Publications
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Clayden JD, Stotesbury H, Kawadler JM, et al., 2022, Structural connectivity mediates the relationship between blood oxygenation and cognitive function in sickle cell anemia., Blood Adv
In sickle cell disease (SCD), the relative importance of reduced hemoglobin and peripheral oxygen saturation (SpO2) on brain structure remains uncertain. We applied graph-theoretical analysis to diffusion MRI data to investigate the effect of structural brain connectivity on cognitive function, alongside presence/absence, number and volume of silent cerebral infarction (SCI). In patients, we investigated the relationships between network properties, blood oxygenation and cognition (working memory, WMI, and processing speed, PSI, indices). Based on streamline counts and fractional anisotropy (FA), we identified a subnetwork with weakened connectivity in 92 SCA patients (49 males; 8.0-38.8 years), compared to 54 non-SCA controls (22 males; 6.7-30.6 years). Multiple regression analyses showed a significant effect of hemoglobin on full-network edge density (p<0.05), and of peripheral SpO2 on streamline-weighted subnetwork efficiency (p<0.01). There were effects of FA-weighted full-network and subnetwork efficiency on WMI (both p<0.05), and of streamline-weighted subnetwork efficiency on PSI (p=0.05) but no effects on SCI. Streamline-weighted efficiency was progressively lower with lower SpO2, with a downstream effect on PSI. In path analysis, indirect relationships between blood oxygenation and cognition, mediated by network properties, were better supported than direct alternatives, with an indirect relationship between low SpO2 and PSI in patients, mediated by structural connectivity efficiency in a subnetwork of the brain differing from controls. Our findings are consistent with the notion that cognitive impairment is primarily mediated by hypoxic-ischemic effects on normal-appearing white matter, and highlight the utility of network-based methods in providing biomarkers of cognitive dysfunction in SCA patients.
Griffin R, Panayiotou A, Allen P, et al., 2022, What is the role of chest X-ray imaging in the acute management of children with sickle cell disease?, Br J Haematol, Vol: 196, Pages: 402-413
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.
Kyrana E, Rees D, Lacaille F, et al., 2021, Clinical management of sickle cell liver disease in children and young adults, ARCHIVES OF DISEASE IN CHILDHOOD, Vol: 106, Pages: 315-320, ISSN: 0003-9888
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- Citations: 4
Renedo A, Miles S, Chakravorty S, et al., 2020, Understanding the health-care experiences of people with sickle cell disorder transitioning from paediatric to adult services: This Sickle Cell Life, a longitudinal qualitative study, Health Services and Delivery Research, Vol: 8, Pages: 1-118, ISSN: 2050-4349
BackgroundTransitions from paediatric to adult health-care services cause problems worldwide, particularly for young people with long-term conditions. Sickle cell disorder brings particular challenges needing urgent action.ObjectivesUnderstand health-care transitions of young people with sickle cell disorder and how these interact with broader transitions to adulthood to improve services and support.MethodsWe used a longitudinal design in two English cities. Data collection included 80 qualitative interviews with young people (aged 13–21 years) with sickle cell disorder. We conducted 27 one-off interviews and 53 repeat interviews (i.e. interviews conducted two or three times over 18 months) with 48 participants (30 females and 18 males). We additionally interviewed 10 sickle cell disease specialist health-care providers. We used an inductive approach to analysis and co-produced the study with patients and carers.ResultsKey challenges relate to young people’s voices being ignored. Participants reported that their knowledge of sickle cell disorder and their own needs are disregarded in hospital settings, in school and by peers. Outside specialist services, health-care staff refuse to recognise patient expertise, reducing patients’ say in decisions about their own care, particularly during unplanned care in accident and emergency departments and on general hospital wards. Participants told us that in transitioning to adult care they came to realise that sickle cell disorder is poorly understood by non-specialist health-care providers. As a result, participants said that they lack trust in staff’s ability to treat them correctly and that they try to avoid hospital. Participants reported that they try to manage painful episodes at home, knowing that this is risky. Participants described engaging in social silencing (i.e. reluctance to talk about and disclose their condition for fear that others will not listen or will not understand) outside hospi
Chakravorty S, Rees D, 2020, Commentary on sickle cell non-invasive prenatal testing article., Br J Haematol, Vol: 190, Pages: 20-21
van Geyzel L, Arigliani M, Inusa B, et al., 2020, Higher oxygen saturation with hydroxyurea in paediatric sickle cell disease, ARCHIVES OF DISEASE IN CHILDHOOD, Vol: 105, Pages: 575-579, ISSN: 0003-9888
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- Citations: 6
Arigliani M, Zheng S, Ruiz G, et al., 2020, Comparison of pulse oximetry and earlobe blood gas with CO-oximetry in children with sickle cell disease: a retrospective review, BMJ PAEDIATRICS OPEN, Vol: 4
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- Citations: 3
