Abstract: Signal Transduction and Targeted Therapy LETTER www.nature.com/sigtrans OPEN 1234567890();,: Real-world evidence for improved outcomes with histamine antagonists and aspirin in 22,560 COVID-19 patients Signal Transduction and Targeted Therapy (2021)6:267 ; https://doi.org/10.1038/s41392-021-00689-y Dear Editor, The COVID-19 pandemic has driven great interest in the therapeutic potential of repurposed drugs with well-established benefits and safety profiles (toxicity, bioavailability, etc.), many of which act via signal transduction pathways. One category of such drugs is those that reduce acid production in gastroenterological contexts. Acid-suppressing drugs belong to two main classes, based on their mechanisms of action: (i) proton-pump inhibitors (PPIs) sterically block H+/K+-ATPase pumps, impeding the final step of acid release in the gastric mucosa. (ii) Histamine H2 receptor antagonists (H2RA) competitively bind the H2R, a type of G-protein coupled receptor (GPCR),1 and block the natural stimulation of its downstream signal transduction cascade by histamine; famotidine (e.g., Pepcid®) and ranitidine (e.g., Zantac®) are exemplary H2RAs. A dense web of functional linkages exists between histamine and H2RAs, on the one hand, and disparate physiological pathways on the other hand. These downstream signaling pathways include gastrointestinal systems (acid reduction) as well as the dysregulated inflammatory cascades (cytokine storm) that likely underlie much of the pathophysiology of COVID-19.1 The mechanistic basis of a putative role of famotidine in COVID-19 likely involves its roles as an H2RA versus, for instance, direct binding to the viral protease 3CLpro (and resultant inhibition), as had been originally suspected from molecular docking studies. Given its many possible mechanistic and regulatory linkages to signal transduction pathways, is famotidine beneficial in treating COVID-19, as gauged by outcomes involving either (i) infection transmissibility, (ii) disease severity indicators (e.g., likelihood of cases reaching the point of ventilation, WHO severity index), or (iii) mortality rates? This question remains unresolved, though not for lack of effort: since a pioneering report2 of positive clinical outcomes with famotidine use in COVID-19, over 10 studies have considered the potential therapeutic benefits of famotidine. As we recently reviewed,3 many of these reports concluded in favor of famotidine use, others found little to no association between famotidine (or PPIs) and 30-day mortality, and a recent study found a negative association for both PPIs and famotidine. These independent studies have been retrospective and observational; most were cohort-based, with some as case-series (e.g., symptom tracking across longitudinal data); most evaluated inpatient cases; and most attempted to account for confounders and other biases (e.g., via propensity-score matching). Given the conflicting reports thus far, particularly the evidence suggesting a beneficial impact of famotidine on mortality and overall disease progression (e.g., mechanical ventilation), we have undertaken the new analysis reported herein. Note that all three parallel tracks of findings—those indicating for and against famotidine, as well as neutral (i.e., no association)— rest upon substantially smaller datasets than were drawn upon in the present work. Are any beneficial effects of famotidine detectable on population-wide, international scales? Is it synergistic..