COVID, ACE2, ibuprofen and grasping for straws

A recent article came out clarifying the potential role of medications in increasing ACE2 receptor expression and possibly implicating these medications in facilitating SARS-CoV-2 binding and the development of COVID-19. thanks to my brother Andrew for bringing this to my attention (see covid ACE2 enhancing meds lancetresp2020 in dropbox, or doi.org/10.1016/S2213-2600(20)30116-8). To me, it had been confusing about the potential role of ACE inhibitors (as used in hypertension, etc), with some speculating that these might be either helpful or harmful. And what is this ACE2 anyway, which I had never heard of before??

Details:

--a study in Wuhan of non-survivors of ICU patients with COVID-19 infection found a high mortality (32 of 52 died, mostly from ARDS): see https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30079-5/fulltext . Comparing the 20 survivors vs the 32 nonsurvivors (noting only the major differences between the two):

    -- survivors were more likely  to be infected in the Huanan seafood market (45% vs 25%) and less likely by exposure by people (10% vs 25%)

    -- no survivors had cerebrovascular disease vs 22% of nonsurvivors

    --10% of survivors had diabetes vs 22% of nonsurvivors

--another study of 1099 patients with confirmed COVID-19 throughout mainland China  (see https://www.nejm.org/doi/10.1056/NEJMoa2002032 , or covid china clinical nejm2020 in dropbox), found that the comorbidities leading to ICU admission/ventilator/death in 67 vs the other 1032 patients:

    --COPD 10% vs 0.5%

    --diabetes 27% vs 6%

    --hypertension 36% vs 14%

    --coronary heart dz 9% vs 2%

    --cerebrovascular dz 6% vs 1%

    --chronic renal dz 3% vs 0.6%

--so, the authors speculate that since the most frequent comorbidities in these articles (and another one they cite) are often treated with ACE inhibitors, that maybe it is the ACE inhibitors themselves that  play a deleterious role (given the SARS-CoV-2 binding to the ACE2 receptors as a means to gain access to target cells, as below)

--ACE2 levels are increased (upregulated) with the following:

    --diabetes, type 1 or 2

    --ACE-inhibitors

    --thiazolidinediones (TZDs)

    --ibuprofen

--and the presumption is that upregulation of ACE2 would facilitate infection with SARS-CoV-2 and might also increase the likelihood of more severe infections, as suggested in the above clinical studies

--it is pretty clear from the above that there is a string of assumptions:

    --assumption 1: that the increased morbidity with SARS-CoV-2 associated with the various comorbidities found in the above clinical trials is in fact causal and not circumstantial. Of course, associations by themselves cannot prove causality. And the association could be circumstantial: there are other associations with these comorbidities that really could be causal, eg: chronic inflammation, immunologic changes, associated frailty, medications taken, associated changes in diet/exercise/other psychosocial issues such as depression, which has a clear association with immunologic function and inflammation…..

    --assumption 2: that the increases in these comorbidities is in fact associated with the use of ACE inhibitors. we only know that these comorbidities are often treated with ACE inhibitors but do not have granular data supporting the association. Is this the old ecological fallacy of attributing an association in a large population, where if looking at the actual individuals there is no or even a negative association

    --asumption 3: that the data supporting many of the associations noted above are from animal models but apply to humans.  For example, the only reference I could find between ibuprofen and ACE2 is a rat study with chemically-induced diabetes (see ibuprofen and cardiac fibrosis in dropbox, or DOI: 10.1159/000375362) which also suggested that it was the ACE2 levels. And if true, does this apply to NSAIDs as a group???

--I should add that the whole ACE2 thing is really pretty complicated and conflicting, to my limited understanding:

    -- there are at least 5 trees in the renin-angiotensin system (much more than we thought a while ago), and one of them involves ACE2.

    --both SARS-CoV and SARS-CoV-2 bind to target cells via ACE2, which is expressed in lung, intestine, kidney, and blood vessels

    --ACE2 is an enzyme involved in the cleaving of both angiotensin I and angiotensin II

        -- but is there a difference between ACE2 levels and ACE2 receptors, as cited in some articles???  But one detailed virologic article states that SARS-CoV-2 “uses ACE2 as its receptor” (see https://jvi.asm.org/content/jvi/early/2020/01/23/JVI.00127-20.full.pdf or covid ACE2 receptor jvirol2020 in dropbox, or doi:10.1128/JVI.00127-20).

        --And in some other studies ACE2 levels may be protective against viral lung injury, likely from its effects on decreasing inflammation caused by the virus (eg see https://www.nature.com/articles/nm1267 )

--so, honestly, it is pretty hard (for me) to synthesize all of this coherently….

So, what is one to do???

--it seems to me that the above trail of logic/string of assumptions may well be true, though with many holes

    -- we need a clearer understanding of the overall relationship between ACE2 levels, the role of the ACE2 receptors if different, and viral transmission/adverse clinical events

--and, given our lack of anything to do other than grasp for straws (as many of us did in the bad old HIV days), focusing on ACE2 levels does offer some hope of perhaps minimizing more severe COVID infections

    --and, it really is not so hard to suggest that patients use acetaminophen instead of ibuprofen (it seems likely that the other NSAIDs are equally involved in ACE2 levels)

    --changing antihypertensives is not as simple: though there is no suggestion that amlodipine is bad (eg see covid ACE2 inc with ARB not amlodipine AmJHtn2015 in dropbox, or doi:10.1093/ajh/hpu086 ), or maybe a little higher BP in some people may be okay for a while??

geoff​

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