Transcranial Doppler Screening Research Articles

Transcranial Doppler Screening Adherence Among Children with Sickle Cell Anemia Seen in the Emergency Department

Background: Annual transcranial doppler (TCD) screening is strongly recommended for patients with sickle cell anemia (SCA) between the ages of 2 to 16 years to identify children at highest risk for stroke. Implementation of this screening and treating identified patients with chronic transfusion has decreased the incidence of overt stroke. Nonetheless, adherence to TCD screening guidelines is poor and many children with SCA do not receive an annual TCD.The purpose of this study is to evaluate adherence to TCD screening among a cohort of patients with SCA seen in the emergency department (ED) for an acute problem. Previous work has demonstrated that SCD-related outpatient visits are important “missed opportunities” for TCD screening. We hypothesized that ED encounters also represent potential opportunities to identify patients in need of TCD screening who do not attend clinic regularly.Methods: We conducted a retrospective chart review of the medical records of all patients with sickle cell disease (SCD) seen in the ED at a large, urban pediatric institution between February 2016 and April 2017. Patients were identified using an ED clinical registry that includes all ED patient encounters. We excluded patients who do not need TCD screening (sickle cell disease genotypes other than SS and Sβ0 thalassemia, age <2 or >16 years, on chronic transfusions, history of hematopoietic stem cell transplant). We also excluded patients documented to previously have inadequate TCD bone windows and patients who did not receive their regular hematology care at the study institution. For eligible patients who had multiple ED encounters during the study period, data was extracted at the time of the first ED encounter during the study period.Eligible patients who had received a TCD in the last year (adherent to TCD screening) were compared to patients who had not received a TCD in the last year (nonadherent to TCD screening). Categorical data was analyzed with the chi-square test. Continuous data was analyzed using the two-sample t-test. P value of <0.05 was considered statistically significant.Results: During the 64 week study period, 739 patients with SCD were seen in the ED. A total of 482 patients were excluded for the following reasons: non-SCA genotype (n=164), age (n=139), followed at outside institution (n=129), chronic transfusion (n=38), prior TCD window problem (n=10), history of transplant (n=2); leaving 257 patients with SCA aged 2-16 years for study. Among this study group, 63 patients (25%) had not received a needed TCD in the last year, including 19 patients (7%) who had never had a TCD. When excluding patients aged 2-2.99 years (n=33) in whom a first TCD may have been planned soon after the ED encounter, a similar proportion of patients still had not received a TCD in the last year (53/224, 24%) but a slightly smaller proportion had never had a TCD (9/224, 4%). Patient age and sex were not associated with TCD screening adherence (p>0.7). Patients adherent to TCD screening were more likely to be taking hydroxyurea (67% vs. 29%, p<0.0001). A recent hematology clinic visit was significantly associated with TCD screening adherence. All patients adherent to TCD screening had a clinic visit in the last year compared to 75% of nonadherent patients, p<0.0001. The mean interval time since the last hematology clinic appointment from the ED encounter was greater for TCD nonadherent patients, 70 vs. 270 days p<0.0001 (Figure).Conclusion: Patients with SCA who present to the ED and are nonadherent to TCD screening guidelines are less likely to have had a recent hematology clinic visit. Therefore, the ED may be an important location for identifying patients lost to regular clinic follow-up in need of a TCD. An intervention that specifically targets this patient population will likely improve TCD screening rates and stroke prevention. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Results from the Displace Consortium: Practice Patterns on the Use of Transcranial Doppler Screening for Risk of Stroke in Children with Sickle Cell Anemia

