We report use of ramatroban in 4 COVID-19 outpatients, 22 to 87 years of age, with acute onset / worsening of respiratory distress and hypoxemia. All four patients experienced decrease in respiratory distress and increase in SpO2, within hours of the first dose and thereby avoided hospitalization. The rapid response to ramatroban is consistent with a massive increase in lipid mediators including thromboxane A2 >> prostaglandin D2.
SARS-CoV-2 induced expression of COX-2 generates PGH2 which is converted into thromboxane A2 >> PGD2. Oxidative stress associated free radicals initiate non-enzymatic peroxidation of arachidonic acid leading to F2-isoprostane generation. PGH2, TxA2 and F2-isoprostanes stimulate thromboxane prostanoid receptors (TPr) which are overexpressed in COVID-19 due to decrease in microRNA-31. TPr stimulation induces pulmonary venoconstriction leading to an increase in transcapillary pressure in pulmonary microvasculature, and transudation of fluid into the alveoli, thereby causing impaired gas exchange and ARDS. TxA2/TPr axis also induces bronchoconstriction and mucus secretion. TxA2 is rapidly converted to 11-dehydro-TxB2in the lungs. PGD2 and 11-dehydro-TxB2 stimulate the DPr2 receptor on Th2 and ILC2 cells leading to release of type 2 cytokines, IL-4 and IL-13. IL-4 promotes vascular permeability thereby exacerbating fluid transudation while IL-13 induces hyaluronic acid accumulation and mucus hypersecretion. Ramatroban inhibits the DPr2 and TPr receptors thereby promoting pulmonary vasorelaxation, bronchorelaxation and improving capillary barrier function, while attenuating the maladaptive type 2 immune response and mucus secretion, thereby alleviating pulmonary edema and ARDS. Tx, thromboxane; PG, prostaglandin; TPr, thromboxane prostanoid receptor; DPr2; D-prostanoid receptor 2; Th2; T helper 2; ILC2; innate lymphoid class 2
“The linkage of cytokine storm in COVID-19 may be nothing more than a tempest in a teapot" (Sinha et al, JAMA, 2020). Recent data has "unmasked the lipid mediator storm occurring in the lungs of patients afflicted with severe COVID-19" (Archambault et al, FASEB, 2021). The most increased COX metabolites were TxB2 >> PGE2 ~ 12-HHTrE > PGD2. TXA2 promotes bronchoconstriction and activate leukocytes and platelets, which is consistent with the enhanced platelet activation and thrombosis in COVID-19 and the strong link between TxB2 and ARDS. PGD2 action via the DPr2 receptor promotes eosinophilia in COVID-19 (Lucas et al, Nature, 2020). "Testing whether blocking the deleterious effects of PGD2 and TxA2 with the dual DPr2/TPr antagonist Ramatroban might be beneficial in COVID-19 is of interest" (Archambault et al, FASEB, 2021).
Cytokine levels in COVID-19 are comparable to that in influenza suggesting a minimal role of cytokines during severe SARS-CoV-2 infection