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Summary: We evaluated the impact of peer reviews in driving improvement in healthcare quality for people with haemoglobinopathy in the United Kingdom. We analysed compliance to four Quality Standards (QS)‐based peer reviews from 2010 to 2020 to evaluate its impact in driving healthcare quality. Seventeen paediatric and 29 adult haemoglobinopathy centres were reviewed in 2010/11 and 2012/13 respectively; 33 paediatric and 33 adult centres were reviewed in 2014/16, and 32 paediatric and 32 adult centres were reviewed in 2018/2020. Compliance with QS and participant feedback were analysed to assess the impact of peer review programmes to drive improvement in quality of care. We noted that haemoglobinopathy centres significantly improved their compliance to QS between the first two review programmes, but not in the final review programme. In comparison to other disease‐group reviews, the haemoglobinopathy departments were less able to address critical peer review recommendations in their own institutions. The peer review programme was unable to drive sustained improvement in healthcare quality, underscoring the need for sustained development and support for haemoglobinopathy services in the National Health Service. Further work is needed to understand why disparities exist among peer review‐driven improvement initiatives within different disease groups. [ABSTRACT FROM AUTHOR]

Diamond-Blackfan anemia (DBA) is a rare bone marrow failure syndrome, usually caused by loss-of function variants in genes encoding ribosomal proteins. The hallmarks of DBA are anemia, congenital anomalies and cancer predisposition. Although DBA usually presents in childhood, the prevalence in later life is increasing due to an expanding repertoire of implicated genes, improvements in genetic diagnosis and increasing life expectancy. Adult patients uniquely suffer the manifestations of end-organ damage caused by the disease and its treatment, and transition to adulthood poses specific issues in disease management. To standardize and optimize care for this rare disease, in this review we provide updated guidance on the diagnosis and management of DBA, with a specific focus on older adolescents and adults. Recommendations are based upon published literature and our pooled clinical experience from three centres in the United Kingdom (U·K.). Uniquely we have also solicited and incorporated the views of affected families, represented by the independent patient organization, DBA U.K., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interests to declare., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Young children with sickle cell anaemia (SCA) often have slowed processing speed associated with reduced brain white matter integrity, low oxygen saturation, and sleep-disordered breathing (SDB), related in part to enlarged adenoids and tonsils. Common treatments for SDB include adenotonsillectomy and nocturnal continuous positive airway pressure (CPAP), but adenotonsillectomy is an invasive surgical procedure, and CPAP is rarely well-tolerated. Further, there is no current consensus on the ability of these treatments to improve cognitive function. Several double-blind, randomised controlled trials (RCTs) have demonstrated the efficacy of montelukast, a safe, well-tolerated anti-inflammatory agent, as a treatment for airway obstruction and reducing adenoid size for children who do not have SCA. However, we do not yet know whether montelukast reduces adenoid size and improves cognition function in young children with SCA., Methods: The Study of Montelukast In Children with Sickle Cell Disease (SMILES) is a 12-week multicentre, double-blind, RCT. SMILES aims to recruit 200 paediatric patients with SCA and SDB aged 3-7.99 years to assess the extent to which montelukast can improve cognitive function (i.e. processing speed) and sleep and reduce adenoidal size and white matter damage compared to placebo. Patients will be randomised to either montelukast or placebo for 12 weeks. The primary objective of the SMILES trial is to assess the effect of montelukast on processing speed in young children with SCA. At baseline and post-treatment, we will administer a cognitive evaluation; caregivers will complete questionnaires (e.g. sleep, pain) and measures of demographics. Laboratory values will be obtained from medical records collected as part of standard care. If a family agrees, patients will undergo brain MRIs for adenoid size and other structural and haemodynamic quantitative measures at baseline and post-treatment, and we will obtain overnight oximetry., Discussion: Findings from this study will increase our understanding of whether montelukast is an effective treatment for young children with SCA. Using cognitive testing and MRI, the SMILES trial hopes to gain critical knowledge to help develop targeted interventions to improve the outcomes of young children with SCA., Trial Registration: ClinicalTrials.gov NCT04351698 . Registered on April 17, 2020. European Clinical Trials Database (EudraCT No. 2017-004539-36). Registered on May 19, 2020., (© 2021. The Author(s).)