Abstract Introduction: Stroke is one of the most devastating complications of sickle cell anemia (SCA). The STOP (Stroke Prevention Trial in Sickle Cell Anemia) protocol has been adopted by National Heart Lung and Blood Institute (NHLBI) as the guideline for stroke screening using transcranial Doppler ultrasound (TCD) and prevention with chronic red cell transfusion therapy (CRCT). Evidence from the STOP I/II studies indicates the protocol is highly effective, yet wide scale implementation has not been achieved. The DISPLACE (Dissemination and Implementation Looking at the Care Environment) project is a multicenter, NHLBI funded consortium of 28 sites across the United States whose purpose is to identify barriers to the implementation of the STOP protocol and test novel methods for overcoming barriers. The purpose of this study was to use data on practice patterns to evaluate current measurement and practice standards at DISPLACE consortia sites. This abstract presents reported TCD screening and CRCT practices. Methods: A practice patterns survey was sent to the principal investigator (PI) for each DISPLACE site via RedCap ©. PIs were hematology/oncology specialty care providers for children with SCA. Sites represent urban and rural regions, large and small academic institutions, and community-based institutions. The survey was developed by the study investigators; questions were predominantly in a multiple-choice format. Items pertaining to TCD screening included: screening technique (including type of TCD); screening frequency; follow-up for abnormal, conditional, and inadequate results; standard value ranges. Results: All 28 PIs completed the survey. About half of the respondents were female (53.5%). Most identified as White (77.8%), followed by Asian (11.1%) and Black or African American (7.4%). Two identified as Hispanic or Latino (7.4%). Slightly more sites reported using standard TCD (57.1%) versus imaging TCD (TCDi) (42.9%). To calculate the time-averaged mean of the maximum (TAMM) velocities and characterize TCD results, nearly all sites use the middle cerebral artery (96.4%); a majority also use the anterior cerebral artery and/or the terminal internal cerebral artery or distal internal cerebral artery (71.4%). Fewer sites use the posterior cerebral artery (35.7%) or the basilar artery (14.3%). In 7.1% of sites, the radiologist determines which vessels to use during the exam. TCD screening is ordered for children with SCA annually in 92.9% of sites and every 6 months in 7.1% of sites. When TCD screening indicates abnormal TAMM velocities, 85.7% of sites initiate CRCT, 7.1% initiate hydroxyurea (HU) therapy, and 3.6% initiate both HU and CRCT. For additional evaluation, an MRI/MRA is obtained at 64.3% of sites. For high conditional results, the most common action is to initiate HU (67.9%). Other responses include obtaining an MRI/MRA (46.4%) and/or repeating the TCD in 2-4 weeks (25.0%), 6-8 weeks (35.7%), or 12-16 weeks (7.1%). Results deemed inadequate led to repeating the TCD in 2-12 weeks (57.1%) or in one year (3.6%), obtaining an MRI/MRA (57.1%), beginning HU therapy (7.1%), or no repeat TCD or change in management (3.6%). Actions for low conditional results include repeating the TCD (71.4%), obtaining an MRI/MRA (32.3%), and/or initiating HU therapy (57.1%). Surprisingly, sites use different TAMM ranges to characterize the normal/abnormal findings (Table 1). Conclusions: Nearly all DISPLACE sites order TCD screening annually, as recommended in the guidelines, with some ordering screening more frequently. A few sites did not report initiation of CRCT per STOP protocol for abnormal TCD results; however, over half of the sites reported following up with an MRI/MRA, which may suggest evaluating for vasculopathy prior to CRCT. Some sites reported beginning HU therapy for abnormal results; this may reflect consideration of patients for whom CRCT is not possible, but data were not collected for confirmation. Interestingly, results suggest a reliance on MRI/MRA since sites commonly reported ordering neuroradiology studies for abnormal, conditional, and inadequate TCD results. This may suggest an unclear pathway for children with borderline TCD results, and an area for future study. While reported value ranges closely approximated those in the STOP protocol, results indicate sites conducting screening with TCDi may use more conservative values than the validated protocol. Disclosures Phillips: NHLBI: Research Funding. Mueller:NHLBI: Research Funding. Schlenz:NHLBI: Research Funding. Melvin:NHLBI: Research Funding. Adams:NHLBI: Research Funding. Kanter:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sancilio: Research Funding; NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Apopharma: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees.

Comprehensive Infant Clinic for Sickle Cell Disease: Outcomes and Parental Perspective

IntroductionComprehensive care for children with sickle cell disease (SCD) includes penicillin prophylaxis, pneumococcal immunization, hydroxyurea therapy, and transcranial Doppler screening for stroke prevention. Along with caregiver education, these strategies have been shown to be effective in reducing early morbidity and mortality in this population. The subspecialty Infant Sickle Cell Clinic was initiated to improve access, education, patient outcomes, and family satisfaction. MethodTelephone surveys were conducted with parents to assess satisfaction with the Infant Sickle Cell Clinic, compliance with guidelines, and comfort level with managing their child's SCD. ResultsThis quality improvement project reported high levels of parent satisfaction and improved outcomes with the proposed approach but also presents areas for improvement. DiscussionOur report presents a unique model of providing care to families with infants newly diagnosed with SCD. The group format serves as a useful model to allow families an interactive educational session with guest speakers.

Transcranial Doppler Ultrasound in Peninsular Arab Patients With Sickle Cell Disease.

Transcranial Doppler ultrasound is used to identify patients with sickle cell disease (SCD) at risk for stroke. We performed transcranial Doppler studies in patients from 4 countries in the Arabian Peninsula (Kuwait, Oman, Iraq, and United Arab Emirates) to document the prevalence of abnormal transcranial Doppler findings. The patients were recruited from outpatient clinics and studied in a steady state. Transcranial Doppler examinations were performed with standard equipment by experienced operators. The time-averaged maximum mean velocity (TAMMV) was documented in the arteries of the circle of Willis. The hemoglobin (Hb) genotype was confirmed, and the fetal Hb level and complete blood counts were determined. There were 415 patients in the study, aged 2 to 18 years (mean ± SD, 8.6 ± 3.5 years). None of the patients had an abnormal TAMMV (ie, > 200 cm/s), whereas only 13 (3.1%), all from Iraq, had conditional values (170-200 cm/s) in the right middle cerebral artery and 7 (1.7%) in the left middle cerebral artery. There were no consistent TAMMV differences among male and female patients or in patients with different Hb genotypes (sickle cell anemia, sickle cell β0- thalassemia, and sickle D). The use of hydroxyurea was associated with a lower TAMMV, whereas a blood transfusion history had no influence. Total hemoglobin, reticulocyte count, serum bilirubin, and fetal Hb values showed varying degrees of association with the TAMMV in the different vessels. This study has demonstrated the rarity of abnormal transcranial Doppler findings among Peninsular Arab patients with SCD. The guidelines for transcranial Doppler screening in this population need further studies and recommendations.

