Identifying adolescent and young adult patients with sickle cell disease at highest risk of death
Authors: Mark T. Gladwin, Gregory J. Kato, Victor R. Gordeuk
Journal: American Journal of Hematology (2020)

There is a critical need to develop prognostic assessments that identify adolescents and young adults with sickle cell disease (SCD) at the highest risk for developing organ system dysfunction and death. We have long appreciated that both complications and mortality have dramatically decreased in children with SCD, but after transition to adulthood, morbidity and mortality increases, approaching a 1% mortality per year. In fact, large meta-analysis of mortality rates in the US suggest that overall survival has not increased significantly in the post-hydroxyurea era.1 Early adulthood mortality has largely been attributed to the circumstances of the adolescent-adulthood medical care transition, with less focus upon the impact of relevant biological factors. With the advent of numerous high-intensity and potentially curative interventions available, from hematopoietic stem cell transplantation to gene therapy and editing, it is imperative that we identify high-risk young patients for interventions that prevent end-organ failure and death. Over the last two decades, a number of risk factors have been described that identify adult patients at high risk of death, most of which relate to the development of systemic vasculopathy, pulmonary hypertension, diastolic heart failure, and chronic kidney disease.2 These include but are not limited to: (a) elevated pulmonary arterial pressures determined by non-invasive Doppler-echocardiography (tricuspid regurgitant jet velocity; TRV ≥2.5 m/sec),1, 3 elevated levels of N-terminal-brain natriuretic peptide (NT-proBNP ≥160 pm/mL),4 or a mean pulmonary arterial pressure or transpulmonary gradient on right heart catheterization (mPAP ≥25 mmHg or TPG ≥12 mmHg)5, 6; (b) Doppler-echocardiographic measures of diastolic left heart disease7, 8; (c) CKD defined by low glomerular filtration rate, macroalbuminuria or proteinuria9; (d) long Q-T on electrocardiogram10; and (e) high extracellular matrix volume on cardiac MRI11 (all recently reviewed).2, 12 Most of these risk factors have been validated in adult cohorts, but some limited data support the same concerns for adolescent and young adult patients. The current study by Shah and colleagues in this issue of the American Journal of Hematology reports on the 7.7 year median follow-up of 95 adolescents and young adults (median age of 24 years at the time of enrollment) who had detailed cardiopulmonary and hematological assessments at baseline.13 Blood biomarkers, comprehensive vascular testing, and echocardiographic assessments included standard laboratory assessments, pulse oximetry, serum lactate dehydrogenase (LDH), plasma cell-free Hgb, high sensitivity CRP (hs-CRP), red blood cell rheologic parameters including elongation index for deformability (LORCA), vascular flow mediated dilation (FMD) as a measure of endothelial shear-mediated nitric oxide production, and echocardiographic assessments of peak TRV, systolic, and diastolic function. Follow-up mortality and cause of death were obtained in 2018 from public records available from Los Angeles County, including medical examiner death certificate information when available. The investigators describe an overall 19% mortality in their cohort. The patients who died demonstrated greater baseline hemolysis, more anemia, higher leukocyte counts, and higher levels of LDH and plasma cell-free hemoglobin. Deceased patients had higher TRV, more abnormal FMD, lower hemoglobin oxygen saturations, and also significantly lower lat E' and lower mitral valve E/A ratio, consistent with diastolic left heart disease. Using linear regression analysis with stepwise backward elimination, they found that higher TRV, decreased lateral mitral annulus early diastolic tissue velocity (lat E'), and increased lateral mitral annular systolic tissue velocity (lat S′) were significant predictors of mortality (P < .0001). The latter finding is consistent with a prior large study by Sachdev and colleagues at the National Institute of Health using Doppler-echocardiographic assessments of pulmonary hypertension (TRV) and tissue Doppler assessment of diastolic heart dysfunction, which reported that high TRV and diastolic dysfunction (specifically lower mitral valve E/A ratio) were each independently associated with risk of death and had a synergistic impact on mortality risk.7, 8 Shah et al. found that a TRV value ≥2.5 m/sec was a strong independent predictor of mortality (P = .018), even in this adolescent and younger adult population.13 With the limitations of a small patient cohort, the authors found that in this younger