Mortality in U.S. Youth; Gene Therapy for Sickle Cell Disease

— Also in TTHealthWatch: updated breast cancer screening guidelines


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 mortality among U.S. youth, updated breast screening guidelines, treating large strokes, and gene therapy for sickle cell disease.

Program notes:

0:34 Sickle cell treatment

1:34 Take out progenitor cells

2:34 Side effects of treatment and cost

3:32 Significantly decreases survival

3:43 Racial and ethnic differences in mortality in U.S. youth

4:45 About twice as high among other ethnicities

5:48 Black youth 8 times more likely to die of asthma

6:40 Treatment of very large strokes

7:40 333 patients within 6 hours

8:45 Practice changing

9:00 Breast cancer screening guidelines update

10:00 Older women and additional screening not known

11:00 Don't apply to some women

12:05 End


Elizabeth: An update to screening for breast cancer.

Rick: Gene therapy for sickle cell disease.

Elizabeth: Racial and ethnic disparities in all-cause and cause-specific mortality among U.S. youth.

Rick: And treating really large strokes.

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, I'd like to turn first to the New England Journal and ask you to talk about what is essentially, I think, a good news story. What about treatment of sickle cell?

Rick: For our listeners that may not know much about sickle cell disease, it's a genetic abnormality and it causes the red blood cells to break up or occlude blood vessels and cause pain, neurologic abnormalities, heart problems, and severe pain in the muscles and bones. It really is a debilitating disease. Our therapies have tried to lessen the symptoms, but to address the issue, we do not have any medications that can actually do that. Hence, gene therapy.

We know that there is an early form of hemoglobin -- it's called fetal hemoglobin -- present in early life. We know the individuals that have sickle cell disease and also have elevated forms of fetal hemoglobin have markedly improved survival and symptoms.

What scientists did was they have taken from individual sickle cell, they have taken out some of their very early red blood cells called progenitor cells. They have genetically modified them so now they make fetal hemoglobin and then they infuse them back into the individuals. That's the genetic therapy known as exa-cel.

They took about 44 patients and provided them therapy with a follow-up of about 19 months, and 30 of those patients have completed that follow-up. Afterward, they were completely free of having any of these vaso-occlusive crises for at least 12 consecutive months. Not a single person needed to be admitted to the hospital, a 97% decrease in causing vaso-occlusive crisis, the severe pain, and a 100% decrease in hospitalization for these individuals. This is a tremendously valuable and important study.

Elizabeth: Just amazing. I just share, as I have shared with you in the past, that probably one of the most abject witnesses of pain I have ever experienced was with a young woman in a sickle cell crisis in the hospital and avoiding that and all the multitude of complications that can follow -- it just seems to me an amazingly powerful goal. Talk to me about the side effects of this treatment and also, of course, the cost.

Rick: There really aren't any side effects from the cells because they are the patient's own cells. But to make sure that they are engrafted into the bone marrow, they receive a form of chemotherapy called busulfan. That's associated with decreased white cells, inflammation of the mucosa of the mouth, and can be associated with infertility.

The cost, unfortunately, is millions of dollars. It will become less expensive as the therapy grows. These individuals consume millions of dollars in healthcare. Even at the current costs, will it be cost-effective? We'll need some analysis to do that.

Elizabeth: Well, I think that your point is well taken regarding how big their hospital bills are relative to their multiple hospitalizations and the complications that arise when they are hospitalized.

Rick: You hate to talk about it just in terms of an economic point of view because, as you mentioned, this disease is really debilitating and it significantly decreases survival. This is actually curative and this is what you hope with genetic therapy.

Elizabeth: This is good news. Let's turn to the really bad news this week. That's a look in JAMA at this racial and ethnic disparities in all-cause and cause-specific mortality among U.S. youth. It's a cross-sectional study that had a temporal analysis from 1999 to 2020 and a comparison of aggregate mortality rates from 2016 to 2020 for youth aged 1 to 19 years using the CDC's WONDER (Wide-ranging Online Data for Epidemiologic Research) database.

They found that there were just shy of half a million deaths among U.S. youth during this period -- the pooled all-cause mortality rate of just shy of 50 per 100,000. They found out that when compared to white youth all the other ethnicities experienced higher rates of death. The all-cause mortality rates compared with white youth were twice as high among American Indians or Alaska Natives. The Asian and Pacific Islander youth were just slightly higher, almost twice as high among Black youth, and among Hispanic youth about twice as high.

The homicide rate is a really daunting statistic. In Black youth, 12.81 per 100,000, which was 10 times that among white youth. Suicide rates are a big problem among American Indian and Alaska Native youth, almost three times as high as that of the white youth. Finally, the firearm mortality rate for Black youth was 4.4 times as high as that for white youth, clearly pointing to a need for intervention. Let me just note also that Black youth had an asthma mortality rate that was just shy of 8 times that of white youth.

Rick: It is disheartening to know that now these causes of death, specifically firearm mortality, has surpassed motor vehicle accidents as a major cause of death in this population ages 1 to 19. It's even more concerning that there are racial inequalities.

