Impact of a paediatric-adult care transition programme on the health status of patients with sickle cell disease: study protocol for a randomised controlled trial (the DREPADO trial).

BACKGROUND: Thanks to advancements in medical care, a majority of patients with sickle cell disease (SCD) worldwide live beyond 18 years of age, and therefore, patients initially followed in paediatric departments are then transferred to adult departments. This paediatric-adult care transition is a period with an increased risk of discontinuity of care and subsequent morbidity and mortality. During this period, the patient will have to manage new interlocutors and places of care, and personal issues related to the period of adolescence. To take into consideration all these aspects, an interesting approach is to use the whole system approach to the patient, as presented in the biopsychosocial approach. The aim of this trial is to evaluate the impact of the proposed biopsychosocial paediatric-adult transition programme. METHODS: The DREPADO study is a multicentre randomised control trial comparing a control group (Arm A) to an interventional group with a paediatric-adult transition programme based on a biopsychosocial approach (Arm B). To be included, patients should have the SS, SC, or Sß form of sickle cell disease and be aged between 16 and 17 years. The randomisation in a 1:1 ratio assigns to Arm A or B. The primary outcome is the number of hospital admissions and emergencies for complications in the index hospital, in the 2 years after the first consultation in the adult department of care. Secondary outcomes consider the quality of life, but also include coping skills such as sense of self-efficacy and disease knowledge. To provide patient and parent knowledge and coping skills, the transition programme is composed of three axes: educational, psychological, and social, conducted individually and in groups. DISCUSSION: By providing self-care knowledge and coping skills related to SCD and therapeutics, helping empower patientsin relation to pain management and emotions, and facilitating the relationship to oneself, others, and care in Arm B of the DREPADO study, we believe that the morbidity and mortality of patients with SCD may be reduced after the proposed paediatric-adult transition programme. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03786549; registered on 17 December 2018; https://clinicaltrials.gov/.

Assessment of iron status and interplay between lipid peroxidation and antioxidant capacity in common hemoglobin variants in Osun State, southwestern Nigeria.

Hemoglobin (Hb) and iron are prooxidants in nature and sources of free radicals in the biological system of all Hb phenotypes. Recent evidence linked abnormal hemoglobin S and C (HbSC) in sickle cell disease (SCD) to various complications in multiple oxidative processes. However, similar studies in relation to abnormal Hb traits are sparse. Besides, reports on activities of antioxidant enzymes and iron status in SCDs are still contradictory. This study assessed the interplay between lipid peroxidation and antioxidant defense capacity in various Hb variants. We enrolled 193 participants with different Hb phenotypes. They were consecutive patients with sickle cell anemia (HbSS, n = 32) and hemoglobin SC (HbSC) disease (n = 28) regularly followed up in a steady state. Other participants were subjects with abnormal Hb traits (HbAS, n = 50; HbAC, n = 33) and normal controls (HbAA, n = 50). The hematocrit (Hct) level, hemoglobin (Hb) concentration, iron status, and biochemical parameters including malondialdehyde (MDA), total antioxidant status (TAS), superoxide dismutase (SOD), and glutathione peroxidase (GPx) enzymes were investigated simultaneously. The MDA and SOD levels were significantly higher (P < 0.05) in Hb variants in order of HbSS>HbSC>HbAC>HbAS when compared with controls. Conversely, GPx and TAS levels showed significant reductions (P < 0.05). Similarly, Hct, Hb, and iron concentrations showed significant reductions (P < 0.05) sequentially following HbAC > HbAS > HbSC > HbSS compared with controls. The results suggest that both SCDs and the carriers were relatively more vulnerable to systemic oxidative stress against normal phenotype, and may be owing to ineffective antioxidant mechanisms needed for keeping spontaneous generations of free radicals in control without necessarily iron-mediated.

Cardiac manifestations in sickle cell disease varies with patient genotype.