Renedo A, Miles S, Chakravorty S, et al., 2019, Not being heard: barriers to high quality unplanned hospital care during young people's transition to adult services - evidence from 'this sickle cell life' research, BMC Health Services Research, Vol: 19, ISSN: 1472-6963
BACKGROUND: Young people's experiences of healthcare as they move into adult services can have a major impact on their health, and the transition period for young people with sickle cell disease (SCD) needs improvement. In this study, we explore how young people with SCD experience healthcare during this period of transition. METHODS: We conducted a co-produced longitudinal qualitative study, including 80 interviews in 2016-2017 with young people with SCD aged 13-21 (mean age 16.6) across two cities in England. We recruited 48 participants (30 female, 18 male): 27 interviews were one-off, and 53 were repeated 2-3 times over approximately 18 months. We used an inductive analytical approach, combining elements of Grounded Theory and thematic analysis. RESULTS: Participants reported significant problems with the care they received in A&E during painful episodes, and in hospital wards as inpatients during unplanned healthcare. They experienced delays in being given pain relief and their basic care needs were not always met. Participants said that non-specialist healthcare staff did not seem to know enough about SCD and when they tried to work with staff to improve care, staff often seemed not prepared to listen to them or act on what they said. Participants said they felt out of place in adult wards and uncomfortable with the differences in adult compared with paediatric wards. Because of their experiences, they tried to avoid being admitted to hospital, attempting to manage their painful episodes at home and accessing unplanned hospital care only as a last resort. By contrast, they did not report having problems within SCD specialist services during planned, routine care. CONCLUSIONS: Our study underscores the need for improvements to make services youth-friendly and youth-responsive, including training staff in SCD-specific care, compassionate care and communication skills that will help them elicit and act on young people's voices to ensure they are involv
Chakravorty S, Dick MC, 2019, Antenatal screening for haemoglobinopathies: current status, barriers and ethics., Br J Haematol, Vol: 187, Pages: 431-440
Sickle cell disease (SCD) and thalassaemia are genetic disorders that are caused by errors in the genes for haemoglobin and are some of the most common significant genetic disorders in the world, resulting in significant morbidity and mortality. Great disparities exist in the outcome of these conditions between resource- rich and resource-poor nations. Antenatal screening for these disorders aims to provide couples with information about their reproductive risk and enable them to make informed reproductive choices; ultimately reducing the likelihood of children being born with these conditions. This review provides an overview of the current status of antenatal, pre-marital and population screening of SCD and thalassaemia in countries with both high-and low prevalence of these conditions, methods of screening in use, and discusses some of the pitfalls, ethical issues and controversies surrounding antenatal screening. It also discusses outcomes of some screening programmes and recognises the need for the establishment of antenatal screening in areas where their prevalence is highest; namely sub-Saharan Africa and India.
Park H, Bhatti S, Chakravorty S, 2019, Effectiveness of hydroxycarbamide in children with sickle cell disease - Analysis of dose-response metrics in a large birth cohort in a tertiary sickle cell centre, PEDIATRIC BLOOD & CANCER, Vol: 66, ISSN: 1545-5009
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- Citations: 2
Kawadler JM, Slee A, Stotesbury H, et al., 2019, Index of Pain Experience in Sickle Cell Anaemia (IPESCA): development from daily pain diaries and initial findings from use with children and adults with sickle cell anaemia., Br J Haematol, Vol: 186, Pages: 360-363
Rooks H, Brewin J, Gardner K, et al., 2019, A gain of function variant in PIEZO1 (E756del) and sickle cell disease., Haematologica, Vol: 104, Pages: e91-e93
Roberts IAG, Chakravorty S, 2019, Thrombocytopenia in the newborn, Platelets, Pages: 813-831, ISBN: 9780128134566
Neonatal thrombocytopenia remains a common clinical problem although most episodes are mild and resolve spontaneously. Most early-onset thrombocytopenias are due to impaired fetal megakaryocytopoiesis associated with placental insufficiency/fetal hypoxia. Severe early-onset thrombocytopenia (presenting < 72 hours of life) is usually due to congenital or perinatal infections, asphyxia or fetal/neonatal alloimmune thrombocytopenia (FNAIT) while late-onset thrombocytopenia (presenting after 72 hours) is usually due to sepsis and/or necrotizing enterocolitis (NEC). Major hemorrhage is uncommon in stable neonates with severe thrombocytopenia while clinically unstable neonates often have a poor outcome. Currently, the only therapy is platelet transfusion. However, there is wide variation in platelet transfusion thresholds worldwide and frequent deviation from transfusion guidelines. Controlled trials of platelet transfusion for severe neonatal thrombocytopenia, now underway, aim to identify the best regimens to treat and prevent hemorrhage and target therapy to neonates at highest risk. In future, improved understanding of fetal/neonatal megakaryocytopoiesis and TPO mimetics may benefit neonates with prolonged thrombocytopenia.
