Pediatric Sickle Cell Disease Research Articles

Associations between Sickle Cell Disease, Pica and Enuresis

Introduction: Sickle cell disease (SCD) is a genetic disorder that impacts the shape and functional capacity of red blood cells. Beyond altered cerebral perfusion, individuals with SCD have higher rates of neurodevelopmental disorders (NDDs), including attention deficit hyperactivity disorder (ADHD), intellectual disability, and specific learning disabilities. Past research has shown that in adolescent populations with either SCD or NDDs, pica, the act of eating non-food items, and enuresis, or involuntary urination, commonly occur. Both pica and enuresis are associated with biopsychosocial issues in typically developing children. However, the etiology of both of these disorders, as well as the confluence of NDDs and SCD on their occurrence, remains unclear. Hypothesis: The objective of this study was to determine the rates of pica and enuresis in a local pediatric SCD clinic and determine if these conditions present differently and/or have different associations in SCD than in the general population. We hypothesized that NDDs would serve as risk factors for both pica and enuresis with both conditions being associated with increased sickle cell severity. Methods: To test these hypotheses, we performed a retrospective chart review on 275 SCD patients. Using Epic, patients who at point visited either Kennedy Krieger Institute or John Hopkins Medical Center for SCD and were in an existing database were queried. Patients in the database ranged from 1 to 17 years old and were predominantly Black, non-Hispanic individuals. Primary keywords searched included: “enuresis, pica, bedwetting, diurnal, nocturnal, eating, non-food, peeing, urination, incontinence.” Results: Pica was reported in 9% (Table 1), while enuresis was reported in 27% of patient charts reviewed (Table 2). Both enuresis (Chi-squared test, p = 0.0050) and pica (Chi-squared test, p = 0.0190) were significantly linked to NDD occurrence, with pica being nearly three times as likely to occur alongside NDDs and/or enuresis. Notably, SCD patients with pica most commonly ate paper or wood, different from the general population with pica primarily eating rocks or dirt. Through the Wilcoxon rank sum test, we also noted no associations between pica and median hemoglobin (p=0.9572), ferritin (p=0.6209), iron serum (p=0.9500), total iron-binding capacity (p=0.1598), iron saturation (p=0.6292), or transferrin (p=0.1765) levels. Beyond this, our data also validate prior results demonstrating that enuresis is associated with both SCD type and hydroxyurea usage. There were no significant differences in rates of enuresis between males and females, unlike what is seen in the general population. Sleep apnea was associated with enuresis, at a higher rate than in the general population (Chi-squared post-hoc residual test, p = 0.0004). Patients with SCD and enuresis had higher mean reticulocyte counts and lower mean hemoglobin levels than patients with SCD without enuresis, consistent with increased hemolysis and worsening SCD severity. Conclusion: These results suggest etiologies for pica and enuresis in SCD patients may differ from the general population. As pica and enuresis commonly occur together with NDDs, there is a clear need for increased standardized screening for these conditions in clinics. Understanding why the risk factors for these conditions in SCD differ from the general population requires further investigation into their respective mechanisms of disease.

Implementation of a Multipronged Intervention to Improvement Inpatient Sickle Cell Disease Care

Introduction: Over the decades, many interventions have been used to improve care for patients with Sickle Cell Disease (SCD). There are 19 whole lifespan SCD centers, 30 pediatric SCD centers, and 28 adult SCD centers compared to 6,129 hospitals and over 220 children's hospitals in the US. The number of providers is insufficient to meet the needs of patients with SCD. Caring for patients without a dedicated Comprehensive SCD Center, such as our institution, can be challenging. Therefore, we developed a framework to leverage expertise in hematology, internal medicine, and emergency medicine to improve SCD patient care processes. In these settings, filling the gap in SCD care requires a multipronged creative approach that is implemented over time in a stepwise fashion. This allows time to adapt the intervention to the local medical system for more enduring change. This project looks at the longitudinal interventions that have occurred at the University of Chicago (UC) to address SCD care and discusses procedures to achieve successful implementation. Methods: In the first step, we identified the key stakeholders to determine the system's needs and goals (Table 1). This involved clinicians and staff who were interested in improving care for patients with SCD. The second step involved stakeholders creating a plan after analyzing the current care. Multipronged interventions were developed and implemented (see Figure 1 for a timeline and list of interventions). The final steps involved provider training. Furthermore, we tracked the progress of our interventions using the Electronic Medical Record (EMR). An EMR review was performed from 7/17/22 to 6/13/23 to evaluate our utilization. Descriptive statistics and Chi-Square were used to evaluate the data. This project was formally determined to be quality improvement and was therefore not overseen by the Institutional Review Board. Results: Regarding the first step, our task force comprises a large multidisciplinary group (see Table 1 for a full list). Next, it was important that we implement sustainable and useful systems (see Figure 1). In the review period, 154 patients were admitted 488 times. The SPP was used or viewed 134 times. Seventy-nine percent (122/154) of admitted patients had an IPP that was used, viewed, or created during their admission. Since the opening of the SCD Day clinic, there have been a total of 1045 SCD-related encounters, with an average of 36 patients a month or 1.7 patients a day. When comparing the review period to the same time in the prior year, the inpatient hydroxyurea protocol did not significantly improve the use of the medication. Hydroxyurea use changed from 64% to 65% of admissions and 65% to 68% of admitted patients. The inpatient SCD consult service received new consult requests in 44% of SCD admissions (214 total times). Lastly, over 100 hospitalists, resident physicians, inpatient teaching team physicians, and hematology physicians were educated along the way regarding changes in our system. Discussion: With time and a multipronged approach, achieving change in a large medical system is possible. The largest hurdle to overcome is funding. This is why our initial interventions focused on the implementation of EMR tools such as SPP, IPP, and educating providers. Though there was an up-front time cost, once completed, these interventions could be iterated on easily. It was not until 2022, that dedicated funding for a consult service could be secured. Having a large multidisciplinary team allows for creative ideas, dividing of tasks, accountability, and expertise in implementation. This does come with a limitation as it is harder to implement changes the larger the group becomes. Thus, a balance of members is vital. Frequent provider education is paramount in disseminating and improving the changes that are in the system. The plan, do, study, act model is a staple in quality improvement. It is important that there is foresight in developing a model to track the quality of care. The EMR's tools should be maximized to aid clinicians as efficiently as possible. Conclusion: Making large changes without funding or an institutional push can be challenging. Small incremental grassroots changes may be necessary until additional funding has been negotiated and secured. Meeting and exchanging ideas as a team and establishing pathways for improvement is a viable initial step.

