Antibiotics, innate immunity, and dysbiosis in pediatric urticarial reactions

Project Summary Antibiotic associated reactions (AAR) occur in 5-10% of children and cause substantial distress to families due to the occurrence of rashes, swelling of the face/hands/feet, fever, and gastrointestinal upset. When hives and joint pain are both present, reactions are labeled as serum sickness like reactions (SSLR), a bothersome reaction due to prolonged, uncomfortable symptoms and lack of response to allergy medications such as antihistamines. Recently, it has become apparent that AAR (including SSLR) are rarely reproduceable (<5%) with re-exposure to the antibiotic in an allergist office. Research studies are needed to identify what causes AAR to occur in the first place and whether antibiotics may play a role in reactions without evidence for classical allergic hypersensitivity reactions. We have recently observed that children may experience repeat episodes of hives and SSLR despite non allergic testing and despite interval tolerance of the antibiotic. The reactions are delayed in onset and unpredictable. We hypothesize that prolonged use of antibiotics induces gut dysbiosis which leads to autoinflammatory reactions in susceptible children. To test this hypothesis, we plan a multi-omics approach, evaluating inflammatory blood markers, immune transcriptomics, fecal microbiota populations and metabolic derangements. We will associate the multi-omics assessments with 2 cohorts of children- those experiencing typical, short lived, antihistamine responsive urticaria and those affected by hives that are atypical- poorly response to antihistamines, prolonged in duration, and associated with painful swelling of joints and extremities. To characterize these 2 urticarial reactions as distinct subsets (not currently defined clinically), we will collect additional clinical information to establish pattern recognition in each cohort. This will include patient recorded outcome measures of urticarial symptoms, medication usage and response, photo documentation of rashes with dermatology confirmation and ultrasound-based assessment of joints for evidence of synovitis. Using computational modeling, we will determine which biomarkers associate strongly to one cohort versus the other cohort. We will accomplish our aims by engaging a multidisciplinary team of allergy/immunology/ rheumatology/ dermatology/infectious disease physician investigators and computational and metabolomics experts. Many children will experience urticarial reactions while taking antibiotics and will presume they are allergic. This study will help identify the scientific basis for occurrence of hives without evidence for classically defined allergy responses, including the possibility that antibiotic disruption of healthy commensals leads to autoinflammatory reactions in susceptible hosts. By identifying novel mechanisms whereby antibiotics lead to urticarial reactions and associating them to well defined, clinical syndromes, we may prevent the accumulation of unnecessary allergy labels and identify effective treatment of children who experience severe reactions such as SSLR.