Cardiac involvement is well characterized in sickle cell anaemia (SCA) but cardiac features associated with Haemoglobin SC (HbSC) disease are mostly unknown. We compared 60 patients with HbSC disease (median age 31 years, 25 men) to 60 SCA patients and 60 controls matched for age and gender. Left ventricular ejection fraction (LVEF), left ventricle (LV) mass index (LVMi), cardiac index and peak tricuspid regurgitation velocity (TRV) were measured using echocardiography. LV filling pressures were assessed using the ratio of early diastolic transmitral velocity to tissue velocity (E/e' ratio). The LVMi was higher in both genotypes compared to controls. However, whereas LV hypertrophy was observed only in 3(5%) HbSC patients, this condition was diagnosed in 27(45%) SCA patients (P < 0·0001). While cardiac index and TRV were similar in HbSC compared to controls, SCA patients exhibited elevated cardiac output and TRV. LVEF was similar in the 3 groups. However, both genotypes had a higher E/e' ratio compared to controls. Cardiac involvement in SCA was related to anaemia and haemolysis, while LV diastolic dysfunction and TRV in HbSC disease patients were related to arterial hypertension and overweight comorbidities. In summary, cardiac involvement and its determinants are different in HbSC disease and SCA. Patient's genotype should be considered with regard to the echocardiographic indications and findings.

Association between oxidative stress and vascular reactivity in children with sickle cell anaemia and sickle haemoglobin C disease.

Oxidative stress and haemolysis-associated nitric oxide (NO) depletion plays a crucial role in the development of vasculopathy in sickle cell anaemia (SS). However it remains unknown whether oxidative stress and haemolysis levels influence vascular function in patients with sickle haemoglobin C disease (SC). Microvascular response to heat (using Laser Doppler flowmetry on finger), oxidative stress biomarkers, NO metabolites, endothelin-1 and haematological parameters were compared between patients with SS and SC. Vascular function, oxidative and nitrosative markers were also measured in healthy (AA) children. SS and SC had increased plasma advanced oxidation protein products (AOPP), malondialdehyde, plasma antioxidant activities and NO end products, compared to AA. SC had lower catalase activity compared to AA and SS. Haemolytic rate, glutathione peroxidase and nitrotyrosine concentrations were significantly increased in children with SS compared to SC and AA. SS and SC had impaired microvascular reactivity compared to AA. In SS, the plateau phase of the response to local thermal heating was negatively associated with nitrotyrosine and AOPP. No association between vascular function parameters and oxidative stress markers was observed in SC. Mild haemolysis in SC, compared to SS, may limit oxidative and nitrosative stress and could explain the better preserved microvascular function in this group.

Micro- and macrovascular function in children with sickle cell anaemia and sickle cell haemoglobin C disease.

It is unclear whether vascular function is affected similarly in children with sickle cell anaemia (SS) and children with sickle haemoglobin C (SC) disease. Therefore, we compared micro and macrovascular functions in healthy (AA) children, children with SS and SC disease, and assessed their association with physical activity. Participants (24 SS, 22 SC and 16 AA), were compared in terms of 1) thermal hyperaemic response (finger pad warming to 42°C) measured by Laser Doppler techniques, 2) arterial stiffness determined by pulse wave velocity, 3) daily energy expenditure related to moderate and intense physical activities estimated by questionnaire and 4) fitness level, evaluated by the six-minute walk test. Response to heating differed between SS, SC and controls. Peripheral microvascular reactivity was lower and pulse wave velocity higher in SS compared to AA. SC had blunted microvascular reactivity in response to heating compared to AA but pulse wave velocity was not different within the two groups. Physical activity and fitness levels were markedly lower in sickle cell patients compared to healthy controls but no association was observed with vascular function. Microvasodilatory reserve is decreased in both SS and SC patients but only SS patients were also characterised by impaired macrovascular function.

Pregnancy in sickle cell-haemoglobin C (SC) disease. A retrospective study of birth size and maternal weight gain.