Liver involvement in sickle cell disease (SCD) is often referred to as sickle cell hepatopathy (SCH) and is a complication of SCD which may be associated with significant mortality. This review is based on a round-table workshop between paediatric and adult hepatologists and haematologists and review of the literature. The discussion was prompted by the lack of substantial data and guidance in managing these sometimes very challenging cases. This review provides a structured approach for the diagnosis and management of SCH in children and young adults. The term SCH describes any hepatobiliary dysfunction in the context of SCD. Diagnosis and management of biliary complications, acute hepatic crisis, acute hepatic sequestration and other manifestations of SCH are discussed, as well as the role of liver transplantation and haemopoietic stem cell transplantation in the management of SCH., Competing Interests: Competing interests: EK, FL, EF, MDa, NHe, SH, MS, FM, VB, AS, AV, MV, BI, ED, NHa, TG, JH, MDe, MS and AD have nothing to disclose. DR is on advisory boards of Novartis and DSMB of AstraZeneca outside the submitted work. GG reports personal fees from Alexion Pharmaceuticals outside the submitted work. SC reports personal fees from Novartis outside the submitted work. VB reports personal fees from Bluebirdbio and from Addmedica, outside the submitted work., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

With the developing COVID-19 pandemic, patients with inherited anaemias require specific advice regarding isolation and changes to usual treatment schedules. The National Haemoglobinopathy Panel (NHP) has issued guidance on the care of patients with sickle cell disease, thalassaemia, Diamond Blackfan anaemia (DBA), congenital dyserythropoietic anaemia (CDA), sideroblastic anaemia, pyruvate kinase deficiency and other red cell enzyme and membrane disorders. Cascading of accurate information for clinicians and patients is paramount to preventing adverse outcomes, such as patients who are at increased risk of fulminant bacterial infection due to their condition or its treatment erroneously self-isolating if their fever is mistakenly attributed to a viral cause, delaying potentially life-saving antibiotic therapy. Outpatient visits should be minimised for most patients, however some, such as first transcranial dopplers for children with sickle cell anaemia should not be delayed as known risk of stroke will outweigh the unknown risk from COVID-19 infection. Blood transfusion programmes should be continued, but specific changes to usual clinical pathways can be instituted to reduce risk of patient exposure to COVID-19, as well as contingency planning for possible reductions in blood available for transfusions. Bone marrow transplants for these disorders should be postponed until further notice. With the current lack of evidence on the risk and complications of COVID-19 infection in these patients, national data collection is ongoing to record outcomes and eventually to identify predictors of disease severity, particularly important if further waves of infection travel through the population., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Pregnancies in women with sickle cell disease (SCD) are associated with a higher risk of sickle and pregnancy complications. Limited options exist for treating SCD during pregnancy. Serial prophylactic exchange blood transfusion (SPEBT) has been shown to be effective in treating SCD outside pregnancy, but evidence is lacking regarding its use during pregnancy. The aim of this study is to assess the feasibility and acceptability of conducting a future phase 3 randomised controlled trial (RCT) to establish the clinical and cost effectiveness of SPEBT in pregnant women with SCD., Methods: The study is an individually randomised, two-arm, feasibility trial with embedded qualitative and health economic studies. Fifty women, 18 years of age and older, with SCD and a singleton pregnancy at ≤ 18 weeks' gestation will be recruited from six hospitals in England. Randomisation will be conducted using a secure online database and minimised by centre, SCD genotype and maternal age. Women allocated to the intervention arm will receive SPEBT commencing at ≤ 18 weeks' gestation, performed using automated erythrocytapheresis every 6-10 weeks until the end of pregnancy, aiming to maintain HbS% or combined HbS/HbC% below 30%. Women in the standard care arm will only receive transfusion when clinically indicated. The primary outcome will be the recruitment rate. Additional endpoints include reasons for refusal to participate, attrition rate, protocol adherence, and maternal and neonatal outcomes. Women will be monitored throughout pregnancy to assess maternal, sickle, and foetal complications. Detailed information about adverse events (including hospital admission) and birth outcomes will be extracted from medical records and via interview at 6 weeks postpartum. An embedded qualitative study will consist of interviews with (a) 15-25 trial participants to assess experiences and acceptability, (b) 5-15 women who decline to participate to identify barriers to recruitment and (c) 15-20 clinical staff to explore fidelity and acceptability. A health economic study will inform a future cost effectiveness and cost-utility analysis., Discussion: This feasibility study aims to rigorously evaluate SPEBT as a treatment for SCD in pregnancy and its impact on maternal and infant outcomes., Trial Registration: NIH registry (www.clinicaltrials.gov), registration number NCT03975894 (registered 05/06/19); ISRCTN (www.isrctn.com), registration number ISRCTN52684446 (retrospectively registered 02/08/19).

