A randomized, placebo-controlled, double-blind trial of canakinumab in children and young adults with sickle cell anemia.

Excessive intravascular release of lysed cellular contents from damaged red blood cells (RBCs) in patients with sickle cell anemia (SCA) can activate the inflammasome, a multiprotein oligomer promoting maturation and secretion of proinflammatory cytokines, including interleukin-1ß (IL-1ß). We hypothesized that IL-1ß blockade by canakinumab in patients with SCA would reduce markers of inflammation and clinical disease activity. In this randomized, double-blind, multicenter phase 2a study, patients aged 8 to 20 years with SCA (HbSS or HbSß0-thalassemia), history of acute pain episodes, and elevated high-sensitivity C-reactive protein >1.0 mg/L at screening were randomized 1:1 to received 6 monthly treatments with 300 mg subcutaneous canakinumab or placebo. Measured outcomes at baseline and weeks 4, 8, 12, 16, 20, and 24 included electronic patient-reported outcomes, hospitalization rate, and adverse events (AEs) and serious AEs (SAEs). All but 1 of the 49 enrolled patients were receiving stable background hydroxyurea therapy. Although the primary objective (prespecified reduction of pain) was not met, compared with patients in the placebo arm, patients treated with canakinumab had reductions in markers of inflammation, occurrence of SCA-related AEs and SAEs, and number and duration of hospitalizations as well as trends for improvement in pain intensity, fatigue, and absences from school or work. Post hoc analysis revealed treatment effects on weight, restricted to pediatric patients. Canakinumab was well tolerated with no treatment-related SAEs and no new safety signal. These findings demonstrate that the inflammation associated with SCA can be reduced by selective IL-1ß blockade by canakinumab with potential for therapeutic benefits. This trial was registered at www.clinicaltrials.gov as #NCT02961218.

The cation-leaky hereditary stomatocytosis syndromes: A tale of six proteins.

This review concerns a series of dominantly inherited haemolytic anaemias in which the membrane of the erythrocyte 'leaks' the univalent cations, compromising the osmotic stability of the cell. The majority of the conditions are explained by mutations in one of six genes, coding for multispanning membrane proteins of different structure and function. These are: RhAG, coding for an ammonium carrier; SLC4A1, coding for the band 3 anion exchanger; PIEZO1, coding for a mechanosensitive cation channel; GLUT1, coding for a glucose transporter; KCNN4, coding for an internal-calcium-activated potassium channel; and ABCB6, coding for a porphyrin transporter. This review describes the five clinical syndromes associated with genetic defects in these genes and their variable genotype/phenotype relationships.

Significant haemoglobinopathies: A guideline for screening and diagnosis: A British Society for Haematology Guideline: A British Society for Haematology Guideline.

Antenatal screening/testing of pregnant women should be carried out according to the guidelines of the National Health Service (NHS) Sickle Cell and Thalassaemia Screening Programme. Newborn screening and, when necessary, follow-up testing and referral, should be carried out according to the guidelines of the NHS Sickle Cell and Thalassaemia Screening Programme. All babies under 1 year of age arriving in the United Kingdom should be offered screening for sickle cell disease (SCD). Preoperative screening for SCD should be carried out in patients from ethnic groups in which there is a significant prevalence of the condition. Emergency screening with a sickle solubility test must always be followed by definitive analysis. Laboratories performing antenatal screening should utilise methods that are capable of detecting significant variants and are capable of quantitating haemoglobins A2 and F at the cut-off points required by the national antenatal screening programme. The laboratory must ensure a provisional report is available for antenatal patients within three working days from sample receipt.

Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria.

BACKGROUND: Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria. RESULTS: A total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group). Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria. Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions. CONCLUSIONS: Among patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo. The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events. (Funded by Alnylam Pharmaceuticals; ENVISION ClinicalTrials.gov number, NCT03338816.).

Males with sickle cell disease have higher risks of cerebrovascular disease, increased inflammation, and a reduced response to hydroxyurea.

Biological sex is important. Male sex is associated with worse outcomes in most measures, including cerebrovascular disease, hospital admissions, and blood transfusions, but not survival. Females also appear to have a better response to hydroxyurea therapy, reduced markers of inflammation, and better liver function.

Difficulties in distinguishing silicosis and pulmonary tuberculosis in silica-exposed gold miners: A report of four cases.

