by Rick Lange, MD, Texas Tech; Elizabeth Tracey, Johns Hopkins Medicine July 16, 2022

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.

This week's topics include factors that contribute to severe outcomes in immunocompromised people with COVID, a new oral medication for severe COVID-19, lack of benefit in knee injections for osteoarthritis, and insight into long COVID.

2:42 Factors related to severe COVID in immunocompromised

4:42 Vaccination does not decrease death risk if hospitalized

8:15 Hyaluronic acid injections in knees in BMJ

9:20 560 million worldwide living with knee OA

10:20 Many of the studies haven't been published

Elizabeth Tracey: What accounts for severe outcomes among immunocompromised adults hospitalized with COVID-19?

Rick Lange, MD: A new oral therapy for high-risk hospitalized adults with COVID-19.

Elizabeth: A real lack of benefit seen in knee injections for osteoarthritis.

Rick: And a study that provides insight into the long COVID symptoms.

Elizabeth: That's what we're talking about this week on TTHealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I'm Elizabeth Tracey, a Baltimore-based medical journalist.

Rick: And I'm Rick Lange, president of Texas Tech University Health Sciences Center in El Paso where I'm also dean of the Paul L. Foster School of Medicine.

Elizabeth: We'll apologize a priori to everybody who is listening. You are in France riding your bicycle so we have a few drop-outs sometimes. Let's turn to, gosh, this week we have got three out of four studies on COVID. So which of your two would you like to start with?

Rick: According to the World Health Organization, about one-quarter of individuals who develop COVID infection continue to experience symptoms 4 to 5 weeks and approximately 1 in 10 have continuing symptoms for 12 weeks. We have called that in the past "long COVID" symptoms, but the more recent scientific expression is called post-acute sequelae of COVID-19, or PASC. This is a study that may provide a little insight into that.

The study is conducted from some investigators at Harvard, who analyzed plasma samples collected from about 37 individuals that had long COVID or PASC and they compared it to 26 individuals that also had COVID. They looked at the different protein biomarkers to see if they could identify some that were associated with PASC. What they had discovered was in this individual study about two-thirds of them had persistent spike proteins detected in their blood, whereas those without long COVID symptoms did not. There might be some sort of persistent reservoir in the body.

Elizabeth: This, let me just mention, is published on their preprint server, medRxiv. I'm interested in any information that may have been in this -- and there may not be any -- about the subtypes of which strain of COVID-19 are we talking about.

Rick: This study actually spans three different viruses that have been present, but the spike protein ends up being relatively conserved across the different types. There are two different subtypes of the spike protein called S1 and S2 and then the combined [one]. It was a combination that was detected in two-thirds of the individuals.

Elizabeth: Clearly, one of the things that we are going to need in order to really nail this down is going to be a whole lot more than 60-something patients and a whole lot more factors assessed.

Rick: I agree. This is a preliminary study. It's a small number of individuals and needs a larger cohort. If there is a persistent reservoir, we need to figure out where that is.

Elizabeth: More to come. Let's turn to Morbidity and Mortality Weekly Report, and this is a look at what are the factors among immunocompromised people that are associated with severe outcomes when in fact they are hospitalized with COVID-19?

This study was conducted looking at ICU admission and in-hospital deaths from March 1st 2020 to February 28th 2022. They looked also among these folks at vaccination status, and this is all part of the COVID-NET Surveillance Network from the CDC. This was a sample of 22,000+ adults hospitalized for COVID-19; 12.2% of this sample were immunocompromised.

They looked at unvaccinated patients and those with immunocompromise clearly have higher odds of ICU admission and in-hospital death than non-immunocompromised people, and also fully vaccinated people for that matter. Of course, non-immunocompromised patients have lower odds of death than especially those who are vaccinated compared to those who are unvaccinated. The rather daunting news in my mind was that among these immunocompromised patients who were hospitalized, their odds of death between those who were vaccinated and those who were not vaccinated did not differ.

They also come to the conclusion that what we really need to do is maintain. among those who were immunocompromised, a lot of the physical separations among their close contacts, also close contact immunization, of course, early testing, prophylactic medication administration, and then early antiviral treatment as soon as they become positive for COVID-19.

Rick: I agree with you. There are some parts of the study that I think are encouraging. For example, one of the facts is that COVID-19 vaccination among immunocompromised persons is highly protective against being hospitalized for an infection. However, as you said, what's disappointing is once they are hospitalized the vaccination does not decrease the result of being in the ICU or death if we want to keep them out of the hospital.

The thing that is otherwise a little bit disconcerting among this particular study is even though when you look at immunocompromised individuals, they only compose about less than 3% of the adult population, yet they accounted for 12% of the adult hospitalizations in the COVID-NET. When we talk about being immunocompromised, these are people with AIDS, on steroid therapy, have solid organ transplant, and people that have multiple myeloma. Let's change gears and talk about something that's really encouraging, and that's a new oral therapy.

Elizabeth: That's right. Let's turn to that and that's in NEJM Evidence.

