On a cold winter afternoon, a brother and sister are at the sickle cell clinic at Johns Hopkins Children’s Center with their mother. Pediatric hematologist Emily Rao, has been caring for the siblings for years.

It’s the family’s first appointment since last summer, although both children were hospitalized the previous month for flu. As Rao chats and asks questions, she scratches out a to-do list for herself on a sheet of paper. 

Fill out paperwork for prescriptions the older child needs to even out the iron load in her blood caused by transfusions. Submit an updated Family and Medical Leave Act form for a too-busy mom who needs time off for the many appointments her children require. Schedule some of those appointments: eye tests, to learn if the children are developing retinopathy, a frequent complication of sickle cell disease (SCD); conventional transcranial Doppler tests, to predict risk of stroke, another all too common outcome.

Sickle cell disease, characterized by misshapen red blood cells that can clump together to block blood flow, “involves just about every organ system in the body,” says Rao. Though the severity varies by patient, the clumped cells typically cause debilitating pain crises in the short term, and organ damage over time. 

The siblings at the sickle cell clinic are among 500 young patients who are finding help navigating those challenges from the six-doctor pediatric hematology team at Johns Hopkins Children’s Center, helmed by James Casella. A member of the Johns Hopkins faculty since 1983, Casella has led studies showing that blood transfusions and the chemotherapy drug hydroxyurea prevent strokes and silent cerebral infarctions — which are detected on a brain scan but show no symptoms — among young patients with SCD.

Casella joins a line of distinguished Johns Hopkins clinicians-researchers — stretching back to longtime Children’s Center Director George Dover — who have pioneered advances that dramatically improved life for children living with this agonizing inherited blood disorder. And now, pediatric hematologist Christopher Gamper is leading a push to make curative bone marrow transplants accessible to more young patients.

Still, the disease’s many cruelties pose decades long, day-to-day challenges for patients and their families, and Johns Hopkins clinicians do everything they can to guide them through a complex dance of medications, screenings and symptom management. They also help parents navigate insurance and prepare children for the day they will transition to adult care.

“Over time, we get to know the families,” Rao says. “We are there for the good days and the bad days.”

Severe Stabbing Pain

Each year, an estimated 2,000 babies across the United States are diagnosed with SCD. The vast majority, about 90%, are Black or African American, and 3%– 9% are Hispanic or Latino. 

For parents, the diagnosis — gleaned through a universal blood test — can be devastating.

Life expectancy is about 20 years shorter for people who have SCD than for people without it. And complications — including acute chest syndrome (during which sickle cells block blood vessels in the lungs) and stroke (when they block other blood vessels) — pose an ever-present source of anxiety.

“It can affect the kidneys, the heart, the bones — basically, wherever your blood goes,” says Dana Furstenau, a member of the hematology team at the Children’s Center. “That’s why sickle cell disease is so awful.”

One former Children’s Center patient, Lea Armstead, now 33, was diagnosed with SCD as a newborn, and didn’t find relief until she became a Johns Hopkins patient as a teen and started taking hydroxyurea.

SCD “does a number on a working parent,” says her mother, Andrea Armstead, who founded the Armstead-Barnhill Foundation for Sickle Cell Anemia to improve outcomes for those living with the disease.

Lea describes her pain crises like this: “It can be any part of your body, but most common are arms and legs. It feels like severe stabbing pain, like you’re being hit repeatedly by a baseball bat all over your body. It’s like childbirth. It’s scary because you never know when it’s going to happen.”

Patients do best when they stay hydrated, minimize stress, eat well and get enough sleep.

“I always think of myself as being really high-maintenance,” says Lea Armstead, who lives in Arlington, Virginia. “Can’t be too hot or too cold. Can’t be too stressed. Can’t get too mad. I have to get plenty of sleep. In theory, it’s all possible, but life is also life. It’s hard to get eight hours of sleep every night and go on walks and eat perfectly healthy. I have a 6-month-old and a full-time job as a nurse practitioner.”

Armstead began treatment at the Children’s Center during her college years, but pediatric patients typically start visiting the Johns Hopkins Comprehensive Sickle Cell Center at about 2 months of age, says Casella.

In a patient’s early years, the Johns Hopkins sickle cell team focuses on teaching parents how to ward off the worst symptoms. A typical regimen includes twice-daily doses of penicillin to prevent potentially fatal infections, and hydroxyurea to improve blood cell quality. Because run-of-the-mill fevers can morph into life-threatening infections, parents learn to seek hospital care if their child’s temperature spikes.

Some patients, particularly if they have already had strokes, go to the hospital once or twice each month for outpatient blood transfusions that remove some of their sickled blood and replace it with healthy donated blood. Patients also get regular screenings to monitor stroke risk and damage to the retina and other organs. “It’s a lot to ask of families,” says Rao.

‘The Go-to Place’

Sickle cell disease was first described in 1910, by Chicago physician James Herrick, who noticed the misshapen red blood cells in a patient from Grenada. He gave the disease its name because the cells had a sickle shape.

Real progress in understanding and treating the disease began in the 1970s, when the National Institutes of Health’s National Heart, Lung and Blood Institute (NHLBI) launched the Cooperative Study of Sickle Cell Disease, a longitudinal look at SCD across 23 health centers.

One of the project’s early studies, in the mid-1980s, was stopped because it was so effective. It found that penicillin, given from ages 4 months to 5 years, could prevent potentially fatal infections in patients with SCD.

As the value of early interventions became clear, Dover, a pediatric hematologist who became interested in sickle cell disease shortly after joining Johns Hopkins in 1972, successfully advocated for universal blood screenings in Maryland.

Across the state, when newborns were found to have SCD, Dover and his colleagues contacted the families, even those not connected with Johns Hopkins, to counsel them about how to care for their children. As a result, Johns Hopkins Children’s Center became “the go-to place for the sickest patients,” says Dover, who retired in 2016.

