I wrote here the other day on the recent recommendation that people taking either ACE (angiotensin-converting enzyme) inhibitors or ARBs (angiotensin receptor blockers) should not alter their treatment regimens because of the coronavirus outbreak. Some background on the angiotensin system is here, and here’s an open-access review for those who know the basics and want to dive much deeper into the details. But now there’s even more to report on the subject, so I wanted to do an update post.

Recall that the coronavirus itself uses the ACE2 protein as an entry point into cells. One worry has been that the use of antihypertensive drugs (of either class mentioned above) might well cause ACE2 expression to increase, which seems as if it could be a bad idea, providing more targets for the virus to latch on to. But this survey of the literature found little evidence that these expression changes even happen. The animal data that show these effects, they report, tend to be via acute injury models or doses that are much higher than human patients encounter, and there seems to be no good evidence that it happens in humans. So that’s one thing to think about: a big part of the worry about antihypertension drugs may not be even be founded on a real problem.

We also have some clinical data: this preprint from a multicenter team in Wuhan retrospectively evaluates 43 patients with hypertension who were taking drugs in these two classes versus 83 hypertension patients who were not taking ACE inhibitors or ARBs, versus. 125 age- and gender-matched controls without hypertension at all. They also compared hospital admission statistics in general to patients’ medical histories. They first confirmed what others have found, that hypertension itself is a risk factor: the patients admitted for treatment had higher levels of hypertension than the general population, and once admitted those patients had higher death rates and longer hospital stays. But when they looked at the hypertension patients who were taking either ACE inhibitors or ARBs, their numbers were better. They had comparable blood pressure numbers to those taking other drugs, but they were a lower percent of critical patients (9.3% versus 22.9%, near miss on statistical significance) and had a lower death rate (4.7% versus 13.3%). The ACE/ARB cohort also had lower inflammation markers (c-reactive protein and calcitonin). So while the data are noisy, there may be a trend towards protection in those taking angiotensin-targeting drugs. All the more reason to heed the advice not to change therapies for people with hypertension.

This recent paper speculates that there could be a biphasic aspect to all this. Note that it assumes that ACE2 may be upregulated by these drugs, which (see above) may not even be the case – if that’s true, then we go from biphasic (bad before infection, good during infection) to more of a pure benefit:

At present, we cannot rule out that long‐term intake of ACEIs and/or ARBs may facilitate SARS‐CoV‐2 entry and virus replication. Conversely, it is yet unknown whether intake of ACEIs and/or ARBs, when infected, is beneficial with regard to pulmonary outcome. Possibly, we are dealing here with a double‐edged sword, depending on the phase of the disease: increased baseline ACE2 expression could potentially increase infectivity and ACEI/ARB use would be an addressable risk factor. Conversely, once infected, downregulation of ACE2 may be the hallmark of COVID‐19 progression. Consequently, upregulation by preferentially using renin‐angiotensin system blockade and ACE2 replacement in the acute respiratory syndrome phase may turn out to be beneficial.

What, though, if you deliberately give someone ACE2 protein? An email correspondent wrote to me a while ago wondering about doing that in a nebulizer, and my response was that it wasn’t a crazy idea, but that I didn’t know if anyone would go to the trouble of making and testing a whole new recombinant protein under the current conditions. I had forgotten about Apeiron! They have been developing an infused (not nebulized) recombinant version of the human ACE2 protein for some years now, and were in a deal with GSK to look at respiratory distress in general. The deal lapsed last year after a good deal of work in the clinic and a refocus at GSK away from respiratory disease in general. The clinical data were consistent with the mechanism: infusing ACE2 enzyme dropped the amount of angiotensin II protein, as it should, since it’s in there clipping it up, and raised the amounts of the shorter product peptides. So the mechanism was operating as it should – the problem was that it didn’t seem to help ARDS patients much (!)

But a viral infection that causes respiratory distress and enters cells through membrane-bound ACE2 proteins, well, that’s different. You could imagine that circulating ACE2 protein would be a decoy for the virus – it would bind as if it’s infecting a cell, but the protein in this case isn’t on a cell surface at all, so you could potentially soak up the virus and take it out of commission. They and their collaborators have just demonstrated this in cell culture, actually: adding the recombinant protein to a viral replication assay seems to have caused a large decrease in viral RNA, whereas adding the mouse version of ACE2 had no effect at all.

Apeiron is jumping back into the clinic, and a trial has already started in China, with one getting underway in Europe as well to see if the treatment can decrease the number of patients going on to ventilators. This will be quite interesting; to the best of my knowledge this and perhaps camostat are the only agents directly targeting the ACE2 viral mechanism (and that one’s being studied as well). And we only have that by good luck, that Apeiron had already been looking at the mechanism for respiratory distress in general. Those earlier failed trials have now provided a quick entry into human studies!