When people have two genes that are associated with sickle cell, they develop the disease, which can distort red blood cells into a sickle, or crescent, shape. When they have only one gene, they are usually asymptomatic. While sickle cell disease carries with it significant morbidity and mortality, being heterozygous (having one gene) has been found to be protective against malaria.
This seems like an odd finding, but it’s possible that this is one of the reasons that the gene for sickle cell disease has survived for so long. While two genes are debilitating, one gene is a potential lifesaver.
In fact, previous small studies have shown that children with sickle cell disease who develop severe malaria have a high mortality rate. The two genes may not be protective or even irrelevant; they may be harmful.
In a recent paper published in Pediatric Blood and Cancer, which was co-authored by IU School of Medicine faculty members Estela Shabani, PhD, and Chandy John, MD, researchers sought to examine whether this was true. Are children with severe malaria (cerebral malaria or severe malarial anemia) higher risk if they have sickle cell disease?
The study took place at Mulago National Referral Hospital, in Kampala, Uganda from 2008 through 2013. Children between 18 months and 12 years of age who had severe malaria were eligible for the study. They were all treated according to usual practice, and were followed up for two years after they were discharged from the hospital with respect to further malarial illness, readmission to the hospital, or death.
Community controls were also enrolled. These were healthy children from the same neighborhoods as those with severe malaria, and they were used as a comparison group.
Over the course of the study, 267 children with cerebral malaria and 232 children with severe malarial anemia were followed, along with 216 community controls.
Heterozygotes (those with one gene, but not two) comprised 19 percent of the community controls, but only 0.9 percent of those with severe malarial anemia and 0.8 percent of those with cerebral malarial. This confirmed, once again, that having one gene protects one from getting malaria at all. In fact, the researchers showed that being heterozygous reduced the risk of severe malaria overall by 96 percent.
Full sickle cell disease was found in 9.5 percent of children with severe malarial anemia, but only 0.4 percent of those with cerebral malaria and none of the community controls. Therefore, in this study, having two genes for sickle cell increased the risk of severe malarial anemia only, but by about 2,800 percent.
The good news, however, is that mortality didn’t differ significantly between those who had sickle cell disease and those who had normal hemoglobin. Children who had both severe malarial anemia and sickle cell disease had a higher incidence of readmission after discharge for all reasons (which could be related to sickle cell disease only), but didn’t have a higher rate of readmission for malaria.
As the authors note:
In conclusion, our study ﬁndings suggest that in children >18 months of age with SCA [sickle cell disease], inpatient mortality from SMA [severe malarial anemia], the most com-mon form of severe malaria, is low and similar to that of children with HbAA [no genes for sickle cell] if timely blood transfusion is provided, and that postdischarge mortality in children with SMA is also similar in children with HbSS [two genes for sickle cell] versus HbAA [no genes for sickle cell].
Of course, this would best be confirmed by a large, prospective study, which the authors do call for. In the meantime, though, this is evidence that children with sickle cell disease are not at increased risk from severe malaria.