Patients with β-thalassemia major (BTM) require regular blood transfusions, supported by appropriate iron chelation therapy (ICT), throughout their life. β-thalassemia is a global disease that is most highly prevalent in Southeast Asia, Africa, and Mediterranean countries. However, the global distribution of patients with β-thalassemia is changing due to population migration, and Northern European countries now have significant thalassemia populations. Globally, many patients with BTM have limited access to regular and safe blood transfusions. A lack of voluntary nonremunerated blood donors, poor awareness of thalassemia, a lack of national blood policies, and fragmented blood services contribute to a significant gap between the timely supply of, and demand for, safe blood. In many centers, there is inadequate provision of antigen testing, even for common red cell antigens such as CcEe and Kell. Policies to raise awareness and increase the use of red blood cell antigen testing and requesting of compatible blood in transfusion centers are needed to reduce alloimmunization (the development of antibodies to red blood cell antigens), which limits the effectiveness of transfusions and the potential availability of blood. Patients with BTM are also at risk of transfusion-transmitted infections unless appropriate blood screening and safety practices are in place. Hence, many patients are not transfused or are undertransfused, resulting in decreased health and quality-of-life outcomes. Hemovigilance, leukoreduction, and the ability to thoroughly investigate transfusion reactions are often lacking, especially in resource-poor countries. ICT is essential to prevent cardiac failure and other complications due to iron accumulation. Despite the availability of potentially inexpensive oral ICT, a high proportion of patients suffer complications of iron overload and die each year due to a lack of, or inadequate, ICT. Increased awareness, training, and resources are required to improve and standardize adequate blood transfusion services and ICT among the worldwide population of patients with BTM. ICT needs to be available, affordable, and correctly prescribed. Effective, safe, and affordable new treatments that reduce the blood transfusion burden in patients with β-thalassemia remain an unmet need., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Venous thromboembolism (VTE) is a major cause of preventable hospital death, accounting for up to 10% of inpatient mortality. National guidelines recommend that all patients should be regularly assessed for VTE risk, and prescribed mechanical and pharmacological prophylaxis accordingly. While previous studies have focused on improving prescription uptake on admission, there has been relatively little emphasis on the inappropriate suspension of prophylaxis during inpatient stay., Objective: The purpose of this project was to identify the reasons and scale of inappropriate suspension of pharmacological VTE prophylaxis for medical inpatients. We subsequently planned to introduce a number of interventions in order to reduce inappropriate suspension., Methods: An initial audit of all medical inpatients was carried out to establish the number with inappropriately suspended pharmacological prophylaxis. We then designed a series of educational meetings and electronic prompting interventions to alert prescribers to these errors, followed by re-audit to assess their efficacy., Results: The number of patients with inappropriately suspended VTE prophylaxis was significantly reduced following introduction of our intervention strategy., Conclusions: Combined education and electronic email prompts are an effective way of alerting practitioners to reduce inappropriate suspension of VTE prophylaxis. With ongoing teaching and integration of prescribing software alerts, this reduction in VTE prescribing errors could be sustained., Competing Interests: Competing interests: None declared.