6 Subjective Sleep Measures and Neurocognitive Outcomes in Pediatric Sickle Cell Disease

Objective:Youth with sickle cell disease (SCD) are at increased risk of neurocognitive difficulties with and without neurological complications. Research has identified disease-related, socioeconomic, and sociodemographic risk factors as independently having significant associations with brain physiology for youth with SCD. Notably, sleep has a profound effect on youth’s neurocognitive abilities including learning, executive function, memory, attention, and processing speed. Furthermore, youth with SCD are at an increased risk for poor sleep measured by self-report questionnaires and by polysomnography (PSG). Within the SCD literature, only a few studies have examined the relationship between sleep and cognition. Of these, the majority examined individuals with SCD and comorbid sleep disorder diagnoses. The aim of this study is to identify associations between subjective sleep measures and neurocognitive outcomes in youth with SCD.Participants and Methods:This study investigated a cohort of 24 youth with SCD (ages 9-16, 11 males, 13 females; HbSS [63%], HbSB+ [8%], HbSC [21%], HbSB0 [8%]) who received sleep questionnaires and a neuropsychological evaluation. Exclusion criteria included a history of neurological disorder (e.g., overt stroke, seizures, or moyamoya disease) or prescribed psychotropic medication. Sleep questionnaires measuring sleep disturbance (e.g., sleep onset, sleep continuity, and sleep quality) and sleep-related impairments (e.g., daytime sleepiness, sleepiness interference with concentration, and difficulty with activities of daily living skills) were collected. Executive function, working memory, processing speed, and verbal comprehension measures were assessed. Demographics and disease-related risk factors were analyzed individually from medical records.Results:All analyses were controlled for age, the time between neuropsychological testing and sleep questionnaires, SCD genotype, and sex. Partial correlations were conducted to explore associations with neurocognitive outcomes. Verbal comprehension was significantly correlated with sleep disturbance (r= -.673, p=.001). Multiple linear regressions revealed that sleep disturbance significantly predicts verbal comprehension (ß= -.572, p=.003). Specifically, verbal comprehension decreased by 4.4 standard points for every one-point increase in sleep disturbance. Additionally, total sleep problems significantly predicted working memory (ß=-.414, p=.044) and processing speed (ß= -.411, p= .046). Specifically, working memory decreased by 3.5 standard points while processing speed decreased by 3.3 standard points for every one-point increase in total sleep problems reported. Sleep parameters did not significantly predict executive function.Conclusions:Results support the association between poor sleep and neurocognitive difficulty in youth with SCD. Three of the participants in this study received a PSG, which further demonstrates the importance of the current findings. This study serves to identify potential risk factors for neurocognitive deficits and provides potential methods for identifying youth with SCD who may need to be referred for a PSG assessment. Research should replicate these findings with increased sample sizes including utilizing PSG and investigating neurobiological effects. Findings may inform future screening tools, treatment approaches, and advanced cognitive initiatives and resources for this population.

