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BMJ 2020; 368 doi: (Published 31 January 2020) Cite this as: BMJ 2020;368:m406

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COVID-19 induced Renin–Angiotensin System (RAS) imbalance may drive acute lung injury: the evidence and therapeutic options

Dear Editor,

Several authors have debated the potential role of angiotensin converting enzyme (ACE) inhibitors (ACEi) and angiotensin receptor blockers (ARBs) in treatment of coronavirus disease 2019 (COVID-19) [1-6], based on the evidence that ACE 2 (ACE2) has been identified as the host receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [7]. We support the hypothesis that dysregulation of the renin angiotensin system (RAS) may serve a central role in the pathophysiology of COVID-19 associated acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). However, we believe that some clarification is needed.

Angiotensin I is converted to angiotensin II (AngII) by ACE. AngII mediates vasoconstrictive, pro-inflammatory and pro-oxidative effects through agonism at AngII receptor type 1 (AT1) [8]. ACE2 converts AngII to angiotensin 1-7 (Ang1-7), which through binding Mas receptor (MasR) mediates anti-inflammatory, anti-oxidative and vasodilatory effects [8]. Hence, the ACE2/Ang1-7/MasR axis opposes the actions of the ACE/AngII/AT1 axis.

COVID-19 appears more severe in patients with hypertension, cardiovascular disease and diabetes [9, 10]. These disorders are associated with decreased baseline levels of ACE2 expression [3]. We postulate here that SARS-CoV-2 binding to ACE2 may attenuate residual ACE2 activity, further skewing the ACE/ACE2 balance to a state of predominant ACE/AngII/AT1 axis signaling, in which AngII causes pulmonary vasoconstriction, and inflammatory and oxidative organ damage, ultimately progressing towards ALI/ARDS [11].

This theory is supported by a recent publication by Liu et al, demonstrating that serum AngII levels in patients with COVID-19 were significantly higher than in non-infected individuals, and more importantly, were linearly associated with viral load and lung injury [12].

As such, we believe that RAS modulation may have a potential role in treatment of selected patients with severe COVID-19 at risk for ALI/ARDS. Since ACEi can lead to cough secondary to accumulation of bradykinin, we believe ARBs, recombinant ACE2 or Ang1-7 may be more favorable treatment options. Of note, a pilot clinical trial of recombinant ACE2 in ARDS showed that the treatment was well tolerated and led to decreased serum AngII and increased serum Ang1-7 levels [13]. To further evaluate the role of RAS modulation in COVID-19, datasets should be analyzed to investigate if use of ACEi and ARBs on admission could be associated with ALI/ARDS and/or mortality in patients with diabetes, hypertension and cardiovascular disease.

Brandon Michael Henry, M.D.
Cincinnati Children’s Hospital Medical Center
3333 Burnet Ave., Cincinnati, OH, USA 45229

Jens Vikse, M.D.
Stavanger University Hospital
Gerd-Ragna Bloch Thorsens gate 8, 4011 Stavanger, Norway

Giuseppe Lippi, M.D.
University Hospital of Verona
Piazzale Scuro 10, 37134 Verona, Italy

7) Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS. Journal of Virology 2020.
8) Tikellis C, Thomas MC. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease. Int J Pept .2012;2012:256294.
9) Guan W-J, Ni Z-Y, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020.
10) Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020
11) Zhang H, Baker A. Recombinant human ACE2: acing out angiotensin II in ARDS therapy. Crit Care. 2017;21(1):305.
12) Liu Y, Yang Y, Zhang C, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020;63(3):364-374.
13) Khan A, Benthin C, Zeno B, et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care. 2017;21(1):234.

Competing interests: No competing interests

12 March 2020
Brandon Michael Henry
Research Fellow
Jens Vikse, Giuseppe Lippi
Cincinnati Children's Hospital Medical Center
3333 Burnet Ave, Cincinnati, OH, 45229