Poster Presentation Lancefield International Symposium for Streptococci and Streptococcal Diseases 2025

A plasma protein biomarker signature that differentiates acute rheumatic fever from related clinical presentations (#212)

Tim Barnett 1 2 , Emmy Okello 3 4 , Casey Shannon 5 , Jenifer Atala 3 , Ryan Brinkman 6 , David Broadhurst 7 , Guillaume Drouart 8 , Christine Everest 8 , Nina Kresoje 8 , Amy Lee 9 , Wenna Lee 1 , Peter Lwabi 3 , Sebastiano Montante 6 , David Martino 8 , Emma Ndagire 3 , Linda Oyella 3 , Rym Ben-Othman 8 , Jafesi Pulle 3 , Craig Sable 10 , Rachel Sarnacki 10 , Michael Serralha 8 , Scott Tebbutt 5 , Andrea Beaton 11 12 , Tobias Kollmann 8 , Jonathan Carapetis 8
  1. Wesfarmers Centre for Vaccines and Infectious Diseases, The Kids Research Institute Australia, Nedlands, WA, Australia
  2. School of Biomedical Sciences, The University of Western Australia, Nedlands, WA, Australia
  3. The Uganda Heart Institute, Mulago Hospital Complex, Kampala, Uganda
  4. Department of Medicine, Makerere University, Kampala, Uganda
  5. Prevention of Organ Failure (PROOF) Centre of Excellence, Vancouver, BC, Canada
  6. BC Cancer Agency, Vancouver, BC, Canada
  7. Centre for Integrative Metabolomics & Computational Biology, Edith Cowan University, Joondalup, WA, Australia
  8. The Kids Research Institute Australia, Nedlands, WA, Australia
  9. Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, BC, Canada
  10. Children's National Hospital, Washington, DC, USA
  11. Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
  12. Department of Pediatrics, The University of Cincinnati School of Medicine, Cincinnati, OH, USA

BACKGROUND

Rheumatic Heart Disease is the most common acquired cardiovascular disease among children and young adults, and remains endemic in most low- and middle income countries. Rheumatic Heart Disease follows acute rheumatic fever (ARF), a systemic inflammatory condition triggered by Group A Streptococcus infection. Timely ARF diagnosis is critical to implement antibiotic prophylaxis to prevent relapses due to recurrent Group A Streptococcus infections. However, no defined biomarkers for ARF and diagnosis is based on non-specific clinical criteria first developed 80 years ago.

METHODS

We undertook unbiased multi-omic testing (proteomics, metabolomics, RNAseq, epigenomics, flow cytometry) of peripheral blood samples from two cohorts in Uganda, contrasting acute and convalescent ARF cases and well-defined controls.

RESULTS

We identified a 5-protein signature that discriminates ARF patients from overlapping clinical presentations in a discovery cohort (receiver operating characteristic-area under the curve (ROC-AUC)=1.0, known alternate diagnosis; ROC-AUC=0.97, unknown alternate diagnosis), which retained very good diagnostic value is a geographically distinct validation cohort (ROC-AUC=0.83, unknown alternate diagnosis). Pathway analysis identified several enriched pathways that support existing knowledge of ARF pathogenesis. We further identified multiple components of the epithelial-mesenchymal transition pathway as highly-associated with acute ARF, suggesting that acute tissue damage and repair is central to ARF pathogenesis.

CONCLUSION

Our results identify new molecular pathways associated with ARF pathogenesis, and clinically useful ARF diagnostic biomarkers. A specific diagnostic test would revolutionise ARF diagnosis and treatment, and reduce the global burden of Rheumatic Heart Disease.