Author Insights: Bone Marrow Transplant an Emerging Option for Adults With Sickle Cell Disease

John F. Tisdale, MD, senior investigator at the National Institutes of Health, and colleagues found a less toxic bone marrow transplant strategy was effective for adults with sickle cell disease. Image: NIH

John F. Tisdale, MD, senior investigator at the National Institutes of Health, and colleagues found a less toxic bone marrow transplant strategy was effective for adults with sickle cell disease. Image: NIH

Although children with sickle cell disease have benefited from the emergence of improved therapies, options for adults with the disorder have lagged and many die in their early 40s. New evidence published today in JAMA suggests that a less toxic bone marrow transplant technique may provide adults with a new option.

Sickle cell disease is caused by a genetic variation that results in the production of sickle-shaped blood cells. These cells can clump together, causing blockages in blood vessels, severe pain, and even stroke. Over time, damage to multiple organs can occur. Blood transfusions, prophylactic antibiotic therapies, and other interventions help manage patients’ symptoms, but only bone marrow transplantation can cure the disease. Although about 400 children have received such transplants to date, adults are less able to tolerate this potentially curative treatment, which involves completely destroying the patient’s own bone marrow and replacing it with marrow cells from a compatible donor.

John F. Tisdale, MD, senior investigator at the National Institutes of Health, and his colleagues found that a less drastic technique for bone marrow transplantation may be a better option for adults. Instead of using radiation to completely eliminate the patient’s own bone marrow before transplant, Tisdale and colleagues reduced the patient’s bone marrow by half. After transplant, the patient has bone marrow containing a mix of his or her own marrow cells and the donor’s marrow cells.

The researchers tested their technique in 30 patients aged 16 years to 65 years. One patient died after a relapse to sickle cell, but 29 survived for an average of 3.4 years without relapse. In 26 patients, the donor cells engrafted without an autoimmune reaction, and 15 were able to discontinue immunosuppressive treatment. Treated patients also required fewer sickle cell–related hospitalizations.

Tisdale discussed the findings with news@JAMA.

news@JAMA: Why did you decide to do the study?

Dr Tisdale: Adults with sickle cell disease not only have a difficult life, with pain and organ damage, but they die early. Despite progress in supportive care, the median age at death for patients with sickle cell remains the early 40s. That hasn’t changed in decades.

news@JAMA: Why hasn’t bone marrow transplantation been as successful for adults as it has for children?

Dr Tisdale: Bone marrow transplant, like most medical therapy, is easier for children to undergo. They tolerate chemotherapy, radiation, and bone marrow transplants better because they have more reserve. Adults tolerate it less well. The older you are the worse you’ll do with a transplant.

news@JAMA: Why don’t all children with sickle cell disease receive bone marrow transplants?

Dr Tisdale: The first bone marrow transplant was in a kid with sickle cell and leukemia. The child had a life-threatening illness and the only cure was bone marrow transplantation. The child was cured of the leukemia and sickle cell. It was next tried in kids with sickle cell who’d had a stroke.

It’s generally reserved for children with sickle cell who have some indication they are not doing well. Children do pretty well with sickle cell, so you don’t want to do something as harsh as a bone marrow transplant to a child who is doing well. There is also some resistance from families because high doses of radiation render the children sterile. Some think it’s better to wait until these children are adults and let them decide.

news@JAMA: How is your approach different?

Dr Tisdale: We tried to make bone marrow transplant safer so it wasn’t such a big trade-off for adults. It’s different in 2 fundamental ways. It doesn’t completely destroy the marrow. In a standard transplant, if the transplant doesn’t “take,” the patient dies because they can’t recover bone marrow. If our strategy doesn’t work, the patient’s own bone marrow comes back and they go back to having sickle cell. We also were striving for [immune] tolerance between donor and recipient.

news@JAMA: What are the next questions you need to answer?

Dr Tisdale: Our next big question is, can we extend this to more patients by loosening the criteria for the donor? What if it required a half match rather than full match? Most patients don’t have a full-match sibling. But virtually everyone has a half match—parents, sibling, or child.

news@JAMA: What’s the main take-home message?