OBJECTIVE: To assess pregnancy and fetal outcomes in Jamaican subjects with sickle cell-haemoglobin C (SC) disease. STUDY DESIGN: A retrospective chart review over 21 years (1992-2012) of all pregnancies in SC disease and a comparison group matched by gender and date of delivery in mothers with a normal haemoglobin (AA) phenotype at the University Hospital of the West Indies, Jamaica. There were 118 pregnancies in 81 patients with SC disease and 110 pregnancies in 110 in the normal comparison group. Corrections were made for repeat pregnancies from the same mother. Outcome measures included maternal weight at 20, 25, 30, 35 and 38 weeks gestation, maternal pregnancy complications, birth weight, head circumference and crown heel length and were used to analyse possible predictors of birth weight. RESULTS: First antenatal visits occurred later in women with SC disease, who also had lower haemoglobin level and lower systolic blood pressure. The prevalence of pregnancy-induced hypertension, pre-eclampsia, ante-partum or postpartum haemorrhage did not differ between genotypes. Maternal weight gain was significantly lower in SC disease and there was a significantly lower birth weight, head circumference, and gestational age. CONCLUSIONS: Pregnancy in SC disease is generally benign but mothers had lower weight gain and lower birth weight babies, the difference persisting after correction for gestational age.

Conjunctival microvascular haemodynamics in sickle cell retinopathy.

PURPOSE: To determine alterations in bulbar conjunctival microvascular haemodynamics in sickle cell retinopathy (SCR) subjects with focal macular thinning (FMT). METHODS: Conjunctival microcirculation imaging and spectral domain optical coherence tomography (SD-OCT) were performed in 22 subjects (eyes) diagnosed with SCR. Based on evaluation of SD-OCT retinal thickness maps, eyes were assigned to one of the two groups: with or without FMT. Conjunctival venular diameter and axial blood velocity were measured in multiple venules in each eye by customized image analysis algorithms. Measurements were then categorized into two vessel size groups (vessel size 1 and 2) and compared between FMT groups. A Pearson correlation coefficient was computed to assess the relationship between retinal thickness and axial blood velocity. RESULTS: Mean age, haematocrit, sickle cell haemoglobin type and median retinopathy score were not significantly different between the two groups (p ≥ 0.1). Retinal thickness in parafoveal and perifoveal temporal subfields was significantly lower in eyes with FMT as compared to eyes without FMT (p ≤ 0.04). There was a significant effect of FMT on axial blood velocity (p = 0.04), while the effect of vessel size was not significant (p = 0.4). In vessel size 1, axial blood velocity was lower in eyes with FMT than in eyes without FMT (p = 0.03), while in vessel size 2, there was no statistically significant difference between FMT groups (p = 0.1). In vessel size 1, there was a significant positive correlation between axial blood velocity and retinal thickness in the perifoveal (r = 0.48, p = 0.02) and parafoveal (r = 0.43, p = 0.04) temporal subfields. CONCLUSION: Conjunctival axial blood velocity in small venules is reduced in SCR subjects with focal macular thinning.

The impact of sickle cell disease on oral health-related quality of life.

PURPOSE: The purpose of this study was to characterize the impact of sickle cell disease (SCD) on oral health and examine its impact on quality of life. METHODS: Fifty-four study subjects were recruited from the sickle cell clinic and 52 control subjects from the adolescent medicine clinic at Nationwide Children's Hospital, Columbus, Ohio. A dental exam was performed to determine each participant's caries burden. The Child Oral Health Impact Profile survey was used to assess their oral health-related quality of life (OHRQoL). RESULTS: Most subjects in both the SCD and control groups rated their overall health and oral health as "good" or "excellent." There was no statistically significant difference in OHRQoL between these groups. Additionally, no significant relationship was found between white blood cell count, medication intake, or the number of sickle cell crises as related to the caries burden. Statistically significant differences were detected in caries burden between the control group and the sickle cell hemoglobin C disease (HbSC) group (P<.02) and between the sickle cell anemia and HbSC subjects (P=.04). CONCLUSIONS: Adolescents with sickle cell hemoglobin C disease had fewer caries than peers with sickle cell anemia or controls, though the cause of this finding is not clear.

[Transitory acute atrioventricular block in an African patient: consider sickle cell anemia]. / Bloc auriculoventriculaire complet transitoire chez un africain: la drépanocytose comme cause.

This case report shows a rare cardiac complication of sickle cell anemia in a young African patient which was an acute paroxysmal atrio-ventricular block. Acute paroxysmal atrioventricular block is a rare complication of polymerization of hemoglobin S during sickle cell disease. Hence, sickle cell anemia should be considered as a cause of auriculoventricular block in black African patients. Cardiac complications of sickle cell anemia are presented in this article.

