‘Toci’ and COVID; Exercise for Arthritic Knees; It’s TTHealthWatch!

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TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine, 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. A transcript of the podcast is below the summary.

This week’s topics include exercise for knee osteoarthritis, tocilizumab for COVID-19, gut flora and their role in health and disease, and heparin and COVID infection.

Program notes:

0:41 Tocilizumab and COVID

1:46 All needed oxygen

2:48 How expensive?

3:18 Exercise and knee osteoarthritis

4:18 High or low intensity strength training

5:18 Very comprehensive study

6:18 Keeping people in the study for 18 months

6:38 Heparin for reducing blood clots in COVID

7:40 Subcutaneous injection

8:41 Study coming shortly

9:10 Human gut microbiome and health

10:10 Driven by healthy and plant-based foods

11:10 Less of one bug in the gut may be associated with cardiovascular disease

12:10 Is it a cause or an effect?

13:15 End

Transcript:

Elizabeth Tracey: Is exercise of any benefit whatsoever in knee osteoarthritis?

Rick Lange: Do people with COVID benefit from a blood thinner?

Elizabeth: A really exhaustive look — so far — at the human gut microbiome and how it may be related to disease.

Rick: And a different anti-inflammatory medication for people with COVID and respiratory problems.

Elizabeth: That’s what we’re talking about this week on TT HealthWatch, 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 the Texas Tech University Health Sciences Center in El Paso, where I’m also the dean of the Paul L. Foster School of Medicine.

Elizabeth: Rick, we’re still top of mind with COVID, so I’m going to let you choose one of yours to start with.

Rick: Elizabeth, let’s talk about this anti-inflammatory agent, and I called it new — it’s actually not new. It’s been used for rheumatoid arthritis, but it’s new for the use of COVID. This was in a particular group of individuals. These are individuals that have decreased oxygen saturation — that is, they’re having hypoxic respiratory problems, lung problems, from COVID.

We know that there are various therapies. Early on, there’s monoclonal antibodies before people get into the hospital; once they get in and they’re mildly affected, remdesivir; but those that are most severely affected — those on a ventilator or about to — benefit from high-dose steroids.

What that alludes to is the fact that our immune system is responsible for some of the lung damage, the inflammation. There is a monoclonal antibody called tocilizumab, which has been used for rheumatoid arthritis because it’s also an inflammatory condition. Specifically, it inhibits what’s called interleukin 6.

They took over 4,000 adults that had COVID that had evidence of inflammation — elevated C-reactive protein — and they all had some requirements for oxygen — some were on a ventilator — and they randomized them to the usual care or a single infusion of tocilizumab. Sometimes, if they wanted to, they could give a second dose the next day, and the simple outcome was, how did they do with regard to mortality?

What they discovered was that the addition of tocilizumab to usual care, 29% of the individuals that received tocilizumab died within 28 days versus 33% of the patients who did not receive it. Overall, that was a 14% reduction in mortality.

Elizabeth: Let’s just remind everyone that this is published on the preprint server medRxiv and that this is part of the RECOVERY trial, that giganto and, in my mind, an incredibly well-designed study that’s taking place in the U.K. that’s looking very rigorously at a lot of these things. We can say that our dexamethasone outcomes were really a result of the RECOVERY trial also.

Let’s go back, though, to “toci” — that’s how I’ve heard people abbreviate it when they’re talking about it — how expensive is this?

Rick: Elizabeth, it doesn’t say in this particular article so I can’t address that, but the paper does allude to the fact that we need to do a cost-benefit analysis. Now, you’re reducing mortality, but you’re right — we do have to ascertain what the cost is and also availability. Now, the nice thing is, it’s not a new medication that we have to look for side effects. It’s been around for a while, so we’re just repurposing it.

Elizabeth: We love those repurposed things because, of course, we already have abundant experience with them and that’s a great thing. Let’s turn to something way more pedestrian in JAMA Internal Medicine. This is a study taking a look at something that’s just so very, very common. That’s knee osteoarthritis.