Rick: This is a medicine called sabizabulin. It's an oral agent that has dual properties. It's antiviral and it's anti-inflammatory. It has been tested in preclinical models. Here, it's being used in high-risk hospice adults. Now, by the way, we have very few therapies that are effective in this group.

They looked at 204 patients, again hospitalized adults with COVID-19, a high risk for dying, or a high risk for being in the ICU or on mechanical ventilation. They randomized them to routine therapy that could include remdesivir, dexamethasone, or whatever else.

The other half -- or [rather] two-thirds of patients -- actually received, in addition to that, sabizabulin, an oral agent administered once a day for up to 21 days. They followed these individuals for 60 days looking at mortality -- that was their primary endpoint -- and secondarily how long were they in the ICU or how long were they on mechanical ventilation, or how long were they in the hospital?

Here is the thing that was really encouraging. With regard to 60-day mortality to tell you how high risk this group was, in those that received routine standard care the mortality at 60 days was 45%. That was cut in half to 20% with the use of sabizabulin in addition to routine therapy. There was a 43% reduction in ICU days, about a 50% reduction in days on mechanical ventilation, and about a 26% reduction in days in the hospital, all versus placebo. By the way, fewer side effects in those that received sabizabulin than those that received just standard care. This is really encouraging news.

Elizabeth: Yeah, and it accounts for why they're publishing it so early. I guess we should thank them for that.

It's an interesting mechanism for me. They described it as a novel microtubule disruptor. I'm wondering about that mechanism. Certainly, that's a mechanism in other types of infections that involve things like retrograde transmission in neurons, but I'm just wondering how it actually works with regard to viral replication.

Rick: OK, so here is what it does. It disrupts the microtubules that are inside the cells and these microtubules are responsible for transporting the virus into the cell within the cell, replicating, and also causing the virus after it's replicated to leave the cell. Microtubules are involved in all of that, so this disrupts those. That's the primary mechanism.

Secondly, it's also anti-inflammatory. We know that the cytokine storm that comes after the viral infection is responsible for the respiratory distress syndrome, the septic shock, and their frequent death. By both inhibiting microtubules, or disrupting them, and being anti-inflammatory, these dual properties are what make it so effective -- even as an oral agent.

Elizabeth: I'm just really fascinated with this. I'm just going to go out on a limb and say that this novel microtubule disruption mechanism, maybe we are going to be hearing a lot more about this in a lot of other meds.

Rick: I wouldn't be surprised that this could be extended to other therapies or other diseases in the future. Speaking of things that have been effective, let's talk about something that is not effective therapy.

Elizabeth: Yes, so this is taking a look at knee injections for knee osteoarthritis. I learned a new word -- I don't know if you knew this one before or not -- viscosupplementation. That's the injection of different things into the knee in an attempt to kind of improve both the volume and the viscosity of the fluid that's normally in the joint. This was something that came over the transom a while ago. I seem to remember us talking about it when we first started hearing about potential for this therapy and it makes intuitive sense.

This is a meta-analysis, of course, where they took a look at 169 trials providing data on almost 22,000, just over 21,000 randomized participants. Their primary outcome measure was pain intensity. They basically found that there really wasn't any evidence to support the use of injections into the knee for osteoarthritis. That's really bad news for the 560 million people worldwide who are living with knee osteoarthritis.

This hyaluronic acid really doesn't help at all, and the bad news is that there is strong conclusive evidence indicating that this strategy is associated with an increased risk of serious adverse events, including infections. It sounds like everybody ought to be putting away those needles.

Rick: Elizabeth, as you mentioned, this is a really incredible study. It's incredibly important because recently one in every seven patients with knee osteoarthritis in the United States have received injections of hyaluronic acid or its derivatives as first-line treatment.

We spent recently over $325 million using this hyaluronic acid injection. About a fourth of that was spent on, as you said, the complications -- that is, large-joint infections that occur because you stick a needle into a joint and the joint itself becomes infected. About one in 25 individuals who receive an injection will develop one of those infections.

The other thing that I thought was really interesting, Elizabeth, is this has been reviewed before in a meta-analysis, but this one included 80 studies that weren't previously reported. Many of those, by the way, haven't been published because they are negative studies. The hyaluronic acid doesn't prove to be beneficial and they just don't publish the studies. That leads to bias. These particular authors were able to come across those studies and identify them, again, to prove that this particular therapy really isn't beneficial.

Elizabeth: A definitely eloquent argument for why we should have some kind of repository for all studies.

Rick: In fact, that's what clinicaltrials.gov does. To start a clinical trial, you have to register it with the government and then they subsequently look to see, "Were the results published or not?" If they aren't, and it's a negative study, then that leads to what we would call publication bias -- they only publish studies that are positive, where the treatment seems like it's more effective than it really is.

Elizabeth: On that note, then, safe time on your bicycle. Don't overuse your knees so you aren't tempted to have an injection. That's a look at this week's medical headlines from Texas Tech. I'm Elizabeth Tracey.

Rick: And I'm Rick Lange. Y'all listen up and make healthy choices.

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