Painful Crises Research Articles

Do Children Less Than 3 Years with Sickle Cell Disease Need to be Routinely Admitted with Fever?

Background Due to functional asplenia, patients with sickle cell disease (SCD) are at increased risk of serious bacterial infection (SBI) with encapsulated organisms. With the advent of prophylactic penicillin, Haemophilus and Pneumococcal vaccination, this risk has decreased, though recommendations for admission in young children are not standardized and based on institutional practice. Historically, our standard at Benioff Children Hospital Oakland (CHO) has been to admit all children with SCD < 3 years with fever due to these historical concerns. We hypothesized that in a well appearing febrile cohort, the risk of complication would be very low (i.e., <3-5%), allowing liberalization of this stringent recommendation. Methods After IRB approval, we conducted a retrospective review of electronic medical records of children with SCD <3 years of age admitted with fever (i.e., ≥38.3ºC) from October 1 st, 2013 to May 30 th 2022 at CHO. We excluded patients who presented with fever and other complications in the emergency department (ED) that would have otherwise required admission including: 1) splenic sequestration; 2) acute chest syndrome (ACS); 3) hypoxia and/or respiratory distress; 4) vaso-occlusive crisis (VOC); 5) hemoglobin (Hb) drop ≥2 g/dL from baseline; 6) severe dehydration; 7) seizures or other neurological concerns; 8) complicated/complex medical history; 9) SARS-CoV-2 infection; 10) age <2 months; 11) soft tissue infection; and 12) UA concerning for infection. Results Sixty-four unique patients with 127 encounters were included with baseline features outlined in Table 1. Ninety-seven encounters were excluded due to presenting signs/symptoms. Rate of bacteremia was 1.6% (2 of 127). Twenty-six of the 127 encounters (20%, 21 unique patients) were deemed complicated, due to: 1) bacteremia (n=2); 2) splenic sequestration (n=6); 3) acute chest syndrome (n=1); 4) worsening anemia requiring transfusion (n=11); 5) pain crisis (n=1); 6) persistent fever (n=4) and 7) norovirus gastroenteritis (n=1). Eighty-five percent were in children 2 years or less. Complicated admissions were statistically longer and had lower hemoglobin and platelets at presentation than uncomplicated admissions (Table 2). There was no difference in age, white blood cell count (WBC) and maximum fever during presentation in the ED (Table 2). Fourteen of 26 complications (54%) occurred in the first two days of admission and the rest thereafter. Conclusions Although the rate of bacteremia was low as expected in children with SCD <3 years of age presenting to the ED with fever and without concerning presenting features, the overall rate of complications during admission for those encounters was much higher than our acceptable a priori threshold. Retrospectively, there were no easily discernible presenting features in this otherwise well-appearing cohort to determine need for admission. Complications often occurred beyond day 2 of admission. The majority of complications occurred in children ≤2 years of age; we therefore will continue to admit all children with SCD and fever ≤ 2 years of age with a low threshold for ongoing admission beyond the 48 hour rule out. Institutional standards must closely monitor for increased adverse events if utilizing more lenient ED discharge criteria in this population.

Preclinical and Clinical Use of AB1, a DNMT1 Protein Depleter, to Upregulate Fetal Hemoglobin in Townes Sickle Cell Disease (SCD) Mice and Patients with SCD

