Muscle Properties, Gross Motor Performance, and Quality of Life in Children With Sickle Cell Disease.

PURPOSE: To explore muscle properties, gross motor performance, and quality of life (QoL) in children with sickle cell disease (SCD) compared with controls and to assess relationships among these outcomes. METHODS: A cross-sectional study of 24 children assessed muscle properties including: knee extension strength by dynamometry; vastus lateralis (VL) and rectus femoris (RF) muscle thickness by ultrasonography; and VL and RF neuromuscular activation (rate of muscle activation [RoA]) by electromyography (EMG). Gross motor performance and QoL were assessed by standardized tests and questionnaires. RESULTS: Children with SCD had impaired knee extension strength, VL EMG RoA, gross motor performance, and QoL compared with children without SCD. Relationships among muscle properties, gross motor performance, and QoL were identified. CONCLUSIONS: These findings indicate that comprehensive muscle properties, gross motor performance, and QoL assessments should be considered to support and develop individualized physical therapy plans for children with SCD.

Reduced blood pressure in sickle cell disease is associated with decreased angiotensin converting enzyme (ACE) activity and is not modulated by ACE inhibition.

BACKGROUND: Sickle cell disease (SCD) incurs vaso-occlusive episodes and organ damage, including nephropathy. Despite displaying characteristics of vascular dysfunction, SCD patients tend to present relatively lower systemic blood pressure (BP), via an unknown mechanism. We investigated associations between BP and renin-angiotensin-system (RAS) components in SCD and determined whether an inhibitor of angiotensin converting enzyme (ACE; often used to slow SCD glomerulopathy) further modulates BP and RAS components in a murine model of SCD. METHODS: BP was compared in human subjects and mice with/without SCD. Plasma angiotensin II, ACE and renin were measured by immunoassay. BP was reevaluated after treating mice with enalapril (25 mg/kg, 5x/week) for 5 weeks; plasma and organs were stored for angiotensin II and ACE activity measurement, and quantitative real-time PCR. RESULTS: Diastolic BP and systolic BP were significantly lower in patients and mice with SCD, respectively, compared to controls. Reduced BP was associated with increased plasma renin and markers of kidney damage (mice) in SCD, as well as significantly decreased plasma ACE concentrations and ACE enzyme activity. As expected, enalapril administration lowered BP, plasma angiotensin II and organ ACE activity in control mice. In contrast, enalapril did not further reduce BP or organ ACE activity in SCD mice; however, plasma angiotensin II and renin levels were found to be significantly higher in enalapril-treated SCD mice than those of treated control mice. CONCLUSION: Relative hypotension was confirmed in a murine model of SCD, in association with decreased ACE concentrations in both human and murine disease. Given that ACE inhibition has an accepted role in decreasing BP, further studies should investigate mechanisms by which ACE depletion, via both Ang II-dependent and alternative pathways, could contribute to reduce BP in SCD and understand how ACE inhibition confers Ang II-independent benefits on kidney function in SCD.

Altered cardiac reserve is a determinant of exercise intolerance in sickle cell anaemia patients.

BACKGROUND: The underlying mechanisms of exercise intolerance in sickle cell anaemia (SCA) patients are complex and not yet completely understood. While latent heart failure at rest could be unmasked upon exercise, most previous studies assessed cardiac function at rest. We aimed to investigate exercise cardiovascular reserve as a potential contributor to exercise intolerance in adult SCA patients. METHODS: In this observational prospective study, we compared prospectively 60 SCA patients (median age 31 years, 60% women) to 20 matched controls. All subjects underwent symptom-limited combined exercise echocardiography and oxygen uptake (VO2 ) measurements. Differences between arterial and venous oxygen content (C(a-v)O2 ) were calculated. Cardiac reserve was defined as the absolute change in cardiac index (Ci) from baseline to peak exercise. RESULTS: Compared to controls, SCA patients demonstrated severe exercise intolerance (median peakVO2 , 34.3 vs. 19.7 ml/min/kg, respectively, p < .0001). SCA patients displayed heterogeneously increased Ci from rest to peak exercise (median +5.8, range 2.6 to 10.6 L/min/m²) which correlated with peakVO2 (r = 0.71, p < .0001). In contrast, the C(a-v)O2 exercise reserve was homogenously reduced and did not correlate with peakVO2 (r = 0.18, p = .16). While haemoglobin level and C(a-v)O2 were similar in SCA subgroups, SCA patients in the lower VO2 tertile had chronotropic incompetence and left ventricular diastolic dysfunction (left atrial peak longitudinal strain was reduced, and both E/e' ratio and left atrial volume index were increased) and were characterized by a reduced cardiac reserve, +5.0[4.2-5.5] compared to +6.7[5.5-7.8] L/min/m² for the rest of the patient cohort, p < .0001. CONCLUSIONS: Altered cardiac reserve due to chronotropic incompetence and left ventricular diastolic dysfunction seems to be an important determinant of exercise intolerance in adult SCA patients.

