Hydroxyurea is associated with later onset of acute splenic sequestration crisis in sickle cell disease: Lessons from the European Sickle Cell Disease Cohort-Hydroxyurea (ESCORT-HU) study.

Acute splenic sequestration crisis (ASSC) is a potentially life-threatening complication of sickle cell disease (SCD), typically occurring in young patients under 5 years of age, with a median age at first episode of less than 2 years. Because a beneficial effect of hydroxyurea (HU) on spleen perfusion and splenic function has been suspected, we hypothesized that HU treatment might be associated with later onset of ASSC in patients with SCD. To investigate this hypothesis, we analyzed data from the ESCORT-HU study on a large cohort of patients with SCD receiving HU, enrolled between January 2009 and June 2017 with a follow-up of 7309 patient-years of observation. The median age at ASSC of the 14 patients who experienced a first episode of ASSC during the study period was 8.0 [IQR: 5.0-24.1] years. The median age at HU initiation was significantly lower in these 14 patients (4.8 [IQR: 3.3-18.7] years) compared to the 1664 patients without ASSC (19.9 [8.8-33.4] years, p = .0008). These findings suggest that ASSC may occur at an unusually late age in patients receiving HU, possibly reflecting longer preservation of spleen perfusion and function secondary to early initiation of HU. Further studies are needed to better characterize the effects of HU on spleen perfusion/function and on the occurrence of ASSC in patients with SCD (ClinicalTrials.gov identifier: NCT02516579; European registry ENCEPP/SDPP/10565).

A study of 28 pregnant women with sickle cell disease and COVID-19: elevated maternal and fetal morbidity rates.

Not available.

Impact of prenatal corticosteroid therapy on sickle cell disease in pregnant women.

OBJECTIVE: To evaluate safety of prenatal corticosteroids in pregnancies of women with sickle cell disease. METHODS: A multicenter observational study of patients with sickle cell disease, comparing vaso-occlusive crises (VOC) requiring hospital care between pregnancies with versus without prenatal corticosteroids. RESULTS: In 40 pregnancies exposed to prenatal corticosteroids, compared with 370 unexposed pregnancies, VOC were not more frequent (62.5% vs 57.9%, P = 0.578) but they were more severe, with more intensive care hospitalizations (25.0% vs 12.9%, P = 0.039), emergency transfusions (44.7% vs 22.7%, P = 0.006), and acute chest syndromes (22.5% vs 8.9%, P = 0.010). These differences persisted after adjustment for severity and type of sickle cell syndrome (for intensive care admission adjusted odds ratio [aOR] 2.73, 95% confidence interval [CI] 1.10-6.79, P = 0.031 and for acute chest syndrome aOR 4.15, 95% CI 1.57-14.4, P = 0.008). VOC occurred on average 1.2 days following steroid administration. When comparing 36 patients receiving corticosteroids for fetal maturation with 58 patients who were hospitalized for obstetrical complications before 34 weeks of pregnancy but that did not receive corticosteroids, VOC incidence was not significantly higher (41.7% vs 31.5%, P = 0.323). CONCLUSION: The present study was the first to study the impact of prenatal corticosteroids on sickle cell disease. They were associated with more severe VOC, suggesting that steroids should be avoided in these women.

Case Report of Myelodysplastic Syndrome in a Sickle-Cell Disease Patient Treated with Hydroxyurea and Literature Review.

The safety profile of hydroxyurea (HU) in patients with sickle-cell disease (SCD) is relatively well known. However, despite the suspected association of HU with myeloid neoplasms in myeloproliferative neoplasms (MPN), and the publication of sporadic reports of myeloid malignancies in SCD patients treated with HU, the possible excess risk imparted by HU in this population having an increasing life expectancy has failed to be demonstrated. Herein, we report one case of myelodysplastic syndrome emanating from the results on safety and effectiveness of HU on the largest European cohort of 1903 HU-treated adults and children who were followed-up prospectively in an observational setting over 10 years, accounting for a total exposure of 7309.5 patient-years. A comparison of this single case with previously published similar cases did not allow us to draw any significant conclusions due to the paucity of these events.

Real-World data on efficacy of L-glutamine in preventing sickle cell disease-related complications in pediatric and adult patients.

