Twice as Nice

St. Jude research suggests the drug hydroxyurea offers twice the benefit to patients with sickle cell disease, including protection against life-threatening infections.

Twice as Nice

When it comes to medication, side effects are rarely good news. But St. Jude researchers searching for new ways to protect children with sickle cell disease from life-threatening infections may have found a welcome side effect. The scientists recently discovered that a drug used to ease the symptoms of sickle cell disease may also safeguard patients’ health by protecting them against dangerous pneumococcal infections.

The drug is hydroxyurea. This inexpensive medicine has been used for years to ease the symptoms of sickle cell disease first in adults and more recently in children as young as 2 years old.

Hydroxyurea is best known for reviving production of fetal hemoglobin. Hemoglobin is the protein that red blood cells use to carry oxygen. Fetal hemoglobin is the main form of the protein at work during the first months of life until a protein known simply as hemoglobin takes over oxygen transport.

For children with sickle cell disease, the switch from fetal hemoglobin to hemoglobin marks the start of a life-long struggle with serious illness. These individuals inherit a mistake in the instructions for assembling hemoglobin. The mistake leaves them at risk for a variety of health problems, including episodes of acute pain, a pneumonia-like illness called acute chest syndrome, strokes and other problems that are all associated with early death.

“Infections are one of the most serious threats to children with sickle cell disease. Our results suggest that hydroxyurea might reduce some of that risk even as it protects against organ damage by increasing production of fetal hemoglobin,” says Jason Rosch, PhD, of St. Jude Infectious Diseases.

Living with sickle cell

About 300,000 individuals worldwide have sickle cell disease. The disease leaves them at a 400-fold increased risk of death due to pneumococcal infection. Immunizations to prevent the infection combined with a daily dose of penicillin to squash it early have helped to reduce, but not eliminate, the risk for patients like Faith Maxwell Brown of Memphis.

Today, Faith is a 13-year-old with a ready laugh who enjoys teasing her mother good-naturedly about which of them does a better job of remembering to take medicine as directed. Faith enjoys ballet, dreams of becoming a pediatrician and sometimes has a hard time taking it easy during the temperature extremes that can trigger serious symptoms in sickle cell patients.

Doctors discovered Faith had sickle cell disease shortly after her birth. Almost immediately, she began taking penicillin to ward off infections. Yet she was hospitalized repeatedly with fevers as an infant and toddler. She was just a month shy of her second birthday when a pneumococcal infection invaded her bloodstream and led to meningitis and a 10-day stint in the hospital. The event caused significant hearing loss in her left ear.

Faith remembers little of the ordeal, but Velma Brown says her daughter needed rehabilitation even after she left the hospital to recover her strength and mobility. Mother and daughter prefer to focus on Faith’s progress, including her ability to manage her disease and take medication as directed.

“She’s at the age when she wants to go here and there. There are lots of school trips. I have more confidence now that she’ll do what she has to do to manage her sickle cell,” Velma says. That includes taking the daily dose of hydroxyurea she began in 2005.

When mother and daughter look at Faith’s red blood cells under the microscope now, they cannot believe the difference. “To see those cells go from something that looks like a banana to something that looks nice and round was like a miracle. I couldn’t believe it,” Velma says.

Satisfying side effect

Rosch and former St. Jude researcher Jeffrey Lebensburger, MD, are interested in hydroxyurea’s impact on the immune system, particularly white blood cells known as neutrophils that help drive inflammation.

Inflammation is usually an important part of the disease-fighting immune response. Individuals with sickle cell disease, however, are at risk for an exaggerated inflammatory response that can damage healthy tissue and lead to life-threatening complications.

Scientists have known for years that along with increasing production of fetal hemoglobin hydroxyurea reduces the number of neutrophils. The most common type of white blood cells, neutrophils play a key role in the body’s defense against bacterial and other infections.

A casual conversation over coffee one day inspired Rosch and Lebensburger to explore the anti-inflammatory properties of hydroxyurea.

That decision led to the first evidence of how a drop in neutrophils might protect against life-threatening pneumococcal pneumonia. Working in a laboratory model, researchers showed that hydroxyurea led to a drop in production of a molecule that helps neutrophils stick to the lining of blood vessels and begin moving to the site of the infection. The same molecule that helps neutrophils leave the blood stream to fight the infection is known to be elevated in patients with sickle cell disease. The molecule is named E-selectin.

When researchers checked blood samples from St. Jude patients enrolled in a national study of hydroxyurea, they found levels of E-selectin dropped following hydroxyurea therapy.

“Suddenly it looked like this drop in the neutrophils count, which had been dismissed as just a side effect of the drug, might be able to reduce the infection risk in these patients as well and not just for pneumococcal infection,” Rosch says.

Researchers are now studying whether hydroxyurea impacts the infection risk facing patients such as Faith. It is the kind of research that might make Faith even more conscientious.

“Whenever I get tired of taking medicine, I just remind myself of how much it is helping me,” she says.

Reprinted from Promise Autumn 2012

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