Invited Symposium 3: Pediatric Neuropsychology Medical Advances and Life Span Outcomes

Abstract & Learning Objectives:Medical advances continue to improve the outlook for pediatric patients with a variety of acquired and congenital medical conditions. Such critical advances have an impact on lifespan outcomes for affected individuals. Neuropsychology plays a critical role in evaluating outcomes and informing clinical care for pediatric patients, with an increasing role in prevention. Neuropsychologists are essential members of interdisciplinary teams and ongoing medical management. Our symposium will present examples of the latest progress made over the last decade in the areas of sickle cell disease, demyelinating disorders, congenital heart disease, and cancer. Highlights include recent research on neurocognitive surveillance for pediatric patients with sickle cell disease including identification of risk and resilience factors and ways to reduce cognitive decline; discovery of the anti-MOG antibody in patients with demyelinating disorders and associated neuropsychological outcomes; advances in the understanding of congenital heart disease, the latest initiatives in the field, and discussion of neuropsychology’s role in the care of these patients; and advances in targeted therapies for childhood cancer, risks associated with cancer and its treatment into adulthood, and an application of a developmental, lifespan approach in the care of childhood cancer survivors. Following each presentation, there will be an opportunity for discussion and questions. Upon conclusion of this course, learners will be able to: 1.Describe recent advances in medical care for pediatric sickle cell disease, demyelinating disorders, congenital heart disease, and cancer2.Explain long-term neuropsychological outcomes in pediatric medical disorders3.Assess the role of neuropsychology in advancing the field across pediatric medical disorders

83 WISC-V Profiles in a Pediatric Sickle Cell Disease Population

Objective:Individuals with sickle cell disease (SCD) are at increased risk for developing impairment across cognitive domains, although the most common deficits are thought to be related to processing speed and executive functions. One of the most common ways of evaluating cognitive functioning is through the administration of intellectual tests. While lower overall intellectual functioning in individuals with SCD compared to healthy controls has been found, the specific pattern of strengths and weaknesses across indices is not well known. Anecdotally, it has been observed at our clinic that individuals with SCD are more likely to show relative or significant weaknesses in visuospatial abilities, but this has not been formally investigated. Further, based on the extant research, individuals with SCD would likely demonstrate lower working memory and processing speed indices, but, as far as we are aware, this has not been investigated either. The purpose of the present study is to examine the intellectual profiles, including areas of relative and significant strengths and weaknesses, of children and adolescents with SCD.Participants and Methods:Participants are children and adolescents (age 6-16) with SCD who were referred for a neuropsychological evaluation at Montefiore Medical Center’s Neuropsychological Assessment Service from 2015 to 2022. These participants (N=54) were identified through a thorough review of patients seen through this service and were administered the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V; Wechsler, 2014). Mean scores were calculated for WISC-V indices. In addition, differences were calculated between WISC-V indices (e.g., VCI-VSI, etc.), and a discrepancy analysis was conducted comparing the base rates of these differences in the present sample to the WISC-V standardization sample.Results:In our sample, the mean total FSIQ of our sample was 85 (SD=14.5). The following mean scores were obtained across indices: VCI, SS=90 (SD=14.5); VSI, SS=86.5 (SD=14.9); FRI, SS=90 (15.5); WMI, SS=89 (SD=15.6); and PSI, SS=82 (SD=17.4). Many of the index score discrepancy base rates were similar to the standardization sample. However, our sample had greater discrepancies between several indices compared to the standardization sample. In particular, the following base rate discrepancies between index scores emerged as being different in our sample compared to the standardization sample: VCI>VSI and VCI>PSI. Notably, a 30+ point difference VCI>VSI was found in 6% of our sample (compared to 1.6% of the standardization sample) and a 30+ point difference between VCI>PSI was found in 12% of our sample (compared to 4.6% of the standardization sample). In addition, a 10+ point difference found between VCI>PSI was found in 50% of our sample (compared to 29% of standardization sample).Conclusions:In our sample, FSIQ and index scores fell approximately 0.5-1.33 SD below the standardization sample means, with the lowest index scores being PSI and VSI. Consistent with the literature, the PSI (but not WMI) emerged as an area most discrepant to other indices (particularly VCI). In line with our observations, the VSI emerged as an area of relative difficulty as compared to the VCI. These results suggest that, in addition to processing speed, visuospatial/constructional ability is an area that warrants consideration in the assessment of individuals with SCD.

Shared decision-making between paediatric haematologists, children with sickle cell disease and their parents: an exploratory study