Vasculopathie cérébrale de l’enfant drépanocytaire : points clés et nouveautés

Cerebral vasculopathy is a common and severe complication of sickle cell disease in children. The pathophysiology consists of progressive damage to the basal intracranial arteries and cerebral microcirculation, while chronic anemia worsens exposure to cerebral hypoxia. It results in stroke and subclinical or poorly symptomatic ischemic lesions. Many clinical, biological, and radiological risk factors have been identified. The prevention strategy through systematic transcranial Doppler screening of large-vessel vasculopathy has revolutionized the management of this disease and has greatly decreased the risk of developing stroke. MRI-MRA is a complementary diagnostic tool for anatomical analysis of parenchymal and vascular lesions, which is used for chronic disease monitoring or in the context of an acute neurological event. New exploration opportunities are offered by submandibular Doppler sonography and indirect evaluation methods of cerebral oxygenation and perfusion. If chronic blood transfusion therapy is used to prevent the occurrence and recurrence of cerebral complications of sickle cell disease, only allogeneic hematopoietic stem cell transplantation can safely and definitively stop the transfusion program. It should therefore be proposed early, before irreversible cerebral or vascular lesions occur. Hydroxycarbamide treatment has recently emerged as a potential substitute for chronic transfusions for the maintenance of transcranial Doppler velocities, but only after an initial treatment by transfusions and provided there is close follow-up. In the long run, cerebral vascular damage can cause progressive cognitive impairment and disability, even in children without radiologically identified lesions, indicating the importance of systematic and repeated neuropsychological testing.

Genetic, laboratory and clinical risk factors in the development of overt ischemic stroke in children with sickle cell disease.

Cerebrovascular disease, particularly stroke, is one of the most severe clinical complications associated with sickle cell disease and is a significant cause of morbidity in both children and adults. Over the past two decades, considerable advances have been made in the understanding of its natural history and enabled early identification and treatment of children at the highest risk. Transcranial Doppler screening and regular blood transfusions have markedly reduced the risk of stroke in children. However, transcranial Doppler has a limited positive predictive value and the pathophysiology of cerebrovascular disease is not completely understood. In this review, we will focus on the current state of knowledge about risk factors associated with ischemic stroke in patients with sickle cell disease. A search of PubMed was performed to identify studies. Full texts of the included articles were reviewed and data were summarized in a table. The coinheritance of alpha-thalassemia plays a protective role against ischemic stroke. The influence of other genetic risk factors is controversial, still preliminary, and requires confirmatory studies. Recent advances have established the reticulocyte count as the most important laboratory risk factor. Clinical features associated with acute hypoxemia as well as silent infarcts seem to influence the development of strokes in children. However, transcranial Doppler remains the only available clinical prognostic tool to have been validated. If our understanding of the many risk factors associated with stroke advances further, it may be possible to develop useful tools to detect patients at the highest risk early, improving the selection of children requiring intensification therapy.

Transcranial Doppler Screening in 50 Patients With Sickle Cell Hemoglobinopathies in Iran.

As previous studies had discordant results with regard to the correlation of transcranial Doppler (TCD) screening and brain MRI, the aim of this study was to find the correlation between TCD values and silent ischemia in sickle cell disease (SCD) patients. In this cross-sectional study, 50 patients with proven diagnosis of sickle cell hemoglobinopathies based on their hemoglobin electrophoresis were included. Demographic data, their physical exam, information with regard to crises history, and their laboratory data were recorded. Brain MRI and TCD were requested for all patients. The mean age of the patients was 10.2±5.8 years. Only 3 patients (6%) showed evidence of ischemia on brain MRI. Normal and ischemic patients were not significantly different with respect to TCD values, sex, splenomegaly, aplastic crisis, and laboratory test results (P-value >0.05). Only platelet count was significantly higher in the ischemic group compared with that in the normal group (P=0.002). The pain crisis was significantly associated with the mean velocity values of RMCA, LMCA, RV, and LV arteries (P-value <0.05). On the basis of our results, there was no significant difference in the mean velocity TCD values between patients with and without evidence of ischemic brain damage in brain MRI. The frequency of silent ischemia was much lower than expected. Further studies with larger sample sizes are needed to elucidate the positive predictive value of abnormal TCD in the prediction of silent ischemia in patients with sickle hemoglobinopathy in certain ethnic groups.

Sickle cell disease: an update on management

Abstract Sickle cell disease (SCD) is a common inherited disease affecting 12–15,000 individuals in the UK with approximately 250 new births per annum. Life expectancy has improved with the majority of those affected now surviving to adulthood, but it is associated with acute and chronic complications including haemolytic anaemia and intermittent episodes of severe bony pain, which may need hospital admission for management. Other acute complications include acute chest syndrome, stroke, priapism, splenic sequestration and red cell aplasia. Individuals with SCD also have an increased risk of infection and may develop renal dysfunction, respiratory complications and bony complications including avascular necrosis. Newborn screening will identify affected individuals and ensures early entrance into comprehensive care, which should include infection prophylaxis and primary stroke prevention by trans-cranial doppler screening. In addition annual review by a specialist team should continue throughout life. Optimal care provision comes from a strong multidisciplinary approach, with easy access to psychological services and an active community support team. With these measures, patients and their families can be educated to manage the minor complications of SCD with minimal impact to their daily lives and to recognize the more serious complications early, allowing quick and effective intervention to reverse the sickling process. Current treatments options are hydroxycarbamide (hydroxyurea), blood transfusion and haematopoietic stem cell transplant.