EVALUATION OF MACULAR FLOW VOIDS ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY AS POTENTIAL BIOMARKERS FOR SILENT CEREBRAL INFARCTION IN SICKLE CELL DISEASE.

PURPOSE: To determine the relationship between macular microvascular abnormalities on optical coherence tomography angiography and silent cerebral infarctions (SCIs) on cerebral magnetic resonance imaging in sickle cell disease. METHODS: Patients (age <18 years old) from our previous pediatric sickle cell disease study cohort who had prior optical coherence tomography angiography and brain magnetic resonance imaging were identified. Brain magnetic resonance imaging images were compared with macular optical coherence tomography angiography scans to identify macular vascular density differences between patients with SCI and without SCI. RESULTS: Sixty-eight eyes from 34 patients who underwent optical coherence tomography angiography were evaluated, of whom 28 eyes from 14 patients met the inclusion criteria for this study. Eight patients (57%) with SCI and 6 patients (43%) without SCI were identified. The mean age (17 years in SCI and 16.3 years in non-SCI) was comparable between groups. There was no statistically significant difference in systemic complications. Deep capillary plexus vessel density was lower in the temporal quadrant in patients with SCI (49.3% vs. 53.7%, P = 0.014). CONCLUSION: Patients with SCI were found to have lower vessel density in the deep capillary plexus compared with those without SCI. This finding suggests that deep capillary plexus vessel density may have utility as an imaging biomarker to predict the presence of SCI.

Heart rate variability associated with acute exercise challenge in children with sickle cell anaemia.

We examined heart rate variability (HRV) during exercise testing in 20 children with sickle cell anaemia (SCA) and 12 controls. Subjects achieved lower median HRV at peak exercise [standard deviation of R-wave to R-wave intervals (SDNN), 2·3 vs 2·9 ms, P = 0·027; logarithmic transformation of high frequency power (lnHF), 0·9 vs 1·3 ln(ms2 ), P = 0·047] and had lower post-exercise HRV across minute-by-minute analysis of recovery. After adjustment for haemoglobin, fitness and SCA status, subjects had lower HRV at the end of recovery with differences increasing as baseline HRV increased. Further investigation of HRV and exercise safety in SCA is warranted.

Exercise-induced changes of vital signs in adults with sickle cell disease.

The six-minute walk test (6MWT) has been used in patients with sickle cell disease (SCD), in conjunction with tricuspid regurgitant velocity (TRV) and plasma N-terminal pro-brain natriuretic peptide (NT-pro BNP), to assess risk of having pulmonary hypertension. Exercise-induced vital sign changes (VSCs) are predictors of clinical outcomes in other diseases. In this study, we assess the predictors and prognostic value of 6MWT VSC in adult SCD patients. Data from a multinational study of SCD patients (Treatment of Pulmonary Hypertension with Sildenafil: walk-PHaSST) were used to calculate the 6MWT VSC. Predictors of VSC were identified by a multivariable analysis, and a survival analysis was conducted by the Cox proportional hazard method. An increase in heart rate was observed in 90% of the 630 SCD adults, 77% of patients had an increase in systolic blood pressure (SBP), and 50% of patients had a decrease in oxygen saturation. TRV (odds ratio [OR] = 1.82, p = .020), absolute reticulocyte count (OR = 1.03, p < .001), and hemoglobin (OR = 0.99, p = .035) predicted oxygen desaturation ≥ 3% during the 6MWT. In the adjusted analysis, SBP increase during the 6MWT was associated with improved survival (hazards ratio = 0.3, 95% confidence interval: 0.1-0.8). Increases in heart rate and blood pressure, as well as oxygen desaturation, are common in adults with SCD during the 6MWT. VSC is associated with markers of anemia and TRV and can be used for risk stratification. Any increase in SBP during the 6MWT was associated with improved survival and may be indicative of a patient's ability to increase stroke volume.