Silicosis and tuberculosis (TB) are both global health concerns, with high prevalence among miners from the South African gold mines. Although knowledge has accumulated about these two conditions as distinct diseases since the early 20th century, and despite progress in technology with multiple diagnostic tools and treatment options available for TB, the challenge of distinguishing and therefore efficiently managing these two conditions in this population remains as current as it was 100 years ago. To illustrate the diagnostic and health service problems of distinguishing TB and silicosis clinically and radiologically in former gold miners from the South African mines living in resource-poor areas, we discuss four cases reviewed for this report by a panel of experts. For each case, occupational history, past and current medical history, physical examination, radiological and laboratory findings are described. Common themes are: (1) poor agreement between radiological and clinical presentation; (2) poor agreement between radiology findings and detection of active TB on sputum Xpert MTB/RIF testing; and (3) difficulty in distinguishing the clinical and radiological presentations of silicosis and tuberculosis. Possible consequences at the population level are undertreatment or overtreatment of TB, and underdiagnosis or overdiagnosis of silicosis. There is a need for training of practitioners who are screening or attending to former gold miners in the clinical and radiological features of combined disease, using a curated database of miners' chest X-ray images. Investment in protocols for management of both acute and chronic silicotuberculosis in ex-miners is needed, as is clinical, epidemiologic, and operations research.

First recorded occurrence of the parasitic barnacle (Anelasma squalicola) on a Greenland shark (Somniosus microcephalus) in the Canadian Arctic.

A solitary Anelasma squalicola specimen was collected from the cloaca of a Greenland shark (Somniosus microcephalus), the first time this association has been recorded. The specimen's identity was confirmed through morphological and genetic assessment (mitochondrial markers: COI and control region). A. squalicola is a species typically associated with deep-sea lantern sharks (Etmopteridae) and, until the present observation, had never been observed at a sexually mature size in the absence of a mating partner. Given the reported negative effects of this parasite on its hosts, monitoring Greenland sharks for additional cases is recommended.

What is the role of chest X-ray imaging in the acute management of children with sickle cell disease?

Children with sickle cell disease (SCD) frequently present to hospital acutely unwell and are often exposed to diagnostic chest X-rays (CXRs). Little evidence exists to determine when CXRs are clinically useful. Using electronic hospital records, we audited CXR use in children aged 0-18 who presented to hospital over the past 10 years in both an inpatient and emergency department setting. From a total of 915 first CXRs, only 28·2% of CXRs (n = 258) had clinically significant findings that altered management or final diagnosis. Of these abnormalities, consolidation represented 52·3%, effusion 8·9%, cardiomegaly 8·4% and sickle cell-related bone changes 6·3%. Indications for CXR of respiratory distress (OR = 3·74, 95% CI 2·28-6·13), hypoxia (OR = 1·86, 95% CI 1·50-2·31) and cough (OR = 1·64, 95% CI 1·33-2·02), were more likely to have significant CXR findings. Patients who had higher peak fever (38·4°C vs. 37·4°C, P = 0·001), higher peak CRP (156·4 vs. 46·1, P < 0·001) and higher WCC (20·2 vs. 13·6, P < 0·001) were more likely to have clinically significant abnormalities on CXR. We found a decision tool using either hypoxia, cough, respiratory distress, T > 38°C, CRP > 50 or WCC > 15 × 109 /l as indications for CXR, to have a sensitivity of 88% (with 95% CI 0·78-0·95) and specificity of 46% (95% CI 0·43-0·50) for clinically significant findings.

Oxygen gradient ektacytometry does not predict pain in children with sickle cell anaemia.

The loss of red blood cell (RBC) deformability in sickle cell anaemia (SCA) is considered the primary factor responsible for episodes of acute pain and downstream progressive organ dysfunction. Oxygen gradient ektacytometry (Oxygenscan) is a recently commercialised functional assay that aims to describe the deformability of RBCs in SCA at differing oxygen tensions. So far, the Oxygenscan has been evaluated only by a small number of research groups and the validity and clinical value of Oxygenscan-derived biomarkers have not yet been fully established. In this study we examined RBC deformability measured with the Oxygenscan in 91 children with SCA at King's College Hospital in London. We found a significant correlation between Oxygenscan-derived biomarkers and well-recognised modifiers of disease severity in SCA: haemoglobin F and co-inherited α-thalassaemia. We failed, however, to find any independent predictive value of the Oxygenscan in the clinical outcome measure of pain, as well as other important parameters such as hydroxycarbamide treatment. Although the Oxygenscan remains an intriguing tool for basic research, our results question whether it provides any additional information in predicting the clinical course in children with SCA, beyond measuring known markers of disease severity.

