Sickle cell disease: a new era
Authors: Shmona Simpson
Journal: The Lancet Haematology (2019)

Sickle cell disease is caused by inherited mutations of the globin gene, and is a multisystem disorder characterised by distortion, stiffness, and adhesion of red blood cells. Every year in Africa, around 230 000 children are born with sickle cell disease and about 90% of them could die before the age of 5. At around 1 year of age, these children begin to have anaemia, pain, stroke, retinopathy, and chronic damage affecting the spleen, lungs, kidney, and major joints. They become particularly susceptible to infection—pneumococcal sepsis is the leading cause of death. Nigeria and Democratic Republic of the Congo bear the majority of Africa's sickle cell disease burden.1Ware RE de Montalembert M Tshilolo L Abboud MR Sickle cell disease.Lancet. 2017; 390: 311-323Summary Full Text Full Text PDF PubMed Scopus (403) Google Scholar Sadly, these child mortality figures are a gross underestimation of the sickle cell disease burden, and do not consider the intersection of sickle cell disease with infectious disease, immunisation, and mental and maternal health, as well as the impact of sickle cell disease on attainment of the Sustainable Development Goals of ending poverty and reducing inequality. Sickle cell disease can be caused by multiple genetic variants. Most estimates of sickle cell disease burden account only for the homozygous HbSS variant, which excludes mortality and morbidity caused by the HbSC variant or thalassaemia. Inclusion of HbSC and thalassaemia would add a further 130 000 children born with severe haemoglobinopathies annually to global estimates. Additionally, pregnancy is a life-threatening complication of sickle cell disease. In low-resource countries, pregnancy in women with sickle cell disease is associated with 22-times the risk of death.2Boafor TK Olayemi E Galadanci N et al.Pregnancy outcomes in women with sickle-cell disease in low and high income countries: a systematic review and meta-analysis.BJOG. 2016; 123: 691-698Crossref PubMed Scopus (58) Google Scholar Notably, understanding of the intersection between sickle cell disease and infection is poor. Child deaths that appear to result from pneumonia, malaria, HIV, tuberculosis, or diarrheal disease might have sickle cell disease as a predisposing factor (figure).3Booth C Inusa B Obaro SK Infection in sickle cell disease: a review.Int J Infect Dis. 2010; 14: e2-e12Summary Full Text Full Text PDF PubMed Scopus (170) Google Scholar The rapid clinical evolution of the disease makes this intersection difficult to determine—in a child with sickle cell disease, febrile illness or non-specific malaise can mean death within hours. These children die undiagnosed and untreated, and possibly with an incorrectly recorded cause of death. The life for those who survive is one dominated by social exclusion and adverse health, in which productive employment is often not achievable. Tremendous financial and psychosocial burden is placed on people living with sickle cell disease and those caring for them. In African countries with the highest burden, the cost of one sickle cell disease-related event requiring hospitalisation exceeds average monthly household income. Catastrophic financial hardship is common, and this financial strain is particularly felt by families of children with multiple annual occlusive crises and single mothers who are responsible for more than three children with sickle cell disease.4Olatunya OS Ogundare EO Fadare JO et al.The financial burden of sickle cell disease on households in Ekiti, Southwest Nigeria.Clinicoecon Outcomes Res. 2015; 7: 545-553Crossref PubMed Scopus (31) Google Scholar, 5McGann PT Grosse SD Santos B et al.A cost-effectiveness analysis of a pilot neonatal screening program for sickle cell anemia in the Republic of Angola.J Pediatr. 2015; 167: 1314-1319Summary Full Text Full Text PDF PubMed Scopus (29) Google Scholar Furthermore, school absenteeism and underachievement are high for children living with sickle cell disease across Africa (figure). Just before World Sickle Cell Day in 2006, WHO estimated that sickle cell disease was responsible for 9–16% of child deaths in West Africa. Since then, the disease has yet to reach prominence on the global child health agenda. To date, there remains a paucity of national screening and intervention programmes in Africa. The high costs of screening, limitations in health-care system infrastructure, and absence of optimal and affordable treatment options create a barrier to sickle cell disease becoming an actionable initiative on the global health agenda. Today marks a new era for sickle cell disease treatment and cure. Reports from the field unequivocally indicate that screening, caregiver education, and pneumococcal prophylaxis have reduced child mortality attributable to sickle cell disease by at least 90% in the middle-income Americas.6Sabarense AP Lima GO Silva LM Viana MB Survival of children with sickle cell disease in the comprehensive newborn screening programme in Minas Gerais, Brazil.Paediatr Int Child Health. 