Inflammation and autoimmunity are interrelated in patients with sickle cell disease at a steady-state condition: implications for vaso-occlusive crisis, pain, and sensory sensitivity.

This study aimed to comprehensively analyze inflammatory and autoimmune characteristics of patients with sickle cell disease (SCD) at a steady-state condition (StSt) compared to healthy controls (HCs) to explore the pathogenesis of StSt and its impact on patients' well-being. The study cohort consisted of 40 StSt participants and 23 HCs enrolled between July 2021 and April 2023. StSt participants showed elevated white blood cell (WBC) counts and altered hematological measurements when compared to HCs. A multiplex immunoassay was used to profile 80 inflammatory cytokines/chemokines/growth factors in plasma samples from these SCD participants and HCs. Significantly higher plasma levels of 35 analytes were observed in SCD participants, with HGF, IL-18, IP-10, and MCP-2 being among the most significantly affected analytes. Additionally, autoantibody profiles were also altered, with elevated levels of anti-SSA/Ro60, anti-Ribosomal P, anti-Myeloperoxidase (MPO), and anti-PM/Scl-100 observed in SCD participants. Flow cytometric analysis revealed higher rates of red blood cell (RBC)/reticulocyte-leukocyte aggregation in SCD participants, predominantly involving monocytes. Notably, correlation analysis identified associations between inflammatory mediator levels, autoantibodies, RBC/reticulocyte-leukocyte aggregation, clinical lab test results, and pain crisis/sensitivity, shedding light on the intricate interactions between these factors. The findings underscore the potential significance of specific biomarkers and therapeutic targets that may hold promise for future investigations and clinical interventions tailored to the unique challenges posed by SCD. In addition, the correlations between vaso-occlusive crisis (VOC)/pain/sensory sensitivity and inflammation/immune dysregulation offer valuable insights into the pathogenesis of SCD and may lead to more targeted and effective therapeutic strategies. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT05045820.

Increasing Visibility of Sickle Cell Disease in Indiana: Establishing Baseline Prevalence Using Integrated Data From Multiple Sources.

OBJECTIVE: The Indiana Sickle Cell Data Collection (IN-SCDC) program aims to provide timely, reliable, and locally relevant information on the sickle cell disease (SCD) population in Indiana to inform public health interventions, research, and policy development. We describe the development of the IN-SCDC program and report the prevalence and geographic distribution of people with SCD in Indiana using an integrated data collection approach. METHODS: Using multiple integrated data sources and case definitions established by the Centers for Disease Control and Prevention, we classified cases of SCD in Indiana during 2015-2019. We calculated the prevalence and incidence of SCD and described characteristics of people with SCD. RESULTS: We identified 1695 people living with SCD in Indiana during the study period. The median age of people living with SCD was 21 years, and 1474 (87.0%) were Black or African American. Most (n = 1596, 91%) resided in metropolitan counties. The age-adjusted prevalence of SCD was 24.7 cases per 100 000 people. The prevalence of SCD among Black or African American people was 209.3 per 100 000 people. The incidence was 1 in 2608 live births overall and 1 in 446 live births among Black or African American people. Eighty-six deaths were confirmed in this population during 2015-2019. CONCLUSIONS: Our results establish a baseline for the IN-SCDC program. Baseline and future surveillance program efforts will help accurately inform standards of care for treatments, identify gaps in coverage and access to care, and provide guidance for legislators and community-based organizations.

Mediators and Moderators of Active Music Engagement to Reduce Traumatic Stress Symptoms and Improve Well-being in Parents of Young Children With Cancer.

OBJECTIVE: This trial examined the effects of proximal/distal mediators and moderators of an Active Music Engagement (AME) intervention on young child/parent distress, quality of life, and family function outcomes. METHODS: Child/parent dyads (n = 125) were randomized to AME or Audio-storybooks attention control condition. Each group received 3 sessions with a credentialed music therapist for 3 consecutive days with data collection at baseline, post-intervention (T2), and 30-days later (T3). Potential proximal mediators included within session child and parent engagement. Potential distal mediators included changes in perceived family normalcy, parent self-efficacy, and independent use of play materials. Potential moderators included parent/child distress with prior hospitalizations, parent traumatic stress screener (PCL-6), and child age. Outcomes included child emotional distress and quality of life; parent emotion, traumatic stress symptoms (IES-R), well-being; and family function. Mediation effects were estimated using ANCOVA, with indirect effects estimated using the percentile bootstrap approach. Moderation effects were tested by including appropriate interaction terms in models. RESULTS: No significant mediation effects were observed. Child distress with prior hospitalizations moderated AME effects for IES-R intrusion subscale scores at T2 (P = .01) and avoidance subscale scores at T3 (P = .007). Traumatic stress screener scores (PCL-6) moderated intervention effects for IES-R hyperarousal subscale scores at T2 (P = .01). There were no moderation effects for child age. CONCLUSIONS: AME is a promising intervention for mitigating traumatic stress symptoms and supporting well-being in parents of children with cancer, particularly for parents who screen high for traumatic stress and whose children are more highly distressed with hospitalization.