In point of fact, as we know, osteoarthritis is the #1 form of arthritis and a leading cause of disability among adults worldwide and the knee, of course, a very common joint to be impacted. In this study, they said, “Hey, if we put people on different types of exercise regimens or usual care, will we be able to ameliorate the pain and the disability that go with knee osteoarthritis?”

They had 377 community-dwelling adults — I would like to have seen more people, frankly — and they also had varying BMIs, so ranging from 20 to 45. They didn’t stratify this. This is one criticism I have of this study because we know that those increasing BMIs really do exacerbate this condition, but in any case, they had one of three groups, a high-intensity strength training group, a low-intensity strength training group, or what they called an “attention control group” where they had this mindfulness kind of based strategy for helping them learn to sort of come to terms with their pain, if you will.

They did have a really long follow-up and that was 18 months. The bad news was that whether you had high-intensity or low-intensity strength training or the attention control, it really did not matter with regard to your pain or more a objective metric that’s known as knee joint compression forces. So, disappointing.

Rick: Elizabeth, as you said, it affects millions of people — specifically over 250 million people worldwide. Now, one of the things I liked about this particular study is it was done extremely well. You said there weren’t a whole lot of people — there were under 400 — but again, they did multiple measurements. They did gait testing on everybody. They did strength testing, muscle volume, fat volume, and inflammatory markers. I mean, this was a very comprehensive study, with the thought that if you could strengthen your leg muscles it would somehow realign the knee a bit better and decrease the osteoarthritis.

Eighteen months, really no benefit. On the one hand, it wasn’t thousands of individuals. On the other hand, it was so well done I think it really puts to rest the fact that high-strength intensity training would be beneficial for knee osteoarthritis.

Elizabeth: I know, but it’s just so disappointing. The other metric that you didn’t mention that they did measure was this area that’s between the adjacent bones in the knee and that also was not improved. That was my hope, that that would be improved, but I didn’t really see anything in there that I thought looked improved by high-intensity exercise.

Rick: No. I mean, the hypothesis was great; it was that if you really strengthen the muscles it will make the joints better. But in this particular case, the low-intensity and the high-intensity strength training, really no different. Again, I applaud the authors for what I think what is an extremely well-done study, and not very easy to do, to keep all these people in this study for 18 months.

Elizabeth: Well, as for me — and I suspect maybe even for thee — I’m going to advocate for doing all of this strength training previous to developing knee osteoarthritis so that we could maybe ameliorate some of that.

Rick: And controlling our BMI too, at the same time.

Elizabeth: You got it. Back to COVID. Let’s turn to the British Medical Journal.

Rick: We talked a minute ago about hypoxic respiratory arrest. The other issue that’s really been plaguing with people with COVID is they seem to have an increased incidence of developing clots, and those clots can contribute to death. We see this even in younger individuals.

It’s been estimated that about 30% of hospitalized COVID patients will develop some evidence of venous thromboembolism — venous clots — so there many people have been advocating about using anticoagulants, not full dose, but low dose, as kind of prophylaxis to prevent that.

There is a randomized controlled trial going on, but even prior to that, these authors attempted to answer the question — Would initial prophylactic use of anticoagulation improve mortality? — by looking at the largest integrated healthcare system in the United States, which is the VA Health System.

They looked at over 4,000 — in fact, almost 4,300 — patients admitted to the hospital with COVID-19. About 84% received prophylactic anticoagulation and they compared those to individuals that did not. These people received primarily subcutaneous, or under-the-skin, injections of heparin or low molecular weight heparin, and they did so within 24 hours of hospitalization, so early initiation of it.

What they found was that it decreased mortality from about 18.7% to 14.3%, about a 34% reduction in mortality overall, and you say, “Well, gosh, that must have increased the risk of bleeding because it was low dose.” It did not do that. It does suggest, until the randomized trials are available, that prophylactic anticoagulation may be beneficial in COVID-hospitalized patients.

