Tricuspid regurgitant jet velocity and myocardial tissue Doppler parameters predict mortality in a cohort of patients with sickle cell disease spanning from pediatric to adult age groups ‐ revisiting this controversial concept after 16 years of additional evidence

Sickle cell disease (SCD) is a monogenic hemoglobinopathy associated with significant morbidity and mortality. Cardiopulmonary, vascular and sudden death are the reasons for the majority of young adult mortality in SCD. To better understand the clinical importance of multi‐level vascular dysfunction, in 2009 we assessed cardiac function including tricuspid regurgitant jet velocity (TRV), tissue velocity in systole(S′) and diastole (E′), inflammatory, rheologic and hemolytic biomarkers as predictors of mortality in patients with SCD. With up to 9 years of follow up, we determined survival in 95 children, adolescents and adults with SCD. Thirty‐eight patients (40%) were less than 21 years old at initial evaluation. Survival and Cox proportional‐hazards analysis were performed. There was 19% mortality in our cohort, with median age at death of 35 years. In the pediatric subset, there was 11% mortality during the follow up period. The causes of death included cardiovascular and pulmonary complications in addition to other end‐organ failure. On Cox proportional‐hazards analysis, our model predicts that a 0.1 m/s increase in TRV increases risk of mortality 3%, 1 cm/s increase in S′ results in a 91% increase, and 1 cm/s decrease in E′ results in a 43% increase in mortality. While excluding cardiac parameters, higher plasma free hemoglobin was significantly associated with risk of mortality (p=.049). In conclusion, elevated TRV and altered markers of cardiac systolic and diastolic function predict mortality in a cohort of adolescents and young adult patients with SCD. These predictors should be considered when counseling cardiovascular risk and therapeutic optimization at transition to adult providers.     

Cardiovascular complications of sickle cell disease

Sickle cell disease (SCD) is the most common inherited blood disorder in the United States, and a global health problem. Pathological features of the abnormal hemoglobin (HbS) result in 2 hallmarks of the disease - recurrent episodes of acute microvascular occlusion and chronic hemolytic anemia - that inflict continuous and insidious damage to multiple organs. With improved childhood survival, SCD in adults has evolved into a chronic degenerative disease with underlying damage to multiple organs including the heart and lungs. Cardiopulmonary complications, including cardiomyopathy, diastolic dysfunction, pulmonary hypertension (PH), and sudden cardiac death are the most common causes of morbidity and mortality. Awareness of the sickle-related cardiovascular phenotypes is important for screening, early diagnosis, and intervention of cardiac complications in this disorder.     

Prospective evaluation of chronic organ damage in adult sickle cell patients: A seven‐year follow‐up study

Organ damage in sickle cell disease (SCD) is a crucial determinant for disease severity and prognosis. In a previous study, we analyzed the prevalence of SCD‐related organ damage and complications in adult sickle cell patients. We now describe a seven‐year follow‐up of this cohort.All patients from the primary analysis in 2006 (n = 104), were included for follow‐up. Patients were screened for SCD‐related organ damage and complications (microalbuminuria, renal failure, elevated tricuspid regurgitation flow velocity (TRV) (≥2.5 m/seconds), retinopathy, iron overload, cholelithiasis, avascular osteonecrosis, leg ulcers, acute chest syndrome (ACS), stroke, priapism and admissions for vaso‐occlusive crises (VOC) biannually. Upon 7 years of follow‐up, progression in the prevalence of avascular osteonecrosis (from 12.5% to 20.4%), renal failure (from 6.7% to 23.4%), retinopathy (from 39.7% to 53.8%) was observed in the whole group. In HbSS/HbSβ⁰‐thal patients also progression in microalbuminuria (from 34% to 45%) and elevated TRV (from 40% to 48%) was observed while hardly any progression in the prevalence of cholelithiasis, priapism, stroke or chronic ulcers was seen. The proportion of patients with at least one episode of ACS increased in the group of HbSS/HbSβ⁰‐thal patients from 32% to 49.1%. In conclusion, 62% of the sickle cell patients in this prospective cohort study developed a new SCD‐related complication in a comprehensive care setting within 7 years of follow‐up. Although the hospital admission rate for VOC remained stable, multiple forms of organ damage increased substantially. These observations underline the need for continued screening for organ damage in all adult patients with SCD.     