Transcranial Doppler screening for stroke risk in children with sickle cell disease: a systematic review.

Background Sickle cell disease (SCD) is one of the most common causes of stroke in children worldwide. Based on the results of the Stroke Prevention Trial in Sickle Cell Anemia (STOP), annual transcranial Doppler ultrasound (TCD) screening for affected children is standard practice. However, the need for TCD surveillance programs could override the accuracy of the screening, affecting the correct stratification of stroke risk and subsequent clinical management of the target population. Aims To shed light on this issue, a systematic review of the literature on TCD screening for children and adolescents with SCD was carried out (CRD42016050549), according to a list of clinically relevant questions, with a particular focus on screening practices in European countries. Quality of the evidence was rated using the grading of recommendations assessment, development and evaluation. Summary of review Thirty-three studies published in English or French were included (5 randomized controlled trials, 8 experimental non-randomized, and 20 observational studies). The quality of the retrieved evidence ranged between low and high, but was rated as moderate or high most of the times. TCD is effective as a screening tool for the primary prevention of stroke in SCD children. There is no high-quality evidence on the effectiveness of alternative screening methods, such as imaging-TCD with or without angle correction or magnetic resonance angiography. No evidence was found on effectiveness of the screening on children on hydroxyurea and with genotypes other than HbSS and HbS/β0. No European data were found on screening rates or adherence of screening practices to the STOP protocol. Conclusions High-quality studies on alternative screening methods that are currently used in real-world practice, and on screening applicability to specific subgroups of patients are urgently needed. Considering the low awareness of the disease in European countries and the lack of data on screening practices and adherence, clinicians need up-to-date guidelines for more uniform and evidence-based surveillance of children with SCD.

Sickle cell anemia in sub-Saharan Africa: advancing the clinical paradigm through partnerships and research

Sickle cell anemia (SCA) carries orphan disease designation in the United States, with ∼2000 affected infants born annually and fewer than 100 000 persons living with this condition.1 Patients with SCA have numerous acute and chronic medical problems, which collectively contribute to life-threatening morbidity, early mortality, and annual domestic medical costs exceeding $1.1 billion.2-6 Worldwide, >300 000 infants are born with SCA each year,7 but <1% of sickle cell births occur in North America and the United Kingdom/Europe, where nearly all SCA research and health care dollars are spent. Millions of persons throughout the world are living with, and unfortunately dying from, this inherited blood disorder without the benefits of proper diagnosis and appropriate clinical care. Although the burden of SCA is truly global, with the highest incidence in Africa, India, the Caribbean, Central America, and South America, the focus of this editorial perspective is SCA within Africa. More than 75% of the global burden of SCA occurs in sub-Saharan Africa,8 where scarce health resources and inadequate awareness among health care providers and the general public contribute to shocking rates of early mortality. With few data from neonatal screening programs, and virtually no prospective natural history studies, true mortality rates are unknown, but an estimated 50% to 90% of infants born with SCA in sub-Saharan Africa die before their fifth birthday.9,10 Without early diagnosis, which allows early preventive treatments including pneumococcal vaccination, penicillin prophylaxis, and parental education, most infants will die of acute complications, most notably bacterial sepsis or severe anemia. Regrettably, death attributed to SCA is missing completely from recent global summaries,11 presumably because of a lack of accurate data, making SCA at best a neglected and, more accurately, an invisible killer of children.12,13 Over the past 40 years, beginning with the landmark US Cooperative Study of Sickle Cell Disease14-16 and Jamaican Cohort Study,17 substantial evidence has accumulated from well-designed prospective research trials. Together, these studies document the life-threatening severity of untreated SCA, but demonstrate unquestionable benefits of penicillin prophylaxis, pneumococcal vaccinations, transcranial Doppler (TCD) screening for primary stroke prevention, safe transfusions for acute and chronic complications, and hydroxyurea as a safe and potent disease-modifying therapy. Unfortunately, the status of SCA in Africa remains stagnant, with most affected persons lacking access to basic diagnostics and clinical care. As SCA finally begins to be addressed in Africa, we must ask whether proven evidence from well-resourced countries is directly transferable, or must additional studies be replicated and verified in the African setting? Are new National Heart, Lung, and Blood Institute (NHLBI) evidence-based guidelines for SCA18 feasible or even appropriate for limited-resource settings? How do we augment these guidelines to be clinically and economically feasible, while remaining effective across sub-Saharan Africa? Acknowledging the unjustifiable disparity in clinical care and outcomes between well-resourced and limited-resource settings for persons with SCA, some institutions that lead and fund sickle cell care and research have begun to take action. Both the NHLBI and American Society of Hematology (ASH) are committing financial and programmatic efforts to address the global burden of SCA in limited-resource settings, particularly in sub-Saharan Africa.19-21 We must think carefully about what is needed to improve outcomes, and how these needs can be met safely and effectively within the clinical and financial contexts of limited-resource settings. Although the HbS mutation is the same worldwide, the environment, infectious exposures, and general health care infrastructure faced by persons living with SCA in Africa are quite different from those in well-resourced settings. With our admittedly Western bias, we suggest that plans to shift our clinical care and treatment paradigms automatically to Africa are neither logical nor likely to succeed. Instead, we advocate for the formation of multidisciplinary partnerships and research collaborations with a shared vision and mutual benefits, with short-term goals of obtaining high-quality data while emphasizing local capacity building and health system strengthening, and long-term goals of helping to develop national (and global) strategies for SCA that are impactful and sustainable. Herein, we offer our subjective summary of opportunities by which sickle cell capacity and outcomes can be improved, based upon our own experiences with African partnerships and research collaborations. Each high burden country should carefully assess its own needs to develop national sickle cell strategies that are in line with their own resources, and offer a plan for sustainability.