Children with sickle cell disease (SCD) face various healthcare choices to be made during the disease process that may impact their lives. Shared decision-making (SDM) could improve their health outcomes. We assessed if, and to what extent, paediatricians engage children with SCD and/or their parents in the decision-making process. In this observational cross-sectional study, paediatric SCD patients and their parents visiting the outpatient paediatrics clinic of a university hospital participated in a SDM baseline measurement. Two evaluators independently and objectively analysed the level of patient involvement in decision-making from the audio-recordings of the consultations using the OPTION-5 instrument, a 0–20-point scale from which scores are usually expressed as a percentage of ideal SDM. The level of SDM, as perceived by patients, parents and paediatricians, was appreciated using the SDM-Q-9 and SDM-Q-Doc questionnaires, respectively. Scores could range from 0% (no SDM) to 100% (exemplary SDM). Twenty-four consultations in which a decision needed to be made about SCD treatment were audiotaped and analysed; six were from each paediatrician. The group consisted of 17 male and 7 female patients from various cultural backgrounds between 2 and 17 years old, with a mean age of 9.4 years (SD 4.2). Median OPTION-5 scores were 25.0% [IQR] 20.0–40.0%; range 0–55%). Median SDM-Q-9 and SDM-Q-Doc scores were 56.7% (IQR 39.4–88.9%) and 68.9% (IQR 57.8–77.8%), respectively.Conclusion: Although subjective scores of SDM were fair, the objectively scored level of SDM among children suffering from SCD leaves room for improvement. This may be realized by increasing knowledge about the benefits of SDM, child-centred SDM interventions and SDM-training for paediatricians that takes into account the complexity of intercultural challenges and risk communication between stakeholders.What is Known:• Children that suffer from sickle cell disease (SCD) are more vulnerable to factors that negatively impact the care that they receive as well as suboptimal health outcomes.• Shared decision-making (SDM) can help children participate in a collaborative decision-making process about their preferred treatment options and improve their health outcomes.What is New:• The level of participation in the decision-making process for patients suffering from SCD and the families that they belong to leaves room for improvement. The impact of intercultural challenges and the quality and consistency of risk-communication between stakeholders in paediatric SDM needs further exploration.• Paediatricians are more confident about their ability to involve the child and parents compared to how children and their parents experience their level of involvement in a shared decision-making process.

Agreement between youth and caregiver report of pain and functioning in pediatric sickle cell disease: PedsQL sickle cell disease module.

Pain is a primary symptom of sickle cell disease (SCD) and is often severe and chronic. To treat SCD-related pain, proper assessment of SCD pain among youth, including the degree of concordance or agreement between youth and caregiver reports of pain, is essential but has not yet been adequately evaluated. In this study, 525 youth with SCD and their parents were evaluated as part of the Sickle Cell Clinical Research and Intervention Program (SCCRIP) to examine pain rating concordance and predictors of concordance. Youth and parents completed the Pediatric Quality of Life Inventory Sickle Cell Disease module (PedsQL-SCD) to measure pain, pain interference, and pain-related constructs. Disease, clinical, and demographic variables were obtained from the SCCRIP database. Intraclass correlations demonstrated moderate-to-poor consistency between youth and caregiver reports of pain and pain interference (ICCs range from 0.17 to 0.54). Analysis of covariance and regression models found that patient age, frequency of hospitalizations and emergency department (ED) visits, economic hardship, and fetal hemoglobin levels were significantly associated with varying pain-rating agreement levels among parent proxy and child self-report pain. Concordance of pain assessments among youth with SCD and their caregivers using the PedsQL-SCD Module was moderate at best, corroborating prior research. Youth factors predicting discordance among pain-related factors included increased ED visits, older age, and female sex. Collectively, these results bolster the use of integrated pain assessments to reduce parent-child discrepancies, thereby improving the adequacy of SCD-related pain assessment and treatment.

Statistical rules for safety monitoring in clinical trials.

Protecting patient safety is an essential component of the conduct of clinical trials. Rigorous safety monitoring schemes are implemented for these studies to guard against excess toxicity risk from study therapies. They often include protocol-specified stopping rules dictating that an excessive number of safety events will trigger a halt of the study. Statistical methods are useful for constructing rules that protect patients from exposure to excessive toxicity while also maintaining the chance of a false safety signal at a low level. Several statistical techniques have been proposed for this purpose, but the current literature lacks a rigorous comparison to determine which method may be best suitable for a given trial design. The aims of this article are (1) to describe a general framework for repeated monitoring of safety events in clinical trials; (2) to survey common statistical techniques for creating safety stopping criteria; and (3) to provide investigators with a software tool for constructing and assessing these stopping rules. The properties and operating characteristics of stopping rules produced by Pocock and O'Brien-Fleming tests, Bayesian Beta-Binomial models, and sequential probability ratio tests (SPRTs) are studied and compared for common scenarios that may arise in phase II and III trials. We developed the R package "stoppingrule" for constructing and evaluating stopping rules from these methods. Its usage is demonstrated through a redesign of a stopping rule for BMT CTN 0601 (registered at Clinicaltrials.gov as NCT00745420), a phase II, single-arm clinical trial that evaluated outcomes in pediatric sickle cell disease patients treated by bone marrow transplant. Methods with aggressive stopping criteria early in the trial, such as the Pocock test and Bayesian Beta-Binomial models with weak priors, have permissive stopping criteria at late stages. This results in a trade-off where rules with aggressive early monitoring generally will have a smaller number of expected toxicities but also lower power than rules with more conservative early stopping, such as the O-Brien-Fleming test and Beta-Binomial models with strong priors. The modified SPRT method is sensitive to the choice of alternative toxicity rate. The maximized SPRT generally has a higher number of expected toxicities and/or worse power than other methods. Because the goal is to minimize the number of patients exposed to and experiencing toxicities from an unsafe therapy, we recommend using the Pocock or Beta-Binomial, weak prior methods for constructing safety stopping rules. At the design stage, the operating characteristics of candidate rules should be evaluated under various possible toxicity rates in order to guide the choice of rule(s) for a given trial; our R package facilitates this evaluation.