Epidemiology and Severity of Illness of MIS-C and Kawasaki Disease During the COVID-19 Pandemic.

BACKGROUND AND OBJECTIVES: Multisystem inflammatory syndrome in children (MIS-C) is a novel, severe condition following severe acute respiratory syndrome coronavirus 2 infection. Large epidemiologic studies comparing MIS-C to Kawasaki disease (KD) and evaluating the evolving epidemiology of MIS-C over time are lacking. We sought to understand the illness severity of MIS-C compared with KD and evaluate changes in MIS-C illness severity over time during the coronavirus disease 2019 pandemic compared with KD. METHODS: We included hospitalizations of children with MIS-C and KD from April 2020 to May 2022 from the Pediatric Health Information System administrative database. Our primary outcome measure was the presence of shock, defined as the use of vasoactive/inotropic cardiac support or extracorporeal membrane oxygenation. We examined the volume of MIS-C and KD hospitalizations and the proportion of hospitalizations with shock over time using 2-week intervals. We compared the proportion of hospitalizations with shock in MIS-C and KD patients over time using generalized estimating equations adjusting for hospital clustering and age, with time as a fixed effect. RESULTS: We identified 4868 hospitalizations for MIS-C and 2387 hospitalizations for KD. There was a higher proportion of hospitalizations with shock in MIS-C compared with KD (38.7% vs 5.1%). In our models with time as a fixed effect, we observed a significant decrease in the odds of shock over time in MIS-C patients (odds ratio 0.98, P < .001) but not in KD patients (odds ratio 1.00, P = .062). CONCLUSIONS: We provide further evidence that MIS-C is a distinct condition from KD. MIS-C was a source of lower morbidity as the pandemic progressed.

The evolving treatment landscape for children with sickle cell disease.

Sickle cell disease is the most common inherited pathological haemoglobinopathy. Over the past 30 years, disease-related morbidity and mortality have improved in high-income countries due to advances in preventive care and treatments. Established disease-modifying therapies, such as hydroxyurea (hydrocarbamide), are continuing to have an important role in the treatment of sickle cell disease, and newer agents also show promise. In the past 5 years, the US Food and Drug Administration approved three additional sickle cell disease-modifying medications, and new gene therapies have been developed as an alternative curative treatment to haematopoietic stem-cell transplantation. In this Review, we discuss the current treatment landscape for paediatric sickle cell disease and emerging innovations in care. We also review the need for close, long-term management for children receiving newer therapies and the importance of ongoing investment in people with sickle cell disease in low-income and middle-income countries.

Inflammation and autoimmunity are interrelated in patients with sickle cell disease at a steady-state condition: implications for vaso-occlusive crisis, pain, and sensory sensitivity.

This study aimed to comprehensively analyze inflammatory and autoimmune characteristics of patients with sickle cell disease (SCD) at a steady-state condition (StSt) compared to healthy controls (HCs) to explore the pathogenesis of StSt and its impact on patients' well-being. The study cohort consisted of 40 StSt participants and 23 HCs enrolled between July 2021 and April 2023. StSt participants showed elevated white blood cell (WBC) counts and altered hematological measurements when compared to HCs. A multiplex immunoassay was used to profile 80 inflammatory cytokines/chemokines/growth factors in plasma samples from these SCD participants and HCs. Significantly higher plasma levels of 37 analytes were observed in SCD participants, with HGF, IL-18, IP-10, and MCP-2 being among the most significantly affected analytes. Additionally, autoantibody profiles were also altered, with elevated levels of anti-SSA/Ro60, anti-Ribosomal P, anti-Myeloperoxidase (MPO), and anti-PM/Scl-100 observed in SCD participants. Flow cytometric analysis revealed higher rates of red blood cell (RBC)/reticulocyte-leukocyte aggregation in SCD participants, predominantly involving monocytes. Notably, correlation analysis identified associations between inflammatory mediator levels, autoantibodies, RBC/reticulocyte-leukocyte aggregation, clinical lab test results, and pain crisis/sensitivity, shedding light on the intricate interactions between these factors. The findings underscore the potential significance of specific biomarkers and therapeutic targets that may hold promise for future investigations and clinical interventions tailored to the unique challenges posed by SCD. In addition, the correlations between vaso-occlusive crisis (VOC)/pain/sensory sensitivity and inflammation/immune dysregulation offer valuable insights into the pathogenesis of SCD and may lead to more targeted and effective therapeutic strategies.

