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COVID-19: What We Know, What We Don’t Know & What is On The Horizon

April 27, 2021
by Saphia Suarez

On March 31, Yale’s Department of Internal Medicine hosted its first event on Clubhouse, a social networking app that allows members to gather in audio chat rooms and discuss issues in a live podcast style. The event focused on current knowledge of COVID-19, a year after the pandemic began in Connecticut.

The following experts participated in the panel discussion:

  • Gary V. Desir, MD, Paul B. Beeson Professor of Medicine; chair, Department of Internal Medicine; chief of internal medicine at Yale New Haven Hospital; and vice provost for Faculty Development and Diversity at Yale University;
  • Mahalia Desruisseaux, MD, associate professor of medicine (infectious diseases);
  • Lynn E. Fiellin, MD, professor of medicine (general medicine) and of public health (behavioral sciences); and chief of the Fitkin Firm, Yale New Haven Hospital;
  • Howard Forman, MD, MBA, FACR, professor of radiology and biomedical imaging in the Institute for Social and Policy Studies of Economics of Management and of Public Health;
  • Manisha Juthani, MD, associate professor of medicine (infectious diseases) and epidemiology (microbial diseases);
  • Naftali Kaminski, MD, Boehringer Ingelheim Pharmaceuticals Professor of Medicine (Pulmonary); and section chief, Pulmonary, Critical Care and Sleep Medicine;
  • Saad B. Omer, MBBS, MPH, PhD, FIDSA, director, Yale Institute for Global Health; and professor of medicine (infectious diseases);
  • Christopher Ruser, MD, associate professor of medicine (general medicine); and chief of primary care, VA Connecticut Healthcare System.

Below are some highlights from the event. The conversation has been edited for brevity.

Q: There's talk about the possibility of another COVID-19 surge. Can you talk about what you are seeing as a trend nationwide?

Desir: The first wave was reasonably short and died down over the summer, and the second wave began in mid-October. Vaccines became available in December. Since then, it's been a race between vaccinating the population and dealing with variants of the virus. So the second wave is very different than the first wave in that it's lasting much longer, though there are not as many patients in the hospital. And over the past several weeks, we've seen an indication of a third wave. We are dealing with the variant B117, which was first discovered in England and appears to be easier to transmit and produces severe disease. The second trend is that we are seeing much younger patients in the hospital now than we saw in the first wave. So I suspect we might see a third wave over the next several months, but the key is going to be, can we vaccinate the population fast enough to mitigate the height of the third wave? Going forward we will be dealing with variants, and it's quite possible that COVID might become an endemic infection just like the flu.

Q: During COVID, everyone in the medical community had to adapt quickly as new information on the virus was coming out. What was learned about the role of the medical and scientific communities during this crisis?

Kaminski: The tension within the medical community was between those who wanted to implement things without evidence and those who wanted to wait for the evidence. This created a little stress initially, and politicians didn't help by getting involved in this discussion and propagating biased claims. What has happened over the last few months has been a little bit different, which is we started having evidence, so we, I think, have a feeling about what are the right or the most effective treatments for those who are affected with COVID-19. I think we have good science to support almost every public health policy that we implemented, but we are dealing with a different side effect, which is what I would call the good, the bad, and the opportunist. So the good is still the same: physicians and scientists who do their duty to support science and communicate it to the public. The bad are some scientists who prefer to develop and promote opinions that fit political agendas rather than science. And the opportunists are people who use the controversy to promote their own websites, likes, and influencer status on social media, rather than educating the public. So what should happen? I think the medical community should go back to its own tradition, which is we should be committed to our patients, to truth, and to science. We have to follow the science, pursue the truth, and communicate the truth. I believe we should avoid the temptation of getting likes and instead speak truth to power. When politicians, when administrators don't follow public health, we have to speak up.

Q: What are the current recommendations for getting vaccinated if you've already had COVID-19?