Background: Sickle Cell Disease (SCD) is an inherited hematologic disorder characterized by lifelong hemolysis, vaso-occlusion and severe complications including pain, acute chest syndrome and stroke among others. Its complex pathophysiology is driven by polymerization of mutated sickle hemoglobin (HbS) in red blood cells. Fetal hemoglobin (HbF) has been well documented to interfere with HbS polymerization, however, γ-globin gene transcription is silenced after birth through the action of a repressor complex including DNA methyltransferase 1 (DNMT1) during hemoglobin switching. We previously demonstrated the ability of AB1, a potent non-cytotoxic agent which depletes DNMT1 protein, to induce HbF in sickle erythroid progenitors. To expand these findings, we aimed to 1) perform preclinical studies in the Townes SCD mouse model to determine the ability of AB1 to induce HbF and deplete DNMT1 protein; and 2) evaluate the safety of oral AB1 in patients with SCD through an open-label, dose escalating phase 1/2 study (NCT05261711). Methods: Preclinical. Townes SCD mice, 4 months old (6 mice per group) were treated by intraperitoneal injections of escalating AB1 doses of 0.5, 1.5 and 3.0 mg/dose, hydroxyurea (HU; 100 mg/kg/dose) alone or HU combined with AB1 (0.5mg/dose) and water control, 5 days/week for 6 weeks. Every 2 weeks, complete blood counts with differentials were performed along with flow cytometry for HbF positive cells (F-cells) and reticulocytes; RT-qPCR for γ- and β-globin mRNA levels was completed and the spleen was harvested for weights and DNMT1 protein levels by Western blot. Clinical Trial. After informed consent, patients with confirmed HbSS or HbSb 0 thalassemia, on stable HU doses (if on treatment), and no recent/chronic transfusions or pain crisis were approached for the study. Patients were enrolled at Duke and Augusta University, starting on 2 mg of AB1 with 4 additional cohorts (4mg, 8mg, 16mg, and 32mg) to be recruited. Doses were taken daily by mouth for 8 weeks. Safety and tolerability (primary outcomes), as well as pharmacokinetics, pharmacodynamics and HbF response (secondary outcomes) were assessed. The F-cells and mean fluorescence intensity were measured by flow cytometry and HbF% by HPLC. Results: Preclinical. In general, SCD mice treated with AB1 showed good weight gain without toxicity. Three deaths occurred in the HU and combination treatment groups along with a significant decrease in platelets, granulocytes, and monocytes; by contrast, one death occurred in the 3mg/kg AB1 group, but the blood or reticulocyte counts were not affected. By week 6, HU increased F-cells by 2.1-fold (p=0.02) compared to a 2.2-fold (p=0.006) and 1.5-fold (p=0.03) increase by AB1 1.5mg/kg and 3.0 mg/kg respectively. Likewise, γ-globin mRNA increased, and β-globin mRNA decreased at the highest dose. Spleen analysis showed decreased weights and an 80% decrease in reactive oxygen species by AB1. Finally, DNMT1 protein levels were depleted by AB1 in spleen tissue. Clinical Trial. The clinical trial opened for enrollment in the winter of 2022. Two patients completed cohort 1 and two patients have enrolled and started cohort 2. Both cohort 1 patients had HbSS with a median age of 29.5 years (range 28-31). No change in total hemoglobin or reticulocyte counts was observed in either subject treated with 2mg AB1 daily. During the treatment period two adverse events occurred (rash-drug related and elevated liver enzymes-unrelated), however there were no serious adverse events. AB1 increased F-cell levels in subject 1 by 5.7-fold (2.9% to 16.4%). Expanded analysis of subject 2 showed an increase in F-cells 3-fold (4.8% to 14.4%) and 3-fold increase in F-reticulocytes. At the lowest 2mg dose, by HPLC analysis both patients had an increase in HbF% from a mean of 6.3% to 7% supporting protein induction by AB1. Discussion: The goal of this project is to develop an oral-active HbF inducer for the treatment of individuals with SCD. Data generated in the SCD mouse showed a significant increase in F-cells and γ-globin gene transcription, along with DNMT1 protein depletion. Subsequent oral AB1 treatment of patients with HbSS confirmed increased F-cells and HbF protein levels without clinical toxicities. These findings support continuing the ongoing phase 1/2 study, which will provide further insights into the ability of AB1 to increase HbF without hematologic side effects in patients with SCD.

Characteristics and Trends of Hospitalizations for Sickle-Cell Related Complications