Assessment of menstrual health in adolescent and young adults with sickle cell disease.

Sickle cell disease (SCD) is associated with hypercoagulability, but adults with SCD also have an increased incidence of bleeding including heavy menstrual bleeding (HMB). HMB is common among adolescent females, but the impact of HMB in pediatric SCD is unclear. The objectives of this study were to examine menstrual health status, knowledge, and quality of life (QOL). We performed a single-institutional multi-clinic cross-sectional study comprised of a five-part survey in pediatric participants with SCD. The survey included the validated Menstrual Bleeding Questionnaire (MBQ) and Self-administered Bleeding Assessment Tool (Self-BAT). Forty-eight participants with a median age of 16years (range: 12-21years) completed the study. The mean age at onset of menarche was 13±1.3years. On the MBQ, 29% reported heavy/very heavy menstrual flow, 61% reported moderate or severe dysmenorrhea, and 96% had menses lasting less than 1week. The Self-BAT revealed that 42% of participants reported a history of HMB. Participants with severe dysmenorrhea or HMB had higher MBQ scores, corresponding to worse QOL. Despite this, less than 20% of participants had attempted any hormonal therapy for menstrual regulation. The odds of hormonal therapy utilization were comparable among participants on hydroxyurea versus not on hydroxyurea (odds ratio 1.58, 95% confidence interval [CI]: 0.33-7.56). The prevalence of HMB and dysmenorrhea is high among adolescents and young women with SCD. Strategies that incorporate menstrual health assessment into routine medical care in this population would help address this important area of pediatric health.

Impaired cerebrovascular reactivity in pediatric sickle cell disease using diffuse correlation spectroscopy.

Cerebrovascular reactivity (CVR), defined as the ability of cerebral vasculature to dilate in response to a vasodilatory stimulus, is an integral mechanism in brain homeostasis that is thought to be impaired in sickle cell disease (SCD). This study used diffuse correlation spectroscopy and a simple breath-hold stimulus to quantify CVR non-invasively in a cohort of 12 children with SCD and 14 controls. Median [interquartile range] CVR was significantly decreased in SCD compared to controls (2.03 [1.31, 2.44] versus 3.49 [3.00, 4.11] %/mmHg, p = 0.028). These results suggest DCS may provide a feasible means to routinely monitor CVR impairments in pediatric SCD.

Penicillin Prophylaxis in Patients With Sickle Cell Disease Beyond Age 5 Years.

Patients with sickle cell disease (SCD) are at increased risk for invasive pneumococcal disease (IPD) caused by Streptococcus pneumoniae. Immunization and antimicrobial prophylaxis may prevent this complication, and landmark clinical trials support discontinuation of antimicrobial prophylaxis at age 5 years. However, antimicrobial prophylaxis continues in some patients indefinitely. The objective of this study was to evaluate the incidence of culture-positive IPD and other infections in the setting of penicillin prophylaxis in the pediatric SCD population. This was a single-center, retrospective cohort study of patients with SCD who continued antimicrobial prophylaxis with penicillin, compared with those whose antimicrobial prophylaxis was discontinued. Included patients were aged 5 to 18 years during the study period and had no history of IPD or surgical splenectomy. Patient charts were reviewed for demographics, immunizations, penicillin prescription history, and microbiologic culture data. Antimicrobial prophylaxis continued beyond age 5 years in 65% of patients, a higher percentage of whom had hemoglobin SS or S beta-zero disease. No patients whose antimicrobial prophylaxis was discontinued experienced IPD; 1 patient who continued antimicrobial prophylaxis died of S pneumoniae sepsis. Rates of other infections were comparable between groups (21% in prophylaxis versus 18% in no prophylaxis). These results support appropriate de-prescribing of antimicrobial prophylaxis in patients with SCD who are not at high risk for IPD. Further multicenter studies are needed to evaluate consequences of antimicrobial prophylaxis with alternative agents on antibiotic resistance, examine provider rationale for continuation of antimicrobial prophylaxis, and assess quality of life effects (e.g., medication adherence, adverse drug reactions) of antimicrobial prophylaxis.

Feasibility and preliminary efficacy of the Balance Program to reduce pain-related disability in pediatric sickle cell disease.