Identifying Barriers to HPV Vaccination for Patients With Sickle Cell Disease and Childhood Cancer Survivors.

Human papillomavirus (HPV) vaccination prevents the development of HPV-associated malignancies. Adolescent and young adult survivors of childhood cancers and patients with sickle cell disease (SCD) are vulnerable patient populations who would significantly benefit from HPV vaccination. In this multimethod study, a retrospective chart review found a notable difference between the rate of HPV vaccinations and other age-appropriate vaccinations in 177 childhood cancer survivors and in 70 patients with SCD. We then sought to describe patient and caregiver beliefs regarding HPV vaccination, through semistructured interviews with 21 patients and 48 caregivers. Interviews were analyzed with a thematic content approach to understand attitudes regarding the HPV vaccination. Qualitative interviews noted that many caregivers and adolescents had baseline misconceptions regarding the HPV vaccination in general and in context with their chronic illness. It was found that a strong recommendation from a trusted subspecialty provider would create reassurance about vaccination and reduce misconceptions and concerns about side effects in the context of a chronic illness. Counseling from subspecialists could have a strong impact on understanding the HPV vaccine in the context of chronic illness. This would likely help overcome many of the barriers to vaccination that are encountered by patients with SCD or oncology survivors.

Pediatric hematology and oncology physician and nurse practitioner views of the HPV vaccine and barriers to administration.

Rates of Human papilloma virus (HPV) vaccination among pediatric survivors of cancer and patients with sickle cell disease are lower than the national average. While recent attention has focused on patient HPV vaccine hesitancy and refusal, less is known about provider-level and system-level barriers to vaccinations in pediatric hematology/oncology (PHO) populations. Applying thematic analysis to qualitative interviews with 20 pediatric hematology/oncology physicians and nurse practitioners, we examine their views regarding HPV vaccination, with a focus on access and barriers to providing HPV vaccination in PHO practices. Results demonstrated that despite 90% of interviewees supporting HPV vaccination in their population, the number of pediatric hematology/oncology providers who reported that they counsel about HPV or provide HPV vaccination was 45%, even in stem cell and sickle cell clinics, where other childhood vaccines are commonly provided. Clinicians identified provider-level, clinic-level, and system-level barriers to giving the HPV vaccination, including but not limited to time/flow constraints, lack of resources, and continued education regarding the HPV vaccine. These barriers impede the ability for pediatric hematology/oncology providers to counsel and provide HPV vaccination to this specialized population.

Understanding caregiver burden with accessing sickle cell care in the Midwest and their perspective on telemedicine.

BACKGROUND: Survival for children with sickle cell disease (SCD) has improved significantly. However, patients with SCD still encounter several impediments to accessing adequate healthcare. Rural and medically underserved areas, such as parts of the Midwest, can exacerbate these barriers, separating children with SCD from subspecialists even further. Telemedicine has been a means to close these gaps in care for children with other special healthcare needs, but few studies have discussed how caregivers of children with SCD perceive its use. METHODS: The objective of this study is to understand the experiences of caregivers of pediatric SCD patients in a geographically diverse area in the Midwest in accessing care, and their perspectives of telemedicine. Caregivers of children with SCD completed an 88-item survey via a secured REDCap link either in-person or via secure text. Descriptive statistics (means, medians, ranges, frequencies) were performed for all responses. Univariate chi square tests were performed to analyze associations, particularly with telemedicine responses. RESULTS: The survey was completed by 101 caregivers. Nearly 20% of families traveled more than 1 hour to reach the comprehensive SCD center. Other than their SCD provider, caregivers reported their child having at least 2 other healthcare providers. Most barriers caregivers identified were financial or resource based. Almost a quarter of caregivers expressed feeling as though these barriers impacted their and/or their child's mental health. Ease of access to team members, as well as scheduling, were common facilitators of care cited by caregivers. The majority were willing to participate in telemedicine visits, regardless of how far they lived from the SCD center, though many noted aspects requiring adaptation. CONCLUSION: This cross-sectional study describes barriers to care experienced by caregivers of children with SCD, regardless of proximity to an SCD center, as well as caregiver perceptions of the usefulness and acceptability of telemedicine for SCD care.