Introduction There are approximately 100,000 people living with sickle cell disease (SCD) in the United States. As per the Center for Disease Control estimates, almost all patients with SCD will require hospitalization more than once a year and visit the emergency department at least 2-3 times a year on average. Previous studies have shown that SCD hospitalization trends are steadily increasing in the country. In November of 2019, two new drugs, crizanlizumab (to decrease the frequency of vaso-occlusive crises) and voxelotor (to increase hemoglobin response), were approved by the Food and Drug Administration (FDA) for the treatment of sickle cell disease. Around the same time, the entire health care system experienced disruption in the form of the COVID-19 pandemic. Hence, we conducted this retrospective study to assess SCD hospitalization trends from 2016-2020 and stratified them across various demographic factors to analyze the underlying causes. Methods We conducted a retrospective study from the National Inpatient Sample (NIS), which is a large all-payer database created by the Health Care Cost and Utilization Project (HCUP). We included all adult patients with a diagnosis of SCD (HbSS, HbSC, Sickle/b thal, and other variants) and identified their trends of hospitalizations for various SCD-related complications like vaso-occlusive crises, heart failure exacerbation, acute kidney injury, stroke, sepsis with and without septic shock, bacteremia, pneumonia, osteomyelitis, acute chest syndrome, splenic sequestration, and priapism. We then did a linear-to-linear analysis and ANOVA test to stratify these trends across various age, gender, income, and location groups. SPSS was used for the statistical analysis. Results Our study included a total of 19,250 patients who had at least one admission for sickle cell-related complications during 2016-2020. The average number of admissions for sickle cell pain crisis steadily increased from 10.2 per 100,000 in 2016 to 14.7 in 2019 and then decreased to 13.9 in 2020. Priapism steadily declined from 2.3% in 2016 to 1.4% in 2020 (p<0.001). Acute kidney injury complicated 4.9% of admissions in 2016 and steadily rose to 5.2% of admissions in 2020 (p = 0.88). Admissions complicated by bacteremia peaked in 2017 (0.9%) but have since been on a decline (0.5% in 2020) (p-0.02). Admissions complicated by pneumonia showed a steady decline from 6% in 2016 to 4.3% in 2020 (p<0.001). Admissions with osteomyelitis, splenic sequestration, acute chest syndrome, heart failure exacerbation, stroke, and sepsis complicated <1% of all admissions and were not statistically relevant. When stratified by age, it was noted that the age group of 18-39 had the most admissions. Females consistently had more admissions than males. Medicaid was the predominant insurance among all the admissions, followed by Medicare. Around 50% of the patients admitted for SCD-related complications were in the 0-25th percentile of median household income quartiles. The majority of admissions were seen in urban teaching hospitals. The majority of these admissions were also seen in the Southern regions. Conclusion Our results show that female patients in the age group 18-39 years, those covered by Medicaid and Medicare, and those in lower income quartiles comprised the majority of admissions for SCD-related complications. This demonstrates disparities in SCD care, wherein patients in lower socio-economic strata may not have access to newer advances in SCD treatment. Although it is optimistic to note that admissions for pain crises had a significant decline from 2019-2020, it remains to be seen whether these numbers are due to new therapies or due to the disruption of healthcare services caused by the pandemic. Analyzing more long-term trends after the year 2020 will help us understand this impact. The overall trend of infections and sepsis has been low, likely due to widespread vaccinations and early antibiotic treatments. It is interesting to note that although there was a downtrend for the majority of SCD complications, the incidence of AKI during admissions is steadily rising, validating the need to focus more on renal care in sickle cell patients.

A Qualitative Study Comparing the Patient and Provider Experience in an Academic Blood Disorder Center