Background: L-glutamine has been shown to play an important role in the regulation of oxidative stress which is one of the key contributors to the pathophysiology of sickle cell disease (SCD). In a Phase 3 clinical trial, L-glutamine demonstrated a significant reduction in SCD-related complications including vaso-occlusive crises (VOCs), hospitalizations, and acute chest syndrome (ACS) compared to placebo in patients with SCD. Objective: The primary objective was to confirm the efficacy of L-glutamine (Endari®) therapy in pediatric and adult patients with SCD at follow-up time points of 24, 48 and 72 weeks. Methods: In the observational study, nineteen patients with SCD were treated orally with L-glutamine twice daily for 72 weeks. Clinical and laboratory parameters were measured at baseline and follow-up time points. Patients with severe VOC and ACS were hospitalized. Blood transfusion was given in case of ACS and uncontrolled pain associated with VOC despite administration of the highest dose of intravenous (IV) narcotic. Results: Compared to baseline, patients had significantly fewer pain crises (median change from 3.0 to 0.0; P < 0.00001), hospitalizations (median change from 3.0 to 0.0; P < 0.00001), days of hospitalization (median change from 15.0 to 0.0; P < 0.00001), and blood transfusions (median change from 3.0 to 0.0; P < 0.00001) at 24, 48, and 72 weeks following L-glutamine therapy. Moreover, there was a drastic decrease in the number of ACS events during this time. A significant increase was observed in mean hemoglobin levels and hematocrit proportions from baseline to 72 weeks (P < 0.001). Conversely, compared to baseline, mean reticulocyte counts and lactate dehydrogenase (LDH) levels were considerably lower at follow-up time points (P = 0.003 and P < 0.001, respectively). No patient reported treatment-related adverse events. Conclusion: Although the sample size was small, our data clearly demonstrated that L-glutamine therapy was safe and significantly improved clinical outcomes and hemolysis parameters in patients with SCD.

Real-Life experience with hydroxyurea in patients with sickle cell disease: Results from the prospective ESCORT-HU cohort study.

Several controlled studies have evidenced good efficacy and short-term and mid-term safety profiles for hydroxyurea (HU), which has become the cornerstone for prevention of sickle-cell disease (SCD)-related vaso-occlusive crises. However, there are few large-scale reports on its long-term use and certain caregivers and patients have concerns about its safety. Following the licensing of HU in Europe for children and adults with severe forms of SCD, ESCORT-HU was designed as a Phase IV observational cohort study. It included 1906 participants, of whom 55% were adults. The most common hemoglobin (Hb) genotypes were HbSS (84.7%) and HbSß+ (7.0%). The median duration of follow-up was 45 months, for a total of 7309 patient-years of observation. The dose of HU after 1 year was 20.6 mg/kg/d for children and 16.3 mg/kg/d for adults. There was a statistically significant decrease in the number of vaso-occlusive episodes lasting >48 h, acute chest syndrome episodes, hospitalizations, and the percentage of patients requiring blood transfusions within the first 12 months relative to the year before enrolment. Neutropenia and thrombocytopenia were the most commonly reported adverse effects. No new HU toxicity was identified. Overall, 125 pregnancies were reported in 101 women and no malformations were observed in the neonates. There were 12 pregnancies for partners of male patients treated with HU. One case of fatal myelodysplastic syndrome was reported, for which a causal association with HU could not be excluded. This cohort study of patients with SCD highlights the positive benefit-to-risk ratio of HU in children and adults.

Cardiovascular phenotypes predict clinical outcomes in sickle cell disease: An echocardiography-based cluster analysis.

This study sought to link cardiac phenotypes in homozygous Sickle Cell Disease (SCD) patients with clinical profiles and outcomes using cluster analysis. We analyzed data of 379 patients included in the French Etendard Cohort. A cluster analyses was performed based on echocardiographic variables, and the association between clusters, clinical profiles and outcomes was assessed. Three clusters were identified. Cluster 1 (n = 123) patients had the lowest cardiac output, mild left cardiac cavities remodeling, mild diastolic dysfunction, and higher tricuspid regurgitation velocity (TRV). They were predominantly female and displayed the most altered functional limitation. Cluster 2 (n = 102) patients had the highest cardiac output and the most remodeled cardiac cavities. Diastolic function and TRV were similar to cluster 1. These patients had a higher blood pressure and a severe hemolytic anemia. Cluster 3 (n = 154) patients had mild left cardiac cavities remodeling, normal diastolic function and lowest TRV values. They were younger with the highest hemoglobin value. Right heart catheterization was performed in 94 patients. Cluster 1 (n = 33) included the majority of pre-capillary PH whilst cluster 2 (n = 34) included post-capillary PH. No PH was found in cluster 3 (n = 27). After a follow-up of 11.4 ± 2 years, death occurred in 41 patients (11%). Cluster 2 patients had the worst prognosis with a 19% mortality rate versus 12% in cluster 1 and 5% in cluster 3 (p log-rank = 0.003). Cluster analysis of echocardiography variables identified three hemodynamic and clinical phenotypes among SCD patients, each predicting a different prognosis.

CAREST--Multilingual Regional Integration for Health Promotion and Research on Sickle Cell Disease and Thalassemia.

Sickle cell disease (SCD) is a significant problem in the Caribbean, where many individuals have African and Asian forebears. However, reliable prevalence data and specific health care programs for SCD are often missing in this region. Closer collaboration between Caribbean territories initiated in 2006 to set up strategies to promote better equity in the health care system for SCD patients led to the formation of CAREST: the Caribbean Network of Researchers on Sickle Cell Disease and Thalassemia. We present the effectiveness of collaborations established by CAREST to promote SCD newborn screening programs and early childhood care, to facilitate health worker training and approaches for prevention and treatment of SCD complications, and to carry out inter-Caribbean research studies.