Chakravorty S, Tallett A, Sathyamoorthy G, et al., 2018, Patient reported experience measure in Sickle Cell disease, Archives of Disease in Childhood, Vol: 103, Pages: 1104-1109, ISSN: 1468-2044
Objectives:To develop Patient Reported Experience Measure surveys for patients with Sickle CellDisease (SCD) to understand their healthcare and lived experience in the UK and fortheir use in future to inform healthcare service development.Design:Picker methodology was used as follows:1. Qualitative scoping by focus group discussions2. Questionnaire development through stakeholder consultations3. Construct validation of questionnaires through cognitive testing4. Further assessment of construct validity by a nationwide pilot surveySetting:Patients with SCD and their carers were eligible. Focus group discussions took place innon-hospital settings, arranged out-of-hours. Cognitive testing took place in specialistSickle Cell clinics. The pilot survey was available to UK participants only and wasadministered through web-based questionnaires, face-to face completion and in sicklecell community events.Participants:Thirty-three patients and carers took part in the focus groups, 21 participants undertookcognitive testing and 722 respondents completed the pilot survey.Results:Findings highlighted a widespread prevalence of poor knowledge about SCD amonghealthcare providers and the public. Poorer experience of care was present in the emergency setting compared to planned care, of which lack of timely provision of painrelief was of concern. Adolescents and young people reported significantly poorerexperience of care in several domains compared to children or adults.Conclusions:The new surveys functioned well, with good evidence of validity, and were accessible tothe SCD patient population, supporting their future use in assessing patient experienceto inform service delivery and improvements in care quality.
Hall R, Gardner K, Rees D, et al., 2018, High body mass index in children with sickle cell disease- a retrospective single-centre audit, BMJ Paediatrics Open, Vol: 2, ISSN: 2399-9772
Objective To assess the prevalence of high body mass index (BMI) in children with sickle cell disease and assess correlation between BMI and disease severity.Design Retrospective chart review followed by statistical analysis.Setting A single tertiary paediatric clinic in inner city London.Patients All patients with sickle cell disease, including homozygous haemoglobin (HbSS) and compound heterozygous Hb (HbSC), age 2–18 years receiving clinical care at the centre, were included in the study.Interventions Height and weight measurements, steady-state laboratory blood tests, hospital admission rates, adjunct therapy such as hydroxycarbamide or blood transfusions and obstructive sleep apnoea (OSA) data were obtained from the hospital electronic patient records.Main outcome measures To study the prevalence of high BMI and to identify any correlation between BMI and disease severity.Results 385 patients were included. 64 children (17%) were overweight or obese, of which a significantly higher number of children with HbSC were obese or overweight (23 out of 91, 25%) compared with those with HbSS (36 out of 273, 13%), p≤0.001. No correlation was found between high BMI and presence of OSA, and markers of disease severity such as admission rates, fetal haemoglobin or lactate dehydrogenase levels.Conclusions High BMI did not correlate with disease severity in this cohort of patients with sickle cell disease. Obesity was more prevalent in females and those with HbSC. Further prospective studies are needed to determine long-term effects of BMI in disease severity and outcome.
