Response to: Neprilysin inhibitor-angiotensin II receptor blocker combination (sacubitril/valsartan)

Acanfora e coll. have interestingly focused attention on possible beneficial role of sacubitril/valsartan administration in COVID-19 patients, even in early stage of COVID infection.1 Despite this argute hypothesis, it’s necessary add some observations. It is pointed that COVID-19 attack and penetrate inside the cells through isoenzyme angiotensin-converting enzyme 2 (ACE2), which is more represented in the mucosa of mouth, nasopharynx, and eye conjunctiva, justifying the initial symptoms of this viral infection (cough, conjunctival erythema, and anosmia). The infection and subsequent extensive tissue inflammation are followed by the loss of the function of ACE2. Physiologically at lung district, ACE2 could mediate anti-inflammatory effects, unlike its isoenzyme angiotensin-converting enzyme 1 that exerts pro-inflammatory properties, until promote reduction of cellular infiltrate and fibrosis in experimental model of acute respiratory distress syndrome.2–4 In this regard, some studies conducted on animal models have shown that the use of angiotensin-converting enzyme inhibitors (ACE-i) and Sartans favours the increase of ACE2 values, with secondary consequent reduction of the inflammatory response in the lung.5,6 On the other hand, increased expression of ACE2 related to ACE-i/Sartans administration could represent a disadvantageous element, allowing greater chance of entry for the virus. Further possible explanations of the heterogeneous effects of these drugs could depend on different explanations; not overall ACE-i and Sartans molecules have the same chemical structures (e.g. different ability to penetrate into different tissues, lipophilia, duration of activity, receptor affinity); distinct polymorphisms of ACE2 (it is widely demonstrated that the Asian population differs from the South American population, as well as in male and female the distribution of polymorphism is different), justifying different susceptibility to such infections as well as different responses to different drug treatments.7,8 The hypotheses of Acanphora et coll appeal widespread scientific attention because the eligible patients for therapy with sacubitril/valsartan have a high rates of comorbidity (hypertension 71.5%, diabetes mellitus 32.5%, chronic kidney disease 23.6%, chronic obstructive pulmonary disease 10.5%, de novo heart failure 38%, as well as predominance of male sex), and the ‘frail’ patients with comorbidities represent those at major risk of fatal and harmful events after COVID infection.9 Finally, despite the use of ACE-i/Sartans could have a double and antithetical action on the tissue damage from COVID-19 infection (on one side favouring the increased expression of the isoenzyme ACE2, fundamental for the regression of inflammation, on the other hand theoretically give greater possibilities to the virus to penetrate inside the cells), to date specific epidemiological and pathophysiological studies are needed in order to be able to give an unambiguous and precise answer to initial speculation, and we must only base ourselves on the recommendations of the main scientific societies, discouraging the suspension of anti-hypertensive treatment with ACE-i or Sartans after COVID infection, and initiate specific treatment in patients with heart failure, hypertension, or myocardial infarction according to current guidelines as tolerated, independently from SARSCoV2.10 Conflict of interest: none declared.