Introduction: Health disparities have been reported in several areas of hematologic and oncologic care. The NCI reports African American males develop cancer 25% more frequently than White males, and they have 43% higher mortality compared to Non-Hispanic Whites in all cancers combined. Hispanic ethnicity is also disproportionately affected in cancer care, in part due to lack of health care access (J Oncol Pract. 2006). Within hematologic care, differences in care and outcomes have been reported in diseases including sickle cell disease (SCD). Patients with SCD experience health disparities, including lack of knowledge on treatment options and misconceptions on opioid addiction (Shapiro et al. 1997). Our goal was to gain firsthand patient accounts of experiences in access and quality of hematological care at the University of Colorado Anschutz Medical Center. Methods: The study aimed to obtain surveys from 40 patients with 20 patients from under-represented minorities (Black, Hispanic, Native American, or Asian) and 20 patients from non-minority groups. Patients aged 18 or older treated in the Division of Hematology at University of Colorado were eligible for the study. Providers from our Division also participated the study. The surveys assessed general beliefs, experiences, and biases in 7 questions (Figure 1). Responses were based on a Likert scale ranging from ‘never’ to ‘very often’. Patients could also participate in an optional interview to further describe their experiences. Enrollment will continue through September 2023. Results: Our interim analysis includes data from 15 patients, 4 non-Hispanic White, 3 Hispanic, and 8 non-Hispanic Black patients. 78 providers from our Division also participated in the survey. Non-Hispanic Black patients were more likely to respond that our healthcare system unfairly treats individuals based on race or ethnic backgrounds, and this was more likely to occur when a patient and healthcare provider were of a different race or ethnic background. This was not the case in the Hispanic patient cohort. Provider responses mirrored the responses from non-Hispanic Black patients, suggesting our providers are aware of disparities in healthcare. However, 78% of providers agreed they had implicit biases they could identify, and although 69% of them agreed theyfelt knowledgeable and informed about issues regarding race and ethnicity, and how these issues may manifest in a healthcare setting, 46% of providers noticed implicit or explicit biases in their colleagues related to race or ethnicity. Individual patient interviews gave further insight into areas where improvement can be made. Black patients, particularly those who volunteered their diagnosis of SCD, expressed there is a lack of knowledge in the treatment of SCD outside of specialized centers. Further, misconceptions about pain crises can lead to undertreatment. One subject stated “With sickle cell disease, sometimes we have a lot of pain even though it may not look like it”... “Because we live with pain every day, when we go to the ER it is because we are in excruciating pain ”. Other underrepresented minority subjects also discussed barriers to their healthcare. One subject stated “In 2016 when I came to the US, I was sick and I went to the Emergency and we were new in town” ... “we didn't have any insurance. I found myself with 20 thousand dollars in hospital bills”.... “I didn't know, and it was too expensive. And it impacted me negatively because I am afraid, being honest, if it wasn't for Medicaid I wouldn't come to the hospital, you wouldn't see me there”. Conclusions: Our results highlight there are differences between the experience of our Black patients compared to non-Black patients. Further, provider questionnaires also highlight discrepancies about how we identify and address biases. Results from this study highlight areas needing improvement within our Division, which will lead to interventions such as bias training for providers. Further, dissemination of information on misconceptions on SCD at our institution, and at the community settings is critical to improving patient care for this patient population. Identifying additional barriers to health care access such as financial needs and lack of insurance is also critical to closing gaps within our healthcare system.

A Patient-Centric Approach to Sickle Cell Disease Clinical Trials: Integrating Patient Perspectives in the RISE UP Phase 2/3 Trial of Mitapivat for Informed Protocol Design and Associated Patient Community Benefit

Background: Sickle cell disease (SCD) is a genetic blood disorder that affects millions of people worldwide. There are currently limited treatment options and a high unmet need; new therapies - and therefore new trials - are essential. Although there is evidence of growing patient (pt) participation in the drug development processes, there is a lingering suspicion among the community that they are not treated as equal partners and too frequently regarded as mere data sources. Involving pts in planning and execution of clinical trials is essential to improve participation and meet the real needs of the patient community. Mitapivat is a first-in-class, oral, allosteric activator of pyruvate kinase (PK), approved by the United States Food and Drug Administration for the treatment of hemolytic anemia in adults with PK deficiency, by the European Union European Medicines Agency, and the Medicines and Healthcare products Regulatory Agency in Great Britain for the treatment of PK deficiency in adults. The RISE UP phase 2/3 trial (NCT05031780) of mitapivat in pts with SCD was therefore devised to use a new approach to clinical trial design and recruitment that considered pt preferences wherever possible. Objective: Using the RISE UP Phase 2/3 trial, redefine best practices in clinical trial design by asking pts with SCD to describe what matters most to them in a trial setting and by involving them in decision making processes and trial awareness communications. Methods: Nine SCD pts and advocates (five from the US, one from Bahrain, one from France and two from the UK) took part in a series of clinical trial design workshops. Four remote advisory board interviews were held with pts (>16 years of age) and advocates to consult on the RISE UP Phase 2/3 clinical trial design. The insights gained from these consultations were incorporated into the proposed trial protocol design that was subsequently shared with Health Authorities (HAs) for their comment from a regulatory perspective. Once finalized, feedback from HAs was presented to the steering committee to determine whether changes requested by HAs met the needs and barriers-to-uptake expressed during partner consultations. In addition, a group of seven patients were involved in the development of the RISE UP phase 2/3 clinical trial awareness campaign, which sought to educate the community about the RISE UP clinical trial and value of pt participation. Results: Pt contributions to the protocol design included modified inclusion/exclusion criteria and the addition of pain (beyond pain crises) and fatigue as study outcomes. An overview of the community feedback is shown in Table 1. In response to pt input, monthly study visits were implemented for seven months, followed by visits every three months. An open label extension period was also added with visits on the second, fourth, eighth, and twelfth weeks of the extension period, followed by every 3 months up to 1.5 years and every six months thereafter. Taking additional pt input into account, the trial was adjusted to include a recommendation for tailored management of SCD pain crises using a daily diary. Additionally, following patient recommendations, the trial approved reimbursement for study-related travel, lodging, and specific non-study assessments. The RISE UP communications campaign was effective, with heightened interest in clinical trial participation generated within the community. Strong social media engagement and digital efforts resulted in increased trial website views, and community education and awareness efforts resulted in increased clinicaltrials.gov views to an average of 2-3 clicks per day. Approximately 278,000 users visited the RISE UP website and the campaign's YouTube video, which launched on World Sickle Cell Day has attracted 3 million views since Q4 2022. Conclusion: To meet the needs of the SCD pt and caregiver community and advance clinical trial research, we implemented a patient-centered approach to clinical trial protocol design and trial recruitment. Overall, this patient-centric approach could be useful in improving community engagement, designing trials that better reflect the needs and concerns of the pt population, and ultimately improving pt participation and diverse representation in clinical trials.