Pulmonary Blastomycosis: A Rare Cause of Acute Chest Syndrome and Prolonged Fevers in a Pediatric Patient With Sickle Cell Disease.

Blastomyces is a fungus found in the soil of regions of North America including the Mississippi and Ohio River Valleys. It can be inhaled into the lungs and cause pneumonia and disseminated disease. Although blastomycosis is not widely reported in the sickle cell literature, sickle cell patients may be at increased risk of complications from blastomycosis pneumonia due to their immune compromise and risk of developing acute chest syndrome. We describe the case of a 13-year-old female with homozygous sickle cell disease who presented with pneumonia and acute chest syndrome and was found to have pulmonary blastomycosis.

Sickle cell disease in sub-Saharan Africa: transferable strategies for prevention and care.

Sickle cell disease can be life-threatening or chronically debilitating for both children and adults. Worldwide, more than 300 000 children are born with sickle cell disease every year, over 75% of whom in sub-Saharan Africa. Increased awareness and early interventions, such as neonate screening and comprehensive care, have led to considerable reductions in mortality in children younger than 5 years in high-income countries. However, sickle cell disease prevention and care have largely been neglected in Africa. Without intervention, 50-90% of affected children in many sub-Saharan African countries die before their fifth birthday. Fortunately, increasing initiatives in sub-Saharan Africa are piloting interventions such as neonate screening and comprehensive care, and as mortality declines, quality of life and increased life expectancy become major targets for interventions. Hydroxyurea (hydroxycarbamide) and haematopoietic stem-cell transplantation have already been shown to be effective therapies in high-income countries, but are either not widely accessible or too expensive for most African populations. These challenges are being alleviated by numerous networks evolving through international collaborations that are positively changing the outlook of sickle cell disease management in sub-Saharan Africa. In this Series paper, we describe the epidemiology, pathophysiology, clinicobiological profile, and psychosocial effects of sickle cell disease in sub-Saharan Africa. We highlight transferable strategies already used for the successful management of the condition and key strategies and recommendations for affordable and comprehensive care on the continent. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Longitudinal study of glomerular hyperfiltration and normalization of estimated glomerular filtration in adults with sickle cell disease.

Glomerular hyperfiltration is common in sickle cell disease (SCD) and precedes proteinuria and declining kidney function. We evaluated hyperfiltration in SCD patients and its "normalization." Routine visit data were collected retrospectively from adult SCD patients in a single centre from 2004 to 2013. Baseline was defined as first available serum creatinine and hyperfiltration as estimated glomerular filtration rates (eGFR) >130 ml/min/1·73 m2 for women and >140 ml/min/1·73 m2 for men. Normalization of hyperfiltration was eGFR reduction to 90-130 ml/min/1·73 m2 for women or 90-140 ml/min/1·73 m2 for men. Among 292 patients, median age was 27 years [interquartile range (IQR):20·0-38·0], and 56·8% had baseline hyperfiltration. Baseline hyperfiltration was inversely associated with age [odds ratio (OR):0·86, 95% confidence interval (CI): 0·82-0·90; P < 0·0001], male sex (OR:0·16, 95% CI: 0·07-0·41; P = 0·0001), haemoglobin (OR:0·76, 95% CI 0·61-0·94; P = 0·01), weight (OR:0·96, 95% CI: 0·93-0·99; P = 0·004), and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACE-I/ARB) use (OR:0·08, 95% CI: 0·01-0·75; P = 0·03), and positively with hydroxycarbamide use (OR:2·99, 95% CI: 1·18-7·56; P = 0·02). Of 89 hyperfiltration patients without baseline proteinuria, 10 (11·2%) developed new-onset proteinuria [median 1·05 years (IQR:0·63-2·09)]. Normalization of hyperfiltration was less likely with higher baseline eGFR [hazard ratio (HR):0·90, 95% CI: 0·86-0·95; P < 0·0001] and more likely in males (HR:6·35, 95% CI:2·71-14·86, <0·0001). Hyperfiltration is common in adult SCD patients, particularly when younger. Decline to normal values is more likely in males, possibly representing kidney function loss rather than improvement in hyperfiltration.

Therapist-oriented home rehabilitation for adults with sickle cell anemia: effects on muscle strength, functional capacity, and quality of life.