Estimating the post‐neonatal prevalence of sickle cell disease in a Brazilian Population

Objective To estimate the prevalence of individuals with sickle cell disease (SCD) in Aracaju, Brazil, using the capture–recapture (CRC) method. SCD is a significant public health problem with long‐term life‐threatening complications. There are no reliable estimates of the number of individuals with this condition in Aracaju, north‐east Brazil. The CRC method has been used to quantify other ubiquitous populations. Method Three independent lists of individuals with homozygous (HbSS) SCD were constructed from patients attending the main specialist ambulatory service, all patients with SCD admitted to three government hospitals and a clinic providing specialist immunisation services to patients with SCD. Individuals were matched to ascertain whether they appeared in one, two or three lists, and population size was estimated using the log‐linear model. Results The lists identified 374 individuals. Two hundred and one appeared in one, 99 in two and 74 in three lists with an estimated number 400 (95% CI 387–418) HbSS SCD individuals; 51.6% patients with SCD were men and age ranged from 1–62 years (median 14). Conclusion The CRC method resulted in a smaller population estimate than expected. The causes of this discrepancy may include list dependence, high mortality with a survival cohort effect and the method of identifying the more severe cases. The CRC method has potential to estimate the size of this population and could supplement neonatal screening to further characterise the SCD population in this region.     

Stem cell transplantation after reduced‐intensity conditioning for sickle cell disease

Sickle cell disease (SCD) is still associated with substantial morbidity and reduced life expectancy. Disease‐related mortality rises to 14% in adolescents and young adults. Overall and disease‐free survival following haematopoietic stem cell transplantation (HSCT) is 90% and 95%, respectively. To reduce transplant‐associated late effects, the feasibility of a highly immunosuppressive reduced‐intensity conditioning (RIC) regimen was explored in children with SCD and a matched sibling donor. Eight patients (median age, 9 yr) and symptomatic SCD were included. The conditioning regimen consisted of fludarabine, melphalan and either thiotepa or total lymphoid irradiation plus antithymocyte globuline or alemtuzumab. The graft was bone marrow in seven and cord blood in one case. The conditioning regimen was well tolerated and no severe infectious complications occurred. All patients displayed mixed chimaerism on day +28. After a median follow‐up of 4 yr, 3/8 patients have mixed leucocyte chimaerism and 8/8 patients have 100% donor erythropoiesis. HSCT from matched sibling donors following a RIC regimen was well tolerated and resulted in cure in all patients studied. If confirmed in larger patient cohorts, these observations will have important implications for the indications of HSCT in children with SCD.     

Estimated pulmonary artery systolic pressure and sickle cell disease: a meta‐analysis and systematic review

Many studies report estimated pulmonary artery systolic pressure (ePASP) in patients with sickle cell disease (SCD) screened by echocardiography. To better understand the prevalence and outcomes of elevated ePASP in clinically stable SCD patients, we conducted a random‐effects meta‐analysis. A total of 45 studies, representing 15 countries and including 6109 individuals, met our inclusion criteria. In most (70%) studies, elevated ePASP was defined by a tricuspid regurgitant velocity of 2·5 m/s. The prevalence of elevated ePASP was 21% (17–26%) in children and 30% (26–35%) in adults. After adjustment for sex, SCD genotype, haemoglobin, hydroxycarbamide (hydroxyurea) treatment, country and publication year, age remained associated with elevated ePASP, yielding a 12% (0·4–23%) higher adjusted prevalence in adults. Few studies reported 6‐min walk tests or mortality outcomes, and estimates were highly heterogeneous. In random effects meta‐analyses, patients with elevated ePASP walked an estimated 30·4 (6·9–53·9) metres less than those without elevated ePASP and had an associated mortality hazard ratio of 4·9 (2·4–9·7).     

