Comment from Gillian McCrea

Tezepelumab (Anti-TSLP) for Long COVID Blocking the upstream alarmin that drives mast cell and type-2 inflammation | For FDA repurposing / advisory review The opportunity A large share of Long COVID symptoms — histamine and mast-cell-activation features, GI problems, POTS, and fibrosis — trace to mast cell and type-2 inflammation. Tezepelumab shuts that off at its upstream switch. An upstream mechanism, broader than one cytokine Tezepelumab (Tezspire) blocks thymic stromal lymphopoietin (TSLP), an epithelial-cell alarmin. Blocking TSLP reduces type-2 cytokine output across T helper 2 memory cells, innate lymphoid cells, and mast cells at once [1] — upstream control rather than blocking a single downstream signal. The target fits Long COVID TSLP is overexpressed after SARS-CoV-2 epithelial damage and can drive post-COVID fibrosis by activating fibroblasts [2]. And persistent mast cell activation is now documented up to two years post-infection in both blood and gut tissue, alongside residual spike protein [3], with mast cell mediators implicated in post-COVID POTS [4]. The precedent is established Tezepelumab is FDA-approved for severe asthma (the NAVIGATOR Phase 3 trial) with a strong safety record, and has been studied in COPD — a well-tolerated, approved upstream anti-inflammatory [1]. The ask A biomarker-gated trial in mast-cell / type-2-high Long COVID — selected by elevated tryptase, TSLP, or a type-2 signature. An approved drug aimed at a measurable inflammatory phenotype. Sources 1. Menzies-Gow A, et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma (NAVIGATOR). NEJM. 2021; blocks TSLP across Th2 cells, ILC2s, and mast cells. FDA-approved (Tezspire). 2. TSLP overexpression after SARS-CoV-2 epithelial damage and its contribution to post-COVID fibrosis via fibroblast activation. 2025. 3. Augustin M, et al. Long-term mast cell activation in systemic and tissue-resident compartments 2 years post-COVID, with residual spike protein. Open Forum Infect Dis. 2025. 4. Mast cell / basophil mediators in post-COVID POTS (COVIVA and immune-profiling studies). 2023–2024.