Endurance training improves oxygen uptake/demand mismatch, metabolic flexibility and recovery in patients with sickle cell disease.

Patients with sickle cell disease (SCD) display lower slope coefficients of the oxygen uptake (V̇O2) versus work rate (W) relationship (delineating an O2 uptake/demand mismatch) and a poor metabolic flexibility. Because endurance training improves the microvascular network and increases the activity of oxidative enzymes, including one involved in lipid oxidation, endurance training might improve the slope coefficient of the V̇O2 versus W curve and the metabolic flexibility of SCD patients. Endurance training may also contribute to improve patients' post-exercise cardiopulmonary and metabolic recovery. Fifteen patients with SCD performed a submaximal incremental test on a cycle ergometer before (SIT1) and after (SIT2) 8 weeks of endurance training. Minute ventilation (V̇ E), ventilation rate, heart rate, V̇O2, carbon dioxide production (V̇CO2), respiratory exchange ratio, carbohydrate/lipid utilization and partitioning (including %Lipidox) and blood lactate concentration were measured during and after SIT1 and SIT2. At baseline, the slope coefficient of the V̇O2 versus W curve positively correlated with total hemoglobin, mean corpuscular hemoglobin and percentage of HbF. After training, the slope coefficient of the V̇O2 versus W curve was significantly higher and the increase in blood lactate concentration was delayed. If patients' energy metabolism apparently relied largely on carbohydrate sources during SIT1, %Lipidox tended to increase at low exercise intensities during SIT2, supporting a training-induced improvement of metabolic flexibility in patients with SCD. Post-exercise recovery of ventilation rate, V̇ E/V̇CO2, heart rate and blood lactate concentration was faster after training. We concluded that exercise training in patients with SCD: (i) ameliorated the oxygen uptake/ demand mismatch, (ii) blunted the metabolic inflexibility, and (iii) improved post-exercise cardiopulmonary and metabolic responses.

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).

Clinical burden and healthcare resource utilization associated with managing transfusion-dependent ß-thalassemia in France.

OBJECTIVE: To describe the clinical burden and healthcare resource utilization associated with managing transfusion-dependent ß-thalassemia (TDT) in France. METHODS: We used the French National Health Data System (système national des données de santé) to identify eligible patients from January 1, 2012, to March 1, 2019. Inclusion criteria were a diagnosis of ß-thalassemia, ≥8 red blood cell (RBC) transfusion episodes per year in ≥2 consecutive years following the diagnosis, and ≥1 year of follow-up data. Patients were excluded if medical records showed evidence of sickle cell disease, α-thalassemia, hereditary persistence of fetal hemoglobin, or hematopoietic stem cell transplant. Clinical complications, mortality, treatment use, and healthcare resource utilization were evaluated. RESULTS: Overall, 331 eligible patients with TDT were identified. Mean age was 26.1 (standard deviation [SD]: 18.0) years, and 50.5% were male. Common clinical complications were endocrine (26.0%), hepatobiliary (22.7%), and cardiopulmonary (18.7%). Fifteen (4.5%) patients died during follow-up, with a mortality rate of 1.16 deaths per 100 person-years (mean age of death: 52.5 years [SD: 22]). Patients had a mean of 13.5 (SD: 5.2) RBC transfusion episodes and 11.2 (SD: 5.3) iron chelation therapy treatments per year. Healthcare resource utilization was substantial, with a mean of 14.8 inpatient hospitalizations (including 13.8 mean inpatient day cases) and 16.9 outpatient prescriptions per patient per year. CONCLUSIONS: Patients with TDT in France experience significant clinical complications, elevated mortality, and substantial healthcare resource utilization driven by frequent RBC transfusion episodes and inpatient hospitalizations. These results reinforce the need for disease-modifying therapies for this patient population.

Predictors of health-related quality of life in a large cohort of adult patients living with sickle cell disease in France: the DREPAtient study.