Health policy for sickle cell disease in Africa: experience from Tanzania on interventions to reduce under‐five mortality

Tanzania has made considerable progress towards reducing childhood mortality, achieving a 57% decrease between 1980 and 2011. This epidemiological transition will cause a reduction in the contribution of infectious diseases to childhood mortality and increase in contribution from non‐communicable diseases (NCDs). Haemoglobinopathies are amongst the most common childhood NCDs, with sickle cell disease (SCD) being the commonest haemoglobinopathy in Africa. In Tanzania, 10 313 children with SCD under 5 years of age (U5) are estimated to die every year, contributing an estimated 7% of overall deaths in U5 children. Key policies that governments in Africa are able to implement would reduce mortality in SCD, focusing on newborn screening and comprehensive SCD care programmes. Such programmes would ensure that interventions such as prevention of infections using penicillin plus prompt diagnosis and treatment of complications are provided to all individuals with SCD.     

High one year mortality in adults with sickle cell disease and end-stage renal disease

Adequate pre-dialysis care reduces mortality among end-stage renal disease (ESRD) patients. We tested the hypothesis that individuals with ESRD due to sickle cell disease (SCD–ESRD) receiving pre-ESRD care have lower mortality compared to individuals without pre-ESRD care. We examined the association between mortality and pre-ESRD care in incident SCD–ESRD patients who started haemodialysis between 1 June, 2005 and 31 May, 2009 using data provided by the Centers for Medicare and Medicaid Services (CMS). SCD–ESRD was reported for 410 (0·1%) of 442 017 patients. One year after starting dialysis, 108 (26·3%) patients with incident ESRD attributed to SCD died; the hazard ratio (HR) for mortality among patients with SCD–ESRD compared to those without SCD as the primary cause of renal failure was 2·80 (95% confidence interval [CI] 2·31–3·38). Patients with SCD–ESRD receiving pre-dialysis nephrology care had a lower death rate than those with SCD–ESRD who did not receive pre-dialysis nephrology care (HR = 0·67, 95% CI 0·45–0·99). The one-year mortality rate following an ESRD diagnosis was almost three times higher in individuals with SCD when compared to those without SCD but with ESRD and could be attenuated by pre-dialysis nephrology care.     

The excess burden of stroke in hospitalized adults with sickle cell disease

This report compares the relative rates and risk factors associated with stroke in adults versus children with sickle cell disease (SCD) in the United States over the last decade. We identified incident strokes in patients with SCD using ICD‐9 codes for acute stroke and SCD and the California Patient Discharge Databases. We estimated SCD prevalence by using the incidence of SCD at birth with adjustment for early mortality from SCD. We identified 255 acute strokes (70 primary hemorrhagic and 185 ischemic) among 69,586 hospitalizations for SCD‐related complications from 1998 to 2007. The rate of stroke in children [<18 years old (310/100,000 person‐years)] was similar to young adults [18–34 years old (360/100,000 person‐years)], but much higher in middle‐aged [35–64 years old (1,160/100,000 person‐years)] and elderly adults [≥65 years old (4,700/100,000 person‐years)]. Stroke was associated with hypertension in children and hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, and renal disease in adults. Most acute strokes (75%) and in‐hospital deaths from stroke (91%) occurred in adults. Our results suggest that the rate of stroke in SCD peaks in older adults and is three‐fold higher than rates previously reported in African‐Americans of similar age (35–64 years) without SCD. Stroke in SCD is associated with several known adult risk factors for ischemic and hemorrhagic stroke. Studies for the primary and secondary prevention of stroke in adults with SCD are urgently needed. Am. J. Hematol. 2009. © 2009 Wiley‐Liss, Inc.     

Hematopoietic stem cell transplantation for sickle cell disease: state of the science

Sickle cell disease (SCD) is an inherited disorder secondary to a point mutation at the sixth position of the beta chain of human hemoglobin resulting in the replacement of valine for glutamic acid. This recessive genetic abnormality precipitates the polymerization of the deoxygenated form of hemoglobin S inducing a major distortion of red blood cells (S‐RBC), which decreases S‐RBC deformability leading to chronic hemolysis and vaso‐occlusion. These processes can result in severe complications including chronic pain, end‐organ dysfunction, stroke, and early mortality. The only proven curative therapy for patients with SCD is myeloablative conditioning and allogeneic stem cell transplantation from HLA‐matched sibling donors. In this review, we discuss the most recent advances in allogeneic stem cell transplantation in patients with SCD including more novel approaches such as reduced toxicity conditioning and the use of alternative allogeneic donors, including matched unrelated donors (MUDs), unrelated cord blood donors (UCBT), and familial haploidentical (FHI) donors. The results to date are very encouraging regarding allogeneic stem cell transplantation for patients with SCD including high survival rates and enabling a greater number of patients suffering from this chronic and debilitating condition to receive curative allogeneic stem cell therapies. However, we still have several areas to investigate and barriers to overcome to successfully cure the majority of patients with severe SCD through allogeneic stem cell therapies.     