Knowing the Dose to Control the Dose: Optimizing Patient-Controlled Analgesia in Adults with Sickle Cell Disease (SCD)

Introduction: Acute painful episodes are the most common cause of hospitalization in SCD. Intravenous (IV) opioids are the analgesic of choice to treat pain requiring hospitalization in adults. On-demand IV opioid dosing can be either via a patient-controlled analgesia (PCA) pump or via intermittent nurse bolus. Advantages of PCA include better analgesia accessibility and relative independence from staff. However, significant variability exists in PCA management. A multicenter, randomized-controlled trial of PCA strategies in SCD was terminated early due to slow accrual, stemming from barriers such as suboptimal communication between inpatient teams. Additional limitations with PCA include technological limitations and incomplete charting through a manual process. We initiated a quality improvement project to understand patterns of PCA use in patients hospitalized for SCD pain crises at our institution. Methods: We performed a retrospective manual chart review on all adult patients diagnosed with SCD pain crises admitted to the University of Cincinnati Medical Center (UCMC) from October 1 through December 31, 2022. Inpatient data collected included reason for admission, length of stay, and documentation of inpatient opioid usage in daily clinical notes. Hospitalizations requiring intensive care admission for severe complications were excluded. Outpatient data collected included demographics and outpatient opioid prescriptions via the state prescription drug monitoring database. The study was approved by the UCMC IRB. Results: Fifteen patients were admitted to UCMC a total of 24 times for SCD pain crises during the 3-month period. The patients ranged in age from 21 years to 73 years (median age 33 years, interquartile range (IQR) 19.5 years) and the majority (11/15) were women. Disease-modifying therapies prescribed included hydroxyurea (8/15, 53%), chronic transfusions (2/15, 13%), chronic transfusions plus hydroxyurea (1/15), voxelotor (1/15), no disease-modifying therapy (2/15). Nine patients were prescribed daily outpatient opioids that included an oral long-acting opioid plus an oral short-acting opioid. Out of the 24 hospitalizations, 11 were for an uncomplicated pain crisis, 10 were complicated by mild acute chest syndrome (mild hypoxia and/or abnormal chest imaging), and 3 patients experienced other treatable complications (2 with Staphylococcus epidermidis bacteremia, 1 with deep venous thrombosis). Five patients were admitted two or more times. Two patients, admitted a total of 5 times, were maintained on nurse-administered IV bolus opioids during their admissions, in addition to oral opioids. The remainder of the patients were treated with a hydromorphone PCA pump with on-demand bolus dosing only, in addition to home long-acting oral opioids when applicable. Two patients were ultimately transitioned from PCA onto nurse-administered bolus IV opioids, due to failure to achieve adequate analgesia with PCA. In 9 out of the 19 admissions using a PCA, daily MME or the equivalent was charted in at least one progress note (47%). The median LOS in the subgroup in which PCA use was charted at least once was 7 (IQR 3.5) days. In the 10 admissions on a PCA in which daily MME was never charted (53%), the median LOS was 11 (IQR 6.25) days. Among patients not receiving outpatient opioids, daily MMEs from the PCA in the first few days of hospitalization (when recorded) ranged from 24 to 520 (median 178, IQR 241) MME. In patients who had daily chronic pain on outpatient opioid therapy, daily inpatient MME from PCA ranged from 360 to 1020 (median 545, IQR 418) MME. In patients with multiple admissions during the study period, the recorded daily opioid use was about two times that in the single admission group (median 673, IQR 500 MME in the multiple admissions group; vs median 329, IQR 351 MME in the single admission group). Conclusions: Our data suggest that length of stay is shortened by ~4 days when clinicians quantify daily opioid use for patients on PCA. In addition, patients with frequent admissions tend to have higher inpatient daily opioid use. This hints that readmission may be partly driven by mild withdrawal when on outpatient opioids at lower MME. A major barrier to data collection was inconsistent documentation of daily opioid use. The next step in our quality improvement project is an educational curriculum on inpatient opioid management for residents and hospitalists.