Fiellin: So first, I would like to just say amen to Naftali's statement regarding our patients and science. And actually, when asked about what we might discuss in this room I posed this as a question that I actually don't necessarily know the answer to, which for me is the best way to learn, and I hope that we'll hear the thoughts of others in the group on this. But what I've experienced in the last three to four weeks is, to the point that Dr. Desir made, this explosion of new cases, clearly a much higher level of infectivity, which has been very striking, which really speaks to the nature of these variants, and also engendered a question for me, which is how to deal with the vaccine. These are groups of people who have not yet had the vaccine available to them, so this is an important question: what is the current policy about getting vaccinated after you've had COVID? My understanding—and I do call out to more expert people on this call, including my dear friend, Dr. Manisha Juthani— is that across the board, yes, you should be vaccinated if you've had COVID-19 for a number of reasons, including that we don't know how long you're protected after you've been sick and recovered from COVID-19. Initially, there were recommendations to wait up to 90 days to get vaccinated if you'd had COVID. That certainly seems to still be the case if you had received treatment with monoclonal antibodies, but now my understanding is, is that generally speaking, people with COVID-19 who had symptoms should wait to be vaccinated until they have recovered from their illness and meet the criteria for discontinuing isolation, and those who were infected with COVID-19 but did not have symptoms should also wait until they meet the criteria before getting vaccinated. But essentially, once you feel well, it's completely fine to go ahead and get vaccinated.

Q: Dr. Omer, would you like to touch upon vaccines and what Dr. Fiellin was discussing?

Omer: Yes, I would be happy to talk about that. And I have the privilege of being on the World Health Organization's COVID-19 vaccine working group that helps develop these recommendations, clinical and public health recommendations, for global use that various countries adapt and adopt, and there is an overlap with some distinctions between the two recommendations, between WHO and CDC. And it was correctly described that currently, the recommendation is that if you have active illness, you recover, and you can receive vaccine. One nuance is that people who have had COVID-19 can wait, if they like, for a few months. For example, in a vaccine shortage situation, they can afford to wait a little bit. But the baseline recommendation is that once you have recovered, as soon as you meet the criteria of coming out of isolation, you should be vaccinated.

Q: The first is, the virus is mutating and other COVID variants are now showing up. So what do we know about the effectiveness of the current vaccines on these variants and achieving herd immunity?

Omer: That's a really good question. First of all, emergence of mutations and mutants and variants, which is a cluster of mutations, is expected. Not all variants are of concern, but there are a few variants that are. And there are three variants that we are keeping a close eye on, such as the B117 variant initially identified in the United Kingdom, the B135 variant initially identified in South Africa, and the P-1 variant initially identified in Brazil.

In the US, as Dr. Desir mentioned, we have a significant increase in the B117 variant. And the reason we are concerned about all three of these variants is because there is substantial evidence that they are more infectious, that they transmit more easily. And there is increasing evidence that they cause more severe disease. So that's the context in which we are thinking about and are a bit worried about these variants.

When it comes to vaccine impact, it's mixed and patchy data, but the big picture is that for some of the vaccines that are not currently authorized, there is some initial indication that there may be some decrease in lab-confirmed symptomatic disease or efficacy against lab-confirmed symptomatic disease of mild to moderate intensity against B135, for example, for the AstraZeneca vaccine. Beyond that, we know that the Johnson & Johnson vaccine works well, even from mild to moderate disease, specifically included for the B135. But for the rest of it, the evidence is limited to lab-based neutralization or lab-based outcomes. And the big picture is that overall, for the variant that is prevalent in the US, especially with the vaccines that are authorized in the US, there may be some diminution of impact on what we call the neutralization using a so-called viral plaque SA, which looks at how antibodies neutralize virus in the lab situation. But clinically, the more severe the outcome, the more assurance we have so far that these existing vaccines seem to work and seem to work reasonably well. So that's the current state of evidence for all of these three variants, particularly the B117 variant, which is the most concerning one at this point in the US.

The other part of this is that while this is the current state of understanding, and that's the current state of things, the vaccine companies and research entities are developing tools to counter any further deterioration or any deterioration in actual effectiveness or efficacy in the future. So we are developing tools like booster doses with the same virus or with the emerging virus and so on and so forth, so that we have these policy options if we need to move to alternative options.

Q: Let's pivot for a bit and talk about the data about the COVID vaccine, specifically for pregnant women and children. Dr. Manisha Juthani, what is known right now about the COVID vaccine in pregnant women and in children?

