Abstract
Rationale
Vancomycin DRESS is strongly associated with HLA-A*32:01. We identified unusual DRESS cases dually sensitized to vancomycin (V) and ceftriaxone (Cf), and aimed to determine cross-reactivity, HLA association and immunopathogenesis.
Methods
CfV DRESS cases associated with concurrent administration of CfV were identified from two centers prospectively and evaluated for age, sex, race/ethnicity, latency, RegiSCAR, IDT(R1-sharing and other cephalosporins), and interferon-gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) and HLA typing. HLA controls included singly-sensitized vancomycin DRESS patients and the VUMC BioVU population with SNP2HLA imputed HLA typing. 10X 5’single-cell(SC)-TCR-RNA-Cite-seq was performed on cells extracted from blister-fluid overlying DRESS-inflamed skin.
Results
Four cases of CfV DRESS were IDT positive to both drugs at 24 hours. Cases were median age of 49 years, 100% white/non-Hispanic, 75% female, median latency of 18 days, and RegiSCAR range 4–7. 3/3 with full HLA typing were HLA-A*24:02 positive compared with 8/79 (10%; pc=0.08) in a cohort of singly sensitized vancomycin DRESS and 10,812/69,256 (16%; p=0.004) white/non-Hispanic individuals from BioVU. In 2/2 cases additional cephalosporin IDT were positive only to the R1-sharing cefepime. 2/3 who had IFN-γ ELISpot were Cf+V+. SC studies identified predominantly CD4+T cells (63%) which were activated(CD71+,ICOS+), TH2 differentiated and skin homing(CCR4+,CXCR3-) with dominantly expanded TCRαβ clonotypes. Distinct CD4+ T-cell populations including T-reg (FOXP3,IL2RA,IL32,CD27) were also identified.
Conclusions
CfV DRESS is a unique entity that appears HLA-A*24:02 rather than HLA-A*32:01 associated. This may suggest in vivo Cf-R1-side-chain-specific interactions with vancomycin and novel mechanisms as highlighted by identification of distinct populations of predominantly activated CD4+ T cells on SC analysis.