OBJECTIVES: Considering the advances in functional rehabilitation in recent decades, therapist-oriented home rehabilitation (TOHR) has been increasingly used in the field of physical therapy because it increases patient compliance and reduces health system costs. The objective of this study was to investigate the effects of TOHR on functional capacity, muscle strength, and quality of life (QoL) in adults with sickle cell anemia (SCA). METHODS: Forty adults with SCA underwent manually guided TOHR for 12 weeks. Before and at the end of training, the following variables were assessed in the participants: distance covered in the 6-min walk test (6MWD); maximal inspiratory pressure (MIP); maximal expiratory pressure (MEP); handgrip strength (HGS); quadriceps strength (QS); and QoL using the Short Form-36 physical component summary (SF-36PCS) and the Short Form-36 mental component summary (SF-36MCS). RESULTS: After TOHR, significant increases were observed in the mean values for the 6MWD, MIP, MEP, HGS, QS, and SF-36PCS and SF-36MCS scores. The relative delta between the pre- and post-TOHR 6MWDs correlated significantly with the relative deltas of MIP (rs = 0.640, p < 0.0001), MEP (rs = 0.587, p < 0.0001), HGS (rs = 0.360, p = 0.022), and QS (rs = 0.351, p = 0.026). When the participants were separated according to their use of hydroxyurea, significant increases were observed in the relative deltas of the 6MWD, MIP and MEP values. CONCLUSIONS: This study shows that TOHR can potentially increase functional capacity, muscle strength, and QoL in adults with SCA. Furthermore, there appears to be a relationship between 6MWD gains and muscle strength gains with TOHR.Trial registration: ClinicalTrials.gov identifier: NCT04705792.

The effect of sickle cell anemia on the linear growth of Nigerian children.

OBJECTIVES: Despite the high prevalence of children with sickle cell anaemia (SCA) in West Africa, there is paucity of data on the height velocity and prevalence of growth failure in SCA patients. With advances in clinical care of SCA patients, could there be a spatial and secular trend in the growth pattern of these children? Hence, the compelling needs to embark on this study. The objectives of the study were to determine the prevalence of growth failure among patients with SCA and its correlation with age, gender and age at diagnosis. METHODS: A Prospective longitudinal study of a cohort of sickle cell anaemic paediatric patients from Pediatrics SCA Clinic, University of Nigeria Teaching Hospital, Ituku Ozalla. Patients were enrolled over a period of two years using a non-parametric convenient sampling method. Their heights were measured at baseline, three months, six months and at 12 months intervals and subsequently plotted on a standard WHO growth chart. The height velocities at different monthly intervals were calculated and compared with the WHO standard normal linear growth rates) for children (used as control) to identify those with GF. (i.e. <10th percentile). The main outcome measures were the mean height velocities at different months' intervals calculated and compared using the repeated measurement analysis of variance (ANOVA) and the Wilcoxon signed test. RESULTS: A cohort of 316 children aged 1-18 years with SCA was evaluated with a male preponderance of 161 (57.4%). The mean age and age at diagnosis were 11.04 ± 5.56 and 4.2 ± 1.7 years, respectively. The prevalence of growth failure and short stature was 84.7%. The burden of GF was highest among post-pubertal participants (94.1%). The most important predictor of growth velocity deficit was age (R2=0.045, standard ß coefficient = -0.22, t=-03.51, p=0.001). CONCLUSIONS: The study demonstrated high prevalence of growth failure in children and adolescents with SCA which intensified with advancement in age and older age at diagnosis.

Critical Role of Hemopexin Mediated Cytoprotection in the Pathophysiology of Sickle Cell Disease.

Circulating hemopexin is the primary protein responsible for the clearance of heme; therefore, it is a systemic combatant against deleterious inflammation and oxidative stress induced by the presence of free heme. This role of hemopexin is critical in hemolytic pathophysiology. In this review, we outline the current research regarding how the dynamic activity of hemopexin is implicated in sickle cell disease, which is characterized by a pathological aggregation of red blood cells and excessive hemolysis. This pathophysiology leads to symptoms such as acute kidney injury, vaso-occlusion, ischemic stroke, pain crises, and pulmonary hypertension exacerbated by the presence of free heme and hemoglobin. This review includes in vivo studies in mouse, rat, and guinea pig models of sickle cell disease, as well as studies in human samples. In summary, the current research indicates that hemopexin is likely protective against these symptoms and that rectifying depleted hemopexin in patients with sickle cell disease could improve or prevent the symptoms. The data compiled in this review suggest that further preclinical and clinical research should be conducted to uncover pathways of hemopexin in pathological states to evaluate its potential clinical function as both a biomarker and therapy for sickle cell disease and related hemoglobinopathies.