Dr Tisdale: Adult patients with sickle cell and their care providers should consider whether a transplant is an option.

Stroke Risk Increased After Shingles Infection

Risk of stroke is increased in the 6-month period following shingles infection. Image: ©iStock.com/RosicaSabotanova

Risk of stroke is increased in the 6-month period following shingles infection. Image: RosicaSabotanova/iStock.com

New evidence suggests that shingles, which can occur in individuals who previously had chicken pox, may be associated with an increased risk of stroke in the weeks to months following a shingles episode.

Shingles, or herpes zoster, which is the result of the same virus (varicella zoster virus) that causes chicken pox, affects 1 million Americans every year. Before a vaccine for shingles became available, one-third of Americans were affected with shingles in their lifetime. Shingles occurs when the dormant virus reactivates in someone who had chicken pox in the past.

The infection targets the nervous system, and can have both short-term and long-term health effects, including the hallmark painful shingles rash that may be followed by persistent nerve-related pain that can last for months to years after the rash resolves. Now, new evidence suggests that the shingles may also be associated with an increased risk of stroke in the weeks after the rash emerges.

In a study released yesterday in Clinical Infectious Diseases, researchers at the London School of Hygiene and Tropical Medicine analyzed medical records from millions of general practice patients in the United Kingdom from 1987 to 2012 and identified more than 6500 individuals with both shingles and arterial stroke during this period. When they looked at the time points at which strokes occurred in relation to the shingles episodes, they found that the rate of stroke was significantly higher during the first 6 months following a shingles episode compared with before a shingles episode (approximately 63% higher during the first month, 42% higher during the second and third months, and 23% higher during the fourth through sixth months.)

Individuals who did not receive antiviral treatment during their shingles episodes had an even higher rate of stroke compared with those who did receive such treatment. In addition, though the case numbers were smaller, individuals in whom shingles affected the trigeminal nerve, a cranial nerve that affects facial sensation, seemed to have a higher rate of stroke than those in whom other nerves were affected.

The authors suggest 2 possible mechanisms in which shingles might increase stroke risk. First, the overall higher level of inflammation in the body during a severe systemic infection causes a state in which the blood is more prone to clotting, which can lead to stroke. Second, the shingles virus can also spread into the nerves of the blood vessel walls, leading to defective blood vessels that are more likely to allow both clots and bleeding, which can lead to stroke.

This study is the first to examine the association between shingles and stroke in a time-dependent fashion, including only individuals with both shingles and stroke, and focusing on the length of time between the 2 events. Previous studies comparing the rates of stroke in individuals who had shingles with those who did not have also found higher stroke risks in persons with prior shingles, but because the characteristics of people who get shingles and those who do not may be very different, many other confounding factors could have affected the results. This approach, on the other hand, allowed patients to serve as their own controls (with the control periods being when they were outside of a 1-year period from infection), which, according to the authors, makes the association more robust.

The authors state that their findings have implications for both clinical medicine and public health, underscoring the importance of antiviral treatment for shingles as well as shingles vaccination, which, in the United States at least, remains underused.

Author Insights: Upward Trend for Blood Pressure in Young Adults Predicts Long-term Heart Risk

Norrina B. Allen, PhD, MPH, of Northwestern’s Feinberg School of Medicine, and colleagues found that blood pressure patterns early in life predict heart risk. Image: Northwestern University

Norrina B. Allen, PhD, MPH, of Northwestern’s Feinberg School of Medicine, and colleagues found that blood pressure patterns early in life predict heart risk. Image: Northwestern University

Blood pressure trajectories during young adulthood may help identify those at greatest risk of cardiovascular disease later in life, according to a study published in JAMA today.

A single high blood pressure reading is a known risk factor for developing the hardening of the arteries associated with an elevated risk of heart attack or strokes. But often high blood pressure doesn’t emerge until middle life, when this process may already be under way.

The new study suggests that blood pressure trends earlier in life may help identify those at highest risk, allowing earlier intervention. Norrina B. Allen, PhD, MPH, associate professor in the department of preventive medicine at Northwestern’s Feinberg School of Medicine, and her colleagues analyzed data on 4681 participants from the CARDIA study. Health information including blood pressure readings and other health data were collected from participants over the course of 25 years from 1985-1986 through 2010-2011.