Juthani: I think there are important questions people have about pregnancy, which is very legitimate. Number one, some people have had concerns about fertility. I don't feel these concerns are based on the science of what we've seen of the vaccines. And there are women who got pregnant during the vaccine trials, which is reassuring from the question of fertility. Now, there are many pregnant women that are currently in clinical trials that we are waiting on the results for, and we also know that there are many pregnant women that have elected to get vaccinated and some that have chosen not to get vaccinated during this time period. And then in terms of children, we got news that the Pfizer vaccine has promising data for children 12 and older, which will likely get added to the emergency use authorization. Of course, it's still subject to review at this point, but the data does look promising, which would be good news before the next school year with trials in children six and older started last week, and two and older starting next week.

And I'd just like to share one story—my friend Dr. Fiellin mentioned, "When can you get vaccinated?" And this is a question we've talked about a lot of recent because we both have seen cases that people have approached us about. Somebody close to me who is a healthcare provider, pregnant, 34 weeks, wanted to wait to get vaccinated because she had some concerns about data that was available to date, so she chose not to. And she was concerned particularly about a possible inflammatory response should she get vaccinated. A lot of people around her, her spouse, the people she works with at work were all vaccinated, but of course, her five-year-old child was not, and he got infected, likely at school, and she then got infected. And so, to me, this is the biggest reason that we need to see the data and hopefully expand vaccination to children as soon as possible, because that is the way that we're really going to be able to protect our society at large.

We also have data in pregnancy now. People who are pregnant and have gotten the vaccine are appearing to have good immune responses and are able to protect their babies as well. So I am most definitely recommending to people who may have waited that they at least get their first shot in their third trimester because I do think there are benefits, both to the pregnant mother and to the unborn child once they are born.

Q: What should we be looking for from the FDA or Moderna, Pfizer, and J&J in the next year that could have a big impact on the course of the pandemic?

Forman: To me, right now, one of the biggest issues is what is the timeline for booster shots that might address some of the variants that are moving along? And whether we ultimately need booster shots or not is also a question worth asking, but whether we need it or not, we want to be prepared. So we need to know from the FDA, what is the timeline, what are the expectations for data in order to give approval, and what type of approval will that look like? I think Moderna already has trials in place for a booster shot that includes, I believe, but it would be nice to see more of that and more transparency about what the expectations are for all the three currently authorized vaccines.

We have missed a lot of opportunities in the last year. We haven't done comparative trials. Going forward, we can avoid a lot of that if we know what the expectations are for authorization and ultimately approval. The original expectation for a lot of the trials are a collection of two years' worth of data and then approval of a vaccine. We've now had a massive deployment of these vaccines in the real world, so the clinical trials start to be of smaller importance compared to the collection of real-world effectiveness data. And it would be useful for us to know when we're going to actually get approval because that will lead to policy changes and directives from the CDC.

Right now it's very difficult to talk about vaccine mandates when we don't even have an approval of any of the vaccines, but if we had a sense of what the expectations are going to be for getting to approval, we might be able to plan a little bit better. So what I'm hoping—and a lot of this is going on behind the scenes and is opaque to me— is that there's more and more collaboration between the three originally authorized vaccines and the FDA so that we can have a more seamless transition to approval and to approved or authorized booster shots.

Q: Some healthcare workers are hesitant about taking the vaccine, and even have said that they won't take it. Would the antibody cocktails be a good alternative option?

Desruisseaux: There are currently two companies that are undergoing clinical trials with their antibody cocktails right now-Regeneron and Eli Lilly-and they've shown some decent data in terms of preventing hospitalization and decreasing viral load in patients who are infected and who they've treated early on with these monoclonal antibodies within three days of their symptoms. And so they've been able to decrease the viral load and decrease the number of medical visits. Right now, there are a couple of trials undergoing, both with Eli Lilly and Regeneron, for their antibody cocktails on prevention. And the one that's most advanced is the one from Eli Lilly. It's the BLAZE-2 trial where they're looking at residents and skilled nursing facilities and assisted living. So this is in patients who are older and more susceptible to severe disease, and what they have found is that with the combination of monoclonal cocktail, there's a decrease in detection of the virus within seven days of the vaccination, and they've been able to see that it prevents infection in those patients. Those trials are still undergoing, but they're also looking at younger patients, though those are not far enough along.

This prevention only occurs with the combination, with the monoclonal antibody cocktail. So for Eli Lilly, for instance, the bamlanivimab monotherapy has no effect on preventing infection. But when you add the etesevimab to the bamlanivimab, when you have that monoclonal antibody cocktail, there is some benefit to it in this older patient population.