Measurement of erythrocyte membrane mannoses to assess splenic function.

Red blood cells (RBCs) lose plasma membrane in the spleen as they age, but the cells and molecules involved are yet to be identified. Sickle cell disease and infection by Plasmodium falciparum cause oxidative stress that induces aggregates of cross-linked proteins with N-linked high-mannose glycans (HMGs). These glycans can be recognised by mannose-binding lectins, including the mannose receptor (CD206), expressed on macrophages and specialised phagocytic endothelial cells in the spleen to mediate the extravascular haemolysis characteristic of these diseases. We postulated this system might also mediate removal of molecules and membrane in healthy individuals. Surface expression of HMGs on RBCs from patients who had previously undergone splenectomy was therefore assessed: high levels were indeed observable as large membrane aggregates. Glycomic analysis by mass spectrometry identified a mixture of Man5-9 GlcNAc2 structures. HMG levels correlated well with manual pit counts (r = 0.75-0.85). To assess further whether HMGs might act as a splenic reticuloendothelial function test, we measured levels on RBCs from patients with potential functional hyposplenism, some of whom exhibited high levels that may indicate risk of complications.

Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria.

BACKGROUND: Induction of delta aminolevulinic acid synthase 1 ( ALAS1) gene expression and accumulation of neurotoxic intermediates result in neurovisceral attacks and disease manifestations in patients with acute intermittent porphyria, a rare inherited disease of heme biosynthesis. Givosiran is an investigational RNA interference therapeutic agent that inhibits hepatic ALAS1 synthesis. METHODS: We conducted a phase 1 trial of givosiran in patients with acute intermittent porphyria. In part A of the trial, patients without recent porphyria attacks (i.e., no attacks in the 6 months before baseline) were randomly assigned to receive a single subcutaneous injection of one of five ascending doses of givosiran (0.035, 0.10, 0.35, 1.0, or 2.5 mg per kilogram of body weight) or placebo. In part B, patients without recent attacks were randomly assigned to receive once-monthly injections of one of two doses of givosiran (0.35 or 1.0 mg per kilogram) or placebo (total of two injections 28 days apart). In part C, patients who had recurrent attacks were randomly assigned to receive injections of one of two doses of givosiran (2.5 or 5.0 mg per kilogram) or placebo once monthly (total of four injections) or once quarterly (total of two injections) during a 12-week period, starting on day 0. Safety, pharmacokinetic, pharmacodynamic, and exploratory efficacy outcomes were evaluated. RESULTS: A total of 23 patients in parts A and B and 17 patients in part C underwent randomization. Common adverse events included nasopharyngitis, abdominal pain, and diarrhea. Serious adverse events occurred in 6 patients who received givosiran in parts A through C combined. In part C, all 6 patients who were assigned to receive once-monthly injections of givosiran had sustained reductions in ALAS1 messenger RNA (mRNA), delta aminolevulinic acid, and porphobilinogen levels to near normal. These reductions were associated with a 79% lower mean annualized attack rate than that observed with placebo (exploratory efficacy end point). CONCLUSIONS: Once-monthly injections of givosiran in patients who had recurrent porphyria attacks resulted in mainly low-grade adverse events, reductions in induced ALAS1 mRNA levels, nearly normalized levels of the neurotoxic intermediates delta aminolevulinic acid and porphobilinogen, and a lower attack rate than that observed with placebo. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02452372 .).

The significance of spleen size in children with sickle cell anemia.

It is well established that splenic dysfunction occurs in early childhood in sickle cell anemia (SCA), although the determinants and consequences of splenic injury are not fully understood. In this study, we examined spleen size and splenic function in 100 children with SCA aged 0-16 years at King's College Hospital in London. Spleen size was assessed by abdominal ultrasound (US) and splenic function by pitted red blood cells (PIT counts). In our cohort, 5.6% of children aged 6-10 years and 19.4% of children aged 11-16 years had no visible spleen on US (autosplenectomy). Splenomegaly was common in all age groups, with 28% of children overall having larger spleens than the average for their age. Only one child had a PIT count suggesting preserved splenic function. We found no correlation between hemoglobin F levels and spleen size, nor was there any difference in spleen size between children treated with or without hydroxyurea. Although there was a trend toward increased spleen length in children with co-inherited α-thalassemia, this did not reach statistical significance. Finally, we found a strong association between erythrocyte deformability measured with oxygen gradient ektacytometry, spleen size, and PIT counts. In conclusion, our results do not agree with the general perception that most children with SCA undergo autosplenectomy within the first decade of life and indicate that loss of erythrocyte deformability contributes to loss of splenic filtration capacity in SCA, as well as phenotypical variations in spleen size.