Identifying and Validating Pediatric Hospitalizations for MIS-C Through Administrative Data.

BACKGROUND: Individual children's hospitals care for a small number of patients with multisystem inflammatory syndrome in children (MIS-C). Administrative databases offer an opportunity to conduct generalizable research; however, identifying patients with MIS-C is challenging. METHODS: We developed and validated algorithms to identify MIS-C hospitalizations in administrative databases. We developed 10 approaches using diagnostic codes and medication billing data and applied them to the Pediatric Health Information System from January 2020 to August 2021. We reviewed medical records at 7 geographically diverse hospitals to compare potential cases of MIS-C identified by algorithms to each participating hospital's list of patients with MIS-C (used for public health reporting). RESULTS: The sites had 245 hospitalizations for MIS-C in 2020 and 358 additional MIS-C hospitalizations through August 2021. One algorithm for the identification of cases in 2020 had a sensitivity of 82%, a low false positive rate of 22%, and a positive predictive value (PPV) of 78%. For hospitalizations in 2021, the sensitivity of the MIS-C diagnosis code was 98% with 84% PPV. CONCLUSION: We developed high-sensitivity algorithms to use for epidemiologic research and high-PPV algorithms for comparative effectiveness research. Accurate algorithms to identify MIS-C hospitalizations can facilitate important research for understanding this novel entity as it evolves during new waves.

Protocol and biomarker strategy for a multi-site randomized controlled trial examining biological mechanisms and dosing of active music engagement in children with acute lymphoblastic leukemia and lymphoma and parents.

BACKGROUND: Music therapy is a standard palliative care service in many pediatric and adult hospitals; however, most research has focused on the use of music to improve psychosocial dimensions of health, without considering biological dimensions. This study builds on prior work examining psychosocial mechanisms of action underlying an Active Music Engagement (AME) intervention, designed to help manage emotional distress and improve positive health outcomes in young children with cancer and parents (caregivers), by examining its effects on biomarkers of stress and immune function. METHODS: This two-group randomized controlled trial (R01NR019190) is designed to examine biological mechanisms of effect and dose-response relationships of AME on child/parent stress during the consolidation phase of Acute B- or T-cell Lymphoblastic Leukemia (ALL) and T-cell Lymphoblastic Lymphoma (TLyLy) treatment. Child/parent dyads (n = 228) are stratified (by age, site, risk level) and randomized in blocks of four to the AME or attention control condition. Each group receives one session (30-minutes AME; 20-minutes control) during weekly clinic visits (4 weeks standard risk B-cell ALL; 8 weeks high risk B-cell ALL/T-cell ALL/TLyLy). Parents complete questionnaires at baseline and post-intervention. Child/parent salivary cortisol samples are taken pre- and post-session (sessions 1-4). Child blood samples are reserved from routine draws before sessions 1 and 4 (all participants) and session 8 (high risk participants). We will use linear mixed models to estimate AME's effect on child/parent cortisol. Examining child/parent cortisol as mediators of AME effects on child and parent outcomes will be performed in an ANCOVA setting, fitting the appropriate mediation models using MPlus and then testing indirect effects using the percentile bootstrap approach. Graphical plots and non-linear repeated measures models will be used to examine dose-response relationship of AME on child/parent cortisol. DISCUSSION: During pediatric cancer treatment there are special challenges that must be considered when measuring cortisol and immune function. In this manuscript we discuss how we addressed three specific challenges through our trial design. Findings from this trial will increase mechanistic understanding of the effects of active music interventions on multiple biomarkers and understanding of dose-response effects, with direct implications for clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04400071.

Side Effects With a Focus on Lymphadenopathy Following COVID-19 Vaccination in Pediatric and AYA Oncology Patients.

The Coronavirus Disease 2019 (COVID-19) pandemic led to the swift development of multiple vaccinations. Vaccine side effects were well-documented in the healthy adult cohort and included fever and lymphadenopathy, however, side effects in the pediatric immunocompromised population have not been reported. This retrospective study investigated vaccine-eligible children and adolescent young adult oncology patients 12 to 35 years old. We found uncommon, mild, and self-limiting side effects among pediatric cancer patients and survivors. This data will help guide pediatric and AYA oncologists in providing anticipatory guidance and serve as a guide to managing lymphadenopathy as a potential confounder of malignancy.

