Eric Topol: 'I Still Have My Guard Up'

This transcript has been edited for clarity.

Abraham Verghese, MD: Welcome to another episode of Medicine and the Machine with my cohost, Eric Topol. Today we want to pause and take a look back at where we are with COVID, which seems to have emerged as the dominant conversation piece for our podcast. I can't think of anyone in the world who is more up-to-date on matters to do with COVID than Eric. And I'm not alone; many others are following him.

We are at an interesting inflection point, Eric, where all around us, in the United Kingdom and South Korea and Hong Kong, it seems they're battling the BA.2 Omicron variant. In the United States, we are either extremely lucky or on the threshold of something disastrous. What is your sense of what's going on and where we are during the past few months?

Eric J. Topol, MD: It's a daunting situation to interpret. As you say, Abraham, many countries in Europe, more than a dozen, have gone through a very severe BA.2 surge. It's still going on in the United Kingdom, but it's starting to trail off in many of those places.

What's interesting is that some countries in Europe, like Sweden, or in Asia, like India and Bangladesh, had BA.2 completely dominate but we didn't see a thing happen. South Africa went through BA.2 after having that initial Omicron major surge in November, and they did extremely well, with a minimal increase in cases.

We know that BA.2 is 30% more contagious than BA.1 Omicron. Also, in the United States, we had a lot of the BA.1.1, which is just one mutation different from the original Omicron variant and nothing like the multiple mutations of the BA.2 variant. In China and in many other countries in Asia, it's BA.2 as well.

South Korea is one of the best-managed countries in the world, but now they have had to deal with unchecked spread. At one point and still today, they are number one in the world for per capita new cases. They test aggressively.

That's one of the things that makes it difficult to interpret the situation in the United States. We have so much home testing that doesn't get recorded centrally, so it's trickier to follow. We're using wastewater; we're using hospitalizations that are mixed with COVID and not COVID. Part of the problem we have with learning what's going on here is, while it looks relatively favorable, we don't have our arms around all the data we need.

Verghese: Does any of this correlate with vaccination status or with immunity from natural infection country by country?

Topol: That's an interesting question, because the vaccines aren't holding up well at all against infection with the Omicron variant. The booster has turned out to be essential to preventing severe disease with hospitalizations, ICU stays, and deaths. Cases are another variable that can mislead. You look at these countries in Europe that were so severely affected, most of them were able to suppress the severe disease. And then in the United Kingdom right now, it's at peak hospitalizations for the pandemic, but almost 66% or more are not COVID-indexed — they're with, not for COVID.

These are issues because it's just so darn infectious, and the virus is just kind of blowing right through vaccines for that reason, including with people who've had three shots. The third shot — now, of course, we're talking about a fourth shot — is vital to protect against progression of the disease, but not for preventing the initial infection or transmission. It does kick in initially for infection protection, but it's about 50% effective and then drops off quickly.

Verghese: That's a distinction I know medical students struggle with. With tuberculosis, for example, the distinction is between someone being infected and therefore having a positive PPD vs being diseased. I guess what you're saying is that the vaccine does not prevent us from acquiring the infection, but it does seem to continue to protect us from severe hospitalization.

Topol: Yes. The unfortunate thing is that the goalposts changed. Initially, when the vaccines rolled out, we saw 95% efficacy against symptomatic infections and severe disease. Now we're trying to eke out 95% just against hospitalizations and deaths. And we get that from a third or fourth shot, at least for some weeks and even up to 4 months or so.

But basically, we can't keep up with this evolving virus. Omicron, both the initial BA.1 and now this more recent BA.2, have thrown us big challenges. BA.2 has more than 50 mutations from the original strain, really challenging our immune system — taking it to the max. We can't afford another variant that's even more evasive to the immune system because it's going to take a big toll on our ability to prevent infection. Our vaccines are essentially outdated.

Verghese: The US Food and Drug Administration (FDA) has said that 50% of our population has been infected with Omicron. Talk about that a bit.

Topol: That's a massive number. Within 10 weeks, to have half of Americans — we're talking about 160-some million Americans — getting Omicron, whether they knew it or not. Those are projections from one of our top data scientists, Trevor Bedford from University of Washington. He's been spot-on for the whole pandemic. He presented that at the FDA yesterday. That's within 10 weeks.