Dual P-Selectin and Complement Inhibition with Subcutaneous IHP-102 Treatment Potently Reduces Lung Vaso-Occlusion in Sickle Cell Disease Mice

One of the most debilitating manifestations of sickle cell disease (SCD) are the excruciatingly painful vaso-occlusive episodes (VOEs), commonly referred to as “pain crises.” Vaso-occlusion, which underlies the pathomechanism of VOE, also causes downstream tissue and organ damage resulting in complications that plummet life-expectancy by more than 20 years. Current treatment options for VOE are limited and all require chronic administration, often with intolerable side-effects, and none fully prevent VOE. An acute VOE rescue therapy that could be administered in the home-setting would transform care for the more than 100,000 people in the U.S. and over 7 million worldwide who suffer from this inherited condition. IHP-102 is a novel glycan-based drug with dual anti-P-selectin and anti-complement activity. It is bioavailable by subcutaneous route of administration and could therefore be self-administered at the earliest sign of VOE. Early intervention in VOE is critical, before ischemia and tissue damage becomes irreversible. This treatment paradigm would also circumvent the wholly inadequate treatment experience that the SCD community has widely described, being treated as an opioid “drug-seeker” when engaging the healthcare system during a debilitating VOE. There are multiple pathomechanisms of VOE. P-selectin is a clinically validated therapeutic target for partially attenuating VOE, while complement has more recently been identified as an important driver of VOE, in part due to hemolysis and ischemia. While several therapeutics targeting P-selectin or complement are currently in clinical development, no therapy targets both pathomechanisms. We have previously shown that IHP-102 inhibits P-selectin mediated cell adhesion in vitro (IC50 = 0.7 µg/mL) and that intravenous administration of IHP-102 reduces lung vaso-occlusion by 75% in Townes SCD mice challenged with oxy-hemoglobin (oxy-Hb). Here, we extend these studies with subcutaneous delivery of IHP-102, achieving greater than 75% reduction in lung vaso-occlusion. This magnitude of effect is greater than that achieved in P-selectin deficient Townes SCD mice (~50% reduction), thus indicating additional activity of IHP-102 beyond P-selectin inhibition. In studies using human serum, IHP-102 inhibits complement by upstream mechanisms, including through inhibition of Factor B. Factor B is responsible for alternative pathway amplification of complement. Its fragment Bb has been found in elevated concentrations during VOE in patient serum, suggesting it plays an important role in the pathomechanism of VOE. By inhibiting Factor B, IHP-102 reduces downstream complement fragments of C3 and C5, which are widely recognized complement targets given their critical role in the complement system and promoting inflammation. The dual anti-complement and anti-P-selectin activity of IHP-102, together with its potential for home-based treatment, offers great potential to fill a major treatment gap for acute VOE. Its potent in vivo activity suggests that this dual target approach could provide robust therapeutic benefit and warrants further investigation toward clinical trials.