The pleiotropic effects of α-thalassemia on HbSS and HbSC sickle cell disease: Reduced erythrocyte cation co-transport activity, serum erythropoietin, and transfusion burden, do not translate into increased survival.

α-Thalassemia is one of the most important genetic modulators of sickle cell disease (SCD). Both beneficial and detrimental effects have been described previously. We use a 12-year data set on a large cohort of patients with HbSS (n = 411) and HbSC (n = 146) to examine a wide range of these clinical and laboratory associations. Our novel findings are that α-thalassemia strongly reduces erythrocyte potassium chloride co-transporter (KCC) activity in both HbSS and HbSC (p = .035 and p = .00045 respectively), suggesting a novel mechanism through which α-thalassemia induces a milder phenotype by reducing red cell cation loss. This may be particularly important in HbSC where reduction in mean cell hemoglobin concentration is not seen and where KCC activity has previously been found to correlate with disease severity. Additionally, we show that α-thalassemia not only increases hemoglobin in patients with HbSS (p = .0009) but also reduces erythropoietin values (p = .0005), demonstrating a measurable response to improved tissue oxygenation. We confirm the reno-protective effect of α-thalassemia in patients with HbSS, with reduced proteinuria (p = .003) and demonstrate a novel association with increased serum sodium (p = .0004) and reduced serum potassium values (p = 5.74 × 10-10 ). We found patients with α-thalassemia had a reduced annualized transfusion burden in both HbSS and HbSC, but α-thalassemia had no impact on annualized admission rates in either group. Finally, in a larger cohort, we report a median survival of 62 years in patients with HbSS (n = 899) and 80 years in those with HbSC (n = 240). α-thalassemia did not influence survival in HbSS, but a nonsignificant trend was seen in those with HbSC.

Combining Cognitive Mapping and indigenous knowledge to improve food environments in regional New Zealand.

ISSUE ADDRESSED: Hawke's Bay has one of the highest rates of childhood obesity in New Zealand. While several initiatives exist aiming to decrease obesity through physical activity, there are few nutritional interventions. This study adopted a systems science and matauranga Maori approach to identify and target underlying drivers of rising childhood obesity and engage the community to improve the food environment. METHODS: Cognitive mapping interviews (CM) with local stakeholders (school principals, Iwi and district health board representatives, education managers and local councillors) were conducted. The aim was to map participants' mental models of the causes of rising childhood obesity and to identify key principles for engaging with the local community in a meaningful, impactful and culturally appropriate way for future action. RESULTS: Eleven interviews were conducted face-to-face and cognitive maps were constructed. Follow-up interviews were carried out online, due to COVID restrictions, to present the maps and for interviewees to make any adjustments. Four composite themes emerged through centrality and cluster analysis of the resulting cognitive maps: the importance of building in matauranga Maori (Maori knowledge and ways of being), the "hauora" of children, working with the community and integrating existing initiatives. Two contextual factors are also considered: the growing need for food security in our communities and the opportunity to start interventions in the school setting. CONCLUSION: Cognitive mapping can produce useful insights in the early stages of community engagement. The six "pou" (pillars) underscore the importance of incorporating indigenous knowledge when embarking on public health interventions, particularly around obesity and in regional communities. SO WHAT?: When designing a public health initiative with a community with a high indigenous population, indigenous knowledge should be promoted to focus on holistic health, working with the community and creating opportunities for cohesion. These founding principles will be used to structure future community actions to improve children's food environments in regional New Zealand.

Improving the laboratory diagnosis of pyruvate kinase deficiency.