Patients with sickle cell disease are frequently excluded from the benefits of transcranial doppler screening for the risk of stroke despite extensive and compelling evidence.

Transcranial doppler was performed in accordance with the Stroke Prevention Trial in Sickle Cell Anemia Protocol. Of the 396 patients, 69.5% had homozygous SS hemoglobin. The TCD result was abnormal in 4.8%, conditional in 12.6%, inadequate in 4.3% and abnormally low in 1% of patients. The highest mean flow velocities were 121±23.83cm/s and 124±27.21cm/s in the left and right middle cerebral artery respectively. A total of 28.8% patients (mean age 9.19±5.92 years) were evaluated with TCD for the first time. The SCD patients were evaluated with TCD at an older age, representing an important missed opportunity for stroke prevention. Since TCD screening in patients with SCD is important to detect those at high risk for stroke, it is recommended that this screening should be made more readily available.

Capacity Building in Transcranial Doppler Screening in Sickle Cell Disease Related-Stroke Prevention in Children in Nigeria

Capacity Building in Transcranial Doppler Screening in Sickle Cell Disease Related-Stroke Prevention in Children in Nigeria

Health Care Utilization By Age and Hydroxyurea Response in Pediatric and Adolescent Patients with Sickle Cell Disease

▪Background: Children and adolescents with sickle cell disease (SCD) have high rates of healthcare utilization which peak around the age of transition from pediatric to adult care. Adherence to evidence based care, including regular clinic visits, annual transcranial doppler (TCD) studies, and hydroxyurea (HU) use, is often suboptimal in this population. Over the past 4 years we have used a registry and patient navigator to improve access to routine care for our patients with SCD. We hypothesized that increased access to clinic and higher rates of HU use would positively impact acute care utilization. The purpose of this study was to 1) assess adherence to clinic visits and TCD rates, 2) describe patterns of acute care utilization, and 3) analyze the association between response to HU and acute care utilization in our patient cohort.Methods: We analyzed data on 208 unique patients with SCD between the ages of birth to 22 years of age who received care through the pediatric hematology program at BMC from April 2013 through March 2016. Demographics (age and genotype) and data on clinic visits, TCD screening, ED visits, inpatient stays, and HU use was obtained from the data ware house based on patients in our SCD registry. We calculated emergency department reliance (EDR), a ratio of clinic adherence relative to acute care utilization, for each patient.TCD rates and HU use were analyzed for patients with HbSS genotype only. Patient were stratified into three HU categories; patients not prescribed HU, those prescribed HU with a HbF response of less than 15%, and those prescribed HU with a HbF response of at least 15%. A Kruskal-Wallis test was used to analyze differences in rates of acute care utilization between the HU groups, Wilcoxon rank-sum test was used to assess whether EDR differed by HbF category, and Spearman's rank correlation was used to test for an association between HbF and EDR.Results: On average over the three year period 78% of patients had two clinic visits per year, 85% of eligible patients were prescribed HU and 96% had annual TCD screening. Acute care utilization was higher among older patients, consistent with the existing literature. Patients in the oldest age bracket had the highest mean EDR at 0.33 (Table 1). Among patients prescribed HU, increased HbF% was associated with lower rates of acute care utilization among all measures analyzed (Table 2). There was also a statistically significant, inverse association between HbF percentage and EDR of -0.2183 (p=0.0275).Conclusion: Through use of a SCD registry and patient navigator we have maintained adherence to biannual clinic visits, TCD screening, and HU uptake much higher than the rates reported in the literature. Our patients also had low rates of EDR at 0.23 which may reflect our clinic's accessibility. Increased levels of HbF, representing better adherence to HU, were associated with less acute care utilization, highlighting the importance of finding ways to increase adherence in our patient population. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Evaluation of a Novel Newborn Screening Follow-up Program for Infants with Sickle Cell Disease

