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From Risk to Protection: Turning PHT Around
CHORI & CHRCO Researchers Team Up to Compare Clinical Differences between Children and Adults with Sickle Cell Disease and Pulmonary Hypertension

“We were really stunned at how prevalent pulmonary hypertension was in children,” says Dr. Hagar. “What this tells us is that youth is no protection against it.”

CHORI clinical scientist Claudia Morris, MD, and Ward Hagar, MD, her colleague at CHRCO, have determined risk factors associated with pulmonary hypertension (PHT) in children with sickle cell disease (SCD). Their comparative study, published in the December issue of the British Journal of Haematology, revealed some surprising discoveries, including an equally high presence of PHT in children as in adults with SCD.

PHT has emerged within the last 5 years as a major, if not the major, cause of death in the sickle cell population, with a 40 percent increased risk of death. While associations of PHT with factors such as age and end-organ damage have been well-characterized in adults in the last few years, Drs. Hagar and Morris’ study represents the first step toward providing an adequate risk profile for PHT in SCD children.

“What was so fascinating about this data was that the clinical profile of children with PHT turned out to be so vastly different than that of the adults,” says Dr. Hagar.

In particular, acute chest syndrome (ACS), while a risk factor in children, was found to be protective in adults.

“Once you’ve had ACS as a complication of SCD, it usually triggers very aggressive treatment with the only two treatments that we currently know effect the underlying disease, which may be why it’s protective,” explains Dr. Hagar.

“Since ACS is a well known risk factor,” adds Dr. Morris, “these patients are receiving the benefits of early care and intervention.”

In contrast, children with a history of ACS were potentially too young to have reaped any protective benefit of treatment yet. In addition, sepsis and asthma were also associated with PHT in SCD children, but not adults.

“People think at first that of course you’d have increased mortality if you have sepsis, makes sense - but this is a history of sepsis, not active sepsis, that puts these kids into a high risk category for pulmonary hypertension,” Dr. Morris says.
While sepsis and asthma might seem unrelated, they, like PHT itself, result from alterations in arginine metabolism, an inflammatory pathway that’s associated with pulmonary hypertension and asthma in general, independent of sickle cell disease.

“In SCD, hemolysis, or the abnormal breakdown of red blood cells, causes increased arginase to be released in the cells, which also causes dysregulation of the arginine metabolism,” says Dr. Morris. “It’s all connected.”

“It all goes back to the idea that sickle cell dysfunction is about far more than just plugged up arteries,” says Dr. Hagar. “It opens up a whole new medical world in the area of nitric oxide, glutamine, glutamate and the arginine pathway.”

While the profiles between adults and children with SCD and PHT were vastly different, Drs. Hagar and Morris don’t believe it’s an indication of different mechanisms, but rather different expressions of endothelial dysfunction at different ages.
“This is a progressive condition,” says Dr. Morris. “The children with SCD are just a young version of what’s going to happen in adulthood.”

All of which points the finger at the need for greater screening for PHT, regardless of how young a patient might be.

“Anyone with SCD really ought to be screened for PHT and asthma, and any child that has had sepsis should be screened as well,” says Dr. Hagar.

Although there is currently no standard of care for the treatment of PHT in SCD, there are NIH guidelines for the treatment of asthma, and these guidelines should be applied to patients with SCD. In addition, the FDA has approved certain drugs for PHT, and CHRCO is one of 11 sites conducting controlled trials. Screening would not only help identify at risk patients who could benefit from such trials, but it could also offer an opportunity to turn the PHT risk to a benefit.

“The fact that ACS morality in adults is now protective is an indication that maybe we can do the same thing here,” says Dr. Morris. “Maybe we can turn these risk factors around by identifying them earlier and treating them aggressively so that they, too, become protective.”

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