They found that young people typically experienced 1 of 5 long-term blood pressure trajectories and that an individual’s risk of developing hardening of the arteries varied by trajectory. Those with blood pressure readings classified as being in the prehypertension range and those with trends of increasing blood pressure readings over time were at higher risk of artery hardening than patients with low and stable blood pressure readings.

Dr Allen discussed the findings with news@JAMA.

news@JAMA: Why did you decide to conduct this analysis?

Dr Allen: We were interested in whether long-term patterns in blood pressure could be used to predict cardiovascular disease risk.

news@JAMA: What did you learn about the predictive value of these blood pressure trends?

Dr Allen: We found that there are 5 distinct blood pressure trajectories and that these 25-year patterns were associated with coronary artery calcification, a marker of cardiac risk.

news@JAMA: Where there any groups in particular who were more likely to fall in a higher-risk trajectory?

Dr Allen: We did find that African Americans and those who smoked or gained weight more quickly were more likely to fall into a higher trajectory pattern.

news@JAMA: Did the long-term trends better predict cardiac risk than 1-time readings?

Dr Allen: We are better able to stratify individuals by their risk for cardiovascular disease. So if you had 2 people who end up with an elevated blood pressure in middle age, one who had ideal blood pressure in young adulthood and one with elevated blood pressure for the entire 25-year period, the one with elevated blood pressure the whole time had a higher risk for cardiovascular disease.

For almost all of the groups, the levels of elevated blood pressure didn’t meet clinical thresholds for hypertension but were above ideal levels. We would recommend lifestyle changes for individuals with elevated blood pressure levels or increasing blood pressure readings early in life.

news@JAMA: Do your findings suggest changes in the way hypertension is currently being treated?

Dr Allen: It’s more a matter of when we start considering markers of heart disease risk. It’s really about prevention. We really should monitor earlier.

news@JAMA: What is the main take-home message for patients and physicians?

Dr Allen: The message is to start thinking about blood pressure and its associated risks early in life and really consider ways to prevent elevated blood pressure or increasing blood pressure before people hit middle age. Individuals experiencing either are at a higher risk for heart disease later in life.

New Studies to Focus on Genetic Makeup of Ethnic Groups and Their Susceptibility to Health Risks

A new research initiative will attempt to illuminate the role that genetic variations play in health risks among ethnically diverse populations. (Image: cosmin4000/iStockphoto.com)

A new research initiative will attempt to illuminate the role that genetic variations play in health risks among ethnically diverse populations. (Image: cosmin4000/iStockphoto.com)

Researchers from 5 institutions are about to begin exploring whether subtle variations in the genetic makeup of ethnically diverse populations account for their differences in risks for conditions like high blood pressure and abnormal blood lipid levels and common diseases such as cancer and heart disease, the National Institutes of Health (NIH) announced today.

The agency is funding the research through 4-year grants of more than $3.8 million in fiscal year 2013 and totaling (based on the availability of funds) almost $14 million over 4 years. The Population Architecture Using Genomics and Epidemiology (PAGE) program of the NIH’s National Human Genome Research Institute will issue the grants.

The current group of grant recipients is the second group of researchers being funded through the PAGE program and the first to focus on ethnically diverse populations. “The goal of the PAGE program is to investigate ancestrally diverse populations to gain a better understanding of how genetic factors influence susceptibility to disease,” said PAGE program director Lucia Hindorff, PhD, in a release.

Much of the genetic research on humans, including that funded by PAGE in its first round of grants, has focused on white individuals, but whites and some nonwhites differ in their degree of risk for various health conditions. For example, black, Hispanic, and Native American individuals tend to have higher incidence of high blood pressure and obesity and are at increased risk for heart disease and stroke compared with whites.