Sickle cell disease and pulmonary hypertension in Africa: a global perspective and review of epidemiology, pathophysiology, and management

Secondary pulmonary hypertension (PAH) has been shown to have a prevalence of 30% in patients with sickle cell disease (SCD) with mortality rates of 40% at 40 months after diagnosis in the United States. The burden of SCD is highest in sub-Saharan Africa, especially in Nigeria (West Africa), where approximately 6 million people are afflicted. The true global incidence, prevalence, and burden of SCD and its associated end organ complications however remain unknown. Chronic hemolysis represents a prominent mechanistic pathway in the pathogenesis of SCD-associated pulmonary hypertension via a nitric oxide (NO) scavenging and abrogation of NO salutatory effects on vascular function, including smooth muscle relaxation, downregulation of endothelial adhesion molecules and inhibition of platelet activation. Many known infectious risk factors for PAH are also hyperendemic in Africa, including Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS), chronic hepatitis B and C, and possibly malaria. Interactions between these infectious complications and SCD-related hemolysis could yield an even higher prevalence of pulmonary hypertension and compound the existing global health systems challenges in managing SCD. Indeed, our preliminary analysis of African immigrants currently in the United States suggests that pulmonary hypertension represents a significant complication of SCD in the African subcontinent. There is clearly a need to include Africa and other parts of the world with high SCD prevalence in future comprehensive studies on the epidemiology and treatment of end organ complications of an aging SCD population world-wide.     

Management of sickle cell disease from childhood through adulthood

Sickle cell disease (SCD) is a genetic disorder characterised by anaemia and “sickling” of red blood cells, leading to chronic haemolytic anaemia, vascular injury, and organ dysfunction. Although children and adults experience many similar symptoms and problems, complications increase with age, leading to early mortality. Hydroxyurea (hydroxycarbamide), the only US Food and Drug Administration-approved treatment, continues to be under-utilised and other treatments available to children are often inaccessible for adults. Haematopoietic stem-cell transplantation is a curative option, but is limited by a lack of donors and concerns for transplant-related toxicities. Although comprehensive programs exist in paediatrics, affected adults may not have access to preventative and comprehensive healthcare because of a lack of providers or care coordination. They are often forced to rely on urgent care, leading to increased healthcare utilisation costs and inappropriate treatment. This problem highlights the importance of primary care during the transition from paediatrics to adulthood.     

Doppler-defined pulmonary hypertension and the risk of death in children with sickle cell disease followed for a mean of three years

Pulmonary hypertension (PH) is associated with increased mortality in adults with sickle cell disease (SCD), but its prognostic significance in children is unknown. Eighty-eight children with SCD were followed after echocardiographic screening for PH. After a mean follow-up of 3 years, all 18 subjects with PH were alive. In our children, as in adults with SCD, PH was associated with increased haemolysis. In contrast, our subjects with PH did not have overt systemic disease observed in adults. PH may be a manifestation of progressive organ damage from chronic haemolysis and systemic vasculopathy that ultimately leads to early death in adulthood.     

