Abnormal Transcranial Doppler Research Articles

Incremental eligibility criteria for the BMT CTN 1507 haploidentical trial for children with sickle cell disease

AbstractThe Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1507 leadership and the data safety monitoring board (DSMB) established incremental entry criteria for children aged 5 to 14.99 years with sickle cell disease (SCD) enrolling in a phase 2 trial of HLA-haploidentical hematopoietic stem cell transplantation. First, the enrollment was limited to overt stroke in the first 10 participants (stage 4). Subsequently, the DSMB reviewed the interim results and expanded the eligibility to include children with silent cerebral infarcts or abnormal transcranial Doppler velocities with magnetic resonance angiography–defined cerebral vasculopathy (stage 3). A third cohort was enrolled after the DSMB reviewed the clinical outcomes in these cumulative initial enrollments (n = 18). Additions to the entry criteria included nonneurologic morbidities (stage 2). Eligibility criteria included the following: (1) life-threatening acute chest syndrome requiring exchange transfusion; (2) right heart catheterization confirmed pulmonary hypertension; (3) persistent systemic hypertension despite maximum medical therapy; (4) acute pain despite maximum medical therapy in the absence of psychosocial factors and unmanaged asthma after adjudication; or (5) 2 major priapism episodes in 12 months or 3 in 24 months. Children with SCD who did not meet the criteria for stages 4, 3, and 2 were not eligible. To our knowledge, for the first time, we introduce a staged strategy for eligibility in a curative therapy trial for children with SCD concordant with 45 Code of Federal Regulations § 46.405(b). The research governance–mandated eligibility strategy used within the BMT CTN 1507 phase 2 study may apply to future pediatric SCD curative therapy trials. This trial was registered at www.ClinicalTrials.gov as #NCT032635590.

The Association Between Sickle Cell Anemia and Cognitive Dysfunction: A Systematic Review.

A kind of hemoglobinopathy known as sickle cell anemia (SCA) is characterized by aberrant hemoglobin molecules. The most frequent neurological side effects linked to SCA include neurocognitive dysfunction, asymptomatic cerebral infarction, and ischemic stroke.This study aims to investigate the relationship between SCA and cognitive dysfunction.We systematically searched electronic databases like PubMed, MEDLINE, Science Direct, and Scopus. Two independent reviewers screened and extracted data from eligible studies.Eighteen studies, including 2,457 participants in total and nearly half of them 1,151 (46.8%) were males, were included in our data. The prevalence of cognitive dysfunction in the adult population ranged from 11.5% to 70%. Cognitive dysfunction among adults was significantly associated with poorer educational status, reduced family income, decreased kidney function, older age, stroke history, and vasculopathy. The prevalence of cognitive dysfunction in children ranged from 10.2% to 68.2%. The decline in cognitive function among adults was significantly associated with children over the age of four, abnormal transcranial Doppler and previous stroke, school absence, age beyond 13, and increased BMI.Cognitive function deficiencies are a defining feature of SCA that affects people of all ages. These findings suggest that if cognitive decline is not slowed down, or better still, stopped, medical interventions targeting a variety of sequelae in this population will be ineffective. Future analyses of this population's cognition should evaluate the environmental and other biological variables.

Sleep Fragmentation and Obstructive Sleep Apnea Are Associated with High Primary Stroke Risk in Children with Sickle Cell Disease

Background Children with sickle cell disease (SCD) are at elevated risk of developing sleep disorders, 1 which may contribute to the sequelae of their disease. One important sequela of SCD exacerbated by sleep disorders is cerebrovascular stroke. Transcranial Doppler (TCD) screening of large intracranial arteries can detect elevated blood velocity and strongly predict stroke in children with SCD. 2 However, the association between stroke risk, as assessed by TCD, and sleep disorders has not been sufficiently investigated. Main Objective To investigate the association between sleep disorders and abnormal TCD examinations in children with SCD. Design/Methods We evaluated associations between sleep disorder severity with TCD examinations in children with SCD. We selected all participants from the Sickle Cell Clinical Research and Intervention Program (SCCRIP), who underwent polysomnography between 2016 - 2020 and had at least one TCD examination. SCCRIP prospectively recruits patients diagnosed with SCD and includes retrospective and longitudinal collection of clinical, neurocognitive, geospatial, psychosocial, and health outcomes data. 3 The severity of sleep apnea was assessed using the apnea/hypopnea index, separated into total and obstructive apnea/hypopnea indices. The number of oxygen desaturation events per hour of sleep as well as the O2 saturation nadir were recorded. Sleep fragmentation was measured by the total arousal index (events per hour of sleep) and sub-categorized into spontaneous and respiratory-related arousal indices. Transcranial Doppler exams were reported as abnormal with timed average mean maximum velocities (TAMMV) of greater than 200 cm/s, high-conditional > 185 cm/s, low-conditional > 170 cm/s, and normal ≤ 170 cm/s. Exact Wilcoxon rank sum test was used to compare sleep outcomes between two groups. The false discovery rate adjusted p-values or q-values were calculated using Benjamini and Hochberg approach to control for multiple comparisons at a level of 0.05. Results Eighty-four patients met inclusion criteria (genotypes SS/SB0 81 (96%), median age 8.3, range 2.2-23.1, 42 male: 42 female). Six patients had abnormal, six high-conditional, 12 low-conditional velocities, while the remainder (60) had normal TCD exams. Patients with abnormal TCD exams exhibited more severe obstructive sleep apnea (mean AHI 25.0 + 9.1 vs. 5.3 + 8.3, p = 0.003), more severe respiratory related arousals (12.7 + 7.9 vs. 3.2 + 4.5, p = 0.008), and higher total arousals (22.9 + 7.7 vs. 12.9 + 5.8, p = 0.01) than those with normal TCD studies at p<0.05.The number of oxygen desaturation events per hour (mean 10.6 + 10.5 vs. 4.5 + 8.0, p = 0.05) was not significantly different among patients with abnormal and normal TCD exams at q<0.05 but the O2 saturation nadir was significantly less in patients with abnormal TCD exams (mean 74.0 + 5.0 vs. 86.8+9.9, p = 0.007) at q<0.05 (Figure 1). Conclusion In pediatric patients with SCD, a link exists between sleep apnea, O2 saturation nadir, sleep fragmentation, and stroke risk. While the findings of this study establish a correlation between sleep disorders and cerebrovascular complications in SCD, further research is still necessary to fully comprehend the exact role of sleep disorders on stroke risk. Nevertheless, this study underscores the importance of addressing sleep apnea and promoting healthy sleep patterns in pediatric patients with SCD to reduce the risk of stroke.