Background: Early detection and interventions have enabled patients with sickle cell disease (SCD) to live well into adulthood. Consequently, the chronicity of SCD allows for the insidious manifestation of multisystem complications, including renal damage. Cystic renal lesions are commonly incidentally discovered on ultrasound and computerised tomography (CT) imaging of the abdomen. Most are benign simple cysts, however, difficulties may be encountered if infection, rupture, haemorrhage or cancerous changes develop. We aimed to determine whether patients with SCD have a higher prevalence of simple renal cysts compared to non-SCD individuals., Methods: Data for a group of 223 patients with SCD who had undergone an ultrasound and/or CT imaging of the abdomen were extracted for comparison with 180 control patients (haemoglobin genotype unknown), matched for age and ethnicity. Scans were evaluated for 198 SCD patients and 180 controls., Results: Renal cysts were found in 58% of the SCD group and 20% of the controls (OR 5.4 (CI 2.6-11.0), RR 2.8 (CI 1.9-4.2)). Bilateral renal cysts were found in 28% of the SCD participants in comparison with 5% of the control group. In those who had one or more cysts identified, the average number of cysts was 3.76 for the SCD group and 1.94 for the controls. Men with SCD were more likely to develop cysts than women (66% vs 53%), as were men without SCD (22% vs 17%)., Conclusions: Simple renal cysts occur more frequently, are more abundant and develop at a younger age in patients with SCD than ethnically-matched controls. Further study of the mechanism underlying cyst formation may shed light on both sickle cell nephropathy and other cystic renal diseases.

We explored transient elastography (TE) and enhanced liver fibrosis (ELF ™ ) score with standard markers of liver function to assess liver damage in 193 well patients with sickle cell disease (SCD). Patients with HbSS or HbSβ 0 thalassaemia (sickle cell anaemia, SCA; N = 134), had significantly higher TE results and ELF scores than those with HbSC (N = 49) disease (TE, 6·8 vs. 5·3, P < 0·0001 and ELF, 9·2 vs. 8·6 P < 0·0001). In SCA patients, TE and ELF correlated significantly with age and all serum liver function tests (LFTs). Additionally, (weak) positive correlation was found with lactate dehydrogenase (TE: r = 0·24, P = 0·004; ELF: r = 0·26 P = 0·002), and (weak) negative correlation with haemoglobin (TE: r = -0·25, P = 0·002; ELF: r = -0·25 P = 0·004). In HbSC patients, correlations were weaker or not significant between TE or ELF, and serum LFTs. All markers of iron loading correlated with TE values when corrected for sickle genotype (serum ferritin, β = 0·25, P < 0·0001, total blood transfusion units, β = 0·25, P < 0·0001 and LIC β = 0·32, P = 0·046). The exploratory study suggests that, while TE could have a role, the utility of ELF score in monitoring liver damage in SCD, needs further longitudinal studies., Competing Interests: The authors declare that they have no competing interests, (© 2016 John Wiley & Sons Ltd.)

