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It begins as a respiratory infection that, mainly in men with diabetes or renal impairment, evolves into a systemic disease, with SARDS, progressive endothelial cell damage, abnormal clotting and impaired cardiovascular and liver function. Some clinical trials are testing biological drugs to limit the immune system dysregulation, \u201ccytokines storm,\u201d that causes the systemic complications of COVID\u201019. The contraindications of these drugs and their cost raise concerns over the implications of their widespread availability.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>Numerous clinical and experimental studies have revealed a role for the nitric oxide (NO)\u2010cyclic GMP\u2010phosphodiesterase type 5 (PDE5) pathway in modulating low\u2010grade inflammation in patients with metabolic diseases, offering cardiovascular protection. PDE5 inhibition favors an anti\u2010inflammatory response by modulating activated T cells, reducing cytokine release, lowering fibrosis, increasing oxygen diffusion, stimulating vascular repair. PDE5 is highly expressed in the lungs, where its inhibition improves pulmonary fibrosis, a complication of severe COVID\u201019 disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and methods<\/jats:title><jats:p>We performed a systematic review of all evidence documenting any involvement of the NO\u2010cGMP\u2010PDE5 axis in the pathophysiology of COVID\u201019, presenting the ongoing clinical trials aimed at modulating this axis, including our own \u201csilDEnafil administration in DiAbetic and dysmetaboLic patients with COVID\u201019 (DEDALO trial).\u201d<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The reviewed evidence suggests that PDE5 inhibitors could offer a new strategy in managing COVID\u201019 by (i) counteracting the Ang\u2010II\u2010mediated downregulation of AT\u20101 receptor; (ii) acting on monocyte switching, thus reducing pro\u2010inflammatory cytokines, interstitial infiltration and the vessel damage responsible for alveolar hemorrhage\u2010necrosis; (iii) inhibiting the transition of endothelial and smooth muscle cells to mesenchymal cells in the pulmonary artery, preventing clotting and thrombotic complications.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion and Conclusion<\/jats:title><jats:p>If the ongoing trials presented herein should provide positive findings, the low cost, wide availability and temperature stability of PDE5 inhibitors could make them a major resource to combat COVID\u201019 in developing countries.<\/jats:p><\/jats:sec>","DOI":"10.1111\/andr.12837","type":"journal-article","created":{"date-parts":[[2020,6,11]],"date-time":"2020-06-11T20:44:05Z","timestamp":1591908245000},"page":"33-38","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Targeting the NO\u2010cGMP\u2010PDE5 pathway in COVID\u201019 infection. 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