Hydroxyurea Improves Intelligence Quotient Scores in Children with Sickle Cell Anemia and Elevated Transcranial Doppler Velocity

Introduction: Structural brain abnormalities resulting from sickle cell disease because of strokes, silent cerebral infarcts (SCI) and other biophysical characteristics of parenchymal damage from repeated sickling affect cognitive functioning. Hydroxyurea therapy reduces transcranial Doppler (TCD) velocities and improves SCI and other neurological outcomes in children with sickle cell anaemia. Hence the objectives of EXpanding Treatment for Existing Neurological Disease (EXTEND, NCT02556099), a phase 2 clinical trial, was to determine whether hydroxyurea titrated to maximum tolerated dose was effective in lowering transcranial Doppler (TCD) velocities and improving cognitive function in Jamaican children with sickle cell anemia (SCA) with increased stroke risk. Methods: Full-Scale Intelligence Quotient (FSIQ), verbal and nonverbal IQ were measured with the Wechsler Abbreviated Scale of Intelligence (WASI-II) at baseline and after 18 months of hydroxyurea treatment in 30 of the 43 enrolled children. Verbal Comprehension Index (VCI) was assessed using the Vocabulary and Similarities subtests. Perceptual Reasoning Index (PRI) was scored with the Block Design and Matrix Reasoning subtests. Members of the team conducting the tests were trained and test results were verified by an experienced member of the Epidemiology Research Unit, Caribbean Institute for Health Research. Participants were enrolled in the EXTEND trial based on a pre-treatment conditional or abnormal TCD velocity. They were assigned to one of three risk categories according to treatment status and stroke history at study enrollment: Group 1 (low stroke risk: no previous stroke, on hydroxyurea treatment n= 12), Group 2 (medium stroke risk: no previous stroke, no hydroxyurea, n=10) and Group 3 (High stroke risk: previous stroke, no hydroxyurea n=8). Anthropometric variables, including height and weight, were recorded as well as oxygen saturation and hematological variables. Differences in post treatment outcome were modelled using mixed linear regression. A p-value of <0.05 was considered statistically significant. Results: There was no difference in mean anthropometric values or gender distribution at baseline by stroke risk category groups (Table 1). The mean(sd) age in years of participants in Group 1 was 8.2(1.7), while for Group 2 the average age was 7.7(2.1) and for Group 3 it was 10.5(2.8). The mean age of Group 3 was significantly greater than Group 1. After 18 months of hydroxyurea treatment, participants were taking an average dose of 25 mg/kg/d, range 13.7 to 34.9 mg/kg/d. On treatment TCD velocities decreased by mean(sd) of 29.5 cm/sec (31.5). Hemoglobin (Hb) concentration was lowest in Group 3 but all groups showed increases during treatment with the rate of increase in Groups 2 and 3 being greater than Group 1 (p<0.001). Absolute neutrophil counts and absolute reticulocyte counts were not different by group, and both decreased significantly post treatment (p<0.001) (Table 1). At both time points, the VCI, PRI and FSIQ mean scores in Group 3 were low [Overall means(sd); 71(11.7), 71(12.6),69(11.6), respectively] and were significantly lower compared with Group 1 (p<0.001) (Table 1). While there was no significant effect of treatment on VCI and PRI scores, the mean FSIQ score increased on average by 2.9 units (95%CI 0.3, 5.4) post treatment among participants. Adjusting for age at enrollment had no effect on the improvement on FSIQ, however adjusting for changes in hemoglobin resulted in an increase in FSIQ by 3.3 units (95%CI -0.4, 7.0) which approached statistical significance (p=0.079). Conclusion: Participants treated with hydroxyurea at maximum tolerated dose for 18 months with or without a previous stroke had significant improvement in hematological variables and neuropsychological scores. Children with sickle cell anemia with high risk of stroke may benefit from routine neuropsychological testing, hydroxyurea treatment in addition to educational interventions.