Aims: Patients with sickle cell disease have significant morbidity and mortality. Pulmonary hypertension is suggested to be an important contributor but its nature and severity in these patients and how best to non-invasively assess it are controversial. We hypothesised that a high-output state rather than primary pulmonary vascular pathology may be the major abnormality in sickle cell disease. This study aimed to evaluate the characteristics and severity of pulmonary hypertension in patients with sickle cell disease using detailed echocardiography., Methods and Results: We undertook a prospective study in 122 consecutive stable outpatients with sickle cell disease and 30 age, gender and ethnicity-matched healthy controls. Echocardiographic evaluation included 3D ventricular volumes, sphericity, tissue Doppler, and non-invasive estimation of pulmonary vascular resistance. 36% of patients had a tricuspid regurgitant velocity ≥2.5 m.s(-1) but only 2% had elevated pulmonary vascular resistance and the prevalence of right ventricular dysfunction was very low. Patients with raised tricuspid regurgitant velocity had significantly elevated biventricular volumes and globular left ventricular remodelling, related primarily to anaemia. In a subgroup of patients who underwent cardiac catheterization, invasive pulmonary haemodynamics confirmed the echocardiographic findings., Conclusions: Elevated cardiac output and left ventricular volume overload secondary to chronic anaemia may be the dominant factor responsible for abnormal cardiopulmonary haemodynamics in patients with sickle cell disease. 3D echocardiography with non-invasive estimation of pulmonary vascular resistance represents a valuable approach for initial evaluation of cardiopulmonary haemodynamics in sickle cell disease.

Aim: To evaluate spectral domain optical coherence tomography (SD-OCT) changes in central retina and choroid in patients with sickle cell disease (SCD)., Methods: Data on visual acuity, severity of sickle cell retinopathy, macular volume scans and choroidal thickness on SD-OCT were analysed from 208 eyes of 107 consecutive patients referred for screening for SCD. The retinal and choroidal thickness of eyes with SCD were also compared with age and ethnicity matched controls., Results: 44% of the eyes of patients with SCD showed discrete areas of retinal thinning in the temporal macular area. Proliferative sickle cell retinopathy was more prevalent in these eyes compared with SCD eyes with normal macular morphology (67% vs. 48%; p=0.0017). The temporal total and inner retinal thickness, macular volume and choroidal thickness were significantly lower in patients with SCD compared with age, gender and ethnicity matched controls. Macular splaying (widening of the macular contour) was noted in 30% of eyes in both groups. The choroidal and retinal thickness values showed good intergrader reliability using weighted κ statistics (0.550-0.9)., Conclusions: Quantitative and qualitative changes on SD-OCT are present in asymptomatic SCD eyes. Proliferative retinopathy is more prevalent in eyes with discrete areas of macular thinning., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

HMIP-2 is a human quantitative trait locus affecting peripheral numbers, size and hemoglobin composition of red blood cells, with a marked effect on the persistence of the fetal form of hemoglobin, HbF, in adults. The locus consists of multiple common variants in an enhancer region for MYB (chr 6q23.3), which encodes the hematopoietic transcription factor cMYB. Studying a European population cohort and four African-descended groups of patients with sickle cell anemia, we found that all share a set of two spatially separate HbF-promoting alleles at HMIP-2, termed "A" and "B." These typically occurred together ("A-B") on European chromosomes, but existed on separate homologous chromosomes in Africans. Using haplotype signatures for "A" and "B," we interrogated public population datasets. Haplotypes carrying only "A" or "B" were typical for populations in Sub-Saharan Africa. The "A-B" combination was frequent in European, Asian, and Amerindian populations. Both alleles were infrequent in tropical regions, possibly undergoing negative selection by geographical factors, as has been reported for malaria with other hematological traits. We propose that the ascertainment of worldwide distribution patterns for common, HbF-promoting alleles can aid their further genetic characterization, including the investigation of gene-environment interaction during human migration and adaptation., (© 2014 The Authors. Annals of Human Genetics published by University College London (UCL) and John Wiley & Sons Ltd.)

