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 severe flu complications for kids; a polygenic risk score for obesity; lifestyle intervention for cognition; and a case report on the intersection of human papillomavirus (HPV), immune dysfunction, and squamous cell carcinoma.

Program notes:

0:44 Flu consequences for young childrenopens in a new tab or window

1:44 Fulminant course

2:44 16 kids of total unvaccinated

3:10 HPV, T-cell receptor signaling, and squamous cell carcinoma

4:10 Unresectable disease

5:10 Thought virus facilitated

6:10 Target in recurrent or metastatic disease

6:26 Nonpharmacologic intervention in older adults to improve cognitionopens in a new tab or window

7:26 More intensive program a little better

8:26 Eat better, exercise more, and use your mind

9:15 Polygenic risk score for obesity

10:15 Explained variance in cohorts

11:15 At birth adds a bit of value

12:08 End

Transcript:

Elizabeth: Can a polygenic risk score tell us about the propensity to become obese?

Rick: Improving cognitive function in later life by lifestyle changes.

Elizabeth: What's the intersection of human papillomaviruses, squamous cell carcinoma, and the immune system?

Rick: And flu can cause brain damage in young kids?

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: Rick, since vaccines have been much in the news recently with this notion of thimerosal being a particular danger, why don't we turn to JAMA and take a look at this negative impact of influenza infection in very young children?

Rick: The technical term for this is called encephalopathy and that medical term really refers to a broad range of brain disorders. Many individuals will be familiar with the fact that flu causes primarily respiratory symptoms, but we've seen an increase in cases of what's called acute necrotizing encephalopathy. Because there have been reported cases anecdotally, pediatricians combed a number of different sources to find out how commonly this might occur more recently, and from the cases, what can we learn about it.

This occurred primarily in young kids, median age of 5 years. Three-fourths of them were otherwise previously healthy. Ninety-three percent of them experienced a high fever. They all experienced mental status changes. About two-thirds or three-fourths had seizures. The course, unfortunately, was fairly fulminant in that it occurred about 2 days from the onset of when the flu started to when they actually developed this. Then the MRI scan showed diffuse brain involvement, but necrotizing or disintegration of brain cells in the thalamic area.

Unfortunately, these kids spent about 22 days in the [intensive care unit], about 30 days in the hospital -- these were the survivors -- and then two-thirds of them were discharged in the hospital had residual neurologic damage. Eighty-four percent of these kids had not received influenza vaccines; influenza A was the most common cause. About 16% had. About 41 cases were reported over the previous couple years. You mentioned the fact that there are people that are concerned about having vaccines. Although there's always a very small risk with vaccines, the risk of having some severe morbidity or mortality from these diseases that they're trying to prevent is really much higher.

Elizabeth: I'm interested in the 16% who had received the influenza vaccine and yet still succumbed to this condition. Was there any further characterization of their immunologic status?

Rick: No, that's a fairly small number of kids. That's 16 kids out of the total. Three-fourths of these kids were otherwise healthy. That implies that the influenza A somehow stimulated the immune system to attack their brain cells. So if we can identify kids that are particularly high risk, and if they develop particularly high fever or seizure, altered mental status, just be able to treat them. Despite that, a significant number of children died.

Elizabeth: Good reason to get the flu vaccine, folks. Since we're talking about viruses, then why don't we turn to the New England Journal of Medicine, and this one was looking at a single patient. It's entitled "Resolution of Squamous-Cell Carcinoma by Restoring T-Cell Receptor Signaling."

I was educated to learn that the beta human papillomaviruses are believed to be facilitators in the pathway that actually enables oncogenesis and subsequent development of cutaneous squamous cell carcinoma. A single patient with both benign and malignant HPV-related disease, including a recurrent, unresectable, invasive, cutaneous squamous cell carcinoma. She also had this genomic integration in the context of these germline pathogenic mutations in an enzyme that's required for T-cell receptor signalling transduction. So she had an aberration in her immune system that was precipitated by this HPV infection, and therefore had this unresectable disease, and the photographs are really revelatory as far as just how severe this condition was.

They tried to resect it. They tried to do a number of other things and then they ultimately ended up doing an allogeneic hematopoietic cell transplantation that ended up restoring her signalling for her immune system and clearing up the vast majority of these squamous cell carcinomas that were virtually all over.

What the authors say is that this reveals a direct role of these beta human papillomaviruses and skin carcinogenesis in people who have defective adaptive T-cell responses. My suspicion is that it's probably more prevalent than that.

Rick: Yeah. So most of the time we associate skin cancers with exposure to ultraviolet [UV] light, older age, certain skin types, and even gender. And as you mentioned, it was thought that human papillomavirus kind of facilitated more of the UV damage, but then it got out of the way, and it was just more of the UV damage that never got repaired. But in this particular patient, the ability to repair the ultraviolet damage was normal. And I realized, as you mentioned, there was this T-cell abnormality, T cells that specifically attach to human papillomavirus.

When they restored it, this particular individual was completely cured. She had 43 different ones. It did establish that human papillomavirus can not only help facilitate cancers, but actually be directly involved in the oncogenic process as well.