Exploring the Experiences of Pediatric Patients with Sickle Cell Disease and Their Families

Background: Sickle Cell Disease (SCD) is a common lifelong genetic disorder of red blood cells, which causes abnormal hemoglobin shape often resulting in pain crises and other serious health complications (Ware, et al., 2017). SCD disproportionally affects people of African descent, and several recent surveys have shown that patients with SCD experience discrimination in healthcare settings (Nelson and Hackman, 2013; Haywood, et al., 2014; Kanter, 2020; Oyedeji and Strouse, 2020). In pediatrics, parents of patients with SCD report higher levels of race-related discrimination in healthcare settings compared to families with other chronic illnesses, as well as decreased satisfaction in several areas of their care (Brousseau, 2009; Oyedeji, 2020; Kanter, et al., 2020). This qualitative project aimed to explore further specific, actionable areas of dissatisfaction and any areas of increased satisfaction among pediatric patients with SCD and their families. Methods: Semi-structured interviews were conducted with pediatric patients with SCD and/or their guardians at one academic institution. Any patient with SCD over the age of eight was eligible to participate in an interview, and parents of a child with SCD of any age were eligible to participate, as well. Interviews were audio-recorded and took place in person in clinic. Recordings were then transcribed verbatim. The interviews were qualitatively coded using standard multi-level semantic analysis, working directly from the transcriptions and audio-recordings. Seven (41%) interviews were independently double-coded, and discrepancies were resolved by consensus. Final codes were analyzed, and major themes were identified. Results: Eighteen pediatric patients with SCD and/or their families were asked to participate in the study, and seventeen (94%) agreed. There were twenty-six total participants. Ten family interviews were conducted, and another seven were conducted with parents only because the patients were younger than eight years old. Fifteen families identified as African American, one family identified as Hispanic, and one family identified as African. Patients and their families described five main areas leading to dissatisfaction in the healthcare setting: (1) Long wait times; (2) Neglect for SCD protocols within emergency departments; (3) Biases against patients with sickle cell disease; (4) Frustration with procedures, specifically with blood draws; (5) Lack of empathy and compassionate listening among healthcare providers. Positive experiences were almost all due to aspects of strong patient-provider relationships. Outside of the healthcare setting, patients and their families emphasized the need for improved education and awareness of SCD within the community. Conclusion: While this qualitative study explored perspectives from only a limited number of pediatric families, these conversations provided insight into specific areas of dissatisfaction among patients with SCD. This research provides actionable items that healthcare providers can apply to help improve the healthcare experiences and the everyday lives of children with SCD. Additional efforts and resources should be directed toward addressing social determinants of health and systemic racism to future improve healthcare experiences of patients with SCD.

Clinical Results of a Randomized Placebo Controlled Trial of Inhaled Mometasone to Promote Reduction in Vaso-Occlusive Events (IMPROVE-II)

Introduction: A subset of patients living with sickle cell disease (SCD) who do not meet diagnostic criteria for asthma exhibit episodic cough or wheeze (ECW), and this is associated with higher rates of vaso-occlusive pain crisis and acute chest syndrome. ECW may be caused by pulmonary inflammation from SCD. In the former IMPROVE trial, 54 patients with SCD and ECW were randomized to receive 16 weeks of placebo or mometasone furoate, an inhaled corticosteroid used to treat pulmonary inflammation. Treatment with mometasone was associated with significant reductions in daily pain, markers of hemolysis, and soluble vascular cell adhesion molecule (sVCAM) (a biomarker of disease severity in SCD) compared to placebo. The IMPROVE-II trial evaluated whether treatment with mometasone over a longer period could improve clinical and biological endpoints in non-asthmatic patients with SCD and ECW. We report here the clinical outcomes from the IMPROVE-II trial. Methods: We conducted a randomized, placebo-controlled, single-center interventional trial. Patients with SCD without asthma were randomized to receive either mometasone furoate 220 mcg or placebo inhaled powder for 48 weeks followed by a 4-week wash out. Key inclusion criteria included age > 18 years with SCD genotype HbSS/HbSβ0 at stable baseline who endorsed ECW. Patients were excluded if they had >15 emergency department (ED) visits for vaso-occlusive pain crisis in the past 12 months or if other treatments for SCD (i.e. hydroxyurea, L-glutamine) were being titrated. The primary outcome was the change in soluble vascular cell adhesion molecule (sVCAM) level with treatment. Clinical outcomes included ED visits and hospitalizations for any reason, and health care visits for acute chest syndrome, pneumonia, stroke, or transient ischemic attack, as well as daily pain (self-report 1-10 scale), and 6 Minute Walk. Adaptive covariate randomization was used to balance covariates including hydroxyurea use (yes/no), age, and previous rate of ED use. Results: A total of 80 patients were randomized and 77 received study treatment; 40 were assigned to mometasone and 37 to placebo (Figure 1). There were no significant differences between treatment groups in patient demographics (Table 1). Treatment with mometasone was associated with higher rates of acute care visits for vaso-occlusive crisis (4 (2/19) vs 1 (1/3) /patient year (50%(25%/75%), p<0.001), hospitalization for acute chest syndrome (mean 0.2 vs 0.1/patient year, p=0.05) and ED utilization (2 (1/5) vs 2 (1/4) /patient year (50%(25%/75%), p0.01). Laboratory outcomes including sVCAM are not yet resulted. Adverse events that were reported by more than 5% of patients are listed in Table 1; there was no difference between rates of adverse (<5%) events between mometasone and placebo. There were no deaths during the study. Conclusions: In individuals with SCD and ECW who do not have asthma, long-term treatment with inhaled corticosteroids did not improve clinical outcomes and may be harmful as they were associated with higher rates of acute care visits for pain crisis, ED visits, and acute chest syndrome. Further analyses of biological endpoints and clinical laboratory data are needed to fully elucidate the effects of inhaled corticosteroids in SCD.