population, the optimal TRV threshold for mortality was 2.58 m/sec, consistent with findings in the PUSH cohort, which defines abnormal TRV in children as ≥2.7 m/sec (>2 SD above the mean in age-matched and gender-matched non-SCD controls),16 compared with the well-validated value in adults of TRV ≥2.5 m/sec (>2 SD above the mean for non-SCD control adults 42 years of age). The study provides some insights into mechanisms of disease. In previous publications evaluating this cohort, the investigators have shown that increasing TRV and decreasing FMD correlate with higher levels of plasma cell-free hemoglobin.14 In the current study,13 they removed plasma cell free hemoglobin from their multi-variate analysis because it is colinear with TRV values. However, when plasma cell free hemoglobin was added to the model in place of TRV it was a significant predictor of mortality, consistent with the analysis of hemolysis in the Walk-PHASST adult cohort.15 This study provides important new insights into cardiopulmonary vascular assessments that help identify adolescent and young adults with SCD at higher risk of disease progression and death, but also has some major limitations. The limitations include a very small cohort size and the preponderance of risk determined by the adult patients in the study. An additional limitation of the statistical analysis and study design includes is the evaluation of a large number of variables in linear regression, and, in particular, the number of variables that are colinear (ie, correlate with each other), such as plasma cell free hemoglobin, LDH, and TRV, which requires selection of variables for association testing. These findings are in line with a recent publication evaluating 510 prospectively enrolled children and adolescents, aged 3-20 years, with sickle cell disease between 2006 and 2010.16 In this report, follow-up for mortality was performed in 497 of the participants at a median of 88 months after enrollment. Survival to 18 years was 99% and to 25 years, 94%, reflecting the striking increased mortality rate after age 18 years. A TRV value ≥2.7 m/sec was observed in 20.0% of patients who died vs 4.6% of those who survived (P = .012). Additional biomarkers associated with mortality were ferritin ≥2000 μg/L, forced expiratory volume in 1 minute to forced vital capacity ratio (FEV1/FVC) <0.80, and neutrophil count ≥10 × 109/L. Consistent with studies in the Los Angeles cohort, the baseline variable most strongly associated with an elevated TRV was a high hemolytic rate. This pediatric risk profile for mortality closely mirrors that of adults, implicating the same pathophysiology. This also supports that patients with SCD at risk of mortality in adulthood may be identified at a young age for developing early intervention strategies for risk reduction. In conclusion, the Shah et al. cohort study provides additional support for screening our adolescent and young adult sickle cell disease patients for biomarkers of cardiovascular dysfunction. We argue that routine screening using Doppler-echocardiography evaluating TRV and tissue-Doppler assessments of diastolic dysfunction, urine GFR and proteinuria assessments, evaluation of the intensity of baseline hemolysis, and even FMD (now available in many vascular laboratories) may help identify more high-risk patients and facilitate challenging deliberations surrounding risk and benefits of curative therapies. A multi-disciplinary guidelines committee commissioned by the American Thoracic Society with expertise in adult medicine, pediatrics, pulmonology, cardiology, and hematology recommended routine yearly or bi-yearly screening of adults with Doppler echocardiography and plasma NT-proBNP.17 The goal of the screening is to identify patients at high risk of death who should undergo more detailed studies to diagnose pulmonary hypertension, chronic thromboembolic pulmonary hypertension, and diastolic heart disease (heart failure with preserved ejection fraction), and who should be offered intensive therapies to ameliorate the course of sickle cell disease.17 In our practice, we perform yearly or bi-yearly assessments of TRV and NT-proBNP or BNP, measure serum creatinine and calculate the glomerular filtration rate frequently, and screen for increased urine protein and macroalbuminuria yearly (>300 mg albumin per gram creatinine and/or protein creatinine ratio >30 mg/mmol). Considering the potential for early disease intervention with prevention of cardiopulmonary and renal complications, and the potentially high risk of interventions that require myeloablative conditioning regimens, it is imperative that large cohort studies of carefully phenotyped adolescent and young adult sickle cell disease patients are initiated to establish risk prediction models. NA