Transcranial Doppler Screening of Children with Sickle Cell Disease for a Large, Multinational Interventional Study: Experience from the Phase 3 HOPE-Kids 2 Trial Investigating the Effect of Voxelotor Treatment on Transcranial Doppler Flow Velocity

Introduction: Transcranial Doppler (TCD) ultrasound is an effective screening tool for identifying children with sickle cell disease (SCD) who are at high risk of stroke. Implementing TCD screening, along with appropriate therapies, for the purpose of primary stroke prevention in resource-constrained settings remains challenging. HOPE-KIDS 2 (NCT04218084) is an ongoing, phase 3, multicenter, double-blind, placebo-controlled trial of voxelotor in children with SCD and elevated arterial cerebral blood flow (measured by time-averaged maximum of the mean velocity [TAMMV]). Our aim is to describe the findings from successful implementation of a standardized TCD screening protocol that was conducted in a multinational setting. Methods: The purpose of HOPE-KIDS 2 is to evaluate the effect of voxelotor treatment on reducing the risk of stroke in participants aged 2 to <15 years with SCD who have conditional TAMMV (170 to <200 cm/s) at baseline. Children aged 2 to <15 years with SCD (HbSS/HbSβ 0) were screened after local sonographers were trained and certified on standardized TCD examination protocol, using the same model of Multi-Dop T digital machine (Compumedics DWL, Germany). TCD assessments were sent for central quality review and interpretation by 2 independent reviewers. STOP criteria were used to classify stroke risk: normal, <170 cm/s; conditional, 170 to <200 cm/s; or abnormal, ≥200 cm/s. Patient baseline characteristics, including clinical measurements of markers of anemia and hemolysis, were measured during study screening. The reasons for patient screen failure were summarized. Results: Between Nov 2020 and Feb 2023, 708 participants consented at 29 sites in Nigeria (n=250; 5 sites), Kenya (n=241; 4 sites), Egypt (n=145; 4 sites), Ghana (n=28; 2 sites), the US (n=17; 8 sites), Italy (n=9; 3 sites), Oman (n=9; 1 site), Saudi Arabia (n=8; 1 site), and the UK (n=1; 1 site). Of these patients, 92.1% (652/708) completed TCD screening examinations (mean [SD] age 7.6 [3.24] years; range 2.0-14.0 years; 50.8% male; 23.0% receiving hydroxyurea). Of the patients who completed TCD screening, the mean (SD) TAMMV was 163.0 (31.26) cm/s, and 47.1% (307/652) had conditional TCD at baseline (29.0% low conditional, 18.1% high conditional). The main reason for screen failure was index TAMMV outside of conditional range (abnormal, n=39 [6.0%]; normal, n=306 [46.9%]). Elevated TAMMV on screening TCD was more common in younger children (2 to ≤8 years vs >8 to <15 years); patients aged 2-8 years comprised 66.8% and 82.1% of the conditional and abnormal TCD categories, respectively. There were 39 assessments that required adjudication, but only 9 were deemed unreadable. Of all patients screened, 36.2% (236/652) fulfilled eligibility criteria for randomization; the characteristics at screening of these patients are summarized (Table). The mean (SD) Hb level and TAMMV at screening for randomly assigned patients was 7.7 (1.06) g/dL and 182.7 (7.53) cm/s, respectively. Conclusions: Clinical sites for the HOPE-KIDS 2 study successfully implemented a standardized, local TCD screening protocol supported by central quality review. For a large interventional trial aimed at reducing the risk of stroke in children with SCD, African and Middle Eastern sites presented relatively few limitations with respect to participant screening.

Sickle Cell Disease-Eligibility for Curative Treatment in Indian Tribal Population-Urgent Need to Stop and Think

Introduction: Sickle cell disease (SCD) is one of the most common hemoglobinopathies, with nearly 40000 children born annually to the tribal population of India. Hematopoietic stem cell transplantation is currently the only curative option available. Patients eligible for transplantation according to the ASH and other guidelines are those with multiple episodes of veno-occlusive crisis, despite disease-modifying treatment, recurrent episodes of acute chest syndrome, osteonecrosis, patients who experienced overt stroke, or abnormal transcranial Doppler ultrasound, requiring frequent admissions to the hospital. Although HSCT is the sole curative treatment, only a fraction of eligible patients receive it in resource-limited settings. To understand the requirements for bone marrow transplantation, we analyzed the number of eligible patients using clinical data. Methods: A cross-sectional prospective research design was used that involved clinical examination and personal interviews with patients and caregivers, with the completion of questionnaires on clinical characteristics and treatment options. Two hundred fifty individuals with S ,invited to outreach clinics, were analyzed Results: Among the 251 surveyed children, 122 (48.6%) were male and 129(51.4%) were female. Among them, 160 (63.7%) children had recurrent episodes of VOC in the past 1 year, despite 116 (72.5%) receiving regular hydroxyurea. Among them, 98 (62%) required multiple admissions for VOC. Episodes of fever were observed in 51 % of the patients. The requirement for admission to a healthcare facility was recorded in 57 % of the patients. Nearly 13 % of the patients required more than three transfusions in the preceding year. Conclusions: There is an urgent need to organize SCD care pathways, as the whooping number of patients (64%) falls within the criteria of eligibility for HSCT, a curative option. The transplant community, along with healthcare providers and non-governmental organizations, should decide on a strategy to offer this important modality of curable alternatives.

Socioeconomic Status and Risk of Stroke As Assessed By Transcranial Doppler: A Displace Study Secondary Analysis