While newborn screening for sickle cell disease (SCD) has improved survival of affected infants through early prescription of prophylactic penicillin and SCD education for the parents, newborn screening follow-up programs are highly variable among states. The novel statewide newborn screening program in Indiana, Sickle SAFE (Screening, Assessment, Follow-up, Education), was started in 2009 and followed infants through the first year of life until 2013 when the program expanded to provide follow-up for the first 5 years of life. Sickle SAFE ensures timely notification and education of families of affected patients and links them to a hematologist. An initial home visit is scheduled and coordinated by the Sickle SAFE Program Coordinator within one month of receipt of abnormal screening results. After the initial home visit, coordinators maintain phone contact with families regularly throughout the enrollment period. An analysis of Georgia Medicaid claims published in 2016 reported that 47.2% of children between 2 and 3 years of age had screening transcranial Doppler (TCD) and 73.6% received PPSV23 (Pneumovax). The current study aims to assess the rates of attainment for recently published quality indicators of pediatric SCD care for children enrolled in Sickle SAFE.A retrospective study was initiated to determine the proportion of children enrolled in Sickle SAFE who received TCD screening between 2 and 3 years of age (HbFS only) and influenza and pneumococcus [PCV (Prevnar) and PPSV23] vaccination. The mean age at confirmatory testing and receipt of penicillin prophylaxis (goal ≤ 2 months) as well as the mean age of the affected infant when families were offered genetic counseling (goal ≤ 6 months) were calculated. From 2009-2012, all positive newborn screens for any sickle hemoglobinopathy were reflexively sent for confirmatory DNA testing. From 2013 onward, only HbFS newborn screens were sent for confirmatory DNA testing. Children who were enrolled in Sickle SAFE less than two years of age were excluded from the PPSV23 and TCD analyses.A total of 141 children were born with SCD and enrolled in Sickle SAFE for at least one year between July 1 2009 and June 30 2015. The majority (56.7%) had HbSS, 32.6% had HbSC, 9.9% were compound heterozygotes for HbS and beta thalassemia and the remaining 0.7% had another sickle hemoglobinopathy. The mean length of follow-up was 2.7 ± 1.0 years. 55.3% were female and 78.7% were African American. 87.2% were publicly insured. Mean age for all patients born with SCD to have confirmatory testing was significantly shorter when confirmatory DNA testing was sent for all affected infants compared to when it was limited to only infants with HbFS [40.3 ±14.1 days (2009-2012) vs. 127.8 ± 173.1 days (2013-2015), p= 1.5E-6]. While the age at confirmatory testing did not differ for infants with HbFS results between the two periods [45.9 ± 14.1 days (2009-2012) vs. 45.8 ± 14.0 days (2013-2015), p=0.98], infants with results other than HbFS were significantly older when confirmatory testing was performed after the process change in 2013 [40.3 ± 14.1 days (2009-2012) vs. 225.3 ± 221.4 days (2013-2015), p=2.6E-6]. Mean age at which genetic counseling was offered to all families with affected children was 26.8 ± 9.9 (range 9-60) days. Mean age at receipt of first dose of penicillin was 28.6 ± 15.0 (range 5-62) days for infants with HbFS, and 29.5 ± 20.1 (range 5-142) days for those with other sickle hemoglobinopathies (p=0.78). 86.5% of enrollees received at least one influenza vaccine while 95.0% had received at least one dose of PCV. Over two-thirds (69.1%) of children with HbFS had TCD screening between the ages of two and three years. 77.3% of Sickle SAFE enrollees who were followed for more than 2 years received PPSV23.Newborn screening for SCD allows for supportive care aimed at reducing morbidity and mortality. Reflex DNA confirmatory testing is an important part of this quality care, regardless of sickle genotype, and our data shows that confirmatory testing is delayed when it is not reflexively performed for all affected infants. The intensive follow-up provided through the Sickle SAFE program increases adherence to quality standards for comprehensive care, as evidenced by a higher rate of TCD screening compared to published data. Education of state departments of health for improved funding and support of programs like Sickle SAFE may help to improve outcomes for affected children. DisclosuresNo relevant conflicts of interest to declare.

Pediatric sickle cell disease: past successes and future challenges.

Once a fatal disease of childhood, more than 95% of patients born today with sickle cell disease (SCD) in developed countries are expected to survive into adulthood, largely because of improvements in supportive and preventive care (newborn screening, penicillin prophylaxis, transcranial Doppler (TCD) screening). Hydroxyurea (HU) therapy, the only oral medication currently available to prevent SCD complications, has become more widespread over the past 20 y. The NHLBI recommends that HU be offered to all patients with HbSS beginning at 9 mo of age, and the recently published Abnormal TCD with Transfusions Changing to HU (TWiTCH) trial has shown HU as an acceptable alternative to transfusion therapy for patients at high risk of stroke. While hematopoietic stem cell transplant (HSCT) is a curative option for SCD, less than 25% of patients have a suitable donor. Alternative stem cell sources from unrelated donors and haplo-identical donors are currently under investigation as are gene therapy trials. This review will focus on early efforts to elucidate SCD pathophysiology as well as supportive and preventive care improvements. Findings from recent multi-center studies (Silent Infarct Transfusion (SIT) Trial and TWiTCH) will be summarized. Finally, HSCT trials and gene therapy will be reviewed.