Elizabeth: I would hearken back to what you said about the first — the toci study, which is that we’ve got a lot of experience clinically with heparin.

Rick: Absolutely. It’s medication that we have around. It’s for a use that we’re used to, that is prophylactic prevention of clots. The real question will be in the randomized controlled trial.

Elizabeth: Which ought to be happening really pretty shortly, I think.

Rick: It is, Elizabeth. I think you and I have already received some wind that the results may be favorable, but we haven’t reported on it because before we report on late-breaking news we want to be able to look at the study to evaluate it in great detail.

Elizabeth: One other thing that I think it’s incumbent upon us to mention about COVID before we leave it is this just-released data relative to the variants that are emerging and increased mortality with them, so a little word of warning. It’s good that we’re getting our arms around a lot more of these clinical aspects.

Rick: Right.

Elizabeth: Enough of the gloom and doom relative to COVID, at least for a minute, and let’s turn to something that I think tickled my fancy in Nature Medicine. This is two studies, actually, that we’re going to treat together looking at the microbiome. That’s all those bugs that are inhabiting our guts.

Of course, we’ve got them everywhere else too. I like to think about those specialized ones that live at the base of our eyelashes, but they analyzed in this impressively large study this microbiome, host metabolism, habitual diet from almost 1,100 what they call deeply phenotyped individuals. That’s pretty impressive.

They did this metagenomic sequencing of over 1,200 gut microbiomes from these 1,100 folks in this Personalized Responses to Dietary Composition Trial or PREDICT-1 study. They looked at all these different microbes, or bugs, and specific nutrients, foods, food groups, general dietary indices. They say that these were driven especially by the presence and diversity of healthy and plant-based foods.

They have had lots of historical difficulty trying to characterize the microbiome because we know that many of these bugs that live in our gut are either anaerobic or facultative anaerobes, and it’s tough to culture those things when you get out there, but what they’re really relying on is this whole genomic kind of analysis.

In the first study, the one that’s taking a look analyzing the microbiomes, they identify one organism, Prevotella copri, and then another bacterial species as indicators of favorable postprandial glucose metabolism, so let me switch to the second steady, since we’re switching them both together. Their title is The Gut Microbiome Modulates the Protective Association between a Mediterranean Diet and Cardiometabolic Disease Risk, which they analyzed with different factors.

They also identify this organism, Prevotella copri, with an increased rate of cardiovascular disease risk when they had less of this particular bug in their gut, so we think this is fascinating. We have been looking for so long for evidence between the gut and overall health and other things that take place, and I just find this to be a very interesting and nerdish kind of pair of studies. How about you?

Rick: You’re right. It was nerdish. This was a very difficult study because of the amount of material — the raw data — that they had. Again, these were, in the larger study, over 1,100 individuals that they had a longitudinal follow-up, so they had detailed long-term diet information, hundreds of fasting and postprandial cardio-metabolic blood markers and in addition to the microbiome as well.

As you suggested, there seems to be a relationship between microbiome, diet, and also a relationship between what are called cardio-protective factors such as lipids, postprandial sugar, that is postprandial glycemic control. Now, the real question is, “Is it a cause or is it effect?” Do these particular microbiomes as a result of the way that they digest nutrients or affect bile acids — and therefore affect triglycerides and cholesterol — are they the cause? Or is the fact that because of the diet, it affects the microbiome? Right now, I’d call it an association, but I don’t think we can prove causation. What are your thoughts?

Elizabeth: I think it’s very provocative. We’ve been talking about this for years and the other question I would add to yours is, “OK, then how about if we spike somebody’s gut with Prevotella copri or one of these other bugs that have been identified as being beneficial? What happens then?” I don’t think we know anything about that.

Rick: You’re right, and this moves from a study that is descriptive to one that it actually is possibly therapeutic. That’s really the thing that I think people find most intriguing.

Elizabeth: No doubt we’re going to be hearing more about this. On that note then, 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.

Last Updated February 19, 2021

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