What you were getting at, Abraham, is that if the United States doesn't hold up well and better than expected in this current wave, the question is, will it be a big spike? If we don't see what's going on in the United Kingdom and other places, it may be because we just took such a big brunt of Omicron from the first wave. We got to the highest level of hospitalizations ever in the pandemic: 160,000.

We were getting confirmed cases at levels that were completely off the charts — unimaginable.

There is cross-immunity, but it isn't perfect. There have been some people who had Omicron and then got BA.2. But they seem to be pretty unusual or uncommon. So that may be the leading explanation if we stay somewhat unscathed.

Verghese: Paradoxically, the rapid antigen tests, even though they're tremendous, have led people to completely abandon PCR testing. And the threshold for rapid antigen tests is so high that I think we're lulled into a sense that nobody has this when, in fact, everybody might have it. We just don't know.

Topol: You're absolutely right. Not only will the rapid antigen test miss some infections, but their threshold for being positive means you have to have quite a high viral load. So, the abandonment of conventional PCR testing and then the inability for us to see that is tricky. However, we were using a lot of rapid tests since the beginning of Omicron. I don't know that it's changed that much in this current second wave with the BA.2. So yes, there are a lot of rapid tests in use, no question. They're difficult to interpret. But I'm not sure it's going to change our sense of testing and case counts that much.

Verghese: God forbid we experience what the United Kingdom is experiencing, but let's say we do. What's changed in terms of therapy? What's changed in terms of our approach to symptomatic outpatients and inpatients who are sicker?

Topol: The biggest thing, of course, is having wide availability of Paxlovid, the pill in a 5-day pack, that combines nirmatrelvir and ritonavir. If that were broadly available, that's a security blanket. Anyone at increased risk, as soon as they had an infection, could take the 5-day course and have a 90% reduction in hospitalizations and deaths.

But we don't have a big supply. Orders were put in for 20 million blister packs, but it turns out we only have 800,000 or so because the government hasn't approved the added COVID relief package. So, at the moment there's this order for the pills but it can't be fulfilled until it's paid for. That's one issue.

The other thing is that if we ever do get enough packs, some resistance will probably emerge over time when the drug is in wide use. We don't have a good backup pill for outpatient use. We need that. There are a few candidates in the hopper, but they're pretty far away in time.

This brings us to the debate at the FDA yesterday by the advisors. We can't live with a 4-month booster schedule. No one wants to do that, but it is all we have now, for protection enhanced from the boosters.

One way to circumvent this problem would be to develop better drugs, but the monoclonal antibodies are not holding up either. And there aren't any other great preventive drugs available. As you know, at least if you get sick, a lot of things can be done to help reduce that massive cytokine storm to help keep people from becoming too critically ill.

One notable thing, Abraham, is that we're down to fewer than 2000 people with COVID in ICUs around the country right now, which is the lowest by far of any time during the pandemic. That tells me that we've gotten much better at this. People are vaccinated, and when they are admitted, we have a lot of tools that we didn't have before. So, hopefully, we can avoid the most critical hospitalizations and deaths.

The biggest problem, as you well know, is that less than 30% of Americans are boosted, and tens of millions of people never had a single vaccine dose, which is amazing. I'm not talking about zero- to 5-year-olds; I'm talking about adults. So, we're vulnerable.

Verghese: It's a good thing that 50% have been exposed to Omicron. I suppose that's a blessing in disguise. I must ask about the monoclonal antibodies. Which monoclonals are holding up, in your opinion?

Topol: This is quite interesting. This is the first time I can remember in medicine that, if you could sequence the patient's virus, it would tell you which treatment to give. But we don't have that capability. We should, but we don't. Nobody gets their actual sequence back.

The Glaxo antibody sotrovimab worked pretty well with BA.1, but it doesn't work with BA.2. So we're down to just a couple of antibodies that seem to have efficacy yet are still not proven with BA.2. For a while, we had a whole bunch of antibodies to select from, but as the virus has evolved, it's become a narrower choice and limited supply. And as mentioned, we have issues about not having enough funds to acquire the doses.

Verghese: One thing I've enjoyed about your tweets is that they keep me abreast of all the amazing science that's going on. If you had to look back over the past year, what have been the biggest breakthroughs on the genetics, and other science, fronts as they relate to this virus and our defenses?

