The DRESS/HLH Overlap Syndrome: A Systematic Review of Clinical Features, Triggers, and Outcomes

Background/Objectives: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome and hemophagocytic lymphohistiocytosis (HLH) are life-threatening conditions characterized by immune dysregulation. Several reports have identified an overlap between these entities; however, clinical characteristics, triggers, and outcomes remain poorly defined. The objective of this study was to characterize the clinical features and outcomes of DRESS/HLH overlap syndrome. Methods: We conducted a PRISMA-guided systematic review of PubMed, Embase, and MEDLINE. Studies were included if they reported cases meeting criteria for DRESS syndrome and HLH. Results: Thirty-six patients were included, 75% female and 27.8% pediatric. Initial misdiagnosis occurred in 30.6% and was associated with higher mortality (45.5% vs. 20.0%). Antibiotics were the most frequent triggers (36.1%) and 11.1% of patients had no trigger identified. Mean latency was 27.9 days for DRESS syndrome and 35 days for HLH, with shorter latency in antibiotic-associated cases. DRESS syndrome and HLH most commonly occurred sequentially (n = 22, 61.1%) and in 52.8% of cases DRESS preceded HLH. Fever and rash were present in 88.9%. Laboratory abnormalities included hyperferritinemia (91.7%), eosinophilia (77.8%), anemia (75.0%), and thrombocytopenia (75.0%). Hepatic involvement was nearly universal (94.4%), followed by renal involvement (36.1%). Viral reactivation was observed in 38.9%, multiorgan failure in 36.1%, and ICU admission in 19.4% of cases. Mortality was 27.8% and higher in steroid-refractory cases and those with multiorgan failure. Treatment included corticosteroids (97.2%), with IVIG (33.3%), etoposide (13.9%), and cyclosporine (5.6%) used in severe cases. Conclusions: DRESS-HLH overlap represents a severe hyperinflammatory syndrome with high mortality. Early recognition and escalation of therapy are essential to improve outcomes. This is the largest and most uniformly characterized cohort of DRESS/HLH overlap reported to date, and the first to stratify mortality by diagnostic accuracy, temporal pattern, corticosteroid responsiveness, and multiorgan failure. Because the syndrome is rare and the evidence base consists almost entirely of single-case reports, multicenter collaboration and a prospective registry are needed to define incidence and optimal therapy.