Knowledge gaps in reproductive and sexual health in girls and women with sickle cell disease.

There is an immediate need to address long-standing questions about the reproductive health of girls and women with sickle cell disease (SCD). There are many SCD-related reproductive risks and uncertainties across girls' and women's reproductive life span, with particularly outstanding concerns about menstruation, contraception, fertility and pregnancy. Extant literature addressing women's reproductive health topics is mostly descriptive; there are few high-quality interventional studies. In 2020, the Centers for Disease Control and Prevention and the Foundation for Women and Girls with Blood Disorders convened an expert panel to assess the knowledge gaps in women's reproductive health in SCD. The panel identified significant limitations to clinical care due to the need for research. The panel also identified prominent barriers to research and care. In this report, we frame these issues, providing a roadmap for investigators, funding agencies, and policy makers to advance care for girls and women with SCD.

Reliability of different estimated glomerular filtration rate as measures of renal function in children with sickle cell disease.

BACKGROUND: There is no reliable marker for detecting early renal disease in early children with sickle cell disease (SCD). Estimation of glomerular filtration rate (eGFR) as derived from the height/plasma creatinine formula is dependent on the accuracy of the creatinine analytical method used. The aim of this study was to evaluate different equations for eGFR. METHODS: Children aged 5-16 years recruited. mGFR was obtained using plasma disappearance of Inutest/Iohexol, serum creatinine (SCr) was measured either by standard laboratory method or by tandem mass spectrometry (MSMS). Estimated GFR was then calculated either by "Bedside Schwartz method" or by the full-age spectrum (FAS) equation. FINDINGS: A total of 79 patients (mean age 9.8 ± 4.0 years). A revised eGFR constant was calculated for Schwartz equation from the slope of the plot of height/plasma creatinine versus mGFR. Mean values for mGFR (132.7 ± 32.1 ml/min/1.73m2) and eGFR methods compared: eGFR from standard SCr was significantly higher (144.2 ± 37.3 ml/min/1.73m2, p = 0.008). The MSMS eGFR showed the lowest SD (SD = 27.5), while both FAS eGFR and FAS-height eGFR showed the highest correlation coefficient (r = 0.67). INTERPRETATION: eGFR calculation based on height and SCr determined with MSMS traceable creatinine is more reliable than Schwartz formula using jaffe/enzymatic methods in SCD children.

Hydroxycarbamide treatment reduces transcranial Doppler velocity in the absence of transfusion support in children with sickle cell anaemia, elevated transcranial Doppler velocity, and cerebral vasculopathy: the EXTEND trial.

EXpanding Treatment for Existing Neurological Disease (EXTEND) investigated whether hydroxycarbamide lowers transcranial Doppler (TCD) velocities in Jamaican children with sickle cell anaemia (SCA) and elevated TCD velocity with or without previous stroke. Forty-three children (age 2-17 years) with baseline maximum time-averaged mean velocity (TAMV) ≥ 170 cm/s were stratified into three risk categories based on treatment status and stroke history: Group 1 (no history of stroke, on hydroxycarbamide, n = 12); and Groups 2 (no stroke, no hydroxycarbamide, n = 21) and 3 (previous stroke, no hydroxycarbamide, n = 10). Open-label hydroxycarbamide at 20 mg/kg/day was commenced, with escalation to maximum tolerated dose (MTD) based on mild marrow suppression (average dose 25·4 ± 4·5 mg/kg/day). TCD was performed every six months with brain magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) at baseline and after 18-months of hydroxycarbamide. The maximum TAMV decreased significantly compared to baseline (24 ± 30 cm/s, P < 0·0001), with similar declines in all groups. Clinical stroke occurred in five children, one in Group 1, none in Group 2, and four in Group 3, P = 0·0032, comparing group incidence rates. Brain MRI/MRA was stable in children without clinical stroke. EXTEND documents the feasibility and benefits of hydroxycarbamide at MTD to lower TCD velocities and reduce stroke risk in children with SCA and no history of primary stroke in low-resource settings without transfusion management.