Transcranial Doppler Screening in a Regional Care Network for Sickle Cell Disease in the United Kingdom

The risk of stroke in children screened with transcranial Doppler ultrasound in the United Kingdom is not known. We evaluated a clinician-led program using a risk assessment modified from the STOP protocol. High-risk classification included abnormal velocities in the anterior cerebral artery, and single abnormal scan if initial velocity >220 cm/s (high abnormal) or if preceded by at least 2 conditional scans. In total, 1653 scans were performed in 542 children, followed for 2235 patient-years. Fifty-eight (10.7%) high-risk subjects were identified, including 18 (31%) with high abnormal, and 15 (26%) with previous conditional scans. In 2 (3%), abnormal velocity was restricted to the anterior cerebral artery. The estimated proportion of children at high risk, scanned before 6 years of age was >20%. There were 4 cases of acute ischemic stroke (AIS) and 2 of acute hemorrhagic stroke. The incidence of all stroke, AIS, and acute hemorrhagic stroke were 0.27, 0.18, and 0.09 per 100 patient-years, respectively. The proportion of children at high risk is higher than most previous estimates, partly as a result of our modified risk assessment. About 2 children per 1000 screened with transcranial Doppler ultrasound progress to AIS.

EXpanding Treatment for Existing Neurological Disease (EXTEND): An Open-Label Phase II Clinical Trial of Hydroxyurea Treatment in Sickle Cell Anemia.

BackgroundCerebral vasculopathy in sickle cell anemia (SCA) begins in childhood and features intracranial arterial stenosis with high risk of ischemic stroke. Stroke risk can be reduced by transcranial doppler (TCD) screening and chronic transfusion therapy; however, this approach is impractical in many developing countries. Accumulating evidence supports the use of hydroxyurea for the prevention and treatment of cerebrovascular disease in children with SCA. Recently we reported that hydroxyurea significantly reduced the conversion from conditional TCD velocities to abnormal velocities; whether hydroxyurea can be used for children with newly diagnosed severe cerebrovascular disease in place of starting transfusion therapy remains unknown.ObjectiveThe primary objective of the EXpanding Treatment for Existing Neurological Disease (EXTEND) trial is to investigate the effect of open label hydroxyurea on the maximum time-averaged mean velocity (TAMV) after 18 months of treatment compared to the pre-treatment value. Secondary objectives include the effects of hydroxyurea on serial TCD velocities, the incidence of neurological and non-neurological events, quality of life (QOL), body composition and metabolism, toxicity and treatment response, changes to brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), genetic and serologic markers of disease severity, and cognitive and pulmonary function.MethodsThis prospective Phase II trial will enroll children with SCA in Jamaica, between the ages of 2 and 17 years, with either conditional (170-199 cm/sec) or abnormal (≥ 200 cm/sec) TCD velocities. Oral hydroxyurea will be administered daily and escalated to the maximum tolerated dose (MTD). Participants will be seen in the Sickle Cell Unit (SCU) in Kingston, Jamaica monthly until achieving MTD, and then every 3 months. TCD will be performed every 6 months.ResultsCurrently, 43 participants have been enrolled out of a projected 50. There was one withdrawal due to immigration, with no permanent screen failures. Of the 43 enrolled, 37 participants have initiated study treatment.ConclusionsThis trial investigates the effects of hydroxyurea treatment at MTD in children with conditional or abnormal TCD velocities before transfusion therapy and may represent an important advance towards establishing a suitable non-transfusion protocol for stroke prevention in children with SCA. The trial outcomes will have profound significance in developing countries where the disease burden is highest.ClinicalTrialClinicalTrials.gov NCT02556099; https://clinicaltrials.gov/ct2/show/NCT02556099 (Archived by WebCite at http://www.webcitation.org/6k1yMAa9G)

Missed Opportunities for Transcranial Doppler Screening Among Children With Sickle Cell Disease.

Transcranial Doppler (TCD) screening rates remain low among children with sickle cell disease (SCD). We assessed TCD screening rates and missed opportunities for TCD screening. Children 2 to 16 years old with SCD enrolled in Michigan Medicaid for ≥1 year (2007-2011) were identified through newborn screening. Receipt of TCD screening and presence of a missed opportunity (≥1 SCD-related outpatient visit, no TCD screening) were identified through administrative claims. Potential correlates of missed opportunities included SCD-related health services, comorbidities, and demographics. Logistic regression with generalized estimating equations modeled associations between a missed opportunity and correlates. Overall, 353 children contributed 1066 person-years. TCD screening was low yearly (10%-32%); missed opportunities occurred in 73% of the person-years. Increasing age (odds ratio [OR] = 1.11; confidence interval CI = 1.07, 1.15), previous TCD screening (OR = 0.26; CI = 0.16, 0.41), and 4 to 5 (OR = 0.48; CI = 0.26, 0.87) or ≥6 outpatient visits (OR = 0.26; CI = 0.14, 0.49) were associated with a missed opportunity. Reduction of missed opportunities is a potential strategy to increase TCD screening rates.

Chapter 18 - Sickle cell disease

Sickle cell disease (SCD) is an inherited hemoglobinopathy caused by a mutation in the sixth amino acid of the β-globin gene (HBB). It is the most common serious genetic diseases in childhood, affecting approximately 1 in 2500 births and 100 000 individuals in the USA, in addition to 300 000 new cases globally each year. Central nervous system injury is the most debilitating frequent complication of SCD and includes stroke, silent cerebral infarct (SCI), and cognitive impairment. Among children with sickle cell anemia (HbSS), 11% had a stroke by age 18 years before the implementation of transcranial Doppler screening. SCI is identified in 27% of children with HbSS by their 5th birthday. Children who develop SCI have greater cognitive impairment compared with either children with HbSS without SCI or siblings without SCD. A recent study of adults demonstrated significant cognitive dysfunction, even in participants with apparently mild SCD.