Background: Transcranial doppler (TCD) screening (Sickle Stroke Screening) identifies children ages 2-16 years with sickle cell disease (SCD) at an increased risk for stroke. Significant barriers to undergoing annual screening exist for patients with SCD. Previous studies have shown that individuals from households on public insurance with limited neighborhood opportunity have increased barriers to receiving adequate healthcare, including routine screening; however it is unknown whether low socioeconomic status (SES) influences TCD results. Methods: We conducted a secondary analysis of the DISPLACE study, which included a cohort of 3243 TCD-eligible individuals aged 2-16 who had at least one TCD screen performed during their year of study enrollment. We utilized insurance type (Medicaid/CHIP or public versus all other insurances) and overall childhood opportunity index (COI) group (Very Low versus all other COI levels [Low, Medium, High, and Very High]) to proxy household- and neighborhood-level SES. We then examined the association between household- and neighborhood-level SES and conditional and/or abnormal TCD screening results. Baseline characteristics of the overall cohort (Table 1) were described by COI group and insurance type. The primary outcome was TCD result at baseline (i.e. a patient's first TCD in the database); categorized as abnormal, high-conditional, and normal (reference group). Multinomial logistic regression analysis was used to assess whether clinical (age, sex [female vs. male], hemoglobin (Hgb) level, white blood cell [WBC] count, presence of clinical hypertension [yes, no], hydroxyurea (HU) prescription at baseline [yes, no]) or socioeconomic factors (insurance type and COI group) were independently associated with TCD result. The multinomial regression accounted for age, Hgb level, WBC count, HU prescription, COI group, and insurance type. All tests were two-tailed and, an alpha level of <0.05 and <0.1 (to reduce type II error in logistic regression) were used to determine statistical significance. Results: The analytic cohort included 3243 children (Table 1), with 1346 (41.5%) children living in Very Low COI neighborhoods and 2180 (67.2%) of households with public insurance. HU was prescribed to 60.7% of individuals, and this varied by COI level (p=0.021), but not insurance type (p=0.758). WBC count was significantly higher in the Very Low COI group (p=0.004) and public insurance group (p<0.001). Hgb level was noted to be significantly lower in the Very Low COI (p=0.031) and public insurance (p<0.001) groups. Bivariate logistic regression analysis revealed that COI group (OR 1.53, p=0.08) and insurance type (OR=1.76, p=0.056) were significantly associated at p<0.1 with abnormal TCD outcome individually. Lack of HU prescription was significantly associated at p<0.05 with abnormal TCD result (Odds Ratio [OR]=20.36, p<0.001), and WBC count (OR=1.05, p=0.055) was significantly associated at p<0.1 with abnormal TCD result individually. In the multinomial logistic regression model (included variables listed above), only lack of HU prescription remained significantly associated at p<0.05 with abnormal TCD result (OR=19.09, p<0.001). Conclusion: The most robust predictive factor determining abnormal or conditional TCD status in this cohort was lack of HU prescription. Public insurance and COI group as proxies for SES were not independently associated with abnormal or conditional TCD results. As such, the disparities seen by individuals from proxied lower SES are likely mediated by utilization of HU. Notably, HU prescription rates differed by COI group, but not insurance type, suggesting possible neighborhood level factors (such as availability of pharmacies dispensing HU) influencing HU prescription that wouldn't be reflected by insurance type. The limitations of using socioeconomic proxies such as COI group and insurance type must be noted, as these proxies assign group characteristics to an individual based on a snapshot in time, which may not be representative of the dynamic nature of one's SES. Nevertheless, these findings highlight the need to better understand the possible association between SES and HU prescription, as limited HU access and utilization could result in significant health disparities in both treatment and outcomes.

Microemboli on Transcranial Doppler in Patients with Sickle Cell Disease: A Single Center Case Series

Background: Stroke remains a major cause of morbidity in patients with sickle cell disease (SCD). Current guidelines recommend that patients with Hemoglobin SS and Hemoglobin S beta zero thalassemia have annual transcranial doppler (TCD) screening and that patients with abnormal velocities should have regular blood transfusions to maintain a maximum HbS level <30% and maintain a hemoglobin level >9 g/dL for at least one year to decrease risk of stroke (DeBaun et al., 2020). While research has shown that patients with velocities >200cm/sec are at increased risk of cerebral infarct, there is no literature to discuss the follow up and management of patients with microemboli on TCD. In the past microemoli were unable to be detected, however TCD is now able to detect such findings (Wan et al., 2022). Studies have been completed on patients with ischemic stroke without SCD and have shown that the presence of microemboli on TCD is associated with a higher rate of recurrence (Das et al., 2020). The presence of emboli has also been shown to recognize patients with asymptomatic carotid stenosis and increased risk for stroke (Markus et al., 2010). Although noted in the general population, the significance of such a finding on an annual TCD screening in patients with sickle cell disease is unknown. Methods:At the Medical University of South Carolina, we performed a retrospective review of all patients with SCD who have had TCDs from 2017 to February 2023 and were found to have microemboli to evaluate management and outcome. Results: We have had 5 patients with an incidental finding of microemboli on their annual TCD since 2017. Three were male with median age of 3 (range 2 to 15 years). Four individuals are HbSS genotype. Mean hemoglobin at the time of TCD was 8.26 ± 1.4 g/dL. TCD velocity was normal in four patients at the time of the TCD, while the remaining individual had a low conditional TCD. Two have a previous history of conditional or abnormal TCDs. The location of the microemboli was variable among patients (Table 1). At the time of microemboli findings on TCD, discussions were held with family regarding options for treatment including chronic partial exchange transfusions and optimization of other disease modifying therapies. Management of all patients included MRI at the time of microemboli, which was normal in only two patients. Three patients were started on chronic manual exchange transfusions for 10 months to 3 years. One out of the 3 continued home HU while receiving transfusions while the remainder were transitioned to HU once chronic transfusions were complete. One patient was not started on chronic transfusions but monitored closely with TCDs due to family choice. On follow up, 4 have had repeat TCDs and all have normalized without any subsequent episodes of microemboli. One patient was found to have silent infarct on MRI at time of TCD and 1 has had follow up MRI 4 years after original TCD with a new silent infarct. Of note, this patient had inconsistent follow up with chronic transfusions after initial abnormal TCD. Importantly, none of our 5 patients had an acute symptomatic ischemic event since the microemboli were noted. Overall, among these patients, 2 have had concern for silent infarct and 3 of 5 started on chronic transfusions (Table 1). Conclusion: This is the first report within the literature of microemboli on annual TCD screening in patients with SCD. As this is a new phenomenon, the significance within the disease course is not known for those with sickle cell disease. Identifying patients with microemboli has been used to help navigate the need for early intervention to prevent stroke. Given that individuals with SCD are already at an increased risk for cerebrovascular events, these findings of microemboli could indicate further risk in these individuals as well and deserve further investigation. Further research is warranted as the significance of such a finding is unknown and further understanding could impact the standard of care of this patient population.