Elizabeth: To me, it begs the question of examining T-cell function in people who have squamous cell carcinoma. And the other thing is we have repeatedly identified human papillomaviruses as being just very, very foundational in a multitude of human diseases, and so maybe we need to look more carefully at those we have dismissed previously.

Rick: OK. Well, I'm going to focus it a little bit more, Elizabeth. Locally advanced or metastatic disease occurs in only 3% to 5% of people with squamous cell carcinoma. Rather than doing it in everybody, I'd probably focus on those individuals that have recurrence or metastatic cancer, and those are the ones that are more likely to have a higher yield.

Elizabeth: Back to our vaccine issue, though. We do have several effective vaccines against human papillomaviruses and maybe it's important to scrutinize these also. Let's move on to your next one.

Rick: Wouldn't it be nice if we could do something nonpharmacologic, something within our control, to actually improve cognition in later life? That's what these investigators at Wake Forest hypothesized. They said, OK, let's take people that are in midlife. They're sedentary. They don't have any cognitive dysfunction. If we do intensive lifestyle changes -- maybe we ask them to exercise on a regular basis, we have them eat a healthy diet, and we also give them some of these brain stimulation exercises -- we can either provide all the information and let them do it or do it in a very structured way, with as many as 38 meetings over the course of several years to make sure that the person is coached, supported, and encouraged. If you go to all that effort, does it improve cognitive function?

It was a 2-year, multicenter randomized clinical trial comparing those two methods for delivering what's called a multidomain lifestyle intervention. They took in individuals that were 60 to 79 years of age, over 2,000 of these individuals. Both groups improved their cognitive function. Now, the ones that had the more intensive did a little bit better. When I say benefited, their executive function got better, processing speed got better, memories got better, showing that lifestyle interventions can improve cognitive function at least over a 2-year period.

Elizabeth: Which of these lifestyle interventions would you add to yours already to try to achieve this kind of a benefit?

Rick: Well, you and I both exercise, we eat healthy, and we're both challenging our minds with the work that we do, so I'm hoping that we're already in that category. But again, this shows that, OK, so maybe you haven't done anything for the first 60 or 70 years of your life. This shows that they are helpful.

The adherence rate, by the way, was about 90%. The interesting thing is for those that self-determined and did this on their own, the adherence rates were still very high and they received benefit too. This translates to being about 1 or 2 years younger than your chronologic age, that is your brain age is 1 or 2 years younger than your chronologic age. Eat better, exercise regularly, and exercise your mind, and you'll benefit.

Elizabeth: Well, that's a lovely take-home message and it sounds fairly simple to employ, as we have observed in many studies of the benefits of exercise. For example, in those who never previously engaged in it, they get a huge benefit. I'm wondering about the incremental benefit that might be realized by people who already are taking these kinds of approaches in their lives.

Rick: Yeah. And, Elizabeth, it's hard to know because this particular study doesn't address it. I have to say, to pull this study off in 2,000 individuals, to follow them over a 2-year period, collect all of this data, this is one of the better studies done, and I think it's a fairly definitive study that shows the benefit of these lifestyle interventions.

Elizabeth: OK. Well, we're already convinced. So to some degree, that's preaching to the choir.

Let's finally turn to Nature Medicine and this is using a polygenic risk score to say, hmm, are you going to become obese? And that was really their objective. The idea in this study is if we can predict using these polygenic scores for body mass index (BMI), could that guide our early prevention efforts and targeted treatment of obesity?

Ginormous data set here. 5.1 million people representing a number of ancestries, not just Caucasians, although the majority were European ancestry, but African American, East Asian, South Asian. They developed an ancestry-specific and multi-ancestry polygenic risk score. They say that their risk score was able to explain about 18% of BMI variation among the U.K. Biobank participants. The risk score actually varied in its ability to explain variance from 11% to 21% in another one of their cohorts. They tried to look at it in the age ranges and when was it useful.

I think this was a really pretty remarkable effort and it's impressive the number of things that they did. And they tried to parse their data across different ages and different ethnicities to see where it was really useful. It's a little bit useful at this point, but not incredibly useful. What are your thoughts?

Rick: I would agree in many respects. It does provide some predictive value. The important thing I think from here is that there is some genetic variation, and it varies from population to population. Part of the reason why there seems to be such a wide variation in this particular study, although they had over 5 million people in this data bank, less than 5% were African ancestry. And, as you know, African ancestry means a bunch of different things. Ugandans are different from the Nigerians, different from South Africans, different from the West Coast and East Coast. So they didn't have a large enough population tested to provide more precise information. It does add some predictive value. At birth, it adds a little bit. A little bit more at age 5.

Here's the thing I thought was really interesting. So you might say, well, it's genetically determined and therefore that we do intensive lifestyle interventions, it's not going to change. I mean, they're just predisposed to being obese. But actually, individuals that had the highest predictive polygenic score lost more weight in the first year. That tells me there's a genetic-environmental component that works together. There may be some genetic predilection to it, but actually lifestyle intervention does help and it helps more in people with a high polygenic score than those with a low one.

Elizabeth: Yep. 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.