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How Clinical Studies Can Change and Save Lives
New England Journal of Medicine Publication Identifies New Thalassemia Subgroup to Target for Newborn Screenings

CHORI clinical scientists Ashutosh Lal, MD, Elliott Vichinsky, MD, and their colleagues have conducted a first-time longitudinal study analyzing the clinical data of patients with hemoblogin H disease (HbH) – a subtype of alpha-thalassemia – over the course of 15 years. Published in the New England Journal of Medicine, the study shows that the hemoglobin Constant Spring (HCS) mutation, found in a subset of patients with HbH, results in a distinct and significantly more severe disease course beginning in infancy.

“Two points our study revealed are really important," says Dr. Lal. "One is that HbH is actually not severe, but follows a predictable, treatable course. The other is that HCS is much more severe, and from a much earlier age, really suggesting that newborn screenings could make a significant difference in treatment outcomes.”

“Our results suggest that newborn screenings could make a significant difference in treatment outcomes.”

Hemoglobin H disease is a subtype of alpha-thalassemia, in which a specific genetic mutation in patients causes the body to produce insufficient amounts of hemoglobin the part of the red blood cell that transports oxygen throughout the body's tissues and organs. The clinical severity of HbH in young children had never been analyzed over time, but with a growing increase in the incidence of HbH in the United States, the state of California added all forms of HbH to their mandatory state newborn screenings.

As a result, Dr. Lal and his colleagues had the unique opportunity to fully investigate the course of HbH and its subset, HCS, during a 15-year period.
“The differences between HbH and HCS were always suspected, but ours is the first longitudinal study in which we followed patients over years and years at a single medical center using uniform guidelines for management.”
The results of the study showed remarkable and significant differences between the regular HbH disease and disease caused by the HCS mutation.

"When children with HCS become sick with an infection and fever, their already low hemoglobin levels can drop even further, to life threatening range that require blood transfusions," says Dr. Lal.

In fact, the results showed that in sharp contrast to patients with HbH, almost 80 percent of HCS patients had at least one transfusion by age 20. Even more significantly, the first transfusion was often before six years of age, if not in infancy.

"These data really do have an implication on whether you diagnose HCS by newborn screening, or whether you do it in the routine way, which more likely than not occurs during an episode of significant illness when a clinician is trying to make a diagnosis in an emergency situation," says Dr. Lal.

In addition, the results also indicate that children with HCS have significantly slower growth than those with HbH.

"While we don't fully understand why this is so, it probably has to do with the impact of such low hemoglobin levels, which means one needs to be very proactive in managing them and that can only happen with early diagnosis," says Dr. Lal.

As a result, Dr. Lal and his colleagues are strongly recommending that HCS be added to newborn screening programs. The test itself is relatively inexpensive and nearly 100 percent accurate.

"With early diagnosis, clinicians could not only help to manage insufficient growth in patients, but they could more aggressively treat infection to prevent the need for transfusions so early in life in these patients," explains Dr. Lal.

Previous proposals by Dr. Vichinsky, Director of Children's Hematology/Oncology division, to expand national newborn screenings to include hemoglobin H disease have not been supported. However, preliminary feedback from leadership in the United States Secretary of Health and Human Services Advisory Committee on Heritable Disorders in Newborns and Children suggests that the proposal may be reconsidered in light of the critical evidence demonstrating the clinical benefits of newborn screening provided by Dr. Lal and his colleagues.
“Using early diagnosis, we can predict the course of the disease and develop proper interventions to ensure that patients with all forms of hemoglobin H disease get the best treatment possible.”


Tuesday, May 17, 2011 8:19 AM

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