Emergency Department Health Care Utilization and Opioid Administration Among Pediatric Patients With Sickle Cell Vasoocclusive Pain Crisis and Coexisting Mental Health Illness.

OBJECTIVES: To determine whether patients with sickle cell disease (SCD) who present to the emergency department (ED) with vasoocclusive pain crises (VOC), and have coexisting mental health (MH) diagnoses, are more likely to have increased health care utilization and more frequent opioid administration compared with those without coexisting MH conditions. METHODS: This is a retrospective study of patients aged 5 to 18 years with SCD who presented to a tertiary care ED with a primary complaint of VOC between January 1, 2013, and December 31, 2017. We excluded patients with sickle cell trait and without a pain management plan in the electronic medical record. Outcomes included ED length of stay (LOS), admission rate, and opioid administration in the ED. Morphine equivalents were used to standardize opioid dosing. Mann-Whitney U and χ2 tests were used for univariate analysis. Multivariable logistic was performed for categorical and continuous outcomes, respectively, after adjusting for confounding factors. RESULTS: We identified 978 encounters. We excluded 196 without a pain management plan and one with inaccurate ED LOS, resulting in 781 encounters (148 patients) for analysis. Coexisting MH diagnoses were present in 75.0% of encounters, with anxiety (83.0%) and depressive disorders (55.9%) being most common. Compared with SCD patients without coexisting MH diagnoses, those with coexisting MH diagnoses had significantly longer ED LOS (252 ± 139 minutes vs 232 ± 145 minutes, P = 0.03), longer median hospital LOS (1.4 ± 3.2 days vs 0.3 ± 2.4 days, P < 0.001) in univariate analyses, but these differences were no longer significant in adjusted regression models. Patients with coexisting MH diagnoses had higher frequency of opioid administration in the ED (85.6% vs 71.4%, P < 0.0001) and higher odds of receiving opioids (adjusted odds ratio, 2.07; 95% confidence interval, 1.28-3.33). CONCLUSIONS: Patients with SCD and coexisting MH diagnoses presenting with VOC have greater odds of receiving opioids compared with patients with SCD without coexisting MH diagnoses. Our results indicate a need for more MH resources in this vulnerable population and may help guide future management strategies.

Hydroxyurea Optimization through Precision Study (HOPS): study protocol for a randomized, multicenter trial in children with sickle cell anemia.

BACKGROUND: Sickle cell disease (SCD) is a severe and devastating hematological disorder that affects over 100,000 persons in the USA and millions worldwide. Hydroxyurea is the primary disease-modifying therapy for the SCD, with proven benefits to reduce both short-term and long-term complications. Despite the well-described inter-patient variability in pharmacokinetics (PK), pharmacodynamics, and optimal dose, hydroxyurea is traditionally initiated at a weight-based dose with a subsequent conservative dose escalation strategy to avoid myelosuppression. Because the dose escalation process is time consuming and requires frequent laboratory checks, many providers default to a fixed dose, resulting in inadequate hydroxyurea exposure and suboptimal benefits for many patients. Results from a single-center trial of individualized, PK-guided dosing of hydroxyurea for children with SCD suggest that individualized dosing achieves the optimal dose more rapidly and provides superior clinical and laboratory benefits than traditional dosing strategies. However, it is not clear whether these results were due to individualized dosing, the young age that hydroxyurea treatment was initiated in the study, or both. The Hydroxyurea Optimization through Precision Study (HOPS) aims to validate the feasibility and benefits of this PK-guided dosing approach in a multi-center trial. METHODS: HOPS is a randomized, multicenter trial comparing standard vs. PK-guided dosing for children with SCD as they initiate hydroxyurea therapy. Participants (ages 6 months through 21 years), recruited from 11 pediatric sickle cell centers across the USA, are randomized to receive hydroxyurea either using a starting dose of 20 mg/kg/day (Standard Arm) or a PK-guided dose (Alternative Arm). PK data will be collected using a novel sparse microsampling approach requiring only 10 µL of blood collected at 3 time-points over 3 h. A protocol-guided strategy more aggressive protocols is then used to guide dose escalations and reductions in both arms following initiation of hydroxyurea. The primary endpoint is the mean %HbF after 6 months of hydroxyurea. DISCUSSION: HOPS will answer important questions about the clinical feasibility, benefits, and safety of PK-guided dosing of hydroxyurea for children with SCD with potential to change the treatment paradigm from a standard weight-based approach to one that safely and effectively optimize the laboratory and clinical response. TRIAL REGISTRATION: ClinicalTrials.gov NCT03789591 . Registered on 28 December 2018.