One reason screenings are so important, Dover notes, is that babies are born without symptoms, because fetal hemoglobin doesn’t sickle. It even inhibits sickling.

Working closely with his adult-side Johns Hopkins counterpart, Sam Charache, sometimes known as “Sickle Sam,” Dover found that two chemotherapy drugs could promote development of the nonsickling fetal hemoglobin.

In 1983, they collaborated on a paper in Proceedings of the National Academy of Sciences, which showed that the anticancer drug 5-azacytidine turned on fetal hemoglobin and therefore kept cells from sickling.

Twelve years later, Charache, director of The Johns Hopkins Hospital’s hematology lab from 1979 – 1995, and Dover were the lead authors of an article in The New England Journal of Medicine demonstrating that a less toxic chemotherapy drug, hydroxyurea, was just as effective in decreasing the frequency of pain crises in patients with sickle cell disease.

But it took nearly two decades for the NHLBI to officially advance hydroxurea as the standard of care for pediatric patients. In 2014, the institute recommended offering hydroxyurea to patients starting at 9 months of age.

However, notes Furstenau, hydroxyurea use by children who have sickle cell disease remains low across the country, with current Johns Hopkins research showing that about 30% of the children by the age of 2 and 40% by age 3 are taking the medication. “At Hopkins, we’re probably above that number,” she says, “but we’re definitely not as high as we would like.”

Furstenau has undertaken research to figure out why. One reason appears to be that parents simply don’t want to give their children a chemotherapy drug, even at low doses, she says. Though hair loss is rare, the medication can interfere with fertility. It can also lower white blood cell counts, requiring frequent monitoring, says Furstenau.

“We’re finding promising results in asking parents, ‘If hydroxyurea were effective in preventing brain complications in your child, would you take it?’ That might be the key to convincing people to start hydroxyurea early,” she says.

Stroke risk is an unfortunate reality for patients with SCD, notes Casella. “If you don’t do anything, one out of nine kids with sickle cell disease will have a stroke by age 21.”

Casella, who is chief of pediatric hematology, joined the Johns Hopkins hematology team as a postdoctoral fellow in 1979, and has led or participated in many studies aimed at reducing the risk of stroke in patients with SCD.

He was among the leaders of the BABY HUG study, the first randomized trial of hydroxyurea for infants with SCD. 

He also co-led the Silent Cerebral Infarct Transfusion (SIT) Trial, published in The New England Journal of Medicine in 2017, which showed that blood transfusions can dramatically reduce the risk of  silent cerebral infarction and stroke in children with SCD. The SIT study found that giving transfusions to children age 5 – 15 who had already suffered a silent cerebral infarct (a “silent stroke”) could avoid subsequent infarcts. 

As is often the case with SCD, advances come with caveats. The transfusions, which basically dilute the sickled blood, are time-consuming, and they can contribute to iron overload in the blood, which requires medications called chelators to reduce the iron load. But the daily regimen of pills and monitoring can be daunting.

In an exam room, a mother says her 5-year-old sometimes spits out his pills, and a 12-year-old girl promises to stick to her regimen, but she’s been saying that for years. Rao understands, and she offers solutions: for the younger child, a switch from pill to liquid, and for the older child, suspending hydroxyurea for the time being, even though it means putting on hold the plan to move away from transfusions.

Expanding the Pool

Some families are now considering bone marrow transplantation, which replaces the faulty blood-forming cells (stem cells) with healthy ones from a donor, allowing the body to produce normal red blood cells with healthy hemoglobin.

Gene therapy is another option at some centers. Although patients are not currently receiving gene therapy at Johns Hopkins, research efforts are underway in pediatric hematology to improve gene therapy for SCD.

Over the past 25 years, 38 pediatric patients with SCD at Johns Hopkins have received curative bone marrow transplants, most with remarkable results, says Gamper. Two of his patients, previously so ill that they spent hundreds of days in hospital beds, are now disease-free and in such good health that they are serving in the military, he says.

But a stem cell transplant is hardly a walk in the park. First, a young patient must undergo an extensive course of chemotherapy to purge the body of blood stem cells, temporarily destroying the patient’s immune system. Then, the patient receives an infusion of stem cells from a healthy donor, followed by another month or so in the hospital.

Hospital discharge is usually possible after six weeks, but complete recovery to restore normal immune function can take a year or longer. While engraftment with the donor stem cells is a permanent cure for SCD, there can be late side effects that include infertility and increased cancer risk.

Until now, a major obstacle with bone marrow transplants, Gamper says, was finding donors with matching tissue types in order to reduce the risk of graft-versus-host disease. Historically, only 25% of siblings would be suitable immune-matched donors.

Gamper collaborated with Robert Brodsky, Johns Hopkins hematology director, to test a novel regimen that allows use of “half-matched” bone marrow donors — which could expand the pool of potential donors to include parents, siblings, aunts, uncles and cousins. After a Johns Hopkins clinical trial demonstrated success, a national study, co-led by Brodsky and published in February in The New England Journal of Medicine, found a success rate of 88% for the treatment — an HLA-haploidentical transplant — in adults.

Gamper notes that results will soon be available for pediatric patients, and he expects a similar degree of success, potentially allowing many more children and teens to benefit from the life-changing cure.

Though painful trade-offs and day-to-day hassles are still the norm for patients with SCD, “there’s room for optimism,” says Casella. Back in the 1970s, when he started treating patients with SCD, little was known about the disease or how to treat it, he says.

"Now, we have a disease-modifying agent that really works, and two curative therapies,” he says. “Bone marrow transplants are established, and now we have gene therapy, which is embryonic. To me, that’s an encouraging landscape.”