Regeneron is currently undergoing trials for individuals 18 and older who have household contacts or any other exposure, so this would likely apply to healthcare workers as well who have exposure to individuals with COVID-19. So they're looking at these individuals to see whether or not the antibody cocktail can prevent infection in those individuals. Those trials are still ongoing, there are no data available yet, but based on the Eli Lilly trial in the older patients, it looks like there might be some promise in prevention using the monoclonal antibody cocktail for prevention.

Q: How has primary care changed since COVID? What are you seeing now in patients with long-term COVID? And how has this changed your approach as a primary care provider?

Ruser: The VA Connecticut is different than some of the other systems in which the current healthcare providers on the call practice in. The VA is the largest single-payer example in the United States, and one of the largest healthcare providers in the world. To give you a sense of how primary care has changed, we take care of about 50,000 veterans across the state. At baseline in January 2020 before the pandemic hit, we would do about 3,000 visits per week across our eight sites just in the state of Connecticut with those 50,000 patients. And at that time, we had existing video and email platforms. From about the end of March into May, over about six weeks, we nearly 100% virtualized primary care, all phone and video. We went from 3,000 or 3,500 in-person visits to almost that same amount via phone and video in just about six short weeks. We also created some special telemedicine clinics, we call them virtual respiratory clinics, whereby patients with COVID-like symptoms could be quickly assessed and then referred to our drive-through testing center. Again, in order to keep them from walking into the emergency room if they weren't that sick and exposing others until we understood the virus better.

But now, we're out of this contemplative phase and we're seeing what this new primary care is going to look like. The data from veterans, and we surveyed thousands of veterans each month, is mixed. For primary care, about 60% at this point would still prefer an in-person visit. In mental health, it's actually pretty evenly split, where the majority are actually preferring virtual care and telemedicine. And how that plays out in terms of what comes next for preventive care and how we do this better with the right percentages of virtual versus in-person and so forth, remains to be seen.

As far as long-term COVID care, a couple of organizations like Yale have set up clinics specifically to deal with this. But what's interesting is, there will be implications on a much broader scale for primary care going forward. COVID is now a new source of chronic renal insufficiency as a newly recognized source of unique acute kidney injury in the hospital and then the subsequent sequelae. COVID is also a unique source of chronic heart disease that hadn't been seen before.

Q: Dr. Kaminski, you have a post-COVID recovery clinic through the pulmonary section. Do you want to touch on what Dr. Ruser mentioned about those patients who are now post-COVID?

Kaminski: Today (March 31) we are holding the ribbon-cutting of a new Winchester Center for Lung Diseases, a 30-room facility with everything you need and the most modern infection control. All the rooms and corridors have negative pressure ventilation. And in there, we have the recovery clinic, which is a multidisciplinary post-COVID clinic. And the reason it is multidisciplinary is because we are finding a large range of symptoms. Some of them are non-specific, others are potentially markers of lung disease and interstitial lung disease, and in some cases, mild fibrosis. One of the most common things that people express is not only that they suffer from the symptoms, but also from the disbelief from their communities, because many of the symptoms don't fit into one disease category. So it's really important to look at the patient from multiple aspects: the neurological, the cardiological, the pulmonary, the psychiatric, and potentially the rehab and occupational side of it. Dr. Desir mentioned he thinks COVID will stay with us as an endemic virus. I'm really concerned that post-COVID symptoms will stay with us as a public health issue, because many of our post-COVID patients, while not extremely sick, have very debilitating symptoms. So again, it's another area for research. We're glad to know that NIH is putting in the money. But my advice to primary care physicians is to believe your patients, what they’re experiencing is not only anxiety, and refer them to a place that has a multidisciplinary unit.

After this discussion, the audience had the opportunity to ask questions.

The event was moderated by Director of Communications Julie Parry; Web & Social Media Strategist Amy Anderson; and Yale MD/MBA student Prerak Juthani.

The Department of Internal Medicine at Yale is among the nation's premier departments, bringing together an elite cadre of clinicians, investigators and educators in one of the world's top medical schools. To learn more, visit Internal Medicine.

Submitted by Julie Parry on April 27, 2021