How do I incorporate red cell genotyping to improve chronic transfusion therapy?

BACKGROUND: Children with transfusion dependent anemia, such as sickle cell disease (SCD) and thalassemia, are at an increased risk for developing red blood cell (RBC) alloantibodies due to their lifelong need for transfusion therapy. With the advent of genotyping, extended RBC antigen typing can be incorporated into chronic transfusion therapy programs (CTTPs) to improve patient care and provide antigen matched blood for this population of patients. STUDY DESIGN AND METHODS: The hospital, blood center (BC), and hematology clinic caring for children requiring long-term transfusion support developed a CTTP. Genotyping was performed at entry to determine patient RBC antigen type. Limited versus extended antigen matching of transfusions was provided based on known RBC antibodies. RESULTS: Fifty patients with the following disorders were enrolled: 20 with SCD, 23 with thalassemia, and 7 with other disorders. At enrollment, nine (18%) had RBC alloantibodies, including six (30%) of patients with SCD and three (13%) with thalassemia. Two children developed antibodies after enrollment; one warm autoantibody following limited "CEK" matched RBCs and one patient with a hemizygous variant RHD allele developed anti-D. Six (30%) patients with SCD had variant RHCE alleles; two had homozygous variant alleles and four had a variant present along with a wild type allele. CONCLUSION: We demonstrate how a CTTP can be developed in a community hospital through collaboration with the blood supplier, hospital, and clinical care team. A model of incorporating RBC genotyping informs risk for alloimmunization and allows consideration of transfusion strategy for providing prophylactic antigen matched blood.

The Impact of Health Equity Coaching on Patient's Perceptions of Cultural Competency and Communication in a Pediatric Emergency Department: An Intervention Design.

PURPOSE: American Indian (AI) children experience significant disparities in health-care access. As a result, they are more likely to use the emergency department (ED) for nonemergent visits than white children. In a recent study, pediatric ED providers have shown an implicit bias for white children over AI children. To combat implicit bias in an ED setting, we created a protocol for training ED providers as health equity coaches. METHODS: The intervention took place during the fall of 2016 and was composed of 4 educational lectures, 6 to 8 hours of service learning in AI communities, and the participant's dissemination of what was learned through formal presentations and informal conversations with other ED staff. We measured the impact of this intervention on the intervention participants with a group interview at the completion of the intervention. RESULTS: The findings from the group interview provide feedback on what was learned during the intervention, how it impacted providers, and feedback on the structure of the intervention. Overall ED providers reported the intervention improved awareness of their implicit bias and ways to improve communication and care for AI patients. Additional institutional policy and procedural changes are necessary to effectively and sustainably address health disparities affecting AI populations. CONCLUSIONS: The participating providers identified their lack of knowledge regarding AI cultures at the start of the intervention and it became clear that their knowledge, comfort, and relationships with AI communities increased as a result of this intervention.

Implicit Bias Training in a Residency Program: Aiming for Enduring Effects.

BACKGROUND AND OBJECTIVES: Implicit bias often affects patient care in insidious ways, and has the potential for significant damage. Several educational interventions regarding implicit bias have been developed for health care professionals, many of which foster reflection on individual biases and encourage personal awareness. In an attempt to address racism and other implicit biases at a more systemic level in our family medicine residency training program, our objectives were to offer and evaluate parallel trainings for residents and faculty by a national expert. METHODS: The trainings addressed how both personal biases and institutional inequities contribute to structural racism, and taught skills for managing instances of implicit biases in one's professional interactions. The training was deliberately designed to increase institutional capacity to engage in crucial conversations regarding implicit bias. Six months after the trainings, an external evaluator conducted two separate 1-hour focus groups, one with residents (n=18) and one with program faculty and leadership (n=13). RESULTS: Four themes emerged in the focus groups: increased awareness of and commitment to addressing racial bias; appreciation of a safe forum for sharing concerns; new ways of addressing and managing bias; and institutional capacity building for continued vigilance and training regarding implicit bias. CONCLUSIONS: Both residents and faculty found this training to be important and empowering. All participants desired an ongoing programmatic commitment to the topic.

Hydroxyurea use in young infants with sickle cell disease.