Stotesbury H, Kirkham FJ, Kolbel M, et al., 2018, White matter integrity and processing speed in sickle cell anemia, NEUROLOGY, Vol: 90, Pages: E2042-E2050, ISSN: 0028-3878
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- Citations: 45
Howard J, Slee AE, Skene S, et al., 2018, Overnight auto-adjusting continuous airway pressure + standard care compared with standard care alone in the prevention of morbidity in sickle cell disease phase II (POMS2b): study protocol for a randomised controlled trial., Trials, Vol: 19
BACKGROUND: In addition to pain, sickle cell anaemia (HbSS) complications include neurocognitive difficulties in attention and processing speed associated with low daytime and night-time oxygen saturation compounded by obstructive sleep apnoea (OSA). In the general population OSA is treated with continuous positive airways pressure (CPAP). The aim of this single-blind, randomised, controlled phase II trial is to compare auto-adjusting CPAP (APAP) with standard care to standard care alone in individuals with HbSS to determine whether the intervention improves attention and processing speed, brain structure, pain and quality of life. METHODS/DESIGN: Eligibility criteria include: ability to provide informed consent; age > 8 years; diagnosis of HbSS; and mean overnight saturation of < 90% for < 30% of the night (i.e. not meeting current criteria for overnight oxygen therapy). Key exclusion criteria are: overnight respiratory support; respiratory or decompensated cardiac failure; chronic transfusion; or contraindications to APAP therapy or magnetic resonance imaging (MRI). Sixty individuals with HbSS (30 children and 30 adults) will be randomised to standard care + APAP or standard care alone for six months. Minimisation factors are: age group (8-11, 12-15, 16-22 and > 23 years); silent infarction on MRI; minimum overnight oxygen saturation > 90% or < 90%; and hydroxyurea use. For APAP individuals, the intervention is administered at home. Adherence and effectiveness are recorded using software documenting hours of use each night and overnight oximetry. Participant support in terms of appropriate facemask and facilitating adherence are provided by an unblinded sleep physiologist. The primary outcome is change in the cancellation subtest from the Wechsler scales. Secondary outcomes include general cognitive functioning, quantitative brain MRI, bloo
de Montalembert M, Brousse V, Chakravorty S, et al., 2017, Are the risks of treatment to cure a child with severe sickle cell disease too high?, BMJ, Vol: 359
Brewin J, Kaya B, Chakravorty S, 2017, How I manage sickle cell patients with high transcranial doppler results., Br J Haematol, Vol: 179, Pages: 377-388
Stroke is one of the most severe complications to affect children with sickle cell anaemia (SCA). Transcranial doppler (TCD) is an accurate and non-invasive method to determine stroke risk. Randomised controlled trials have demonstrated the efficacy of chronic transfusion therapy in stroke prevention based on risk stratification determined by TCD velocities. This has led to the regular use of TCD monitoring for children with SCA in order to determine stroke risk. Significant resource allocation is necessary to facilitate training, quality assurance and failsafe arrangements for non-attenders. In a subgroup of patients, chronic transfusions for primary stroke prevention can be replaced by hydroxycarbamide therapy, provided careful monitoring is undertaken; including repeat TCD studies at frequent intervals. The authors propose an evidence-based algorithm for the management of abnormal TCD velocities and discuss the role of this test in other clinical contexts, such as in Haemoglobin SC disease.
Greenwood S, Deane C, Rees OL, et al., 2017, The significance of inadequate transcranial Doppler studies in children with sickle cell disease, PLOS ONE, Vol: 12, ISSN: 1932-6203
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- Citations: 7
Piel FB, Tewari S, Brousse V, et al., 2017, Associations between environmental factors and hospital admissions for sickle cell disease, Haematologica, Vol: 102, Pages: 666-675, ISSN: 0390-6078
Sickle cell disease is an increasing global health burden. This inherited disease is characterized by a remarkable phenotypic heterogeneity, which can only partly be explained by genetic factors. Environmental factors are likely to play an important role but studies of their impact on disease severity are limited and their results are often inconsistent. This study investigated associations between a range of environmental factors and hospital admissions of young patients with sickle cell disease in London and in Paris between 2008 and 2012. Specific analyses were conducted for subgroups of patients with different genotypes and for the main reasons for admissions. Generalized additive models and distributed lag non-linear models were used to assess the magnitude of the associations and to calculate relative risks. Some environmental factors significantly influence the numbers of hospital admissions of children with sickle cell disease, although the