The latest grantees—from the University of North Carolina, Chapel Hill; Fred Hutchinson Cancer Research Center, Seattle; University of Southern California, Los Angeles; University of Hawaii, Honolulu; and Mount Sinai School of Medicine, New York City—will use large epidemiological studies and data sets that include whites, blacks, Hispanics, Native Americans, Native Hawaiians, and Japanese Americans. “There are often population-related biological pathways that contribute to disease, so looking at many traits and diseases together gives a more complete picture of the role of genetic variation,” Hindorff said.

Managing Atrial Fibrillation Requires a More Personalized Approach, Say European Researchers

European researchers are calling for the continued development of personalized management of atrial fibrillation to reduce mortality among patients with the condition. (Image: JAMA, ©AMA)

European researchers are calling for the continued development of personalized management of atrial fibrillation to reduce mortality among patients with the condition. (Image: JAMA, ©AMA)

Left untreated, atrial fibrillation, a rapid and irregular heartbeat, doubles the risk of heart-related deaths and carries up to a 5-fold increased risk for stroke. And even though treatment with anticlotting medication can prevent two-thirds of all strokes in patients with atrial fibrillation, applying all the evidence-based therapies available, including antiarrhythmic drugs and catheter ablation (a procedure that destroys abnormal heart tissue), barely lowers death rates.

Personalized management is the only way to close the mortality gap for patients with atrial fibrillation, according to a consensus paper from the German-based Atrial Fibrillation competence NETwork and the European Heart Rhythm Association. The consensus paper was published online today in the European Journal of Pacing, Arrhythmias, and Cardiac Electrophysiology and presented during the European Society of Cardiology Congress in Amsterdam, the Netherlands.

Some personalized management of atrial fibrillation is already in place, such as using stroke risk scores based on clinically measurable risk factors to guide decisions on anticoagulant therapy or assessing the severity of atrial fibrillation symptoms to help determine rhythm control therapy. But there is still plenty of room to improve the management of this condition because current therapies offer only small reductions in mortality, said lead author Paulus Kirchhof, MD, of the University of Birmingham in England, in a release. For example, “the new oral anticoagulants have improved mortality by just 5% to 10%,” said Kirchhof. Every fourth patient with atrial fibrillation is hospitalized at least once a year because of atrial fibrillation, which points to the high morbidity and health care costs associated with this condition, he noted. “The hope is that within the next few years, we will be able to propose personalized management of AF and thereby reduce the excess mortality associated with the disease,” said Kirchhof.

The authors said understanding atrial morphology and damage, performing brain imaging, gathering information on genetic predisposition, identifying systemic or local inflammation, and developing markers for cardiac strain are opportunities to personalize the management of atrial fibrillation. They caution, however, that such factors require validation in the context of existing risk factors.

In the United States, an estimated 2.7 million people have atrial fibrillation.

Noninvasive Brain Stimulation Is Promising for Poststroke Aphasia

Infographic - Thiel-Brain StimulationNew research offers stroke survivors with aphasia the hope that noninvasive brain stimulation could help them recover at least some speech and language functions.

Aphasia affects more than one-third of all patients who have had a stroke, stripping away varying degrees of their abilities to grasp language, read, write, or speak. For decades, skilled speech and language therapy has been considered the only effective treatment, but often with limited results.

Earlier case series and feasibility studies had shown that noninvasive brain stimulation could improve deficits from poststroke aphasia, but randomized, sham-controlled trials were lacking. So a team of researchers in Canada, Germany, and the United States recruited 24 patients treated for poststroke aphasia at a rehabilitation hospital in Cologne, Germany. Thirteen patients received transcranial magnetic stimulation (TMS) directed to a region in the right side of the brain and 11 got sham stimulation. TMS uses a handheld magnetic coil that delivers low-intensity stimulation.

The protocol included stimulation for 20 minutes followed by 45 minutes of speech and language therapy for 10 days. All the patients had experienced a stroke on the left side of the brain, where language networks are located. The investigators used stimulation to inhibit functions in the right side of the brain, allowing the language networks on the left side to get a stronger workout from speech and language therapy.

“This is similar to physical rehabilitation where the unaffected limb is immobilized with a splint so that the patients must use the affected limb during the therapy session,” lead author Alexander Thiel, MD, of McGill University in Montreal, Canada, said in a statement.