Hemorheological alterations, decreased cerebral microvascular oxygenation and cerebral vasomotion compensation in sickle cell patients.

Sickle cell anemia (SS) is characterized by a reduced cerebral microvascular oxygen saturation (cerebral TOI), which is not associated with hemoglobin concentration. Cerebral TOI has never been studied in sickle cell-hemoglobin C disease (SC). We focused on the relationships between hemorheological alterations and cerebral TOI in sickle cell patients with no cerebral vasculopathy and on the usefulness of TOI variability to assess the cerebral vasomotion activity. The blood rheological profile, the level of cerebral TOI (spatial resolved spectroscopy) and the cerebral TOI variability, which reflects vasomotion activity, were compared between 20 healthy subjects (AA), 21 SC patients, and 21 SS patients. Cerebral TOI exhibited the following order: AA > SC > SS. The low cerebral TOI in SS patients was related to red blood cell aggregation and deformability properties. The cerebral TOI variability of SS and SC patients was increased above healthy values and vasomotion activity was negatively associated with the reduced cerebral TOI in SS patients. We demonstrated that (1) blood rheology could be involved in the reduced cerebral TOI in SS patients but not in SC patients; (2) vasomotion activity is increased in SS and SC patients to compensate for the reduced cerebral TOI.

Opioid patient controlled analgesia use during the initial experience with the IMPROVE PCA trial: a phase III analgesic trial for hospitalized sickle cell patients with painful episodes.

Opioid analgesics administered by patient-controlled analgesia (PCA)are frequently used for pain relief in children and adults with sickle cell disease (SCD) hospitalized for persistent vaso-occlusive pain, but optimum opioid dosing is not known. To better define PCA dosing recommendations,a multi-center phase III clinical trial was conducted comparing two alternative opioid PCA dosing strategies (HDLI­higher demand dose with low constant infusion or LDHI­lower demand dose and higher constant infusion) in 38 subjects who completed randomization prior to trial closure. Total opioid utilization (morphine equivalents,mg/kg) in 22 adults was 11.6 ± 2.6 and 4.7 ± 0.9 in the HDLI andin the LDHI arms, respectively, and in 12 children it was 3.7 ± 1.0 and 5.8 ± 2.2, respectively. Opioid-related symptoms were mild and similar in both PCA arms (mean daily opioid symptom intensity score: HDLI0.9 ± 0.1, LDHI 0.9 ± 0.2). The slow enrollment and early study termination limited conclusions regarding superiority of either treatment regimen. This study adds to our understanding of opioid PCA usage in SCD. Future clinical trial protocol designs for opioid PCA may need to consider potential differences between adults and children in PCA usage.

Results from transcranial Doppler examination on children and adolescents with sickle cell disease and correlation between the time-averaged maximum mean velocity and hematological characteristics: a cross-sectional analytical study.

CONTEXT AND OBJECTIVE: Transcranial Doppler (TCD) detects stroke risk among children with sickle cell anemia (SCA). Our aim was to evaluate TCD findings in patients with different sickle cell disease (SCD) genotypes and correlate the time-averaged maximum mean (TAMM) velocity with hematological characteristics. DESIGN AND SETTING: Cross-sectional analytical study in the Pediatric Hematology sector, Universidade Federal de São Paulo. METHODS: 85 SCD patients of both sexes, aged 2-18 years, were evaluated, divided into: group I (62 patients with SCA/Sß(0) thalassemia); and group II (23 patients with SC hemoglobinopathy/Sß(+) thalassemia). TCD was performed and reviewed by a single investigator using Doppler ultrasonography with a 2 MHz transducer, in accordance with the Stroke Prevention Trial in Sickle Cell Anemia (STOP) protocol. The hematological parameters evaluated were: hematocrit, hemoglobin, reticulocytes, leukocytes, platelets and fetal hemoglobin. Univariate analysis was performed and Pearson's coefficient was calculated for hematological parameters and TAMM velocities (P < 0.05). RESULTS: TAMM velocities were 137 ± 28 and 103 ± 19 cm/s in groups I and II, respectively, and correlated negatively with hematocrit and hemoglobin in group I. There was one abnormal result (1.6%) and five conditional results (8.1%) in group I. All results were normal in group II. Middle cerebral arteries were the only vessels affected. CONCLUSION: There was a low prevalence of abnormal Doppler results in patients with sickle-cell disease. Time-average maximum mean velocity was significantly different between the genotypes and correlated with hematological characteristics.