Sickle cell disease (SCD) pain is associated with functional impairment, and treatment is often limited to pharmacological approaches with unwanted side effects. Although behavioral interventions exist for non-SCD pain populations, interventions designed to address pain-related impairment in SCD are lacking. Twenty youth (9-17 years) with SCD completed a four-week telemedicine pain intervention (NCT04388241). Participants and caregivers completed baseline and post-intervention PROMIS pain measures and the Treatment Evaluation Inventory-Short Form (TEI-SF). Descriptive analyses assessed feasibility and acceptability. Reliable Change Index analyses assessed for significant post-intervention changes in pain functioning. Paired t test analyses compared baseline and post-intervention opioid prescription fills. All participants completed at least one treatment session. Eighteen (90%) youth completed all sessions. Youth (100%) and caregivers (94%) rated the intervention as moderately or highly acceptable on the TEI-SF. Forty-seven percent of caregivers and 44% of youth reported reliably significant improvements in pain interference after the intervention (median T-score differences: 24.8 and 23.5, respectively). Sixty-five percent of caregivers (T-score improvement difference: 19.3) and 31% of youth (T-score improvement difference: 32) reported improvements in pain behaviors. There was no significant difference in opioid prescription fills pre- and post-intervention (P>0.05). The Balance Program is feasible, highly acceptable, and can be delivered remotely to reduce barriers to care. Approximately half of youth and caregivers reported significant declines in pain interference following the intervention, with substantial improvements in functioning for treatment responders. Behavioral pain interventions are important adjunctive treatments to uniquely address functional impairment associated with acute and chronic pain in SCD.

Longitudinal Assessment of Macular Thickness and Microvascular Changes in Children with Sickle Cell Disease

To longitudinally assess macular thickness and microvascular changes in children with sickle cell disease (SCD). A retrospective consecutive series. Children with SCD aged ≤ 18 years who had an ophthalmic examination at Boston Children's Hospital between January 1998 and August2022. Qualitative and quantitative analyses of both OCT and OCT angiography (OCTA) images were performed. Total retinal thickness measured on macular OCT, superficial capillary plexus and deep capillary plexus (DCP) vessel density (VD), and foveal avascular zone (FAZ) area measured on 6-× 6-mm OCTA scans. International Classification of Diseases, 10th Revision, code search identified 303 pediatric SCD patients who underwent ophthalmic examination during the study period. OCT and OCTA images were acquired on 104 (17.2%) and 60 (9.9%) eyes at presentation and on 159 (26.2%) and 100 (16.5%) eyes at final visit, respectively. Overall, temporal retinal thinning was noted qualitatively in 35.6% of SCD patients at presentation and 39.6% at final visit. Of those patients with macular thinning, 94.6% and 90.5% had peripheral sickle cell retinopathy (SCR) at presentation and final visit. On quantitative OCT analysis, HbSS eyes had a lower retinal thickness in the fovea and temporal parafovea compared with HbSC (P < 0.05). Eyes with peripheral SCR had a larger FAZ at presentation compared with eyes without peripheral SCR (P= 0.004), a lower DCP VD at final visit in the inferior temporal macula (P= 0.03), and a higher DCP VD at final visit in the superior nasal macula (P= 0.01). Eighty eyes of 40 patients had OCT, and 34 eyes of 20 patients had both OCT and OCTA images acquired at both initial and final visits. At final visit, retinal thickness decreased at the fovea, inferior perifovea, and temporal perifovea compared with presentation (P < 0.05). In parallel, VD DCP in the superonasal quadrant increased at final visit (P= 0.03). Macular retinal thinning was progressive and observed in eyes with and without peripheral SCR. Over time, there was a compensatory increase in DCP VD in the nasal macula on OCTA. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Associating a standardized reporting tool for chest radiographs with clinical complications in pediatric acute chest syndrome.

Acute chest syndrome (ACS) is an important cause of morbidity in sickle cell disease (SCD). A standardized tool for reporting chest radiographs in pediatric SCD patients did not previously exist. To analyze the interobserver agreement among pediatric radiologists' interpretations for pediatric ACS chest radiographs utilizing a standardized reporting tool. We also explored the association of radiographic findings with ACS complications. This was a retrospective cohort study of pediatric ACS admissions from a single institution in 2019. ICD-10 codes identified 127 ACS admissions. Two radiologists independently interpreted the chest radiographs utilizing a standardized reporting tool, a third radiologist adjudicated discrepancies, and κ analysis assessed interobserver agreement. Clinical outcomes were correlated with chest radiograph findings utilizing Pearsons' χ2 , ttests, and Mann-Whitney U tests. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Interobserver agreement was moderate to near-perfect across variables, with κ analysis showing near-perfect agreement for opacity reported in the right upper lobe (0.84), substantial agreement for right lower lobe (0.63), and vertebral bony changes (0.72), with moderate agreement for all other reported variables. On the initial chest radiograph, an opacity located in the left lower lobe (LLL) correlated with pediatricintensive care unit transfer (p = .03). Pleural effusion on the initial chest radiograph had a 3.98 OR (95% CI: 1.35-11.74) of requiring blood products and a 10.67 OR (95%CI: 3.62-31.39) for noninvasive ventilation. The standardized reporting tool showed moderate to near-perfect agreement between radiologists. LLL opacity, and pleural effusion were associated with increased risk of ACS complications.