Plasma levels of advanced glycation end products are associated with haemolysis‐related organ complications in sickle cell patients

Oxidative stress plays an important role in the pathophysiology of sickle cell disease (SCD). Plasma levels of advanced glycation end products (AGEs) are increased under oxidative conditions and are associated with disease severity in diabetes and inflammatory diseases. We investigated whether AGEs are increased in sickle cell patients and whether they are associated with SCD‐related complications. Plasma levels of the AGEs pentosidine, N^ε‐(carboxymethyl)lysine (CML) and N^ε‐(carboxyethyl)lysine (CEL) were measured using single‐column high performance liquid chromatography with fluorescence detection (pentosidine) and ultra performance liquid chromatography‐tandem mass spectrometry (CML and CEL). Plasma levels of pentosidine and CML were increased in HbSS/HbSβ⁰‐thalassaemia (n = 60) and HbSC/HbSβ⁺‐thalassaemia (n = 42) patients during steady state as compared to healthy HbAA controls (n = 30) without increments during painful crisis. CEL levels were comparable between all groups. Pentosidine and CML levels correlated significantly to haemolytic rate during the clinically asymptomatic state while pentosidine was significantly related to the number of haemolysis‐related organ complications. The increased plasma AGE levels in sickle cell patients and their association with haemolysis and haemolysis‐related complications suggest AGEs might be implicated in the pathophysiology of the haemolytic phenotype of SCD. Measurement of AGEs might be useful in predicting organ complications in SCD.     

Sickle cell disease in Saudi Arabia: the phenotype in adults with the Arab‐Indian haplotype is not benign

Sickle cell disease (SCD) in Saudi patients from the Eastern Province is associated with the Arab‐Indian (AI) HBB (β‐globin gene) haplotype. The phenotype of AI SCD in children was described as benign and was attributed to their high fetal haemoglobin (HbF). We conducted a hospital‐based study to assess the pattern of SCD complications in adults. A total of 104 patients with average age of 27 years were enrolled. Ninety‐six per cent of these patients reported history of painful crisis; 47% had at least one episode of acute chest syndrome, however, only 15% had two or more episodes; symptomatic osteonecrosis was reported in 18%; priapism in 17%; overt stroke in 6%; none had leg ulcers. The majority of patients had persistent splenomegaly and 66% had gallstones. Half of the patients co‐inherited α‐thalassaemia and about one‐third had glucose‐6‐phosphate dehydrogenase deficiency. Higher HbF correlated with higher rate of splenic sequestration but not with other phenotypes. The phenotype of adult patients with AI SCD is not benign despite their relatively high HbF level. This is probably due to the continued decline in HbF level in adults and the heterocellular and variable distribution of HbF amongst F‐cells.     

Optimal management of chronic graft‐versus‐host disease in children

Chronic graft‐versus‐host disease (GVHD) is a major complication after allogeneic haematopoietic stem cell transplantation (HSCT). Not only is it the major cause of late mortality in HSCT patients, but it also accounts for significant morbidity. Much of the literature on chronic GVHD has focused on adults. Chronic GVHD is of major importance in children, especially since they have years to live following the complications of chronic GVHD and its therapy. The goal is to review incidence, manifestations, and therapies, especially when applicable to the paediatric population.     

Elevated tricuspid regurgitant jet velocity,reduced forced expiratory volume in 1 second,and mortality in adults with sickle cell disease

Cardiopulmonary disease is the leading cause of mortality in adults with sickle cell disease (SCD). Elevated tricuspid regurgitant jet velocity (TRJV) and reduced forced expiratory volume in 1 second (FEV₁) %predicted are associated with early mortality in SCD; however their relationship and combined effect on survival is unknown. We investigated the relationship between TRJV and FEV₁ %predicted, and their combined effect on mortality, in a retrospective cohort of 189 adults with SCD who underwent both pulmonary function testing and echocardiography. Nineteen (9.9%) of 189 patients died over a median follow‐up of 1.4 years; cardiopulmonary disease was the major cause of death in 52.6%. FEV₁%predicted was negatively associated with TRJV (Spearman rho, ?0.34, P < 0.001). Individuals with FEV₁%predicted ≤70% were more likely to have an elevated TRJV ≥2.5 m/second, compared to those with FEV₁%predicted >70% [45.8% versus 17.1%; odds ratio (OR) 4.1 (95% Confidence interval ([CI] 2.1–8.0); P = 0.001]. In a multivariable cox regression model, the combination of TRJV ≥2.5 m/second and FEV₁%predicted ≤70% predicted earlier mortality [hazard ratio (HR) 4.97 (95% CI 1.30‐18.91; P = 0.019)] after adjusting for age, sex, and nephropathy. Both FEV₁ %predicted ≤70% and TRJV ≥2.5 m/second were independently associated with nephropathy [OR 4.48 (95% CI 1.51–13.31); P = 0.004] and [OR 3.27 (95% CI 1.19–9.00); P = 0.017], respectively. In conclusion, pulmonary and cardiac impairment are associated with, and contribute to mortality in SCD. Therapies aimed at improving reduced FEV₁%predicted and elevated TRJV could improve survival in patients with SCD. Am. J. Hematol. 92:125–130, 2017. © 2016 Wiley Periodicals, Inc.     