The asthma data points to the fact that even though Black youths are approximately 1.5 times more likely to develop asthma, they were 8 times more likely to die from the disease. That means that there are differences in availability of either medications or adequate healthcare afterwards. There are substantial differences -- socioeconomic differences, income differences, educational differences, and services that are available -- that account for these disparities. It's a national tragedy that needs to receive national attention.

Elizabeth: It has to be comprehensive and, of course, we could point to baseline levels of depression and anxiety among this population as being contributors.

Rick: Yes. Elizabeth, anxiety and depression are related to the circumstances they're in, oftentimes, their social circumstances, the inadequacy of care. This is a tragedy that needs to be addressed on a national level with the same sort of fervency that we address motor vehicle accidents.

Elizabeth: I absolutely agree. Let's turn back to the New England Journal.

Rick: I serve this up as treatment of very large strokes. We know that in most cases a stroke is caused by a clot that interrupts blood flow to a certain part of the brain. If you can actually dissolve that clot, either by giving a medication or by extracting it -- that's called a thrombectomy -- you can actually improve outcomes. You're less likely to die and less likely to have severe neurologic abnormalities.

Unfortunately, most of the randomized trials that have looked at thrombectomy have excluded individuals that have really, really large strokes. How do we determine how large they are? Well, we do imaging, either MRI or CT scans.

They assign, based upon how big the stroke is, a value of from 0 to 10, the lower numbers meaning the larger strokes. Most individuals with a score of 0, 1, or 2 were never enrolled in the previous trial. These investigators said, "Well, gosh, what happens if we take out these clots in these really big strokes?" You say, "Well, obviously it will help." But there is always a risk after you've treated the stroke that you could have bleeding into that area.

In this study, they took 333 patients, all determined to have a very large stroke. They presented within 6 1/2 hours of symptom onset and they randomized them to receive either routine medical care or they received a thrombectomy plus routine medical care.

The therapy with thrombectomy was so much better they thought it was unethical to continue the trial. At the end of the trial, there were more people dead in the control group, about 55%, versus those that had gotten thrombectomy, about 36%. The patients that had severe neurologic deficits were more likely to be in those that received medical therapy. Now, there was a slight increase in intracerebral hemorrhage. Overall, in patients with acute stroke and a very large infarct, thrombectomy resulted in better functional outcomes and lower mortality rates.

Elizabeth: Does this require any more of a specialized skill set than it does just in general to perform thrombectomy?

Rick: This is standard of care. It's just never been extended to those with the largest strokes for fear that it will actually make things worse, not better.

Elizabeth: It sounds like this is going to be practice-changing.

Rick: I would agree with you.

Elizabeth: Okay. Finally, let's turn back to JAMA and take a look at this update to screening for breast cancer guidelines by the U.S. Preventive Services Task Force (USPSTF). The last time they did this was in 2016.

They cite a few statistics. Breast cancer is the second most common cancer and the second most common cause of cancer death among U.S. women. It's estimated 43,170 women died of breast cancer in 2023. We know that non-Hispanic white women have the highest incidence of breast cancer and non-Hispanic Black women have the highest mortality rate.

After they reviewed all of the data, they concluded with what they call a B recommendation, or moderate certainty, that biannual screening mammography in women aged 40 to 74 years has a moderate net benefit. This is a departure from their previous recommendations, and just really a slight departure in my mind with regards to that recommendation beginning at 40 years. They waffled a little on that the last time and said this could be individually determined based on a woman's preferences, history, and so forth.

They note that the balance of benefits and harms in screening mammography in women 75 years of age or older and the balance of benefits and harms of supplemental screening for breast cancer, with either ultrasound or MRI, relative to breast density is not known. We need to have some more research conducted here so that we can nail down this question. I would just note about that, that insurance reimbursement for women who have dense breasts and then are recommended to have either MRI or ultrasound subsequently is denied sometimes based on these kinds of recommendations. In their call for comments, they heard that a lot and I think they are going to hear that a lot subsequent to this.

Rick: It's probably worth mentioning the fact that these recommendations do apply to women that have an increased risk of breast cancer, such as they have a family history of breast cancer or they have dense breast tissue. However, these recommendations do not apply to individuals that have a genetic marker or a syndrome associated with a high risk of breast cancer. These are the BRCA genes. It doesn't apply to women that have a history of high-dose radiation to the chest at a young age or to women who have previous breast cancer or a high-risk breast lesion on previous biopsies. They are entirely different recommendations.

There is still uncertainty over what to do with women over the age of 75. I appreciate the fact that they do talk about the imaging, what imaging is best, and what do we know about imaging. Elizabeth, were you surprised that they were recommending every 2 years rather than every year?

Elizabeth: I was not at all surprised by that. In fact, I think I adopted that myself with the last set of recommendations and it appears to be okay. The other organizations, of course, review what their recommendations are and there is still some dispute, I guess, about the proper screening interval. More to come undoubtedly.

On that note, that's a look at this week's medical headlines from Texas Tech. I'm Elizabeth Tracey.

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