Transcranial Doppler ultrasonography in bacterial meningitis: A systematic review.

Bacterial meningitis remains a global threat due to its high mortality. It is estimated that >1.2 million cases of bacterial meningitis are reported annually. Intracranial vasculopathy is an important, under-documented complication, easily detected by transcranial Doppler (TCD) ultrasonography. Following the PRISMA Guidelines, we reviewed the utility of TCD in bacterial meningitis. This is a systematic review of observational studies on the use of TCD in patients with CSF-proven bacterial meningitis. Characteristic changes in TCD parameters along the course of the disease, correlation of TCD findings with neuroimaging, and functional outcomes were evaluated. Nine studies were included with a total of 492 participants (mean age of 42). The most common TCD finding was intracranial arterial stenosis of the MCA (50%-82%) and ischemia (33%) was the predominant neuroimaging finding. The presence of an abnormal TCD finding increased the risk of poor outcomes as high as 70%. Patients diagnosed with bacterial meningitis who underwent TCD show alterations in cerebral blood flow, correlating with imaging findings and poor outcomes. It aids in the diagnosis of its sequelae and can predict the prognosis of its outcome. TCD is a cost-effective, reliable modality for diagnosing vasculopathy associated with bacterial meningitis. It may prove useful in our armamentarium of management. Large prospective studies with long-term follow-up data may help establish the use of TCD in bacterial meningitis.

Genetic Variation and Sickle Cell Disease Severity

Sickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD remain poorly understood. To assess all reported genetic modifiers of SCD, evaluate the design of associated studies, and provide guidelines for future analyses according to modern genetic study recommendations. PubMed, Web of Science, and Scopus were searched through May 16, 2023, identifying 5290 publications. At least 2 reviewers identified 571 original, peer-reviewed English-language publications reporting genetic modifiers of human SCD phenotypes, wherein the outcome was not treatment response, and the comparison was not between SCD subtypes or including healthy controls. Data relevant to all genetic modifiers of SCD were extracted, evaluated, and presented following STREGA and PRISMA guidelines. Weighted z score meta-analyses and pathway analyses were conducted. Outcomes were aggregated into 25 categories, grouped as acute complications, chronic conditions, hematologic parameters or biomarkers, and general or mixed measures of SCD severity. The 571 included studies reported on 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries. Of the 17 757 extracted results (4890 significant) in 1552 genes, 3675 results met the study criteria for meta-analysis: reported phenotype and genotype, association size and direction, variability measure, sample size, and statistical test. Only 173 results for 62 associations could be cross-study combined. The remaining associations could not be aggregated because they were only reported once or methods (eg, study design, reporting practice) and genotype or phenotype definitions were insufficiently harmonized. Gene variants regulating fetal hemoglobin and α-thalassemia (important markers for SCD severity) were frequently identified: 19 single-nucleotide variants in BCL11A, HBS1L-MYB, and HBG2 were significantly associated with fetal hemoglobin (absolute value of Z = 4.00 to 20.66; P = 8.63 × 10-95 to 6.19 × 10-5), and α-thalassemia deletions were significantly associated with increased hemoglobin level and reduced risk of albuminuria, abnormal transcranial Doppler velocity, and stroke (absolute value of Z = 3.43 to 5.16; P = 2.42 × 10-7 to 6.00 × 10-4). However, other associations remain unconfirmed. Pathway analyses of significant genes highlighted the importance of cellular adhesion, inflammation, oxidative and toxic stress, and blood vessel regulation in SCD (23 of the top 25 Gene Ontology pathways involve these processes) and suggested future research areas. The findings of this comprehensive systematic review and meta-analysis of all published genetic modifiers of SCD indicated that implementation of standardized phenotypes, statistical methods, and reporting practices should accelerate discovery and validation of genetic modifiers and development of clinically actionable genetic profiles.

Relationship between hemoglobin, hemolysis, and transcranial Doppler velocities in children with sickle cell disease: Results from a long-term natural history study in Italy in the era of multimodal therapy.

Stroke and cerebral vasculopathy are leading causes of morbidity and mortality in patients with sickle cell disease (SCD). Transcranial Doppler (TCD) is a reliable and validated predictor of stroke risk. Children with conditional or abnormal TCD are at an increased risk for stroke, which can be mitigated by red blood cell transfusion or hydroxyurea. Elucidating the relationship between cerebral hemodynamics and hemolytic anemia can help identify novel therapeutic approaches to reduce stroke risk and transfusion dependence. This long-term, real-world study was designed to evaluate the prevalence of TCD imaging (TCDi)-assessed flow velocities in children and to interrogate their relationship with markers of anemia and hemolysis. In total, 155 children (median follow-up 79.8 months, 1358.44 patient-years) had 583 evaluable TCDi results. Only patients with HbSS or HbSβ0 had abnormal (1.6%) or conditional (10.9%) TCDi. Children with abnormal or conditional TCDi had lower hemoglobin (Hb) and higher hemolysis markers. A linear correlation was detected between TCD velocity and Hb: an Hb increase of 1 g/dL corresponded to decreases in velocity in the internal carotid and middle cerebral arteries (6.137 cm/s and 7.243 cm/s). Moreover, patients with Hb >9 g/dL presented a lower risk of TCDi-associated events. These results support the need to optimize disease-modifying treatments that increase Hb and reduce hemolysis for stroke prevention in young children with SCD.