BACKGROUND: Hydroxyurea (HU) reduces complications and improves quality and duration of life in sickle cell disease. Evidence supports the use of HU starting after nine months of age. PROCEDURES: We performed a retrospective study of patients starting HU at less than five years of age between January 1, 2008, and December 31, 2016. We evaluated clinical events, laboratory data, and toxicity between three different age groups: cohort 1 (0-1 year), cohort 2 (1-2 years), and cohort 3 (2-5 years). RESULTS: Sixty-five patients were included in the analysis. The mean age was 7.2 months (n = 35), 19.5 months (n = 13), and 35.5 months (n = 17) for cohorts 1, 2, and 3, respectively. Cohort 1 had higher hemoglobin (P = 0.0003) and MCV (P = 0.0199) and lower absolute reticulocyte count (P = 0.0304) at 24 months of age compared with cohort 3. The absolute neutrophil count (ANC) was lower compared with both older cohorts (P = 0.0364, 0.0025). The mean baseline hemoglobin F in cohort 1 was 31.5% compared with 19.7% and 16.5% in cohorts 2 and 3, respectively (P = 0.002, P < 0.0001). The mean duration of therapy was 31.3 months, 57.6 months (P = 0.018), and 29.1 months (P = 0.401), respectively. Mean Hb F levels remained higher in cohort 1 (29.9%) compared with cohorts 2 and 3 (20.4%, P = 0.007; 20.6%, P = 0.003). Cohort 1 experienced fewer hospitalizations (P = 0.0025), pain crises (P = 0.0618), and transfusions (P = 0.0426). There was no difference in toxicity between groups. CONCLUSION: HU is safe and effective in patients 5 to 12 months of age and generated a more robust response compared with initiation in older patients.

Efficacy of systemic sirolimus in the treatment of generalized lymphatic anomaly and Gorham-Stout disease.

BACKGROUND: Generalized lymphatic anomaly (GLA) and Gorham-Stout disease (GSD) are rare complicated lymphatic malformations that occur in multiple body sites and are associated with significant morbidity and mortality. Treatment options have been limited, and conventional medical therapies have been generally ineffective. Emerging data suggest a role for sirolimus as a treatment option for complex lymphatic anomalies. PROCEDURE: Disease response was evaluated by radiologic imaging, quality of life (QOL), and clinical status assessments in children and young adults with GLA and GSD from a multicenter systematic retrospective review of patients treated with oral sirolimus and the prospective phase 2 clinical trial assessing the efficacy and safety of sirolimus in complicated vascular anomalies (NCT00975819). Sirolimus dosing regimens and toxicities were also assessed. RESULTS: Eighteen children and young adults with GLA (n = 13) or GSD (n = 5) received oral sirolimus. Fifteen patients (83%) had improvement in one or more aspects of their disease (QOL 78%, clinical status 72%, imaging 28%). No patients with bone involvement had progression of bone disease, and the majority had symptom or functional improvement on sirolimus. Improvement of pleural and pericardial effusion(s) occurred in 72% and 50% of affected patients; no effusions worsened on treatment. CONCLUSIONS: Sirolimus appears effective at stabilizing or reducing signs/symptoms of disease in patients with GLA and GSD. Functional impairment and/or QOL improved in the majority of individuals with GLA and GSD with sirolimus treatment.

Ceftriaxone-induced drug reaction mimicking acute splenic sequestration crisis in a child with hemoglobin SC disease.

BACKGROUND: Acute splenic sequestration crisis is a complication of sickle cell disease (SCD) occurring when intrasplenic red blood cell (RBC) sickling prevents blood from leaving the spleen, causing acute splenic enlargement. Although typically seen in young children, it has been reported in older children with hemoglobin (Hb)SC disease, eventually resulting in functional asplenia. Ceftriaxone is a frequently used antibiotic of choice for children with SCD, because of its efficacy against invasive pneumococcal disease. CASE REPORT: We report a case of a 9-year-old female with HbSC disease, who had a fatal reaction after receiving a dose of ceftriaxone in the outpatient clinic for fever. Her Hb level decreased abruptly from 9.3 to 2.3 mg/dL. RBC clumps with no visible hemolysis were observed in the postreaction sample. Autopsy examination revealed marked splenomegaly with acute congestion and sickled cells in the spleen and liver. Serologic testing revealed a positive direct antiglobulin test with polyspecific antibody, anti-C3, and anti-C3d, but negative with anti-immunoglobulin G. Ceftriaxone-dependent RBC antibodies were detected in her serum and RBC eluate when tested in the presence of the drug. CONCLUSION: We report a new presentation of ceftriaxone-induced drug reaction in a patient with SCD mimicking an acute splenic sequestration crisis. Review of the literature for cases of ceftriaxone-induced drug reactions in pediatric patients revealed nine previously reported cases of ceftriaxone-induced immune hemolytic anemia in children with SCD since 1995, but none with an initial presentation suggestive of acute splenic sequestration crisis.

