Sickle Cell Disease (SCD)

Sickle cell disease (SCD) is a pediatric disease that is fatal in countries that do not have access to comprehensive care for patients with this disease and do not practice newborn screening (NBS). In the United States, the all-cause rates of death due to SCD in Black children from 1983 through 2002 were 0.78 in infants 0 to 3 years old and 0.43 in children 4 to 9 years old.¹ The advent of the pneumococcal vaccine in 2000 played a major role in reducing mortality.² Following the introduction of the vaccine, decreases in mortality of 68% in infants 0 to 3 years old and 39% in children 4 to 9 years old were observed.² In parts of Africa, the mortality rate in children younger than 5 years can reach 90% in regions that do not practice NBS and early intervention.³ In African countries with effective NBS, the mortality rates in children younger than 5 years are one-tenth those in surrounding countries that have not implemented universal NBS.⁴ 

In developed countries, children with SCD that is recognized early by NBS are likely to live into adulthood, although their overall life expectancy is decreased by 20 to 30 years without curative hematopoietic stem cell transplant.⁵ Other factors that affect prognosis include genotype, hemoglobin level, number of crises per year, and the presence of neurologic or renal disease. Additionally, the use of hydroxyurea has decreased mortality in patients with SCD.⁶ 

One study of patients with SCD across 3 tertiary care facilities in the United States reported that the hemoglobin SS and Sβ⁰ genotypes confer a worse prognosis than the SC and Sβ⁺ genotypes. Overall survival in patients with the SS or Sβ⁰ genotype is 58 years, with a median age at death of 43 to 44.5 years. The median overall survival of patients with the SC or Sβ⁺ genotype is 66 years (P=0.0031 vs the SS and Sβ⁰ genotypes). These numbers are an improvement over those in older mortality studies, which reported the expected survival of patients with hemoglobin SS to be 42 to 48 years and the survival of those with hemoglobin SC to be 60 to 68 years.⁶ The numbers are consistent with those in studies from other high-income countries. For example, a study of 712 patients in the United Kingdom reported that the median survival of patients with the SS or Sβ⁰ genotype was 67 years.⁷  

A history of any cerebrovascular event is associated with decreased survival (hazard ratio [HR], 1.9464; P=0.0005). Similarly, the presence of proteinuria and a decreased glomerular filtration rate (GFR) are also associated with decreased longevity (HR for each decrease in GFR of 1 mL/min, 1.068; P <0.0001).⁶ 

An inverse relationship exists between the number of pain crises per year and mortality. The median survival for patients who have 0 to 4 pain crises per year is 61 years, whereas it is 53 years for those with more than 4 pain crises per year (HR, 3.6982; P <0.0001).⁶

Hydroxyurea boosts fetal hemoglobin (HbF) levels and is associated with positive outcomes and prolonged survival in patients with SCD. Those with a high response to therapy, marked by increased levels of HbF, derive the greatest benefit. Patient who received the recommended therapeutic dose of 15 to 35 mg/kg per day were more likely to attain optimal HbF levels and survive longer (HR, 0.36; 95% CI, 0.17-0.73; P=0.005).⁸ 

Infection remains a leading cause of death in children with SCD, including infection with malaria in countries where it is endemic.^9,10 The lower mortality rates in developed countries are attributed to early penicillin prophylaxis, vaccination, and access to a comprehensive care team. In developed countries, mortality is attributed to acute chest syndrome and multiorgan failure.¹¹   

References 

1. Yanni E, Grosse SD, Yang Q, Olney RS. Trends in pediatric sickle cell disease-related mortality in the United States, 1983-2002. J Pediatr. 2009;154(4):541-545. doi:10.1016/j.jpeds.2008.09.052

2. Data & statistics on sickle cell disease. CDC. Centers for Disease Control and Prevention. Reviewed December 16, 2020. Accessed November 23, 2021.

3. Grosse SD, Odame I, Atrash HK, Amendah DD, Piel FB, Williams TN. Sickle cell disease in Africa: a neglected cause of early childhood mortality. Am J Prev Med. 2011;41(6 Suppl 4):S398-405. doi:10.1016/j.amepre.2011.09.013

4. Sickle-cell disease: a strategy for the WHO African region. World Health Organization. Regional Committee for Africa; 2011. Accessed November 23, 2021.

5. Sedrak A, Kondamudi NP. Sickle cell disease. StatPearls [Internet]. Updated September 6, 2021. Accessed November 23, 2021.

6. Elmariah H, Garrett ME, De Castro LM, et al. Factors associated with survival in a contemporary adult sickle cell disease cohort. Am J Hematol. 2014;89(5):530-535. doi:10.1002/ajh.23683

7. Gardner K, Douiri A, Drasar E, et al. Survival in adults with sickle cell disease in a high-income setting. Blood. 2016;128(10):1436-1438. doi:10:1182/blood-2016-05-716910 

8. Fitzhugh CD, Hsieh MM, Allen D, et al. Hydroxyurea-increased fetal hemoglobin is associated with less organ damage and longer survival in adults with sickle cell anemia. PLoS One. 2015;10(11):e0141706. doi:10:1371/journalpone.0141706 

9. Ogun GO, Ebili H, Kotila TR. Autopsy findings and pattern of mortality in Nigerian sickle cell disease patients. Pan Afr Med J. 2014;18(30). doi:10.11604/pamj.2014.18.30.4043

10. McAuley CF, Webb C, Makani J, et al. High mortality from Plasmodium falciparum malaria in children living with sickle cell anemia on the coast of Kenya. Blood. 2010;116(10):1663-1668. doi:10:1182/blood-2010-01-165249 

11. Quinn CT, Rogers ZR, McCavit TL, Buchanan GR. Improved survival of children and adolescents with sickle cell disease. Blood. 2010;115(17):3447-3452. doi:10.1182/blood-2009-07-233700

Reviewed by Harshi Dhingra, MD, on 11/22/2021.

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Kyle Habet, MD

Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.