Analyses of the soluble levels of sCD40L, sCD62P and sCD40 in pediatric sickle cell anemia patients with abnormal transcranial Doppler

IntroductionSerum levels of sCD40L, sCD40 and sCD62P were evaluated in sickle cell anemia (SCA) patients aged between 2 and 16 years with normal transcranial Doppler (TCD) and no stroke (G1, n = 24); in SCA patients with abnormal TCD (G2, n = 16); in SCA patients with a previous history of stroke (G3, n = 8), and; in healthy controls (aged 2 to 13 years; n = 26). ResultsThe levels of sCD40L were significantly higher in the G1, G2 and G3 groups, compared to controls (p = 0.0001, p < 0.0002 and p = 0.004, respectively). Among patients with SCA, higher levels of sCD40L were found in the G3 group, compared to the G2 group (p = 0.03). In the sCD62P analysis, high levels in G3, compared to G1 (p = 0.0001), G2 (p = 0.03) and G4 (p = 0.01), and G2 also had high levels, compared to G1 (p = 0.04). The G1 patients had a higher sCD40L/sCD62P ratio, compared to G2 (p = 0.003) and controls (p < 0.0001). The sCD40L/sCD40 ratios were higher in G1, G2 and G3, compared to controls (p < 0.0001, p = 0.008 and p = 0.002, respectively). ConclusionIt was concluded that the combination of TCD abnormality, associated with levels of sCD40L and sCD62P, may contribute to a better assessment of the risk for stroke in pediatric SCA patients.Favor pedir para os autores corrigirem esta frase, pois NÃO é uma sentença completa em inglês: Our data suggest that decreased values of the s[LSM1] CD40L/sCD62P ratio involving two inflammatory mediators produced in platelet activation, being unprecedented in the literature.

5616493 MACHINE LEARNING TO IDENTIFY CHILDREN WITH SICKLE CELL DISEASE AT VERY LOW HIGH RISK OF ABNORMAL OR CONDITIONAL TRANSCRANIAL DOPPLER SCREENING.

Background: Annual Transcranial doppler (TCD) screening is an important strategy to mitigate the risk of stroke in children with sickle cell anemia (SCA). While an abnormal TCD is strongly associated with increased chance of stroke, the risk factors for an abnormal doppler study are not well understood. Identifying children at very low risk could help to ensure appropriate focus on screening children at the highest risk. Machine learning presents an opportunity to develop a risk prediction model, incorporating complex interactions between variables. Aim: Identify potential predictive features for normal TCD screens by applying machine learning algorithms to clinical data collected for a multi-site collaboration, Dissemination and Implementation of Stroke Prevention Looking at the Care Environment (DISPLACE).1 Methods: We analyzed clinical data collected for the 28-site DISPLACE study, which included 5116 patients in whom a TCD was indicated.1 For the current study, we included patients, aged 2-16 years, who had both hemoglobin and TCD results reported in the same year between 2012-2016 (N = 2234); after excluding patients who had prior studies with abnormal or conditional results, our analysis dataset included 22 predictive features (maximum missingness: 25.7%) for 1825 children (N = 30 with abnormal, N = 122 with conditional results). We applied traditional logistic regression, logistic regression with LASSO, and tree-based classifiers to 19 features including historical, biometric, vital sign, and laboratory data, to predict the risk of abnormal or conditional TCD. Results: In univariate logistic regression models, all 19 features had a statistically significant relationship with TCD outcome. Eight features (age, hemoglobin, heart rate, systolic blood pressure, oxygen saturation, weight, mean corpuscular volume, and percent reticulocytes) were shown to be of consistently high importance across different machine learning models. Conclusion: Next steps include development of ensemble models to optimize predictive performance and internal validation on our hold-out test set. Machine learning shows promise for identifying low risk children with SCD who may not require annual TCD screening, such that TCD resources can be appropriately directed to higher risk children to mitigate the risk of stroke.Reference 1. Kanter et al, J Pediatr Hematol Oncol 2021; 43:e1062-8

Evaluation of transcranial Doppler use in patients with acute liver failure listed for emergency liver transplantation.

Acute liver failure (ALF) is characterized by hepatic encephalopathy (HE) often due to intracranial hypertension (ICH). The risk/benefit-balance of intraparenchymal pressure catheter monitoring is controversial during ALF. Perform an evaluation of transcranial Doppler (TCD) use in patients with ALF listed for emergency liver transplantation. Single center retrospective cohort study including all patients registered on high emergency LT list between 2012 and 2018. All TCD measurements performed during ICU stay after listing and after LT (when performed) were recorded. TCD was considered abnormal when pulsatility index (PI) was >1.2. Among 106 patients with ALF, forty-seven (44%) had a TCD while on list. They had more severe liver and extrahepatic organ failure. When performed, TCD was abnormal in 51% of patients. These patients more frequently developed ICH events (45% vs. 13%, p=.02) and more frequently required increase in sedative drugs and vasopressors. While 22% of patients with normal TCD spontaneously survived, all of those with abnormal TCD died or were transplanted (p=.02). All transplanted patients who had abnormal exams normalized their TCD within 2 (1-2)days after LT. TCD may be a useful non-invasive tool for ICH detection and management, then guide sedation withdrawal.