Sex and frequency of pain episodes are associated with acute pain trajectories in adolescents with sickle cell disease.

Acute pain episodes are a major cause of health care utilization (HCU) in sickle cell disease (SCD), and adolescence is associated with increased pain frequency. We sought to determine whether there were differences in acute pain trajectories by sex and frequency of pain episodes among adolescents with SCD who presented to the emergency department (ED). Retrospective review of electronic health records from a large, multicampus, pediatric SCD program. Of the 113 adolescents included, the mean age was 16.6 (SD 0.9), 41.6% (n = 47) were female, 77.9% (n = 88) had HbSS or a similarly severe genotype, and 43.4% (n = 49) had ≥3 episodes of HCU for pain, which we defined as having history of high HCU for pain. Those with a history of high HCU for pain had higher mean pain intensity scores at presentation, were more likely to receive either intravenous or intranasal opioids, and were more likely to be hospitalized. In a model considering the 3-way interaction between sex, history of high HCU for pain, and follow-up time from the initial pain intensity score, adjusted for opioid per kilogram body weight, and prescription of hydroxyurea, adolescent female patients with high HCU for pain had the slowest decline in pain intensity during treatment for acute pain in the ED. Sex and history of high HCU for pain are associated with acute pain trajectories in adolescents with SCD presenting to the ED. These novel findings should be confirmed in future prospective studies.

Practice Patterns for Addressing Developmental-Behavioral Concerns in Sickle Cell Specialty Care.

Children with sickle cell disease (SCD) are at elevated risk for neurodevelopmental and behavioral disorders. This report describes developmental-behavioral practice patterns among sites who were part of the Dissemination and Implementation of Stroke Prevention Looking at the Care Environment (DISPLACE) consortium in the context of current guidelines for addressing these concerns. An internal survey was developed for the Principal Investigators of the DISPLACE study to identify developmental-behavioral clinical practices across the 28-site consortium, including methods for identification, referral practices, access to psychologists, and barriers to services. Descriptive data were pulled from the survey to describe practice patterns. Most sites used informal methods to detect developmental-behavioral concerns, though over 1/3 of sites were using a structured protocol. The most common referral indications for further developmental and neuropsychological evaluation were parent, provider, or school concerns or stroke. Evaluations were predominantly completed by pediatric neuropsychologists and pediatric psychologists. Despite most sites reporting access to a psychologist within the SCD clinic, sites also reported long waitlists and difficulty accessing providers for evaluation and treatment services. Insurance difficulties were also a common barrier. A range of additional barriers were reported at the patient, provider, organizational, and policy/socio-environmental levels. Many sites in the DISPLACE consortium were adhering to existing care guidelines for pediatric SCD; however, there was also wide variation in practices for which guidelines are absent or unclear. Additional work is needed to inform guidelines, to specify the role of psychology within specialty SCD care, and to overcome barriers to care. Optimal developmental-behavioral care for children with SCD involves collaboration among specialty care providers and pediatric psychologists; however, these efforts may be hampered by dispersed or unclear guidelines and several barriers to care. Future studies and guidelines have the potential to improve care by providing clear, consistent, and unified care recommendations specific to psychologists and related care professionals who are supporting children with SCD.

Hospitalizations among children with sickle cell disease enrolled in the Kumasi Sickle Cell Pan African Consortium (SPARCo) database: A cross sectional study.

Sickle cell disease (SCD) is the commonest monogenic haemolytic disorder in Africa. Despite strides made in its management, a significant proportion of patients are hospitalized from the various complications of the disease. This study set out to describe the main causes and outcomes of hospitalizations among pediatric patients with SCD. A cross-sectional study was conducted at the Pediatric Emergency Unit of Komfo Anokye Teaching Hospital within a period of 12 months to recruit pediatric SCD patients. This study looked at causes of admission, length of hospital stay (LOS), and outcome of admission. Of the 201 SCD patients recruited, 57.2% were males and majority were of SCD-SS phenotype 83.1%. The median age was 6 years. The three leading causes of hospitalization were Vaso-occlusive pain events (VOPE) (39.8%), acute chest syndrome (ACS) (25.9%), and infections (12.4%). Ten (5.0%) of the patients presented with a stroke. High admissions were observed in June (12.4%) and November (16.9%). The median (interquartile range [IQR]) LOS was 6 days (IQR: 4-10). Six (3.0%) of the patients died from complications of the disease during hospitalization. VOPE, ACS, infections, and acute anaemia from hyperhaemolysis were observed as the most common causes of admissions among SCD patients. A good outcome of discharge was seen in most of the patients that were hospitalized with a median length of stay of 6 days. This study also strengthens the importance of a good SCD database with patient follow-ups for better outcomes in SCD patients.