Background: Sickle cell disease (SCD) is an inherited autosomal recessive disorder exhibiting a range of symptoms and acute and/or chronic complications that affect the quality of life. This study aimed to assess health-related quality of life (HRQoL) and to identify the associated factors in adult patients with SCD in France. Methods: DREPAtient is a cross-sectional, multicenter study conducted from June 2020 to April 2021 in France and in certain French overseas territories where SCD is highly prevalent. Sociodemographic and clinical data were collected online. HRQoL was assessed by the French version of the 36-Item Short Form Survey (SF-36) questionnaire. HRQoL determinants were identified using multivariable linear regression analysis. Results: In total, 570 participants were included, mostly women (68.9%), with a mean age of 33.3 (±10.7) years. The highest mean score HRQoL was found in the Physical functioning domain (67.5 ± 21.8) and the lowest mean score in the General Health perception domain (37.7 ± 20.3). The mean score of the physical composite (PCS) and mental composite (MCS) of SF-36 summary scores was 40.6 ± 8.9 and 45.3 ± 9.8, respectively. Participants receiving oxygen therapy (ß = -3.20 [95%CI: -5.56; -0.85]), those with a history of femoral osteonecrosis (-3.09 [-4.64; -1.53]), those hospitalized for vaso-occlusive crisis (VOC) or acute chest syndrome (ACS) (-2.58 [-3.93; -1.22]), those with chronic complications (-2.33 [-4.04; -0.62]), female participants (-2.17 [-3.65; -0.69]), those with psychological follow-up (-2.13 [-3.59; -0.67]), older participants (-1.69 [-3.28; -0.09]), and those receiving painkillers (-1.61 [-3.16; -0.06]) reported worse PCS score. By contrast, those who had completed secondary or high school (4.36 [2.41; 6.31]) and those with stable financial situation (2.85 [0.94, 4.76]) reported better PCS scores. Worse MCS scores were reported among participants with psychological follow-up (-2.54 [-4.28; -0.80]) and those hospitalized for VOC/ACS in the last 12 months (-2.38 [-3.99; -0.77]), while those who had relatives' support (5.27 [1.92; 8.62]) and those with stable financial situation (4.95 [2.65; 7.26]) reported better MCS scores. Conclusion: Adults with major SCD reported poor physical and mental HRQoL scores. Hospitalization for VOC/ACS, chronic complications, use of painkillers, perceived financial situation, and support from relatives are important predictors of HRQoL in SCD patients. Interventions to improve HRQoL outcomes SCD should be considered.

Cardiac diastolic maladaptation is associated with the severity of exercise intolerance in sickle cell anemia patients.

This pilot study focusing on Sickle Cell Anemia (SCA) patients offers a comprehensive and integrative evaluation of respiratory, cardiovascular, hemodynamic, and metabolic variables during exercise. Knowing that diastolic dysfunction is frequent in this population, we hypothesize that a lack of cardiac adaptation through exercise might lead to premature increase in blood lactate concentrations in SCA patients, a potential trigger for acute disease complication. SCA patients were prospectively included in PHYSIO-EXDRE study and underwent a comprehensive stress test with a standardized incremental exercise protocol up to 4 mmol L-1 blood lactate concentration (BL4). Gas exchange, capillary lactate concentration and echocardiography were performed at baseline, during stress test (at ∼ 2 mmol L-1) and BL4. The population was divided into two groups and compared according to the median value of percentage of theoretical peak oxygen uptake (% V ˙ O 2 p e a k t h ) at BL4. Twenty-nine patients were included (42 ± 12 years old, 48% of women). Most patients reached BL4 at low-intensity exercise [median value of predicted power output (W) was 37%], which corresponds to daily life activities. The median value of % V ˙ O 2 p e a k t h at BL4 was 39%. Interestingly, diastolic maladaptation using echocardiography during stress test along with hemoglobin concentration were independently associated to early occurrence of BL4. As BL4 occurs for low-intensity exercises, SCA patients may be subject to acidosis-related complications even during their daily life activities. Beyond assessing physical capacities, our study underlines that diastolic maladaptation during exercise is associated with an early increase in blood lactate concentration.

Diagnosis and management of pyruvate kinase deficiency: international expert guidelines.

Pyruvate kinase (PK) deficiency is the most common cause of chronic congenital non-spherocytic haemolytic anaemia worldwide, with an estimated prevalence of one in 100 000 to one in 300 000 people. PK deficiency results in chronic haemolytic anaemia, with wide ranging and serious consequences affecting health, quality of life, and mortality. The goal of the International Guidelines for the Diagnosis and Management of Pyruvate Kinase Deficiency was to develop evidence-based guidelines for the clinical care of patients with PK deficiency. These clinical guidelines were developed by use of GRADE methodology and the AGREE II framework. Experts were invited after consideration of area of expertise, scholarly contributions in PK deficiency, and country of practice for global representation. The expert panel included 29 expert physicians (including adult and paediatric haematologists and other subspecialists), geneticists, laboratory specialists, nurses, a guidelines methodologist, patients with PK deficiency, and caregivers from ten countries. Five key topic areas were identified, the panel prioritised key questions, and a systematic literature search was done to generate evidence summaries that were used in the development of draft recommendations. The expert panel then met in person to finalise and vote on recommendations according to a structured consensus procedure. Agreement of greater than or equal to 67% among the expert panel was required for inclusion of a recommendation in the final guideline. The expert panel agreed on 31 total recommendations across five key topics: diagnosis and genetics, monitoring and management of chronic complications, standard management of anaemia, targeted and advanced therapies, and special populations. These new guidelines should facilitate best practices and evidence-based PK deficiency care into clinical practice.