Minireview: Clinical severity in sickle cell disease: the challenges of definition and prognostication

Abstract

Sickle cell disease (SCD) is a monogenic, yet highly phenotypically variable disease with multisystem pathology. This manuscript provides an overview of many of the known determinants, modifiers, and correlates of disease severity in SCD. Despite this wealth of data, modeling the variable and multisystem pathology of SCD continues to be difficult. The current status of prediction of specific adverse outcomes and global disease severity in SCD is also reviewed, highlighting recent successes and ongoing challenges.

Keywords: Biomarkers; disease severity; models; outcomes; phenotype; prediction; prevention; prognosis; sickle cell anemia; sickle cell disease; survival.

Figure 1

Phenotypic variability in the rates of acute painful episodes and acute chest syndrome (ACS). This contour plot depicts the lifetime rates of pain and ACS for members of the Dallas Newborn Cohort. Acute pain is depicted in blue and ACS in red. The rate (events/year) is indicated on the y axis. The width of the blue and red regions is proportional to the number of subjects who have the indicated event rate

Figure 2

Putative biomarkers of painful events identified in the monocyte proteome of children with HbSS. Two representative biomarkers (proteins) from the study are shown. Membrane moesin correlated negatively with pain rate (inpatient painful events/5 years), and cytosolic alpha actinin correlated positively with pain rate. (Data for the graphs obtained from Hryniewicz-Jankowska et al.)

Figure 3

The CSSCD early predictive model. The estimated probability of severe SCD by 10 years of age is shown according to the leukocyte count in the second year of life, occurrence of severe anemia during the second year of life, and the occurrence of dactylitis before 1 year of age. In the CSSCD infant cohort, 3% were classified as high risk, 53% were classified as medium risk, and 44% were classified as low risk. (Reproduced with permission from Miller et al.)

Figure 4

The network of associations among death, clinical complications, and laboratory values in SCD. The factors colored in red are sufficient alone to predict the risk of near-term death. The factors colored in blue are associated with predictive factors in red. Abbreviations: ACS, acute chest syndrome; AVN, avascular necrosis; BUN/creatinine, ratio of BUN to creatinine; Sys BP, systolic blood pressure; Hb, total hemoglobin concentration; %HbF, percentage of fetal hemoglobin; WBC, white blood cell (total leukocyte) count; Hb genotype, the genotype of SCD. (Reproduced with permission from Sebastiani et al.)