Ending Malaria's Global Toll on Children

As a professor at the Indiana University School of Medicine and researcher at Indiana University’s Herman B Wells Center for Pediatric Research, John leads a collaborative research group that studies malaria in Kenya and Uganda.

Humans typically get malaria from the bite of Anopheles mosquitoes infected by Plasmodium species—a parasite that can infect human blood. The mosquito becomes a host for the parasite when it takes a blood meal from an infected human. It transmits the disease at its next meal by injecting another human with its infected saliva.

John became interested in malaria during the mid-1990s, when researchers were discouraged about their efforts to defeat the disease. Despite aggressive eradication programs by the World Health Organization, malaria was making a comeback, partly because once-effective drugs were beginning to lose their punch.

Researchers were banding together to find better treatments, but there weren’t many experts studying the disease from a children’s health perspective. With so many children dying from malaria each year, John saw the need for pediatricians to get involved. “Children’s health is what we care about, so we ought to care about this disease that kills millions of children,” he says.

Over the past three decades, John and his colleagues at Makerere University in Uganda and the Kenya Medical Research Institute in Kenya have applied a two-pronged approach to conquering the vector-born disease:

1) Understand why severe disease occurs in malaria, so it can be prevented in the millions of children currently affected by malaria, and

2) Work toward eliminating malaria in areas of Africa, a more complex and prolonged task, but one that will ultimately yield the greatest benefit to child health.

Research at the Wells Center aims to answer several questions about malaria, including:

• Why do some kids develop severe malaria while others don’t? John and other scientists want to know all the factors that lead to severe malaria. Which parasite factors contribute to severe malaria? How do a child’s immune response or genetic makeup increase or decrease risk of severe malaria? With this knowledge, John believes we can develop therapies that target the prevention and complications of severe malaria.

• How can we protect children from the neurodevelopmental damage malaria can cause? Some children get cerebral malaria, a particularly serious form of the disease that can cause them to go into a coma. It also causes long-term cognitive impairment in 25 percent of its hosts.

In a more common form of the disease—severe malarial anemia—children don’t seem as ill, yet they often have brain damage comparable to kids affected by cerebral malaria. In fact, they suffer a loss of up to 11 IQ (intelligence quotient) points when compared to children who have never had malaria. “This poses a huge public health burden for children in Africa, where there are millions of cases of severe malarial anemia and cerebral malaria every year,” he says.

John and his colleagues Drs. Robert Opoka, Richard Idro and Paul Bangirana of Makerere University, study the body’s immune response to malaria, variations in the parasite and what happens to cells that line the body’s blood vessels. Their goal is to understand what causes brain damage and discover treatments that might protect the brain. “Obviously, the first priority is to keep children from dying, but with a quarter of them having long-term brain damage that affects their thinking, malaria harms their ability to get a job and be productive adults,” says John. “So we have to think about survival, as well.”

• What is the relationship between immunity and seasonal malaria? Some parts of the world have malaria all the time; others only have seasonal malaria. When kids aren’t constantly exposed to malaria, John and his colleagues want to know what happens to their immunity. “We know that without exposure, kids lose some of their immunity, but so far, that hasn’t been well-defined,” John says. “If their immune response is gone because they haven’t been exposed, does it mean they are more at risk when malaria returns?” John and his colleague Dr. George Ayodo of the Kenya Medical Research Institute are studying this question in highland areas of Kenya.

• How safe is a well-known drug for sickle-cell disease in areas of the world where malaria is a problem? Kids with sickle-cell disease are less likely to get severe malaria. When they do get it, they are more likely to die. John and his colleagues, including Drs. Robert Opoka and Christopher Ndugwa of Makerere University, and Dr. Russell Ware from Cincinnati Children’s Hospital and Medical Center, are looking at whether hydroxyurea—a drug used to treat sickle cell disease in U.S. children who are not exposed to malaria—increases or decreases risk of malaria in children with sickle cell disease in African areas with malaria.

Hydroxyurea is a very effective treatment sickle cell disease, but it could alter the risk of severe disease from malaria. Hydroxyurea increases hemoglobin F levels in the blood, protecting against malaria. So hydroxyurea treatment could be helpful in fighting malaria in children with sickle cell disease, but it could also increase their risk of severe malaria disease. Reason: some studies suggest the drug increases ICAM 1 (intercellular adhesion molecule), a receptor that the parasite finds attractive. “Before we roll out hydroxyurea for sickle cell disease across Africa, we want to make sure that it’s actually safe to give,” he says.

John spends up to three months each year in Kenya and Uganda. “I have wonderful collaborators in Kenya and Uganda. We work well together, and learn a lot from each other, so I enjoy my time there a great deal,” he says.

For studies of severe malaria, participants are recruited at the hospital, where parents can volunteer their children’s participation in research. For studies on malaria transmission, the research team visits villages to explain their research questions about malaria transmission to village elders. “We ask if their village would be interested in participating, and we have community-wide discussions to answer questions,” he says. During times of high and low transmission, researchers collect samples to assess immunity.

Through basic science and translational research, his group is part of a global effort to gain better clinical knowledge of malaria and apply it to improving child health in Kenya, Uganda and beyond. Solving the problem of malaria is relevant not only to African children, but also to children in Indiana.

Although local transmission of malaria is no longer a problem in the United States, more than 1,000 people develop malaria each year after returning to the United States from an area where malaria transmission occurs. It’s a statistic that hits close to home for John and his colleagues at the Ryan White Center for Pediatric Infectious Disease and Global Health. During a recent five-week period, they cared for five children who acquired malaria after travel.

John remains optimistic that his life’s work will help eliminate malaria and its devastating effect on families in other parts of the world and thus prevent Indiana travelers from acquiring malaria. “Good clinical and epidemiology research and public health policy effectively ended local malaria transmission in the United States,” he says. “It goes to show you what is possible.”