Increased theta band EEG power in sickle cell disease patients.

OBJECTIVE: Pain is a major issue in the care of patients with sickle cell disease (SCD). The mechanisms behind pain and the best way to treat it are not well understood. We studied how electroencephalography (EEG) is altered in SCD patients. METHODS: We recruited 20 SCD patients and compared their resting state EEG to that of 14 healthy controls. EEG power was found across frequency bands using Welch's method. Electrophysiological source imaging was assessed for each frequency band using the eLORETA algorithm. RESULTS: SCD patients had increased theta power and decreased beta2 power compared to controls. Source localization revealed that areas of greater theta band activity were in areas related to pain processing. Imaging parameters were significantly correlated to emergency department visits, which indicate disease severity and chronic pain intensity. CONCLUSION: The present results support the pain mechanism referred to as thalamocortical dysrhythmia. This mechanism causes increased theta power in patients. SIGNIFICANCE: Our findings show that EEG can be used to quantitatively evaluate differences between controls and SCD patients. Our results show the potential of EEG to differentiate between different levels of pain in an unbiased setting, where specific frequency bands could be used as biomarkers for chronic pain.

Invasive pneumococcal disease in children with sickle cell disease in the pneumococcal conjugate vaccine era.

Invasive pneumococcal disease (IPD) in children with sickle cell disease (SCD) can be devastating. We sought to assess the impact of IPD in children with SCD since licensure of the pneumococcal conjugate vaccines (PCVs). We found 11 cases of IPD giving an incidence of 417 per 100,000 person-years, much higher than that reported in children without SCD. Although all isolates were sensitive to penicillin, 89% of isolates were nonvaccine serotypes. Further study is needed to characterize the incidence of and risk factors for the development of IPD in SCD in the PCV era to help drive better prevention strategies.

Translating sickle cell guidelines into practice for primary care providers with Project ECHO.

BACKGROUND: Approximately 100,000 persons with sickle cell disease (SCD) live in the United States, including 15,000 in the Midwest. Unfortunately, many patients experience poor health outcomes due to limited access to primary care providers (PCPs) who are prepared to deliver evidence-based SCD care. Sickle Treatment and Outcomes Research in the Midwest (STORM) is a regional network established to improve care and outcomes for individuals with SCD living in Indiana, Illinois, Michigan, Minnesota, Ohio, and Wisconsin. METHODS: STORM investigators hypothesized that Project ECHO® methodology could be replicated to create a low-cost, high-impact intervention to train PCPs in evidence-based care for pediatric and young adult patients with SCD in the Midwest, called STORM TeleECHO. This approach utilizes video technology for monthly telementoring clinics consisting of didactic and case-based presentations focused on the National Heart, Lung and Blood Institute (NHLBI) evidence-based guidelines for SCD. RESULTS: Network leads in each of the STORM states assisted with developing the curriculum and are recruiting providers for monthly clinics. To assess STORM TeleECHO feasibility and acceptability, monthly attendance and satisfaction data are collected. Changes in self-reported knowledge, comfort, and practice patterns will be compared with pre-participation, and 6 and 12 months after participation. CONCLUSIONS: STORM TeleECHO has the potential to increase implementation of the NHLBI evidence-based guidelines, especially increased use of hydroxyurea, resulting in improvements in the quality of care and outcomes for children and young adults with SCD. This model could be replicated in other pediatric chronic illness conditions to improve PCP knowledge and confidence in delivering evidence-based care.

Genetic Modifiers of White Blood Cell Count, Albuminuria and Glomerular Filtration Rate in Children with Sickle Cell Anemia.

Discovery and validation of genetic variants that influence disease severity in children with sickle cell anemia (SCA) could lead to early identification of high-risk patients, better screening strategies, and intervention with targeted and preventive therapy. We hypothesized that newly identified genetic risk factors for the general African American population could also impact laboratory biomarkers known to contribute to the clinical disease expression of SCA, including variants influencing the white blood cell count and the development of albuminuria and abnormal glomerular filtration rate. We first investigated candidate genetic polymorphisms in well-characterized SCA pediatric cohorts from three prospective NHLBI-supported clinical trials: HUSTLE, SWiTCH, and TWiTCH. We also performed whole exome sequencing to identify novel genetic variants, using both a discovery and a validation cohort. Among candidate genes, DARC rs2814778 polymorphism regulating Duffy antigen expression had a clear influence with significantly increased WBC and neutrophil counts, but did not affect the maximum tolerated dose of hydroxyurea therapy. The APOL1 G1 polymorphism, an identified risk factor for non-diabetic renal disease, was associated with albuminuria. Whole exome sequencing discovered several novel variants that maintained significance in the validation cohorts, including ZFHX4 polymorphisms affecting both the leukocyte and neutrophil counts, as well as AGGF1, CYP4B1, CUBN, TOR2A, PKD1L2, and CD163 variants affecting the glomerular filtration rate. The identification of robust, reliable, and reproducible genetic markers for disease severity in SCA remains elusive, but new genetic variants provide avenues for further validation and investigation.

