Changing the Natural History of Sickle Cell Disease
Changing the natural history of sickle cell disease (SCD) begins as early as childhood and continues throughout adulthood. Targeting the underlying pathophysiology of SCD has the potential to reduce the cumulative burden of SCD that can result from cardiovascular, pulmonary, and renal complications.
What do we know about the natural history of SCD?
Associate Professor, Division of Hematology and Oncology
“VOC continues to be a major contributor to hospitalizations and reduced quality of life in adults with SCD. It is important to understand that the more time an individual spends in the hospital, the more they increase their risk for mortality, and this is especially true for adults.”
While we have an abundance of data on SCD throughout childhood, we are still trying to understand the natural history of SCD in adults. Generally, it is important to distinguish between different groups of adults based on their past care, which may range from excellent long-term care to poor care. Although we know that survival rates vary among adult patients with SCD, we cannot always predict the underlying conditions or comorbidities that will increase their mortality risk. We do know, however, that a second peak of stroke occurs in young adults. Although ischemic strokes are more common in children, hemorrhagic strokes are more prevalent in young adults. These individuals have ongoing hemolysis and inflammation that damages blood vessels, which can lead to an aneurysm as well as other complications.
Another ongoing concern for adults with SCD is vaso-occlusive crisis (VOC), which continues to be a major contributor to hospitalizations and reduced quality of life. It is important to understand that the more time an individual spends in the hospital, the more they increase their risk for mortality, and this is especially true for adults. In many ways, pediatric treatment of VOC in the hospital is much safer than for adults, for reasons that may be iatrogenic (eg, busier adult floors) and/or disease related (ie, adults with SCD tend to be more unwell/debilitated). Consequently, reducing the frequency of VOC should help to improve outcomes; whether this is because of decreased end-organ damage or the prevention of more iatrogenic factors is unclear. For instance, acute chest syndrome (ACS), the most common cause of death in adults with SCD, can develop during hospitalizations for VOC, during which hypoventilation may be exacerbated by lying in bed with ongoing high-dose opioid administration. Therefore, we can hypothesize that, by decreasing the frequency of VOC (and admissions), we may decrease the risk of mortality in this patient population.
Professor of Pediatrics and Medicine
“Now that pediatric mortality from SCD is less than 1% in high-income countries, the current focus is to prevent end-organ damage, and we have strong evidence that the antecedents of the progressive renal, cardiovascular, and pulmonary complications in adults actually begin in childhood.”
The clinical history of SCD is evolving because we now have 4 US Food and Drug Administration–approved drugs available. Now that pediatric mortality from SCD is less than 1% in high-income countries, the current focus is to prevent end-organ damage, and we have strong evidence that the antecedents of the progressive renal, cardiovascular, and pulmonary complications in adults actually begin in childhood.
With current evidence-based care, the median survival in adults with SCD is approximately 48 years, so SCD is still a life-threatening disease of young adults. Renal involvement contributes considerably to the diminished life expectancy of patients with SCD. In fact, renal involvement accounts for a significant proportion of deaths in adults with SCD. A 2015 population-based cohort study found that the 1-year mortality rate among patients with SCD and end-stage renal disease after starting dialysis was approximately 26%. Further, not seeing a nephrologist within 6 months of the end-stage renal disease diagnosis, a modifiable risk factor, predicts early death.
With increased longevity in SCD, cardiovascular complications are also increasingly evident, including progressive proliferative systemic vasculopathy, pulmonary hypertension, and left ventricular diastolic dysfunction. A tricuspid regurgitation jet velocity of greater than 2.5 m/sec or a continuous measurement of greater than 3.0 m/sec may indicate pulmonary hypertension and is a clear risk factor for earlier mortality in adults with SCD. Yet, that same parameter does not impart the same risk for mortality or even morbidity among children with SCD. Interestingly, with respect to pulmonary function, it has been expected that multiple episodes of ACS would increase the likelihood of future restrictive lung disease, but we found no evidence of this in our Annals of the American Thoracic Society study, nor did we find evidence that current lung disease predicts future ACS or pain episodes.
