Columbia Physicians Target Neglected Cause of Childhood Disability and Death in Uganda

December 18, 2019

Even into the 1970s, children born with sickle disease in the United States rarely survived to adulthood. That began to change in the 1980s after the introduction of newborn screening and a succession of treatments, and today over 95% of children born with sickle cell reach their 18th birthdays.

But the outlook is still dismal for children with sickle cell disease in Sub-Saharan Africa, where 75% of all people with sickle cell disease are born.

Normal and sickled red blood cells
Normal and sickled red blood cells. Image: CDC / Janice Haney Carr.

“There are so many patients there and the effects from disease are devastating compared to what we see here,” says sickle cell specialist Nancy Green, MD, professor of pediatrics at Columbia University Vagelos College of Physicians and Surgeons. “At least 50% of children with the disease die before their fifth birthday. Childhood strokes are common.”

Green and a team of colleagues from Columbia and Makerere University in Uganda are now trying to improve the lives of children with sickle cell disease with one of the treatments that helped to transform the disease in the United States and other high-resource nations.

 

Stroke Exacts a Major Toll in Children with Sickle Cell

Starting this fall, Green and Richard Iwa Idro, a pediatric neurologist at Makerere, and their team will test if the drug hydroxyurea can prevent strokes and neurocognitive dysfunction caused by more subtle brain injury in children with sickle cell disease.

In regions of the world where little preventive care is available, strokes in children with sickle cell peak between ages 1 and 10. In the United States and other high-resource countries, preventive treatment has dramatically reduced sickle cell’s effects on the brain.

map of sickle cell disease and stroke in africa
Map of stroke prevalence among children with sickle cell disease in sub-Saharan Africa. (Only countries with published studies are shown). Image from Global Pediatric Health / CC BY-NC 4.0.

Green and Idro’s team of pediatricians and neurologists recently documented the impact of cerebrovascular disease on Ugandan children with sickle cell, the first in-depth analysis of the impact on the brain of children with sickle cell anemia in Africa. 

The results revealed that a shockingly high number of Ugandan children with sickle cell are affected by brain abnormalities. One-fifth of the children had evidence of some brain damage, evidenced by poor performance on neurocognitive tests, a high risk of stroke revealed by transcranial doppler readings, and/or a documented stroke.

Many children also had experienced “silent strokes,” which are detectable only with MRI scanning. “Silent strokes increase the likelihood of a full-blown stroke in the future and the cumulative effects of silent strokes can impair cognitive function,” Green says. “The same extent of strokes in the U.S. hasn’t been seen in over two decades.”


Can Hydroxyurea Reduce the Impact of Stroke?

Based on these findings, Green and Idro received funding from the NIH to conduct a clinical trial to see if hydroxyurea—a mainstay of sickle cell treatment in the United States—can reduce the incidence and impact of cerebrovascular disease on Ugandan children.

Although hydroxyurea has been used since the ‘90s in the United States to reduce strokes and other complications from sickle cell, the drug was only recently found to be safe for children in Africa, where endemic malaria and other infections are complicating factors.

The trial will enroll children between the ages of 3 and 9, who will be monitored for three years. Because recent studies have found that the drug reduces some of sickle cell’s other complications in African children, all participants in the trial will receive the drug. 

Green now travels to Uganda three or four times a year to work on the trial. “Sickle cell is a major public health issue in much of Africa,” she says. “We are eagerly anticipating the chance to enhance the care of people with sickle cell in Uganda, and Africa in general. In Uganda, the government is responsible for the health care of most people. If we show that the drug helps reduce strokes and other impacts on the brain from sickle cell disease, we hope there will be increased impetus for the government to make the drug more broadly accessible.”

 

Long-standing Collaboration between Columbia and Makerere

The trial stems from a partnership between the pediatrics departments of Columbia University and Makerere University that began earlier this decade. Through Green, the two departments have worked together to tackle sickle cell in Uganda, and additional faculty collaborations address other children’s health issues there.

Dr. Nancy Green (fifth from left) with members of her sickle cell research team in Uganda
Nancy Green (fifth from left) with members of her sickle cell research team in Uganda. Photo: Nancy Green.

Approximately 20,000 children are born in Uganda each year with sickle cell disease–1% to 2% of all births in the country. The Ugandan Ministry of Health has committed itself to improving medical care for sickle cell and reducing mortality. 

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Other collaborators in the sickle cell project from Columbia University Irving Medical Center are Philip LaRussa, MD, professor of pediatrics; Mitchell Elkind, MD, MS, professor of neurology and epidemiology (in the Gertrude H. Sergievsky Center); and Amelia Boehme, PhD, assistant professor of epidemiology (in neurology and in the Sergievsky Center).

The study of the impact of cerebrovascular disease on Ugandan children with sickle cell, titled “Burden of Neurological and Neurocognitive Impairment in Pediatric Sickle Cell Anemia in Uganda (BRAIN SAFE): A Cross-Sectional Study,” was published Oct. 25 in BMC Pediatrics.

Additional authors: Deogratias Munube (Makerere University College of Health Sciences), Paul Bangirana (Makerere), Linda Rosset Buluma (Makerere), Bridget Kebirungi (Makerere), Robert Opoka (Makerere), Ezekiel Mupere (Makerere), Philip Kasirye (Makerere), Sarah Kiguli (Makerere), Annet Birabwa (Makerere), Michael S Kawooya (Makerere), Samson K Lubowa (Makerere), Rogers Sekibira (Makerere), Edwards Kayongo (Makerere), Heather Hume (University of Montreal), Mitchell Elkind (CUIMC), Weixin Peng (CUIMC), Gen Li (CUIMC), Caterina Rosano (University of Pittsburgh), Philip LaRussa (CUIMC), Frank J Minja (Yale), and Amelia Boehme (CUIMC).

The study was funded by the NIH (1R21HD089791).

The authors declare no competing interests.