Natural history and variability in albuminuria in pediatric and murine sickle cell anemia

AbstractIt is critical to characterize the natural history of albuminuria in patients with sickle cell anemia (SCA); however, these data are currently lacking and affecting evidence-based guidelines. We performed a natural history study of the development of pediatric albuminuria. We identified participants with hemoglobin SS/SB0 thalassemia ≥5 years with albumin to creatinine ratio (ACR) measurements performed at a steady-state clinic visit. Participants were characterized as either persistent, intermittent, or never albuminuria. We determined the prevalence of persistent albuminuria, use of ACR ≥100 mg/g as a predictor, and variation in ACR measurements. We mirrored this study to determine the variation in albuminuria measurements in the SCA murine model. Among 355 participants with HbSS/SB0 thalassemia with 1728 ACR measurements, we identified 17% with persistent and 13% with intermittent albuminuria. Thirteen percent of participants with persistent albuminuria developed an abnormal ACR before 10 years of age. A single ACR measurement ≥100 mg/g was associated with 55.5 times (95% confidence interval, 12.3-527) higher odds of having persistent albuminuria. Among participants with ACR ≥100 mg/g, we identified significant variability in the results of repeated measurements. The median ACR at the initial and next measurements were 175.8 mg/g (interquartile range [IQR], 135-242) and 117.3 mg/g (IQR, 64-292). The human variability in ACR was mirrored by ∼20% variability in albuminuria in murine model. This evidence suggests adopting standards for repeating ACR measurements, consider screening for ACR before 10 years of age, and using an ACR >100 mg/g as a risk factor for progression. Pediatric and murine renoprotective clinical trials need to consider the high variability in repeated ACR measurements.

Cognition and education benefits of increased hemoglobin and blood oxygenation in children with sickle cell disease.

Among individuals with sickle cell disease (SCD), decreased hemoglobin is associated with lower oxygen saturation (SpO2) and increased risk of stroke, both of which are associated with lower intelligence quotient (IQ) scores. Thus, increasing hemoglobin and SpO2 in individuals with SCD may increase IQ and educational attainment. A cohort simulation model was built to determine academic performance and educational attainment based on cognitive function (measured by IQ) of a pediatric SCD cohort randomly assigned to treatment and control groups. The model contained two key stages: childhood (<10 years) and adolescence (≥10 years). In stage 1, increased hemoglobin and increased SpO2 (assigned to the treatment group) were determinants of higher IQ, prevention of IQ deterioration over time. Increased hemoglobin was also a determinant of decreased stroke risk. In stage 2, improvement in adolescent IQ as a result of treatment was a determinant of academic performance. In a simulated cohort of 2000 children and adolescents with SCD (52.5% female, 50% treated), stroke incidence was predicted to be 44.4% lower among the treated group than the untreated group (4.5% versus 8.1%, respectively). The average IQ among the treated group was estimated to be 91.1 compared with 82.9 in the untreated group (a 9.9% difference; P<0.001). Finally, high school (≥12 years of education) completion rates were estimated to be 64.7% higher among the treated group: 76.1% of the treated group was projected to complete high school compared with 46.2% of the untreated group. Our model predicts that an average improvement in hemoglobin of 1.1 g/dL (11 g/L) among individuals with SCD may be associated with improved neurocognition and educational outcomes. These improvements may also generate benefits not captured by our model, including improved quality of life, employment, and income.

Empowering patients with sickle cell anemia and their families through innovative educational methods.

Sickle cell disease (SCD) is a group of inherited blood disorders caused by a mutation in the beta subunit of hemoglobin (HbS). SCD will hereafter be referred to as sickle cell anemia (SCA) as this is the term our patients and their families prefer. There are approximately 5000 Canadians living with SCA including children. Pediatric SCA patient education can: improve knowledge, decrease hospitalization, improve medication possession ratio, lead to better SCA-related functioning, and lower pain impact. Innovative educational materials were developed to improve knowledge and self-efficacy regarding the illness management of patients and parents/guardians. Patients (n=5; aged 8-18) with SCA and parents (n=5) of patients (aged 0-18) were recruited via flyers sent directly to patients and distributed through partner patient organization Sickle Cell Awareness Network of Saskatchewan. Patient and parent focus groups were held separately over Zoom to receive feedback for the video. An additional interview was held for a participant that required a translation of the video. Audio recordings were transcribed using Zoom and Otter.ai. The coding of transcripts was facilitated by NVivo (QSR International Pty Ltd, 2022, release 1.6.2). The thematic analysis centered around SCA management concepts relevant to the research aims. Important themes that emerged included 'Age Appropriateness', 'Empowerment', 'Knowledge Gaps', 'Linguistic Accessibility', 'Medication Adherence', 'Strength in Community', and 'Transition to Adult Care'. The video was well received, and "brought peace of mind". Patient feedback was incorporated into the final version of the educational materials.