While there has been a decrease in the rate of overt strokes in children, silent strokes still occur in 39% of patients with SCD by the age of 18 years. Kassim and colleagues reported a prevalence of 53% in adults (median age, 30 years). Based on pediatric studies, the only secondary prevention for silent stroke is regular blood transfusion, but we simply do not know what the optimal treatment may be for all patients. There is hope that, by targeting the underlying processes involved in SCD and its complications, we may continue to change the natural history of SCD and improve outcomes by reducing end-organ damage.
Associate Professor of Pediatrics
“It has only been in the last decade or so that we have had pediatric patients consistently treated with hydroxyurea. Thus, I agree that we are still trying to understand the natural history of SCD in adults, including the impact of our pediatric treatments on outcomes in adults.”
I believe that early intervention with treatments such as hydroxyurea has significantly changed the natural history of SCD. However, it has only been in the last decade or so that we have had pediatric patients consistently treated with hydroxyurea. Thus, I agree that we are still trying to understand the natural history of SCD in adults, including the impact of our pediatric treatments on outcomes in adults. Historically, hydroxyurea was only offered to pediatric patients who had complications from SCD, such as recurrent VOC or ACS. Now, we recommend that all children with SCD take hydroxyurea on a regular basis, and that we should aim for the maximum tolerated dose. We begin educating families about hydroxyurea at the first clinic visit and will typically start treatment by the time the child is 9 months of age. We know that some of the complications and the end-organ damage that we see in patients with SCD occur very early in life. For instance, the spleen typically has auto infarcted by the time patients are elementary school–aged. With hydroxyurea, we are able to preserve partial splenic function. Now that we have had many pediatric patients consistently take hydroxyurea throughout their childhood, we will have a clearer picture on how their disease has progressed or has been modified by hydroxyurea when they reach adulthood.
Ansari J, Moufarrej YE, Pawlinski R, Gavins FNE. Sickle cell disease: a malady beyond a hemoglobin defect in cerebrovascular disease. Expert Rev Hematol. 2018;11(1):45-55.
Carden MA, Little J. Emerging disease-modifying therapies for sickle cell disease. Haematologica. 2019;104(9):1710-1719.
Cohen RT, Strunk RC, Rodeghier M, et al. Pattern of lung function is not associated with prior or future morbidity in children with sickle cell anemia. Ann Am Thorac Soc. 2016;13(8):1314-1323.
DeBaun MR, Kirkham FJ. Central nervous system complications and management in sickle cell disease. Blood. 2016;127(7):829-838.
Estcourt LJ, Fortin PM, Hopewell S, Trivella M, Doree C, Abboud MR. Interventions for preventing silent cerebral infarcts in people with sickle cell disease. Cochrane Database Syst Rev. 2017;2017(5):CD012389.
Kassim AA, Pruthi S, Day M, et al. Silent cerebral infarcts and cerebral aneurysms are prevalent in adults with sickle cell anemia. Blood. 2016;127(16):2038-2040.
Lê PQ, Gulbis B, Dedeken L, et al. Survival among children and adults with sickle cell disease in Belgium: benefit from hydroxyurea treatment. Pediatr Blood Cancer. 2015;62(11):1956-1961.
McClellan AC, Luthi JC, Lynch JR, et al. High one year mortality in adults with sickle cell disease and end-stage renal disease. Br J Haematol. 2012;159(3):360-367.
Nath KA, Hebbel RP. Sickle cell disease: renal manifestations and mechanisms. Nat Rev Nephrol. 2015;11(3):161-171.
Nouraie M, Darbari DS, Rana S, et al. Tricuspid regurgitation velocity and other biomarkers of mortality in children, adolescents and young adults with sickle cell disease in the United States: the PUSH study. Am J Hematol. 2020 Apr 3. doi: 10.1002/ajh.25799. [Epub ahead of print]
Willen SM, Gladwin, MT. What is the role of screening for pulmonary hypertension in adults and children with sickle cell disease? Hematology Am Soc Hematol Educ Program. 2017;2017(1):431-434.