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Don’t panic: five minutes with . . . Kai Zacharowski

BMJ 2020; 368 doi: (Published 17 March 2020) Cite this as: BMJ 2020;368:m1092

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Rapid Response:

Re: Don’t panic: five minutes with . . . Kai Zacharowski

Dear Editor,

The view from outside the ICU is that the final response to COVID-19 is to attempt to put more oxygen into lungs that can’t pass it on to the heart.

COVID-19 is a clinical syndrome arising as a result of infection of SARS-COV-2 infection.

ACE1 & 2
Angiotensin Converting Enzyme 1 (ACE1) cells convert Angiotensin I to its active form, Angiotensin II, which causes peripheral blood vessels to contract and helps maintain systemic (body) blood pressure..
Angiotensin Converting Enzyme 2 (ACE2) cells convert the active Angiotensin II to an inactive form, Angiotensin 1-7 .(1) ACE inhibitors have no activity against ACE2 and may actually lead to upregulation of ACE2. (2)
Angiotensin II causes contraction of small vessels via the PDE5 receptor (3). Under physiological conditions ACE2 protects the small vessels of the lung from active Angiotensin II.

Mode of Infection
The Current Virus (SARS-COV-2) is known to target ACE2 cells in the lung (4) (5)

Putative mode of action
ACE2 cells are present in the lower respiratory tract. At present there is no evidence that SARS-COV-2 reduces expression of ACE2 but this is an assumption that is consistent with clinical observations of the disease, COVID-19 which leads to pneumonia and reduced oxygenation. Risk factors observed for poor outcomes in COVID-19 are associated with prior upregulation of ACE2 (2): this is consistent with the assumption that SARS-COV-2 acts by reducing expression of ACE2.
Thus SARS-COV-2 reduces ACE2 expression, thereby exposing small vessels in the lung to be exposed to (vasoconstricting) Angiotensin II which acts on the vessels via PDE5, leading to the clinical findings in COVID-19. Vasoconstriction leads to reduce flow through the (downstream) gas exchange alveoli with the consequences of
• Reduced gas exchange and therefore reduced oxygen supply to the systemic (body) circulation
• Reduced blood-borne immune response to the virus
• Increased pressure in the Pulmonary (lung) artery with shunting (overflow) of deoxygenated (used) blood to the systemic circulation.

An immediately available Treatment
Drugs to prevent Angiotensin II having these effects via the PDE5 receptor are already available in the form of Sildanafil and Tadafil, which are considered safe enough to be sold, without prescription by pharmacies in the UK. These drugs appear to have significant promise in addressing COVID-19, assuming that the known SARS-COV-2 targeting of ACE2 cells leads to reduced ACE2 expression in those cells. In a previous rapid response I report Tadafil being used effectively in a similar historical case (6) in the community. Sildanafil has an iv form that could be used in the ICU to support ventilation, perhaps the pharmaceutical industry could develop a formulation that could be delivered via the airways, for example by nebulisation.

The evidence appears to support community use of oral PDE-5 inhibitors in COVID-19 and hospital use of parenteral forms in order to protect the limited number of ICU beds and shorten ventilator time.

1. Tikellis, C.,Thomas, M.C. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease International Journal of Peptides Volume 2012, Article ID 256294, doi:10.1155/2012/256294
2. Lei Fang, George Karakiulakis, *Michael Roth Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? 2020
3. Dongsoo Kima, Toru Aizawab, Heng Weic, et al. Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: A mechanism by which angiotensin II antagonizes cGMP signaling J Mol Cell Cardiol. 2005 January ; 38(1): 175–184. doi:10.1016/j.yjmcc.2004.10.013
4. Hoffmann et al., 2020, Cell 181, 1–10 April 16, 2020 a 2020 Elsevier Inc.,
5. Zhou, P., Yang, X., Wang, X. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020).
6. Ashworth AJ. Enhanced recovery from respiratory infection following treatment with a PDE-5 inhibitor: a single case study Prim Care Respir J 2012; 21(1): 17-18

Competing interests: No competing interests

18 March 2020
Andrew J Ashworth
GP & Occupational Physician
Bonhard Medical