Results from transcranial Doppler examination on children and adolescents with sickle cell disease and correlation between the time-averaged maximum mean velocity and hematological characteristics: a cross-sectional analytical study / Resultados do estudo do Doppler transcraniano em crianças e adolescentes portadores de doença falciforme e correlação entre a velocidade média máxima e características hematológicas: um estudo transversal analítico

CONTEXT AND OBJECTIVE: Transcranial Doppler (TCD) detects stroke risk among children with sickle cell anemia (SCA). Our aim was to evaluate TCD findings in patients with different sickle cell disease (SCD) genotypes and correlate the time-averaged maximum mean (TAMM) velocity with hematological characteristics. DESIGN AND SETTING: Cross-sectional analytical study in the Pediatric Hematology sector, Universidade Federal de São Paulo. METHODS: 85 SCD patients of both sexes, aged 2-18 years, were evaluated, divided into: group I (62 patients with SCA/Sß0 thalassemia); and group II (23 patients with SC hemoglobinopathy/Sß+ thalassemia). TCD was performed and reviewed by a single investigator using Doppler ultrasonography with a 2 MHz transducer, in accordance with the Stroke Prevention Trial in Sickle Cell Anemia (STOP) protocol. The hematological parameters evaluated were: hematocrit, hemoglobin, reticulocytes, leukocytes, platelets and fetal hemoglobin. Univariate analysis was performed and Pearson's coefficient was calculated for hematological parameters and TAMM velocities (P < 0.05). RESULTS: TAMM velocities were 137 ± 28 and 103 ± 19 cm/s in groups I and II, respectively, and correlated negatively with hematocrit and hemoglobin in group I. There was one abnormal result (1.6 percent) and five conditional results (8.1 percent) in group I. All results were normal in group II. Middle cerebral arteries were the only vessels affected. CONCLUSION: There was a low prevalence of abnormal Doppler results in patients with sickle-cell disease. Time-average maximum mean velocity was significantly different between the genotypes and correlated with hematological characteristics.

CONTEXTO E OBJETIVO: Doppler transcraniano (DTC) detecta risco de acidente vascular cerebral (AVC) em crianças com anemia falciforme (AF). O objetivo foi avaliar os resultados ao DTC nos diferentes genótipos da doença falciforme (DF) e correlacionar a velocidade média-máxima (VMMáx) às características hematológicas. TIPO DE ESTUDO E LOCAL: Estudo transversal analítico realizado no setor de Hematopediatria da Universidade Federal de São Paulo. MÉTODOS: 85 pacientes com DF, 2-18 anos, ambos os sexos, foram avaliados e divididos em: grupo I (62 com AF ou Sß0 talassemia); e grupo II (23 com hemoglobinopatia SC ou Sß+ talassemia). DTC foi realizado e revisado por um único investigador usando um aparelho de ultrassonografia Doppler com transdutor de 2MHz, conforme critérios do protocolo STOP (Stroke Prevention Trial in Sickle Cell Anemia). As variáveis hematológicas avaliadas foram: hematócrito, hemoglobina, reticulócitos, leucócitos, plaquetas, hemoglobina fetal. Análise univariada e coeficiente de Pearson calculados para parâmetros hematológicos e VMMáx, P < 0,05. RESULTADOS: As média das VMMáx foram de 137 ± 28 cm/s e 103 ± 19 cm/s nos grupos I e II, respectivamente. Houve correlação negativa da VMMáx com hematócrito e hemoglobina no grupo I. Houve um (1,6 por cento) resultado anormal e 5 (8,1 por cento) condicionais no grupo I; no grupo II, todos estavam normais. Artérias cerebrais médias foram as únicas acometidas. CONCLUSÃO: Houve baixa prevalência de resultados anormais ao DTC em pacientes com DF. A VMMáx foi significativamente diferente entre os genótipos da DF e apresentou correlação com variáveis hematológicas.