TCD with Transfusions Changing to Hydroxyurea (TWiTCH): Hydroxyurea Therapy As an Alternative to Transfusions for Primary Stroke Prevention in Children with Sickle Cell Anemia

Transcranial Doppler (TCD) screening in children with sickle cell anemia (SCA) identifies abnormally elevated cerebral artery flow velocities that confer an elevated risk for primary stroke. Chronic transfusions offer effective stroke prophylaxis in this setting, but must be continued indefinitely and lead to transfusional iron overload. An alternative treatment strategy that offers similar effective protection against primary stroke, and provides control of iron overload, is needed. TCD With Transfusions Changing to Hydroxyurea (TWiTCH, NCT01425307) was an NHLBI-funded Phase III multicenter randomized clinical trial comparing 24-months of standard treatment (transfusions) to alternative treatment (hydroxyurea) in children with SCA and abnormal TCD velocities. All eligible children had received at least 12 months of transfusions. TWiTCH had a non-inferiority trial design; the primary study endpoint was the 24-month TCD velocity obtained from a linear mixed model, controlling for baseline (enrollment) values, with a non-inferiority margin of 15 cm/sec. The transfusion arm maintained children at HbS <30%; an elevated liver iron concentration (LIC) identified by R2 MRI FerriScan® was managed with chelation. The hydroxyurea arm included an overlap period with transfusions until a stable maximum tolerated dose (MTD) of hydroxyurea was reached; transfusions were then replaced by serial phlebotomy to reduce iron overload. In both arms, TCD velocities were obtained every 12 weeks and reviewed centrally, with local investigators masked to the results. A centralized TCD alert algorithm monitored changes from enrollment velocities. A total of 159 children were enrolled but 38 failed screening due primarily to severe vasculopathy on brain MRA or inadequate TCD exams; 121 children were randomized (61 to transfusions, 60 to hydroxyurea) with balanced characteristics including enrollment maximum TCD velocities (145 ± 21 versus 145 ± 26 cm/sec), age, duration of transfusions, serum ferritin, and LIC. Study participants randomized to transfusions maintained an average HbS <30% throughout the study, while those on hydroxyurea reached MTD after 7 ± 2 months at an average dose of 27 mg/kg/day, with expected hematological changes including HbF ~25% throughout the treatment period. After 37% of the participants exited the study, a scheduled interim analysis suggested the primary study endpoint was likely to be achieved. NHLBI allowed the study to continue until 50% of the children exited, at which time the statistical analysis was confirmed and the study was terminated; all remaining participants moved to the exit phase. The final analysis included 42 on the transfusion arm who completed all treatment, 11 with truncated treatment, and 8 withdrawn; the hydroxyurea arm included 41 who completed all treatment, 13 with truncated treatment, and 6 withdrawn. The final calculated TCD velocities (mean ± standard error) in the transfusion and hydroxyurea arms were 143 ± 1.6 and 138 ± 1.6 cm/sec, respectively; by intention-to-treat analysis, the p-value for non-inferiority = 8.82 x 10-16 and by post-hoc analysis the p-value for superiority = 0.046. Among 29 new neurological events, all centrally adjudicated by masked reviewers, there were no strokes but 6 transient ischemic attacks (3 in each arm). One child (transfusion arm) was withdrawn per the TCD alert algorithm after developing on-study TCD velocities >240 cm/sec. Exit brain MRI/MRA exams documented no new parenchymal abnormalities but one child (transfusion arm) developed new vasculopathy. Sickle cell related serious adverse events were more common in the hydroxyurea arm than the transfusion arm (23 to 15), but none was related to study treatment or study procedures. Iron overload improved more in the hydroxyurea arm than in the transfusion arm, with a greater average change in serum ferritin (-1085 compared to -38 ng/mL, p<0.001) and LIC (average -1.9 compared to +2.4 mg/g dry weight liver, p=0.001). In the multicenter Phase III TWiTCH trial, which treated children with SCA and abnormal TCD velocities but without severe MRA vasculopathy, hydroxyurea at MTD was non-inferior and possibly superior to chronic transfusions for maintaining TCD velocities. Serial phlebotomy effectively managed iron overload. Hydroxyurea may represent an effective alternative to indefinite transfusions for the prevention of primary stroke in this high risk population. DisclosuresWare:Eli Lilly: Other: DSMB membership; Bayer Pharmaceuticals: Consultancy; Bristol Myers Squibb: Research Funding; Biomedomics: Research Funding. Off Label Use: Hydroxyurea for children with SCA. Owen:Novartis: Speakers Bureau. Rogers:BioRad Labs: Consultancy; Apopharma: Consultancy; Baxter: Consultancy; Glaxo Smith Kline: Consultancy. Kwiatkowski:Shire Pharmaceuticals and Sideris Pharmaceuticals: Consultancy; Sideris Pharmaceuticals: Consultancy; Novartis: Research Funding; ISIS: Membership on an entity's Board of Directors or advisory committees. Heeney:Sancillio: Consultancy; Eli Lilly: Research Funding. Nottage:Janssen Pharmaceuticals: Employment. Cohen:Novartis: Consultancy; ApoPharma: Other: DSMB member.