A Really Neglected Disease

Sickle cell disease is a textbook example of evolution at work.  It results from a single gene mutation that allows hemoglobin to polymerize, leading to a number of bad results for the person unlucky enough to get two copies of the mutant gene (homozygotes), but in those with only one copy (heterozygotes), it confers a selective advantage in regions where malaria is endemic since the polymerized hemoglobin and fragile red blood cells make it harder for the malaria parasite to reproduce in the blood (Wikipedia article).  Hence, in people whose forbearers moved out of historically malarial regions a few generations ago (Africa, Central and South America, the Mediterranean, Middle East, and India), the incidence of the mutation is many times higher in indigenous people than in emigrants (e.g., 4% in West Africans vs. 0.25% in African-Americans).  The primary bad results for the afflicted are anemia and fatigue, but also an occasional blockage of blood flow by the inelastic red blood cells, resulting in pain and organ damage (especially in the spleen), stroke, and decreased resistance to infection (NHLBI).  In the US, the estimated 70,000 to 100,000 people with sickle cell disease manage their disease with palliative treatments for their acute pain episodes, which occur about once per year, close medical monitoring, and maybe bone marrow transplants, hopefully paid for through their insurance plans (c.f., Sickle Cell Disease Association).  What about the rest of the world?

Worldwide prevalence data are lacking.  The WHO reports incidence data; each year over 300,000 babies with severe forms of sickle cell and another hemoglobin disorder, thalassemia, are born worldwide, the majority in low and middle income countries (WHO Fact Sheet).  In Africa, a 2006 WHO report states that 200,000 sickle cell infants are born each year and the disease contributes the 5% of the under-the-age-of-five deaths, to more than 9% of such deaths in West Africa, and to up to 16% of under-five deaths in individual West African countries (WHO 2006 Report).  However, there is evidence that sickle cell disease may be contributing to a greater percentage of childhood mortality, mostly likely by decreasing resistance to infection.  A study in Kenya that looked at hospitalized children under the age of 14 from 1998 to 2008 found that 6% those with bacterial infections were also sickle cell children (Williams et al. 2009).   Further, in an article on the publication, the authors note that one quarter of all child-deaths in the study region were attributable to sickle cell anemia (All Africa article).   Hence, using the WHO number that about 5 million under-five deaths in Africa each year (WHO data) and some loose extrapolation, the number dying attributable to the underlying sickle cell disease could be 250,000 to as many as 1.25 million.  This may be compared the under-five world-wide mortality that WHO attributes to:  respiratory infections (1.8 million), diarrhea (1.5 million), malaria (1 million), and HIV/AIDS (370,000).  To quote a quote from the study’s lead author:  “To date, sickle cell anemia has not enjoyed a high priority on African health agendas, despite the relatively high impact it has on childhood mortality, which far exceeds estimates for HIV.  HIV commands vast attention from the international community, yet sickle cell anemia is virtually invisible on the international health agenda (All Africa article).”

So what could be done to reduce the contribution of sickle cell anemia to childhood mortality in Africa, and the other places with relatively weak pediatric care?  Genetic screening and counseling of prospective parents would help, but this is a technology- and skill-intensive approach.  Pumping up public health through improved water quality and increased childhood immunizations clearly would help.  Post natal screening for anemia (low hemoglobin) or microscopic examination of blood cells would easily identify children with sickle cell and who are at risk of infection, and they could receive additional attention, e.g., vaccinations, dietary supplements like folic acid, and daily penicillin to prevent infections.  One study has suggested that education, screening, and follow up of the infants helps (Rahimy et al. 2008) and does mass vaccination against pneumococcal infection (Science News article).

As for a drug treatment, although hydroxyurea is used to treat adults, its long term consequences are suspect (c.f., US News article).  An affordable therapeutic specific to children is needed, but pediatric meds, in general, and the disease have had a low profile in the pharma/biotech industry.  There are a few companies working on drugs that address the condition (as opposed to its consequences).  Emmaus Medical has a dietary supplement (L-glutamine) in trials (Emmaus Medical).  HemaQuest Pharmaceuticals has a short chain fatty acid derivative in trials since 2008 that they claim induces fetal hemoglobin and red blood cell production (HemaQuest).   AesRx, in my neighboring town of Newton, MA, has a small molecule in development that is intended to increase the affinity of the deviant hemoglobin for oxygen, thus reducing the tendency for the red blood cells to sickle (AesRx).

As for the international health community, it is evidently focused elsewhere and the only major UN/WHO action I could find was declaration, in 2009, of June 19th as “World Sickle Cell Awareness Day’ (Children’s National PR).  Sickle cell disease did not make the recent G-Finder list of neglected diseases (Moran et al. 2009) nor does it qualify for the FDA’s priority review voucher consideration (FDA Priority Review Guidance).  And it’s not on BIOVentures for Global Health’s radar (BVGH Neglected Disease Pipeline).  Sounds like a double-bottom line business opportunity to me.

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