Side effects following COVID-19 vaccination in pediatric patients with sickle cell disease.

Vulnerable patient populations have seen decreased rates of vaccination against SARS-CoV2-19 (COVID-19) due to hesitancies and distrust, magnified by a paucity of data for certain populations. The rate of COVID-19 vaccination in children with sickle cell disease (SCD) remains low despite the risk for severe complications, resulting in continued infections and hospitalizations from COVID-19. We sought to describe vaccine reactions, including vaso-occlusive crises, emergency department visits, and hospitalizations, in children with SCD. Our findings will start to provide the necessary vaccine side effect data to inform patients, caregivers, and clinicians considering the COVID-19 primary vaccination series.

A Quality Improvement Initiative to Decrease Time to Analgesia in Patients With Sickle Cell and Vaso-Occlusive Crisis: A Population With Disparities in Treatment.

INTRODUCTION: Vaso-occlusive crises (VOCs) are the leading cause of emergency department (ED) visits and hospitalizations in patients with sickle cell disease (SCD). Timely administration of analgesia, within 60 minutes of patient registration, is the standard of care for SCD patients with VOCs. Patients with VOCs have longer times to initial analgesia compared to similar painful conditions. The primary aim of the project is to have 75% of patients with VOCs receive initial analgesia within 60 minutes of being registered, the current recommended time frame from the National Heart, Lung, and Blood Institute (NHLBI). METHODS: A multi-disciplinary team used quality improvement (QI) methodology to develop a plan involving multiple Plan-Do-Study-Act (PDSA) cycles. A rapid evaluation process was employed which included notification of a patient with a VOC being placed in a room, rapid evaluation by all team members and use of an electronic order set. RESULTS: The aim was met 72% of the time during our intervention period, compared to 17% pre-intervention. Average time to initial analgesia was decreased from 61 minutes to 42 minutes (p-value < 0.001), while time to disposition was also decreased when time goals were achieved. CONCLUSION: Using a rapid evaluation process we were able to decrease time to initial analgesia in a patient population that has previously experienced delays in care and decrease overall time to disposition.

Evaluation of Individualized Pain Plans for Children With Sickle Cell Disease Admitted for Vaso-occlusive Crisis at Riley Hospital for Children.

OBJECTIVE: Vaso-occlusive crisis (VOC) is the most common problem reported by patients with sickle cell disease (SCD). The objective of this study was to evaluate the impact of individualized pain plans in pediatric patients with SCD admitted for VOC. METHODS: This was a pre- and post-study of patients with SCD admitted to Riley Hospital for Children for VOC from July 1, 2019, through July 1, 2020. The primary outcome was length of inpatient stay for VOC. Secondary outcomes included final pain score, days on scheduled opioids, days on breakthrough opioids, and average morphine milligram equivalents (MME) used per day. RESULTS: Nine patients were included. The mean age was 16 years (range, 10-20 years). Key clinical findings were decreases in median [IQR] for final pain scores (7 [4.5-9] vs 6 [2.5-8], p = 0.396) and number of days of breakthrough opioid use (5 [3-8] vs 4 [2.5-5.5], p = 0.233). Following implementation of an individualized pain plan, there was an increase in median average MME per day (65.94 [53.1-97.7] vs 82.85 [41-114.3], p = 0.844). Median length of stay and days on scheduled opioids remained the same. CONCLUSIONS: This study demonstrated that use of individualized pain plans in a small population of patients with SCD might result in decreased pain scores and decreased days on breakthrough opioids.

Pediatric hematology/oncology physician and nurse practitioner attitudes towards the COVID-19 vaccines: A qualitative study.

As of 05/28/2021, SARS-CoV-2 (COVID-19) had caused 3.9 million infections in the United States (US) pediatric population since its discovery in December of 2019. The development and expansion of vaccination has markedly changed the shape of the epidemic. In this qualitative study, we report on pediatric hematology/oncology provider views on the COVID-19 vaccine prior to approval in the adolescent population <16 years of age. Results from interviews with 20 providers across the state of Indiana showed that most were supportive of the COVID-19 vaccine for healthy adults. However, the majority also expressed a need to see more data on the safety and effectiveness of COVID-19 vaccinations in pediatric hematology/oncology populations. While they recognized the public health importance of vaccination, their duty to protect their patients led to a need for more specific safety and efficacy data.