Arterio‐venous fistula for automated red blood cells exchange in patients with sickle cell disease: Complications and outcomes

Erythrocytapheresis (ER) can improve outcome in patients with sickle cell disease (SCD). A good vascular access is required but frequently it can be difficult to obtain for sickle cell patients. Arterio‐venous fistulas (AVFs) have been suggested for ER in SCD supported by limited evidence. We report the largest cohort of ER performed with AVFs from three French SCD reference centers. Data of SCD patients undergoing ER with AVFs in the French SCD reference center were retrospectively collected. The inclusion criteria were: SS or Sβ‐Thalassemia and AVF surgery for ER. SCD‐related complications, transfusion history, details about AVF surgical procedure, echocardiographic data before and after AVF, AVF‐related surgical and hemodynamical complications were collected. Twenty‐six patients (mean age 20.5 years, mean follow‐up 68 months [11–279]) were included. Twenty‐three patients (88.5%) required central vascular access before AVF. Fifteen AVFs (58%) were created on the forearm and 11 (42%) on the arm. Nineteen patients (73%) had stenotic, thrombotic or infectious AVF complications. A total of 0.36 stenosis per 1,000 AVF days, 0.37 thrombosis per 1,000 AVF days and 0.078 infections per 1.000 AVF days were observed. The mean AVF lifespan was 51 months [13–218]. One patient with severe pulmonary hypertension worsened after AVF creation and died. We report the first series of SCD patients with AVF for ER, demonstrating that AVFs could be considered as a potential vascular access for ER. Patients with increased risk for hemodynamic intolerance of AVFs must be carefully identified, so that alternative vascular accesses can be considered. Am. J. Hematol. 92:136–140, 2017. © 2016 Wiley Periodicals, Inc.     

A survey on patient perception of reduced-intensity transplantation in adults with sickle cell disease

The development of reduced-intensity conditioning (RIC) and the success of BMT for paediatric sickle cell disease (SCD) have raised the possibility of revisiting this prospect in adults as well. In a chronic debilitating disorder managed with supportive therapy, the patients' perception is critical in the advancement of any potential curative therapy. To explore this aspect, we undertook a questionnaire-based survey on 30 adults with SCD. Sixty two per cent of the patients were ready to accept a transplant-related mortality (TRM) >10%; 30% of them a TRM >30%. A risk of graft failure (GF) >10% was acceptable to 64%, with a risk >30% acceptable to 41%. Infertility was acceptable to only 50%. Chronic graft-versus-host disease (GVHD) was unacceptable to the majority (80%). Seventy six per cent% of patients had a full sibling and 60% were willing to participate in a clinical trial of RIC transplantation. This survey suggests that the majority of adults with SCD might be willing to consider a curative option such as RIC transplantation even with a high TRM or GF. The major concerns relate to chronic GVHD and infertility. There is an urgent need to explore RIC transplants in SCD patients within the framework of a clinical trial, considering patient perception regarding cure and complications.     

Outcome of children with sickle cell disease admitted to intensive care – a single institution experience

We retrospectively audited children with sickle cell disease (SCD) admitted to paediatric intensive care (PICU) at King’s College Hospital between January 2000 and December 2008. Forty‐six children with SCD were admitted, on 49 separate occasions. Ages ranged from 4 months to 15 years (median 7·6 years). Three children died in PICU, however two presented to hospital in cardiorespiratory arrest; overall mortality was 6%. The most common reason for admission was acute chest syndrome (43%). 88% of admissions required blood transfusion, of which 74% had exchange blood transfusions. The mortality among children with SCD admitted to PICU is low.