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BOSTON — In the world of Ralph Baric, PhD, not much is a coincidence.

So he perked up when he saw that SARS-CoV-2, the virus that causes COVID-19 illness, enters the lungs through ACE2 receptors, and that people with hypertension have worse outcomes than those with any other underlying condition.

"I've thought it needed to be explored in more detail for quite a while," said Baric, a professor of epidemiology, microbiology, and immunology at the UNC Gillings School of Global Public Health in Chapel Hill, North Carolina, who has been studying coronavirus outbreaks for decades.

Baric isn't alone. As the National Institutes of Health and private companies scramble to test existing and novel treatments for COVID-19, researchers and doctors are trying to determine whether the spike in serious COVID-19 illness in those with baseline hypertension is a coincidence of age and general ill health, or if it speaks to the role ACE2 receptors play in both hypertension and COVID-19 infection. And if there is an association, they want to know whether ACE inhibitors help or hurt people at highest risk for severe COVID-19 disease.

"It's really important to say that these are all theoretical musings" right now, said Chris Longenecker, MD, from Case Western Reserve University School of Medicine in Cleveland, who watched Baric's presentation at the virtual Conference on Retroviruses and Opportunistic Infections (CROI) 2020, which is now online.

"There is no evidence that I'm aware of that they have clinical benefits at this time," Longenecker told Medscape Medical News.

During the same session, Zunyou Wu, MD, PhD, chief epidemiologist at the Chinese Center for Disease Control and Prevention, presented data showing that more than 40% of people with severe infection had baseline hypertension. Among those with severe illness, the next most common comorbidity was diabetes, at about half that rate. Similar data have been described elsewhere, as reported by Medscape Medical News.

SARS-CoV-2 and ACE2

It turns out that SARS-CoV-2 was nearly tailor made for the human body. Although it seems to have emerged from bats or species that bats feed on, current thinking is that there are a number of these "SARS-like" viruses already in bat communities that use ACE2 receptors to invade cells. The receptors exist in multiple species, and in humans they dot the hearts and lungs.

In addition, they play a role in the development of hypertension and diabetes, and are present in greater numbers in people with cardiovascular disease.

Usually, even if a virus exists in bats, it takes several rounds of mutations before it moves from the original host species to another species and then to humans. And it can also take some time for a virus to go from a relatively benign infection to something that becomes epidemic.

But Baric and other researchers who have been sequencing existing bat coronaviruses now believe that bat populations are "seeded with preprogrammed viruses that have been designed to use multiple bat ACE2 receptors. By random chance, some of those can actually directly use humans or a secondary reservoir host," he said.

In other words, the viruses can jump the line and go directly from a bat-only virus to a human virus. "And in some cases, these viruses may be capable of programming directly to the epidemic range," Baric explained.

The fact that SARS-CoV-2 targets ACE2 receptors could be significant, Baric said. For instance, ACE2 is on a sex-linked chromosome, meaning that women express the receptor at higher levels than men. But according to Wu's data, men have worse COVID-19 outcomes than women.

And then there's the issue of ACE inhibitors. Reinin–angiotensin–aldosterone system inhibitors, which include ACE inhibitors, cause an increase in the expression of ACE2 receptors, according to a recent comment in Nature Reviews Cardiology.

"The safety and potential effects of antihypertension therapy with ACE inhibitors or angiotensin-receptor blockers in patients with COVID-19 should be carefully considered," write the Chinese researchers. "Whether patients with COVID-19 and hypertension who are taking an ACE inhibitor or angiotensin-receptor blocker should switch to another antihypertensive drug remains controversial, and further evidence is required."

This increased expression of ACE2 receptors was discussed in a recent BMJ letter, in which Swiss researchers point out that "we need rapid epidemiological and preclinical studies to clarify this relationship."

If there is an association between ACE inhibitors and the virus, "we might be able to reduce the risk of fatal COVID-19 courses in many patients by temporarily replacing these drugs," they write.

However, ACE2 has been shown to play a protective role in influenza-induced acute respiratory distress syndrome and, with age, ACE2 expression drops, said Baric, who agrees that more research is needed.

"There is probably some direct relationship to the level of ACE2 expression and disease severity," he said. "And it probably plays some role in the age-related" severity trends we've seen in COVID-19.

Small-molecule drugs designed to bind to ACE2 and prevent infection by SARS were assessed in a 2013 study. "It's a very good idea to go back and re-explore the use of these drugs, both in vitro and in improved animal models," Baric said.

Unanswered Questions

For the CROI audience, the issue of hypertension and COVID-19 raised more questions than answers.

After the session, Keri Althoff, PhD, from the Johns Hopkins Bloomberg School of Public Health in Baltimore, asked, by tweet, the number of smokers in the population Wu reported on, and the number of patients taking antihypertensive medication, but has not yet heard back from Wu, she told Medscape Medical News.

https://twitter.com/kerinalthoff/status/1237421074997968896

Longenecker said he is tempted to take a step back from the dynamics of ACE2 receptors and ACE inhibitors, and wonders whether the relation between hypertension and worse COVID-19 outcomes might simply be over-represented in older people.

"Older people have higher rates of hypertension, higher rates of cardiovascular disease," he told Medscape Medical News. "That may be an explanation. It may have nothing to do with the angiotensin receptor. Either way, these are things worth exploring."

Epidemiology of COVID-19 Now and in the Future

So far, SARS-CoV-2 has spread farther and faster than SARS, and it has different clinical characteristics. For instance, Wu showed that, unlike the original SARS outbreak in the early 2000s, when viral shedding began days after symptoms emerged, viral shedding of SARS-CoV-2 can start 24 to 48 hours before symptoms appear.

"For SARS patients, wearing a mask is good enough to stop transmission," Wu explained. "For COVID-19, both patients and healthy people need to wear masks to stop transmission."

The virus is also less deadly than SARS, said John Brooks, MD, from the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention at the Centers for Disease Control and Prevention (CDC), during his presentation.

Still, given current data and depending on how well the United States does in testing and treating people with the virus, the likely death rate from COVID-19 will be between 0.5% and 3.5%, according to the CDC.

"COVID-19 could be 5 to 35 times more deadly than seasonal influenza," Brooks said. On Wednesday, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, told a Congressional hearing that he expects COVID-19 to be 10 times as deadly as the flu.

Conference on Retroviruses and Opportunistic Infections (CROI) 2020. Presented March 10, 2020.

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