Acute splenic sequestration in an adult with hemoglobin S-C disease.

Acute splenic sequestration crisis is a common, potentially life-threatening complication of sickle cell anemia in children that is uncommon in adults.We present the case of a 44-year-old gentleman with undiagnosed hemoglobin S-C disease who developed intense back pain, marked abdominal distension, systemic inflammatory response syndrome, and multisystem organ failure that first presented as acute splenic sequestration crisis. The hemoglobinopathy SC is a disease caused by heterozygous-globin chain mutations with over-lapping clinical features of sickle cell disease with changes in the frequency of these manifestations reflected by the combination of characteristics of hemoglobin C and hemoglobin S. In hemoglobin S-C disease, autosplenectomy is rare and splenomegaly usually persists until adulthood;vasoocclusive complications are seen less habitually and become evident at a later time compared with sickle cell disease. The diagnosis of hemoglobin S-C disease is essentially done by exclusion. Transfusion of red blood cells is the treatment of choice, but splenectomy is indicated if transfusion therapy fails. A review of the literature and keypoints for the emergency practitioner are included.

Normal sublingual microcirculation during painful crisis in sickle cell disease.

Obstruction of the microcirculation is the most important cause of painful crisis in sickle cell disease (SCD). Extensive microvascular obstruction has been observed in mouse models of SCD. A technique to determine the extent of the microcirculatory obstructions in humans may be helpful in the clinical setting and for research purposes. Therefore, we measured sublingual microcirculation longitudinally in patients with SCD admitted with painful crisis. Sublingual microcirculation was recorded with side-stream darkfield (SDF) imaging and semi-quantified with a microvascular flow index (MFI) on a range from 0 to 4 (arbitrary units; from 0 (no flow) to 4 (hyperdynamic flow)). Thirteen consecutive adult sickle cell patients admitted with painful crises were included and provided 47 measurements of MFI in 14 episodes of painful crisis. Seven patients provided baseline measurements and seven healthy controls were studied. The mean (+/-standard error of the mean) MFI during painful crisis was 2.6+/-0.1 and did not change during the painful crisis. The mean MFI of patients with SCD during steady state (2.7+/-0.1) and the mean MFI of the controls (2.7+/-0.1) were not different from the mean MFI during painful crisis. During painful crisis irregular microvascular perfusion, expressed by the distribution width of the microvascular blood flow velocity, correlated negatively (r=-0.484; P=0.002) with hemoglobin concentration. We conclude that sublingual microcirculatory blood flow velocity is not disturbed in sickle cell patients during painful crisis.

Lung function and somatic growth in patients with hemoglobin SC sickle cell disease.

OBJECTIVE: To investigate the changes in lung function and somatic growth that occur over time in children with hemoglobin SC (Hb-SC) sickle cell disease (SCD). METHODS: Measurements of lung function and somatic growth were performed in patients with Hb-SC twice with an interval of 50.2 +/- 26.0 months. Comparisons were made with a group of patients with hemoglobin SS (Hb-SS) SCD, matched by age, race, and gender who underwent similar testing and served as controls. RESULTS: Indices of lung function in patients with Hb-SC were and remained within the normal range in the two testing periods and they were significantly higher than those measured among patients with Hb-SS. However, there was significant and similar decline (as percentage from baseline) over time in both groups (forced vital capacity, FVC: -3.7 +/- 9.4 vs. -3.8 +/- 14.2; forced expiratory volume in the first second, FEV1: -7.4 +/- 9.3 vs. -6.8 +/- 15.2; forced expiratory flow at 25-75% of FVC, FEF(25-75): -13.7 +/- 20.6 vs. -12.1 +/- 24.7 for Hb-SC and Hb-SS respectively). The body mass index (BMI, percentile) was significantly (P < 0.05) higher among patients with Hb-SC (49 +/- 36 vs. 26 +/- 18) and increased over time in both groups (50 +/- 33 vs. 32 +/- 31). CONCLUSION: Lung function is generally normal among children with Hb-SC, but it declines over time in a fashion similar to that observed among patients with Hb-SS SCD. The decline is slow and it is not associated with changes in somatic growth. Our findings suggest that patients with Hb-SC should probably have the same close follow-up as patients with Hb-SS.