Brain-derived neurotrophic factor and neuroimaging in pediatric patients with sickle cell disease

BackgroundThe risk of neurological complications is increased in children with sickle cell disease (SCD), such as silent cerebral infarction (SCI) and stroke. Brain-Derived Neurotrophic Factor (BDNF) is a nerve growth factor associated with elevated transcranial Doppler (TCD) velocities and increased risk of stroke in SCD patients. So, we assessed the BDNF level in children with SCD and its relation to neurological complication as silent stroke.MethodsA comparative cross-sectional study was conducted on 40 patients with SCD, recruited from the Hematology Unit, Pediatric Department, Menoufia University Hospital, and 40 healthy children as controls. Laboratory investigations including BDNF were done. TCD was done for all patients and Magnetic Resonance Imaging (MRI) was done on high-risk patients.ResultsBDNF levels were significantly higher in children with SCD than in controls with a significant relation to TCD findings. There was a statistically significant diagnostic ability of BDNF in the prediction of SCD complications as its sensitivity was 89.5%, specificity (95% CI) was 80% with a cut-off point >0.69, AUC = 0.702, and p = 0.004).ConclusionSerum BDNF levels were higher in sickle disease patients who had abnormal transcranial Doppler. BDNF had a significant diagnostic ability in the detection of SCD complications.ImpactSilent stroke is a very serious complication in children with sickle cell disease, so regular follow up should be every six months.BDNF is considered a potential biomarker for stroke risk prediction in patients unable to receive TCD.

Optimizing the Frequency of Transcranial Doppler (TCD) Exams in Children with Sickle Cell Anemia

Background Transcranial Doppler (TCD) screening of the large intracranial arteries can detect elevated blood velocity and is a strong predictor of stroke risk in children with sickle cell anemia (SCA, HbSS and HbSβ0-thalassemia). Initiation of chronic blood transfusion for patients with confirmed abnormal TCD velocities (time-averaged mean velocity, TAMV≥200 cm/sec) is shown to effectively reduce primary stroke. Current guidelines recommend annual TCD screening for children with SCA ages 2-16 years. Screening intervals were developed following evidence from the STOP studies1 (Figure 1). The estimated prevalence of normal TCD velocities is 83%2 and these children will have received 15 TCD exams from ages 2 to 16 if all results remain within normal range. The cumulative incidence of conversion from normal to conditional TCD velocities is dependent on age, whereby the risk is four times lower in children >10 years, compared to those <10 years of age3. Although TCD screening is non-invasive and safe, it consumes time and requires specialized equipment and trained examiners. Identifying sub-populations for whom TCD screening frequency could be safely reduced could lessen time burden on patients and caregivers and could be cost saving. Main objective To estimate the risk of TAMV conversion from normal to conditional or abnormal categories among children with SCA relative to age. Design/Method We included all participants with SCA from the Sickle Cell Clinical Research and Intervention Program, a longitudinal lifetime cohort of patients with SCD with at least one TCD measurement available both before and after age 10 years. We classified participants into two groups based on TCD screening results before 10 years of age; one group with all normal TCDs, and the other group with at least one non-normal TCD. We then compared the time to first non-normal study after ten years of age between the two groups using the log rank test. Time to first conversion was defined as time from age 10, to time of conversion if conversion occurred, or time to last follow up if no conversion occurred. We correlated the number of TCD exams before age 10 with time to first conversion using the Cox proportional regression model. Exposure to chronic transfusion or hydroxyurea before age 10 and age at first TCD measurement were covariates and were correlated with the time to first conversion. Results Of the 614 patients with TCD screening, 297 had SCA and at least 1 screening before and after age 10 (Table 1). Of these, 174 patients had only normal TCD screening before age 10 and the remaining 123 patients had at least 1 non-normal TCD screening before age 10. During the time they were followed,no patients with only normal TCD screenings before age 10, regardless of exposure to hydroxyurea or transfusions, had a conditional or abnormal TCD exam. Conversely, 41.5% of patients with at least one non-normal TCD before age 10 had a conditional or abnormal TCD screening after age 10. Conclusion In a large retrospective cohort study analysis of children with SCA, patients with TCD exams consistently within the normal range under age 10 years were not at risk of conversion to conditional or abnormal TAMV. These results suggest that children with SCA with all normal TCD velocities before age 10 years may not require additional TCD screening exams after age 10. These results translate to 6 fewer TCD exams per each child with SCA over age 10 with all prior normal TCD exams, potentially conserving resources and reducing burden on patients, families, and the health system. De-implementation studies to reduce the use of TCD screening exams in low-risk cases are needed

THE ROLE OF HYDROXYUREA IN INCREASING PULSE OXIMETRY AMONG PATIENTS WITH SICKLE CELL DISEASE

To identify the influence of hydroxyurea (HU) on oxygen saturation levels among patients with Sickle Cell Disease (SCD). A cross-sectional study was carried out that evaluated the use of HU for at least 1 year and the oxygen saturation measured on the oximeter in patients recruited in a SCD cohort in Brazil. A total of 275 patients were evaluated and 132 were included in this study. Inclusion criteria were (i) SS genotype, (ii) age over 18 years, (iii) HU use for more than 1 year (iv) no HU use, (v) active follow-up. Patients who did not use HU were the control group. The HU group had 57 patients with a mean age of 32 (±13.38) years, 50.88% women and 49.12% men. The means of Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Heart Rate (HR) and Oxygen Saturation (SpO 2 ) in this group were, respectively, 117.95 (±15.52) mmHg, 65.39 (±11.22) mmHg, 81.40 (±14.55) bpm and 93.02 (±14.55)%. The Control group consisted of 32 patients, the mean age was 30.50 (±10.92) years, 56.25% were women and 43.75% were men. The means of SBP, DBP, HR and SpO 2 in the control were respectively 114.69 (±12.37) mmHg, 62.44 (±9.37) mmHg, 80.19 (±15.66) bpm and 90.16 (±6.16)%. The difference between SpO 2 in the groups was statistically significant (p = 0.01). In the other variables evaluated there was no statistical significance. Oxygen desaturation is common in SCD and predicts clinical severity. Hypoxemia is associated with risk of stroke, abnormal transcranial Doppler velocities, elevation of tricuspid regurgitation, diastolic dysfunction, increased incidence of vaso-occlusive crises and chest syndrome sharp. Pulse oximetry is a non-invasive method of measuring oxyhemoglobin saturation. Peripheral perfusion, external light sources, and skin color and device quality should be observed. HU is the primary therapy in SCD and is capable of increasing the production of fetal hemoglobin (HbF). Studies have shown a strong correlation between peripheral SpO 2 and HbF level, so treatments that elevate HbF should impact desaturation and be beneficial for complications associated with hypoxia. In the United Kingdom, there is already a recommendation from the HU for the treatment of chronic hypoxemia in SCD. The measurement of SpO 2 is crucial for effective management in SCD. The association between HbF and SpO 2 reaffirms the importance of interventions that are able to increase both, like the HU. This study shows that the patients under use of HU had a significantly higher SpO 2 when compared to patients without it.

Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease

AbstractChildren with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (−19.4 mL/100 g/min) and OEF (−8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, −0.9 mL/100 g/min; P = .024; OEF, −3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.

Neurocognitive functioning in children with sickle cell anemia and history of abnormal transcranial doppler ultrasonography.

Transcranial doppler (TCD) ultrasonography can be used to identify stroke risk in children with sickle cell anemia. Previous studies have reported mixed findings on neurocognitive outcomes in children with elevated TCD. This study examined associations between TCD velocity and neurocognitive outcomes in children and adolescents without prior history of stroke. Participants were selected from the Sickle Cell Clinical Research Intervention Program cohort. The highest recorded mean maximum TCD velocity was selected for analysis, along with participant's most recent data from serial neurocognitive surveillance. A total of 200 children with sickle cell anemia completed neurocognitive testing (109 males, 91 females; mean age 12.7 years [SD=3.56]). Most participants were prescribed hydroxyurea (72%) at the time of neurocognitive testing and nearly 16% had a history of chronic transfusions prior to neurocognitive evaluation. Mean age at time of highest TCD value was 6.6 years (SD=2.5) and 13.5% of screenings were abnormal (≥200cm/s). Mean interval between TCD and most recent neurocognitive evaluation was 6.1 years (±3.5). There were no significant differences in the interval between TCD and neurocognitive testing across normal, conditional, and abnormal groups. Maximum TCD velocity was not significantly associated with neurocognitive outcomes in multivariate models. History of elevated TCD in the absence of overt stroke should not be considered a risk factor for poor neurocognitive outcomes in children and adolescents with sickle cell anemia on modern disease-modifying therapy.

Primary Prevention of Stroke in Children With Sickle Cell Anemia in Nigeria: Protocol for a Mixed Methods Implementation Study in a Community Hospital.

BackgroundIn Nigeria, approximately 150,000 children with sickle cell anemia (SCA) are born annually, accounting for more than half of all SCA births worldwide. Without intervention, about 11% of children with SCA will develop a stroke before their 20th birthday. Evidence-based practices for primary stroke prevention include screening for abnormal transcranial Doppler (TCD) measurements coupled with regular blood transfusion therapy for at least one year, followed by hydroxyurea (HU) therapy indefinitely. In high-resource countries, this strategy contributes to a 92% decrease in stroke incidence rates. In 2016, as part of a capacity building objective of the Stroke Prevention Trial in Nigeria (1R01NS094041: SPRING), TCD screening was adopted as standard care at Barau Dikko Teaching Hospital in Kaduna. However, with just 70 radiologists and only 3 certified in TCD screening in the state, just 5.49% (1101/20,040) of eligible children with SCA were screened. Thus, there is a need to explore alternate implementation strategies to ensure children with SCA receive standard care TCD screening to decrease stroke incidence.ObjectiveThis protocol describes a study to create a stroke prevention program in a community hospital in Kaduna through task shifting TCD screening to nurses and training medical officers to initiate and monitor HU utilization for stroke prevention.MethodsThis study will be conducted at 2 sites (teaching hospital and community hospital) over a period of 3 years (November 2020 to November 2023), in 3 phases using both quasi-experimental and effectiveness-implementation study designs. In the needs assessment phase, focus groups and structured interviews will be conducted with health care providers and hospital administrators to identify barriers and facilitators to evidence-based stroke prevention practices. Results from the needs assessment will inform intervention strategies and a process plan to fit the needs of the community hospital. In the capacity building phase, nurses and medical officers at the community hospital will be trained on TCD screening and HU initiation and monitoring. In the implementation phase, children with SCA aged 2-16 years will be recruited into a nonrandomized single-arm prospective trial to determine the feasibility of initiating a task-shifted stroke prevention program by recording recruitment, retention, and adherence rates. The Reach and Effectiveness components of the RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance) framework will be used to evaluate implementation outcomes between the community and teaching hospitals.ResultsThe needs assessment phase of the study was completed in February 2021. Manuscript on findings is currently in preparation. Capacity building is ongoing with TCD training and sickle cell disease and stroke education sessions for nurses and doctors in the community hospital. Recruitment for the implementation trial is expected to commence in July 2022.ConclusionsThis study proposes a structured, theory-driven approach to create a stroke prevention program in a community hospital in Kaduna, Nigeria, to decrease stroke incidence among children with SCA. Results will provide preliminary data for a definitive randomized clinical trial in implementation science.International Registered Report Identifier (IRRID)PRR1-10.2196/37927