After treatment, language assessment tests showed that patients treated with TMS had about 3 times greater improvements that those who received sham stimulation. Thiel and his colleagues said their findings, published online today in the journal Stroke, are the first to show that stimulation along with speech and language therapy to reactivate language networks on the left side of the brain can restore some language functions. The biggest improvement was measured in anomia—the inability to name objects—which is among the most debilitating aphasia symptoms.

Thiel said that stimulation likely is most effective within about 5 weeks after a stroke because genes that control recovery processes are active within that window. Larger studies are scheduled to begin later this year at 4 sites in Canada and 1 German site.

Author Insights: Study Reinforces Need for Speed When Treating Ischemic Stroke

A study by Jeffrey L. Saver, MD, Geffen School of Medicine at the University of California, Los Angeles, and colleagues reinforces the need to quickly treat ischemic stroke to improve patient outcomes. (Image: UCLA Department of Neurology)

A study by Jeffrey L. Saver, MD, Geffen School of Medicine at the University of California, Los Angeles, and colleagues reinforces the need to quickly treat ischemic stroke to improve patient outcomes. (Image: UCLA Department of Neurology)

Sooner is much better than later when giving clot-busting medication to treat patients with ischemic stroke, confirms research appearing today in JAMA.

Intravenous tissue-type plasminogen activator (tPA), a medication that dissolves blood clots, is used to treat the hallmark of ischemic stroke, a clot in an artery that blocks blood flow to the brain. Imaging studies have shown that after blood supply to the tissue is interrupted, the amount of irreversibly injured brain tissue expands rapidly, with 2 million additional neurons lost each minute, so acting quickly to dissolve such a clot is essential for positive outcomes following a stroke.

In the JAMA study, researchers analyzed data from 58 353 patients with acute ischemic stroke who were treated with tPA within 4.5 hours of symptom onset. Patients were treated in 1395 hospitals participating in the Get With The Guidelines–Stroke registry launched by the American Heart Association and American Stroke Association. The researchers looked at outcomes associated with the speed (in 15-minute increments) with which treatment was initiated after the onset of stroke symptoms. They found that faster treatment was associated with reductions in in-hospital death and symptomatic intracranial bleeding and increases in the likelihood patients were walking independently at discharge and were discharged to home.

Lead author Jeffrey L. Saver, MD, David Geffen School of Medicine at the University of California, Los Angeles, discussed his team’s findings.

news@JAMA: Why did you do this study?

Dr Saver: There has been evidence that time is an important factor when using a clot buster, but the evidence base was fairly small and the degree of impact of time delay was not well quantified.

news@JAMA: What new insights does your study offer?

Dr Saver: It demonstrates the magnitude of the impact of timeliness for administering tPA; for every 15 minutes you reduce administration, 2 more patients out of 100 have an improved outcome.

news@JAMA: There has been concern by some clinicians treating ischemic stroke that administering tPA increases the risk of brain bleeding, but your study suggests otherwise.

Dr Saver: Our study shows for the first time that hemorrhage is increased the longer it takes to administer tPA, and it suggests the way to reduce the bleed risk is to treat earlier and to have organized emergency medicine and emergency neurology departments implement the changes in care in response to that data.

news@JAMA: In recent years, research has shown tPA to be to some degree effective in treating ischemic stroke up to 4.5 hours after symptom onset, and because of that, there is concern this larger window may subconsciously cause clinicians to forget about the urgency of treatment. What does your study say about that mind-set?

Dr Saver: Although data has come out showing that worthwhile degrees of benefit are obtained even after 3 hours following onset of stroke, the best benefit is obtained in the first hour. The real time difference in outcomes is 1 minute, so we can’t dawdle.

news@JAMA: Does your study remind patients and family members to act quickly if a stroke is suspected?

Dr Saver: It’s important that patients and family members know that stroke is now highly treatable but that every minute counts. So if symptoms occur suddenly, call 911 to get to the hospital right away. It takes up to 60 minutes in even the best hospitals to perform the needed imaging tests and blood work before administering tPA.