Moderate endurance exercise is not a risk for rhabdomyolysis or renal failure in sickle cell trait carriers.

This study tested the hypothesis that trained sickle cell trait (SCT) carriers are not subjected to greater risk of rhabdomyolysis or renal failure in response to moderate submaximal exercise than subjects with normal hemoglobin (CONT). Blood markers in 11 trained SCT carriers and 12 control counterparts were measured before and after 40 min of exercise at 55% of peak power output (Ppeak) conducted in thermoneutral environment. Body weights decreased with exercise in the same proportion in the two groups (from 65.1 ± 7.0 kg to 64.1 ± 7.0 kg and from 70.2 ± 6.6 to 68.6 ± 6.6 kg at the end of exercise in SCT and CONT, respectively). Heart rate and rectal temperature increased in the two groups in response to exercise, but the groups remained closely matched. Serum urea, CRP, CK and LDH were similar in the two groups and remained unchanged in response to exercise. Creatinine, Na(+), K(+), Cl(-) and myoglobin concentrations increased above baseline in response to exercise, with changes of the same magnitude in the two groups. In summary, the results of the present study suggest that moderate submaximal exercise is not unsafe from a biochemical point of view for sportsmen carrying SCT.

A hemodynamic study of pulmonary hypertension in sickle cell disease.

BACKGROUND: The prevalence and characteristics of pulmonary hypertension in adults with sickle cell disease have not been clearly established. METHODS: In this prospective study, we evaluated 398 outpatients with sickle cell disease (mean age, 34 years) at referral centers in France. All patients underwent Doppler echocardiography, with measurement of tricuspid-valve regurgitant jet velocity. Right heart catheterization was performed in 96 patients in whom pulmonary hypertension was suspected on the basis of a tricuspid regurgitant jet velocity of at least 2.5 m per second. Pulmonary hypertension was defined as a mean pulmonary arterial pressure of at least 25 mm Hg. RESULTS: The prevalence of a tricuspid regurgitant jet velocity of at least 2.5 m per second was 27%. In contrast, the prevalence of pulmonary hypertension as confirmed on catheterization was 6%. The positive predictive value of echocardiography for the detection of pulmonary hypertension was 25%. Among the 24 patients with confirmed pulmonary hypertension, the pulmonary-capillary wedge pressure was 15 mm Hg or less (indicating precapillary pulmonary hypertension) in 11 patients. Patients with confirmed pulmonary hypertension were older and had poorer functional capacity and higher levels of N-terminal pro-brain natriuretic peptide than other patients. In contrast, patients who had a tricuspid regurgitant jet velocity of at least 2.5 m per second without pulmonary hypertension and patients with a tricuspid regurgitant jet velocity of less than 2.5 m per second had similar clinical characteristics. CONCLUSIONS: In this study of adults with sickle cell disease, the prevalence of pulmonary hypertension as confirmed on right heart catheterization was 6%. Echocardiographic evaluation alone had a low positive predictive value for pulmonary hypertension. (Funded by the French Ministry of Health and Assistance Publique-Hôpitaux de Paris; ClinicalTrials.gov number, NCT00434902.).

Effects of hydration and dehydration on blood rheology in sickle cell trait carriers during exercise.

This study compared the hemorheological responses of a group of sickle cell trait (SCT) carriers with those of a control (Cont) group in response to 40 min of submaximal exercise (exercise intensity, 55% aerobic peak power) performed in two conditions: one with water offered ad libitum, i.e., the hydration (Hyd) condition, and one without water, i.e., the dehydration (Dehyd) condition. Blood and plasma viscosities, as well as red blood cell rigidity, were determined at rest, at the end of exercise, and at 2 h recovery with a cone plate viscometer at high shear rate and 37 degrees C. The SCT and Cont groups lost 1 +/- 0.7 and 1.6 +/- 0.6 kg of body weight, respectively, in the Dehyd condition, indicating a significant effect of water deprivation compared with the Hyd condition, in which body weight remained unchanged. Plasma viscosity increased with exercise and returned to baseline during recovery independently of the group and condition. As previously demonstrated, resting blood viscosity was greater in the SCT carriers than in the Cont group. Blood viscosity increased by the end of exercise and returned to baseline at 2 h recovery in the Cont group in both conditions. The blood viscosity of SCT carriers did not change in response to exercise in the Dehyd condition and remained elevated at 2 h recovery. This extended hyperviscosity, in association with other biological changes induced by exercise, could be considered as a risk factor for exercise-related events in SCT carriers, similar to vasoocclusive crises, notably during the recovery. In contrast, the Hyd condition normalized the hyperviscosity and red blood cell rigidity of the SCT carriers, with blood viscosity values reaching the same lower values as those found in the Cont group during the recovery. Adequate hydration of SCT carriers should be strongly promoted to reduce the clinical risk associated with potential hyperviscosity complications.