Topol: There's been so much. We've learned a lot about the genetics of people that either gives them protection from or vulnerability to common or rare variants. It isn't of practical interest because you can't really use that to help segment risk. We know that a group could be together in a room with an infectious person, and certain people are totally resistant and others are highly vulnerable. I think we're understanding that better now but it doesn't change things too much.

I think the biggest cluster of papers, which have been so remarkable, have been those on the long-COVID status at 1 year. The three biggest were, first, the cardiovascular study from the Department of Veterans Affairs, of hundreds of thousands of people with millions of controls. The number of people who had late issues with heart failure and stroke and arrhythmias was striking and confirmed by other studies.

Second was the UK Biobank brain scan study. To me, this was one of the most important studies of all. The population had baseline MRIs before they got COVID, and the follow-up showed loss of gray matter, atrophy of the brain, and cognitive decline in people with mild to moderate infections, compared with controls. Very concerning.

Finally, in the long-COVID category, multiple studies have come out showing emerging, late diabetes — not present in the initial 30 days after COVID infection, but present at 6 months or 1 year — 20%-40% more developed type 2 diabetes compared with controls without COVID. Where did that come from? Even if that percentage turned out to be in the single digits or 15% — all of the studies show between 20% and 40% right now — just think about how many people have had COVID and will then manifest late type 2 diabetes.

These long-COVID papers are of great interest. But we still have nothing to treat COVID. All we have is prevention. People don't adequately respect the importance of avoiding the infection so we can avoid long COVID.

Verghese: The symptoms of long COVID are so nonspecific and just the kind of thing that can be easily dismissed by patients and the healthcare system. In the United Kingdom right now, they don't use PCR testing, so they have no way of even establishing who's got what. It's truly a challenge.

The bottom line is that we should work hard to avoid acquiring this virus, to do everything we can to protect ourselves. Get vaccinated, and when the infection levels rise, masks, too, would be critical. What is your personal practice now when you're out and about and when you travel?

Topol: I'm still wearing a mask when I go to the grocery store or I'm in a place where there are a lot of people and I don't know their status. When we have a conference room gathering with people I know, I'm not worried about wearing a mask. Also, fortunately, we've got good filtration and state-of-the-art prevention there. But I still have my guard up. Being an old dog, it doesn't matter how many boosters you get.

We have come a long way to get through this. We may well see in the months ahead a more challenging variant than we've already seen. That's why I think keeping our guard up is essential. I hope we'll get a much better vaccine that takes on all of the variants. It's doable. I'm convinced of that.

Going back to the science papers, there have been more than 20 different candidates for universal pan-betacoronavirus vaccine. If we could jump on that and go into high gear, maybe we could get one that is ready in the months ahead or certainly within a year.

This has been a long hypermarathon — just amazing. It's hard for people, certainly for my family and I, to stay on guard and not forget about it. It's always in the background.

Verghese: When we started this podcast, we had no sense of what was coming and of COVID being on the horizon and how much it has colored our lives. But it certainly has made for wonderful discussions. I've learned a lot, and it's been a pleasure to host this with you. I guess the message for our listeners is to be careful out there, stay informed, and protect yourselves and your families.

Topol: That's it. I think there's a lot of vulnerability still. We don't want this virus to beat us as, in so many ways, it already has. We know how we can deal with it. It's challenging. But if we in the United States get through with a relatively low burden from this BA.2 wave, that will be great. We may wind up having several good months and maybe even years ahead. It's possible, and I hope that the worst is behind us. That would be wonderful. But most days, I'm feeling a higher level of concern that it's not likely. We'll see.

It is a joy to have these conversations with each other and with our guests. We've had probably 40 or 50 experts to interview and learn from. That's one of my great defenses for dealing with the pandemic: getting the stimulation from these conversations, reading papers, and trying to keep up. That's one way to keep from getting too depressed. There are a lot of great advances on the science side, and it's thrilling to see that.

Verghese: It's good to focus on that. Thanks to all of our listeners for joining us for another episode of Medicine and the Machine. We hope you'll continue to join us for interesting guests and stimulating conversation. Special thanks to my cohost, Eric, for everything he does. I look forward to our next episode.

This podcast is intended for US healthcare professionals only.

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