recent data demonstrate that IFN-γ and IL-1β combinations can differentiate CRS from sepsis with 97% accuracy 5. A systematic review consolidating cytokine profiles, clinical parameters, and microbiologic data across studies would establish validated diagnostic algorithms to prevent inappropriate treatment delays 1, 5.
6. Long-Term Outcomes and Durability of Biologic Response in CRS
Examine long-term efficacy, safety, and treatment discontinuation strategies for biologics in chronic rhinosinusitis. The EPOS 2020 guidelines specifically call for "studies with larger populations and longer follow-up for all biologics" and ask "is biological treatment life long?" 1. Current systematic reviews show short-term efficacy of biologics in CRSwNP 7, but data on treatment duration, relapse rates after discontinuation, and long-term safety profiles are insufficient 1. This review should also address age-based treatment shifts and potential autoimmunity effects 1.
7. Combination Strategies: Surgery Plus Biologics in CRS
Systematically evaluate the optimal integration of endoscopic sinus surgery with biologic therapy for CRSwNP. EPOS 2020 explicitly identifies the need to determine "how to choose between or combine surgery and biologicals" 1. No current studies address this critical clinical question 1, 7. The review should examine whether biologics reduce surgical need, whether surgery enhances biologic response, optimal timing of each intervention, and whether specific endotypes predict differential responses to combined approaches 1.
8. Novel Anti-Cytokine Agents Beyond IL-6 Blockade for CRS
Review emerging therapies targeting alternative cytokine pathways (IL-1, JAK inhibitors) for CRS management. While tocilizumab dominates CRS treatment 1, 2, anakinra (IL-1 receptor antagonist) shows promise in high-grade CRS 1, and baricitinib (JAK inhibitor) may block downstream IL-6 signaling while inhibiting viral entry 1, 3. A systematic review of these alternative mechanisms could identify second-line agents for tocilizumab-refractory CRS or patients with contraindications to IL-6 blockade 3.
9. CRS in Bispecific Antibody Therapy: Distinct Pathophysiology and Management
Compare CRS characteristics, severity, and optimal management between CAR T-cell therapy and T-cell engaging bispecific antibodies. Emerging evidence suggests CRS incidence and severity differ between these platforms, with bispecific antibodies potentially causing lower-grade CRS but requiring agent-specific management protocols 1. Current guidelines acknowledge these differences but lack systematic comparative data 1. This review should examine whether management strategies validated for CAR T-cell CRS apply to bispecific antibody-induced CRS 1.
10. Pediatric-Specific CRS Management Strategies
Systematically review age-related differences in CRS presentation, severity, and treatment response in pediatric versus adult populations. While tocilizumab is FDA-approved for CRS in patients ≥2 years 2, pediatric-specific data remain limited 1. Children under 2 years show concerning rates of hypersensitivity reactions (54.5%) and treatment discontinuation (36.4%) 2. A systematic review examining age-stratified outcomes, dosing strategies, and toxicity profiles would inform pediatric-specific management algorithms 1, 2.
Critical Methodological Considerations
All proposed reviews should:
- Utilize ASTCT consensus grading criteria for CRS to ensure comparability across studies 1
- Stratify by underlying disease etiology (hematologic malignancy, solid tumor, autoimmune disease) 1
- Distinguish between CRS and other immune-related adverse events (ICANS, macrophage activation syndrome) 1
- Include both efficacy and safety outcomes, with particular attention to infection risk and long-term immunosuppression effects 1, 2
- Address quality of life and functional outcomes beyond laboratory and imaging parameters 1, 7