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<p>Malaria is one of the leading causes of illness and death in African children. I’ve worked for the past 21 years in Kenya and then Uganda to decrease malaria and its complications in children, most recently as a faculty member at IU School of Medicine. For nearly all of those 21 years, I’ve been aware [&hellip;]</p>

IU Malaria, Sickle Cell Research Named Among Blood’s Most Outstanding Manuscripts of 2017


Malaria is one of the leading causes of illness and death in African children. I’ve worked for the past 21 years in Kenya and then Uganda to decrease malaria and its complications in children, most recently as a faculty member at IU School of Medicine. For nearly all of those 21 years, I’ve been aware of children with sickle cell anemia in the areas where we do malaria studies, and the lack of research and good clinical care for these children.

That is why I am honored that a research paper about my work to study the best treatments for children suffering from these diseases was chosen as one of the top 10 most outstanding manuscripts of 2017 by editors of the journal Blood, which published more than 1,000 papers last year.

Sickle cell disease exists because of malaria. Having one copy of the sickle cell gene (known as having sickle cell trait) leads to dramatic protection from malaria, particularly severe malaria: it’s estimated to reduce deaths from malaria by almost 80 percent. Having two copies of the gene leads to sickle cell anemia (SCA). Children with SCA don’t appear to be protected from malaria, certainly not like the children with sickle cell trait, and they might be at increased risk of death from malaria. They also have a lot of complications from the sickling of their red blood cells that having two of the genes causes, and this sickling gave the disease its name. Children with SCA have frequent pain crises from periodic sickling of their red cells, and this can lead to damage of many organs of the body, an increased risk of infection and a high risk of stroke.

One of the biggest advances in care of children with SCA in the United States and Europe has been the use of daily hydroxyurea from a young age. In these children, hydroxyurea dramatically decreases the number of pain crises, decreases signs of organ damage and appears to decrease the risk of stroke. Children in the U.S. with SCA have been getting hydroxyurea for the past decade or so, and it looks like hydroxyurea could end up leading to longer and better lives for these children as they move into adulthood. But 90 percent of children with SCA live in Africa, in areas where there has historically been malaria, and these kids are not getting hydroxyurea.

We designed the NOHARM (Novel use Of Hydroxyurea in an African Region with Malaria) study to answer the question of whether hydroxyurea was both effective and safe in children with SCA living in African areas with malaria. Some things hydroxyurea does seem likely to decrease the risk of malaria in children, while others could potentially increase the risk of severe malaria. Since severe malaria is a known cause of death in children with SCA, if hydroxyurea increased the risk of severe malaria, this could have devastating consequences. However, if it does not increase the risk of malaria, and it decreases pain crises and hospitalizations, it could revolutionize care for African children with SCA.

We designed our study as a placebo-controlled study so we could determine if hydroxyurea was both safe and effective in children with SCA living in regions with malaria. With a placebo, we could tell whether malaria risk was increased, decreased or the same, and also know whether it was effective against complications of SCA. I’d hoped to do studies to improve health in African children with SCA for years, but never could find a pediatric hematology researcher to collaborate with, and since I am an infectious disease expert and not a sickle cell expert, this was an insurmountable barrier. Fortunately for me, I met Russell Ware, one of the world’s experts on hydroxyurea use in SCA and a pediatric hematology researcher at Cincinnati Children’s Hospital and Medical Center. He was already doing studies of hydroxyurea in African children and was intrigued by the malaria question. And fortunately for both of us, Professor Christopher Ndugwa, who had founded the Mulago Hospital Sickle Cell Clinic, one of the earliest clinics for African children with SCA, in 1968, was still working at Mulago and was interested in the study. With the added expertise of Bob Opoka, a long-time collaborator on malaria studies; Heather Hume, a pediatric hematologist from University of Montreal working six months of the year at Mulago Hospital; and Phillip Kasirye, a Mulago Hospital pediatric hematologist, we were able to write up the study. Addmedica, the French pharmaceutical company, generously donated all of the study drug, and we obtained funding from the Doris Duke Charitable Foundation to do the study.

From the start, the study was a labor of love. Cincinnati Children’s Hospital and Medical Center, the University of Minnesota and Indiana University all contributed substantial resources to the study, and additional support from the Fogarty International Center and the Doris Duke Charitable Foundation for U.S. and Ugandan fellows to work on the project allowed us to do a big study of high quality on a small budget. At the end of the first year, when we compared placebo to hydroxyurea, we were delighted to find no evidence of increased risk of malaria (though overall malaria events were low) or infection, but a 45 percent reduction in sickle cell complications, including a reduction of hospitalizations.

We believe the study paves the way for the implementation of hydroxyurea as standard care for treatment of African children with SCA living in areas with malaria. However, a few additional questions need to be answered before widespread implementation. First, the best dosing regimen has to be determined. The NOHARM study used a fixed dose of 20 mg/kg/day of hydroxyurea, but US and European centers give a maximum tolerated dose that can go up to 35 mg/kg/day. We are conducting a follow-up study, the NOHARM Maximum Tolerated Dose (MTD) study, to determine which dose is most safe and effective. Since we know the 20 mg/kg/day dose is effective, if we can show it is close to the effectiveness of MTD, and with similar or lower risk of side effects, it would be much simpler to implement a fixed dose regimen. On the other hand, if MTD does result in significantly better outcomes, without concerning worsening in toxicities, then we would need to figure out how to implement this type of more complicated dosing.

The NOHARM study also had very close follow-up and monitoring, at a level and with types of testing that would not be available in rural clinics. So with MTD, we are seeing if less frequent monitoring might work, and we still need to determine whether we can do without or use surrogate markers for some of the more complex tests that are hard to obtain even in Kampala. We also need to monitor for malaria and complications in children in areas where malaria transmission is higher than it is in Kampala. Finally, of course, hydroxyurea needs to be available at low cost, ideally funded by ministries of health as part of standard of care for children with SCA, if there is to be any hope of widespread use. In the meantime, assessment of which children might benefit most greatly from hydroxyurea could help to get it to those who need it most.

So there’s quite a bit more work to be done, but we believe NOHARM is the important first step in getting what could be life changing hydroxyurea therapy to African children with SCA. To be a part of something that big is truly exciting for all of us on the NOHARM team.


Photo: NOHARM study team members lead children study participants in a song to celebrate the completion of the study. During the celebration, the NOHARM team presented and explained the study results to the participants and their parents or caregivers.

The views expressed in this content represent the perspective and opinions of the author and may or may not represent the position of Indiana University School of Medicine.
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Chandy John

Chandy C. John, M.D., M.S., holds the Ryan White Endowed Chair in Pediatric Infectious Diseases and is director of the Ryan White Center for Pediatric Infectious Disease and Global Health at Indiana University. Dr. John is an active clinician, specializi...