associations identified are complicated. Our study suggests that meteorological factors are more likely to be associated with hospital admissions for sickle cell disease than air pollutants. It confirms previous reports of risks associated with wind speed (risk ratio: 1.06/stan-dard deviation; 95% confidence interval: 1.00-1.12) and also with rainfall (1.06/standard deviation; 95% confidence interval: 1.01-1.12). Maximum atmospheric pressure was found to be a protective factor (0.93/standard deviation; 95% confidence interval: 0.88-0.99). Weak or no associations were found with temperature. Divergent associations were identified for different genotypes or reasons for admissions, which could partly explain the lack of consistency in earlier studies. Advice to patients with sickle cell disease usually includes avoiding a range of environmental conditions that are believed to trigger acute complications, including extreme temperatures and high altitudes. Scientific evidence to support such advice is limited and sometimes con
Chakravorty S, Tallett A, Sathyamoorthy G, et al., 2016, USING A NEW PATIENT FEEDBACK SURVEY TO EXPLORE EXPERIENCES OF LIVING WITH SICKLE CELL DISEASE IN THE UK, Publisher: OXFORD UNIV PRESS, Pages: 60-61, ISSN: 1353-4505
Fordham NJ, Ajitsaria R, Karnik L, et al., 2016, Haemophagocytic Lymphohistiocytosis responding to withdrawal of gluten: a case report, Journal of Medical Case Reports, Vol: 10, ISSN: 1752-1947
IntroductionThis is the first documented case of a patient with Haemophagocytic Lymphohistiocytosis (HLH) in association with coeliac disease. There was complete clinical and biochemical remission of HLH following the introduction of a gluten free diet.Case presentationA seven-year old Caucasian girl presented with fevers, maculopapular rash with a recent history of tonsillitis. Blood tests revealed thrombocytopenia (64 x 109/L), anaemia (80g/L), hypofibrinogenaemia (1g/L) and hyperferritinaemia (71378µg/L). A bone marrow revealed evidence of haemophagocytosis, but tests for the genetic or familial associated HLH syndromes were negative. Screening tests for known secondary causes was negative. She was diagnosed with HLH, and following treatment with the HLH-2004 protocol these symptoms, in addition to the biochemical and haematological markers completely resolved. The patient presented again ten months later with fever, rash, and biochemical abnormalities suggestive of HLH. Tissue transglutamase was markedly raised and blood tests revealed a genetic susceptibly to coeliac disease in the form of HLA DQ2 positivity. She commenced a gluten free diet and there was complete symptomatic and biochemical response without any further chemotherapy. She had further episodic rashes, each associated with the accidental intake of gluten. ConclusionThis is to our knowledge the first documented case of HLH in association with coeliac disease. There was no other secondary cause found; she initially responded to chemo-immunotherapy specific for HLH but relapsed within a few months of cessation of treatment and then achieved complete remission on gluten withdrawal alone.
Tewari S, Piel F, Brousse V, et al., 2016, ASSOCIATION BETWEEN ENVIRONMENTAL FACTORS AND HOSPITAL ADMISSIONS FOR SICKLE CELL DISEASE: A RETROSPECTIVE TIME SERIES ANALYSIS, 21st Congress of the European-Hematology-Association, Publisher: FERRATA STORTI FOUNDATION, Pages: 127-128, ISSN: 0390-6078
Bain BJ, Chakravorty S, 2016, Phytosterolemia, American Journal of Hematology, Vol: 91, Pages: 643-643, ISSN: 1096-8652
Roberts I, Chakravorty S, 2016, Neonatal haematology, POSTGRADUATE HAEMATOLOGY, 7TH EDITION, Editors: Hoffbrand, Higgs, Keeling, Mehta, Publisher: JOHN WILEY & SONS LTD, Pages: 870-884, ISBN: 978-1-118-85432-7
de la Fuente J, O'Boyle F, Harrington Y, et al., 2015, Haploidentical BMT with a Post-Infusion of Stem Cells Cyclophosphamide Approach Is Feasible and Leads to a High Rate of Donor Engraftment in Haemoglobinopathies Allowing Universal Application of Transplantation, 57th Annual Meeting of the American-Society-of-Hematology, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
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- Citations: 17
O'Boyle F, Hing S, Harrington Y, et al., 2015, Fludarabine/Treosulfan/Thiotepa/ATG Conditioning for Related Transplantation in Haemoglobinopathies Leads to Early and Sustanined Engraftment with Low Incidence of VOD and GvHD, 57th Annual Meeting of the American-Society-of-Hematology, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Thompson J, Mkandawire C, Chakravorty S, et al., 2015, A pilot study of assessing cognition in children with sickle cell disease using a new software package the cogstate battery, 57th Annual Meeting of the American Society of Hematology, Publisher: American Society of Hematology, ISSN: 0006-4971
Bain BJ, Chakravorty S, Ancliff P, 2015, Congenital acute megakaryoblastic leukemia, AMERICAN JOURNAL OF HEMATOLOGY, Vol: 90, Pages: 963-963, ISSN: 0361-8609
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- Citations: 5
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