2015; 35: 329-332Crossref PubMed Google Scholar, 7Serjeant GR Serjeant BE Mason KP et al.Newborn screening for sickle cell disease in Jamaica: logistics and experience with umbilical cord samples.J Community Genet. 2017; 8: 17-22Crossref PubMed Scopus (3) Google Scholar Evidence suggests these low-cost, life-saving interventions will be efficacious in sub-Saharan Africa5McGann PT Grosse SD Santos B et al.A cost-effectiveness analysis of a pilot neonatal screening program for sickle cell anemia in the Republic of Angola.J Pediatr. 2015; 167: 1314-1319Summary Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 8Kuznik A Habib AG Munube D Lamorde M Newborn screening and prophylactic interventions for sickle cell disease in 47 countries in sub-Saharan Africa: a cost-effectiveness analysis.BMC Health Serv Res. 2016; 16: 304Crossref PubMed Scopus (38) Google Scholar and the transition from emergency to outpatient management could reduce the financial burden of sickle cell disease on the health-care system. Numerous pilot studies in Africa are showing that early vaccination encounters can be leveraged to conduct screening and enrol those affected into care (Nnodu O, Centre of Excellence for Sickle Cell Disease Research & Training, University of Abuja, personal communication). Furthermore, the landscape of sickle cell disease financing, treatment, and potential cure has changed. The technology to diagnose the disease has become more affordable, less cumbersome, and even available at the point of care. In 2017, the US Food and Drug Administration (FDA) approved Endari, marking their first approval of a disease-modifying agent for sickle cell disease in 20 years. In an attempt to stimulate the drug pipeline, both the FDA and European Medicines Agency have granted fast track, orphan, and rare paediatric disease designations for compounds for treatment of sickle cell disease and thalassaemia. Today, there are tens of candidates in clinical development for treatment of sickle cell disease, with several having reached phase 2 development. In 2018, the Bill & Melinda Gates Foundation made a first of its kind grant towards a functional cure for sickle cell disease with gene therapy.9The Harvard GazetteBoston Children's Hospital to receive $1·5M grant to fight sickle cell disease.https://news.harvard.edu/gazette/story/newsplus/boston-childrens-hospital-to-receive-1-5m-grant-to-fight-sickle-cell-disease/Date: Dec 19, 2018Date accessed: March 11, 2019Google Scholar A new public–private partnership between the Government of Ghana, Sickle Cell Foundation of Ghana, and Novartis will make disease modifying hydroxyurea available to all Ghanaian children.10Ministry of HealthRepublic of GhanaMOH and Novartis sign MOU on treatment of sickle cell disease at World Economic Forum 2019.http://www.moh.gov.gh/moh-novartis-foundation-signs-mou-on-treatment-of-sickle-cell-disease-at-world-economic-forum-2019/Date: 2019Date accessed: March 21, 2019Google Scholar A future in which the sickle cell disease community can survive and thrive is within reach. All children with this disease must share that bright future by being equal beneficiaries of these medical and systems innovations. For this to happen, these children must first be screened. The compound effect of sickle cell disease on infectious disease deaths, poverty, economic growth, and maternal and child deaths is slowing progress towards key development indicators for sub-Saharan Africa. Technological, medical, and systems innovation has made sickle cell disease more detectable, treatable, and curable than ever before. In the leadup to realisation of the Sustainable Development Goals, African children with sickle cell disease and their families will be left behind if this disease remains neglected. I am an employee of the Bill & Melinda Gates Foundation. The Bill & Melinda Gates Foundation is a private non-profit philanthropic organisation with a mission to ensure that more children survive and thrive. The manuscript content does not necessarily reflect the views of Bill Gates, Melinda Gates, or the Bill & Melinda Gates Foundation. As referenced in the text, The Bill & Melinda Gates Foundation has recently given a grant to Boston Children's Hospital to advance the delivery of a gene therapy to cure sickle cell disease.