Sickle cell disease is not so benign

Sickle cell disease (SCD) is historically considered as a benign hemoglobinopathy. There is currently no formal or internationally accepted risk stratification system to determine the long term outlook for affected individuals. Thus Rotz et al in this paper took on this important task to modify the current stem cell transplant assessment from a binary yes-or-no checklist of inclusion criteria, into a more quantitative determination based on the clinical presentations. The authors started with 2 large clinical databases, Cooperative Study of Sickle Cell Disease (CSSCD) and screening and treatment of pulmonary hypertension in sickle cell disease (Walk-PHaSST), and identified several laboratory and clinical parameters associated with increased mortality. They then applied these set of parameters to their contemporary cohort of patients at Case Western Reserve University Hospital (CWRU-UH). At a glance, adults with SCD have low mortality; 3-year mortality in CSSCD was 9.0%, 2-year mortality in Walk-PHaSST, 4.1%, and 2-year mortality at CWRU-UH, 2.5%. However, with a closer look at Table 3, one would easily see that several factors singly yielded predictive mortality of near 10% (e.g. WBC >13.5 k/uL, BNP >160 pg/L, or LDH >600 units/L). Many 2-factor combinations yielded mortality rates >15%. Additionally, Figure 2 indicated that as much as 75% of adults with SCD (at CWRU-UH) met the HSCT criteria from alternative donors.

How are these different rates explained? First, the burden of organ dysfunction is shifting from mainly stroke and spleen dysfunction in children, to sickle related nephropathy,¹ hepatopathy,² pulmonary diseases,³ and endocrinopathies in adults. The quality of life has been reported to be suboptimal and the morbidity from SCD is significant.^4–6 So while the mortality rate may be relatively low in a short time interval, these rates accumulate over time because the organ damages do not reverse without curative therapy. Hydroxyurea cannot replace transfusions in secondary stroke prophylaxis, and whether it can stabilize organ function or reverse damage are still under investigation. Second, the clinical manifestation of SCD has expanded to incorporate laboratory and other testing results, as seen in this manuscript. These parameters have not redefined the disease – it is still a hemolytic anemia driven by polymerization of sickle hemoglobin tetramers – but they provided robust datasets to estimate morbidity and mortality.⁷ The authors make this important distinction between morbidity and mortality in their traffic light stratification. During the assessment for transplant, morbidity risk (based mostly on clinical history of vaso-occlusive crisis, acute chest syndrome, stroke, and others) is complemented by mortality risk (based on laboratory or testing results): green light, proceed to any transplantation because mortality rate alone exceeds 15%; yellow light, some alternative donor transplantation can be considered in those with intermediate mortality rate OR high morbid conditions; and red light, standard of care transplantation (matched sibling donors) in those with low mortality rate AND moderate morbid conditions.

Patients with SCD still die 2 decades younger than unaffected individuals.⁸ The findings in this paper add to a growing body of literature that SCD leads to multi-organ dysfunction, and hence not as benign as previously thought. Patients and family now have the benefit of being presented with predictive mortality rates during the pre-transplant consultation, juxtaposed with the risk of the transplant related complications to make treatment decisions.⁹ These rates are tremendously helpful as the transplant community continue to expand the donor pool to make transplantation more accessible to affected individuals.