Training providers on issues of race and racism improve health care equity.

Race is an independent factor in health disparity. We developed a training module to address race, racism, and health care. A group of 19 physicians participated in our training module. Anonymous survey results before and after the training were compared using a two-sample t-test. The awareness of racism and its impact on care increased in all participants. White participants showed a decrease in self-efficacy in caring for patients of color when compared to white patients. This training was successful in deconstructing white providers' previously held beliefs about race and racism.

Multimodal therapy in the treatment of a venolymphatic malformation of the axilla and chest wall in an infant.

We report our staged multimodal treatment of a female infant with a very large complex venolymphatic malformation of the axilla and chest wall. We successfully managed the patient's severely restricted arm mobility and consumptive coagulopathy with surgical debulking followed by medical therapy with the mammalian target of rapamycin inhibitor sirolimus. The diseased burden reduced in size throughout therapy, and hematologic parameters reached and maintained normal levels. Normal health and limb functionality were restored with no observed adverse side effects of medical therapy. This case presents a previously unreported and potentially promising method to treat severe vascular malformations.

Race matters: perceptions of race and racism in a sickle cell center.

BACKGROUND: Health care disparities based on race have been reported in the management of many diseases. Our goal was to identify perceptions of race and racism among both staff and patients/families with particular attention to provider attitudes as a potential contributor to racial healthcare disparities. PROCEDURE: A confidential survey addressing issues of race and health care was given to all patients with sickle cell disease and their families upon arrival to clinic. The survey was made available online to all staff in the hematology/oncology program. Free text comments were obtained. RESULTS: We received completed surveys from 112 patients/families. Surveys were completed by 135 of 158 staff members (85% return rate). The majority (92.6%) of patients/families identified as black, while 94.1% of staff identified as white (P < 0.001). More patients/families felt that race affects the quality of health care for sickle cell patients (50% vs. 31.6%, P = 0.003). More staff perceived unequal treatment of patients, especially in the inpatient setting (20.9% vs. 10.9%, P = 0.03). CONCLUSIONS: Provider attitudes contribute to continued racial health care disparities. We propose training health care providers on issues of race and racism. Training should provide critical thinking tools for improving medical providers' comfort and skills in caring for patients who are of a different race than their own.

Transition planning for youth with sickle cell disease: embedding neuropsychological assessment into comprehensive care.

OBJECTIVE: Sickle cell disease (SCD) conveys a high risk of neuropsychological impairment due to chronic anemia, hypoxemia, cerebrovascular ischemia and stroke, in addition to causing pain and other biomedical complications. Few families accessed neuropsychological testing via the traditional referral system. In this paper, we describe a successful alternative strategy for addressing cognitive and behavioral needs of youth with SCD. METHOD: The Sickle Cell Disease Program for Learning and Neuropsychological Evaluation (SCD-PLANE) was embedded in 2007 into the SCD Comprehensive Clinic of Children's Hospitals and Clinics of Minnesota. SCD-PLANE includes brief neuropsychological testing, individualized recommendations, patient education and advocacy, interdisciplinary collaboration, and follow-through to assure patients' access to recommended resources. The purpose of SCD-PLANE is to identify and recommend interventions for cognitive, academic, emotional, behavioral, or social problems affecting child development and transition to adulthood. RESULTS: Access to neuropsychological testing improved dramatically and is well accepted by SCD patients and families. Test results reveal increased risk of problems with executive function, speed of processing, graphomotor function, academic achievement, and parent-reported anxious/depressed symptoms, despite normal intelligence and language abilities. Patients' needs had not been previously identified or served by schools or other community agencies. CONCLUSIONS: The SCD-PLANE, providing brief neuropsychological testing embedded within routine annual visits to SCD Comprehensive Clinic, is an effective approach to detect unmet developmental, educational, and behavioral needs within an underserved high-risk population. As youth move towards adulthood, considering cognitive, academic, and mental health status facilitates successful health care transitions.