Objective: Lung disease (LD) in systemic juvenile idiopathic arthritis and adult-onset Still disease (Still-LD) is a severe manifestation strongly associated with HLA-DRB1*15 alleles and drug-associated immune reactions (DAIR), including eosinophilia, non-Still disease rashes, and elevated liver function tests. Despite the high morbidity and mortality of these phenomena, pathogenesis remains poorly understood. This study investigates whether Still-LD and DAIR are associated with pathogenic antigens through hypersensitivity reactions to Aspergillus fumigatus, for which HLA-DRB1*15 is a known risk allele, or drug reaction with eosinophilia and systemic symptoms (DRESS), which is frequently associated with human herpesvirus (HHV) reactivation.
Methods: Pediatric and adult subjects were drawn from the National Institutes of Health Still disease cohort. Subjects with Still-LD and/or DAIR were identified by chart review. Serum samples were analyzed for anti-A. fumigatus IgE using ImmunoCap assay, and Epstein-Barr virus (EBV), cytomegalovirus (CMV), and HHV 6 (HHV-6) antibodies were analyzed by luciferase immunoprecipitation systems. Subjects were screened for EBV, CMV, and HHV-6 by nucleic acid amplification tests and/or Viral Transcript Usage Sensor (VIRTUS) analysis of whole-blood RNA sequencing data.
Results: Fifty-four subjects were included in the study, 11 had LD and DAIR, and 8 had DAIR alone. Thirty-three subjects were tested for anti-A. fumigatus antibodies and all were negative. Forty-nine subjects were tested for CMV, EBV, and HHV-6; 2 were positive for EBV, both of whom did not have Still-LD or DAIR.
Conclusion: The absence of anti-A. fumigatus IgE antibodies and detectable herpesvirus nucleic acids in subjects with Still-LD and DAIR does not support a mechanistic association with hypersensitivity to A. fumigatus or with HHV reactivation.