Haemolytic anaemia is variable among patients with sickle cell anaemia and can be estimated by reticulocyte count, lactate dehydrogenase, aspartate aminotransferase and bilirubin levels. Using principal component analysis of these measurements we computed a haemolytic score that we used as a subphenotype in a genome-wide association study. We identified in one cohort and replicated in two additional cohorts the association of a single nucleotide polymorphism in NPRL3 (rs7203560; chr16p13·3) (P = 6·04 × 10(-07) ). This association was validated by targeted genotyping in a fourth independent cohort. The HBA1/HBA2 regulatory elements, hypersensitive sites (HS)-33, HS-40 and HS-48 are located in introns of NPRL3. Rs7203560 was in perfect linkage disequilibrium (LD) with rs9926112 (r(2)  = 1) and in strong LD with rs7197554 (r(2)  = 0·75) and rs13336641 (r(2)  = 0·77); the latter is located between HS-33 and HS-40 sites and next to a CTCF binding site. The minor allele for rs7203560 was associated with the -∝(3·7) thalassaemia gene deletion. When adjusting for HbF and ∝ thalassaemia, the association of NPRL3 with the haemolytic score was significant (P = 0·00375) and remained significant when examining only cases without gene deletion∝ thalassaemia (P = 0·02463). Perhaps by independently down-regulating expression of the HBA1/HBA2 genes, variants of the HBA1/HBA2 gene regulatory loci, tagged by rs7203560, reduce haemolysis in sickle cell anaemia., (© 2013 Blackwell Publishing Ltd.)

A study published in 1981 examined the causes of hospital admission for a cohort of children with sickle cell disease (SCD). Since that time, the incidence and prevalence of SCD has increased markedly in the UK, and there have been many changes in the management of this disease. We undertook a study examining the causes of hospital admission of children with SCD to the same hospital as the previous study, over the 2-year period from 2008 to 2009. We found that the numbers of children being cared for by our hospital had dramatically increased over the last 50 years, but rates of hospital admission had significantly fallen (41 hospital admissions per 100 patient-years, compared with 111.3 admissions per 100 patient-years in the original study). This fall in admission rates is accounted for by 2 major components: acute painful episodes (15.7 admissions per 100 patient-years compared with 39.3 in the previous study) and admission for elective blood transfusion (0.2 admissions per 100 patient-years compared with 26.7 in the previous study). It is interesting to note that, 541 elective transfusions were carried out during the study period, but in a day-care setting rather than requiring overnight admission. This study illustrates the changes in management of SCD over the past 30 years, and reflects the overall trend common to most hospital specialties of increasing community and ambulatory care.

Transfusion of red blood cells is a major therapeutic option in sickle cell disease (SCD). There is strong evidence for its efficacy, particularly in primary and secondary stroke prevention in children, however, its use in other areas remains controversial. This study assessed the patterns of transfusion in the adult cohort attending King's College Hospital over a 10-year period, from 2000 to 2009. Total blood usage has increased significantly (P = 0·006) during this time, with 78% of the blood received by only 6% of the patients. The increase is explained by increased automated red cell exchange and increased usage for planned and acute transfusions for sickle-related complications., (© 2011 Blackwell Publishing Ltd.)

Fetal hemoglobin (HbF, α(2)γ(2)) is a major contributor to the remarkable phenotypic heterogeneity of sickle cell anemia (SCA). Genetic variation at 3 principal loci (HBB cluster on chromosome 11p, HBS1L-MYB region on chromosome 6q, and BCL11A on chromosome 2p) have been shown to influence HbF levels and disease severity in β-thalassemia and SCA. Previous studies in SCA, however, have been restricted to populations from the African diaspora, which include multiple genealogies. We have investigated the influence of these 3 loci on HbF levels in sickle cell patients from Tanzania and in a small group of African British sickle patients. All 3 loci have a significant impact on the trait in both patient groups. The results suggest the presence of HBS1L-MYB variants affecting HbF in patients who are not tracked well by European-derived markers, such as rs9399137. Additional loci may be identified through independent genome-wide association studies in African populations.