Pyruvate kinase (PK) deficiency is an autosomal recessive disease caused by mutations in the PKLR gene, which reduce erythrocyte PK enzyme activity and result in decreased energy synthesis in red cells, causing haemolytic anaemia. Historically, the investigation into pyruvate kinase deficiency (PKD) has been led by a red cell enzyme assay determining PK enzyme activity per unit of haemoglobin. For our laboratory, the reference range was set by Beutler et al. in 1977 when the test was first established. The introduction of genetic testing permitted the creation of reference sample datasets, with positive controls having two pathogenic variants causing disease. This permitted re-assessment of the enzyme assay's sensitivity and specificity, and was used to reassess the reference range of the enzyme assay. Using sequenced samples, we have devised an enzyme assay, DNA testing workflow, which minimises false negative/positive results and improves the diagnostic efficiency. This combined enzyme-DNA testing strategy should improve the diagnostic accuracy whilst limiting the number of expensive DNA tests. During this evaluation, 10 novel genetic variants were identified and are described.

EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks.

BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.

Genome wide association study of silent cerebral infarction in sickle cell disease (HbSS and HbSC).

Not available.

The association between silica exposure, silicosis and tuberculosis: a systematic review and meta-analysis.

BACKGROUND: While the association between occupational inhalation of silica dust and pulmonary tuberculosis has been known for over a century, there has never been a published systematic review, particularly of experience in the current era of less severe silicosis and treatable tuberculosis. We undertook a systematic review of the evidence for the association between (1) silicosis and pulmonary tuberculosis, and (2) silica exposure and pulmonary tuberculosis controlling for silicosis, and their respective exposure-response gradients. METHODS: We searched PUBMED and EMBASE, and selected studies according to a priori inclusion criteria. We extracted, summarised and pooled the results of published case-control and cohort studies of silica exposure and/or silicosis and incident active tuberculosis. Study quality was assessed on the Newcastle-Ottawa Scale. Where meta-analysis was possible, effect estimates were pooled using inverse-variance weighted random-effects models. Otherwise narrative and graphic synthesis was undertaken. Confidence regarding overall effect estimates was assessed using the GRADE schema. RESULTS: Nine studies met the inclusion criteria. Meta-analysis of eight studies of silicosis and tuberculosis yielded a pooled relative risk of 4.01 (95% confidence interval (CI) 2.88, 5.58). Exposure-response gradients were strong with a low silicosis severity threshold for increased risk. Our GRADE assessment was high confidence in a strong association. Meta-analysis of five studies of silica exposure controlling for or excluding silicosis yielded a pooled relative risk of 1.92 (95% CI 1.36, 2.73). Exposure-response gradients were observable in individual studies but not finely stratified enough to infer an exposure threshold. Our GRADE assessment was low confidence in the estimated effect owing to inconsistency and use of proxies for silica exposure. CONCLUSIONS: The evidence is robust for a strongly elevated risk of tuberculosis with radiological silicosis, with a low disease severity threshold. The effect estimate is more uncertain for silica exposure without radiological silicosis. Research is needed, particularly cohort studies measuring silica exposure in different settings, to characterise the effect more accurately as well as the silica exposure threshold that could be used to prevent excess tuberculosis risk.

Pitfalls in the Diagnosis of ß-Thalassemia Intermedia.

We present case histories of three patients who had ß-thalassemia (ß-thal) trait with 'unusual severity' managed as ß-thal intermedia (ß-TI) where the basis of disease severity could not be explained with routine hematological and genetic investigations. The clinical diagnosis of 'thalassemia intermedia' was justifiable as they had a ß-thal mutation and disease severity that did not fit in with either ß-thal trait or with ß-thal major (ß-TM). As mutations of α, ß, and γ genes could not explain the unusual severity of the disease, further analysis with next-generation sequencing (NGS) for red cell diseases was carried out, which led to the diagnosis of coexisting membranopathies. This case series highlights the inherent difficulty in the diagnosis of ß-TI with certainty in some patients where the genetic basis is not clear-cut.

Emerging therapies in sickle cell disease.

Despite sickle cell disease (SCD) being the most common and severe inherited condition worldwide, therapeutic options are limited. To date, hydroxyurea remains the main treatment option in SCD. However, in the last decade the numbers of interventional clinical trials focussing on therapies for SCD have increased significantly. Many new drugs with various pharmacological targets have emerged and, although the majority have failed to show benefit in clinical trials, some have produced encouraging results. It seems probable that more drugs will soon become available for the treatment of SCD. Furthermore, promising clinical trials with improved outcomes have recently changed the perspective of curative therapies in SCD. Nevertheless, the application of novel therapeutic agents and potential curative treatments will most likely be limited to high-income countries and, thus, will remain unavailable for the majority of people with SCD in the foreseeable future.