The Effect of Tucaresol on Translational MRI Estimates of Cerebral Physiology in Townes SCD Mice

Sickle Cell Disease (SCD) is characterized by severe hemolytic anemia and low Hct. This contributes to elevated cerebral cerebrometabolic strain, as evidenced by increased cerebral blood flow (CBF), increased blood oxygen extraction fraction (OEF), and increased incidence of silent cerebral infarct. Recent reports have shown that approved and experimental therapies ameliorate these physiological indicators of strain in SCD patients using advanced MRI-based techniques (Fields, et al., Blood, 2019; Hulbert, et al., Blood 2022), but the effect on these same MRI endpoints has not been demonstrated in animal models of SCD. The purpose of this work was to perform these same measurements in Townes SCD mice treated with tucaresol, which is known to increase the oxygen affinity hemoglobin, thus building a translational platform for non-invasive assessment of these endpoints to support characterization of novel therapies and their relationship to cerebrometabolic strain that leads to end organ damage in the brain. All animal procedures were performed under an IACUC-approved protocol. Forty-three male Townes SCD mice were assigned to two treatment groups (n=21 / 22, mean age = 8.1±0.8 / 8.4 ±0.6 weeks, mean weight = 26±2 / 26±2 g). Animals were anesthetized and scanned on a 9.4 T Bruker MRI scanner at MGH. CBF was measured using a pseudo-continuous arterial spin labeling sequence (pCASL) (Hirschler, et al., NMR in Biomedicine, 2018), and OEF was estimated from a T2 measurement in the superior sagittal sinus using a TRUST sequence (Wei, et al., Magn. Reson. Med., 2018) and a hematocrit measure which was taken from a tail vein bleed immediately following the scan. Following anesthesia recovery from the first imaging timepoint, animals were placed in cages according to group assignment and drinking water was replaced by one of two masked dosing solutions. prepared off-site by an independent team, containing either 1.14 mM tucaresol or pH and color-matched water. The tucaresol concentration was chosen to approximate an oral dose of 60 mg/kg/day comparable to a clinical dose and be consistent with previous studies. After two weeks of ad lib exposure to the dosing solutions, the scanning and blood sampling procedure was repeated. A terminal cardiac punch was also performed under anesthesia to assess tucaresol blood exposure. Due to technical challenges Hct measures were not performed in the first five animals from each group, and two animals had Hct measures at only the second timepoint. CBF is reported in whole bilateral striatum. Whole blood analysis revealed tucaresol exposures of 0.1-0.6 mM in the active arm. While still within the range for hemoglobin modification, the exposures were similar but somewhat lower than the exposures of 0.5-1.6 mM reported from oral gavage at 30 mg/kg twice per day in SCD mice (Knee et al. Blood, 2016). Table 1 shows CBF, Hct, and OEF values at baseline and after two weeks of dosing for each group. OEF values assume arterial oxygen saturation of 1. Spaghetti plots in figure 1 display changes in these values for individual animals. CBF elevations are observed very early in clinical SCD populations and begin to plateau as the disease progresses, but OEF has been shown to increase as the disease progresses (Juttukunda, et al., J. Magn. Reson. Imaging, 2019). As a result, therapeutic interventions in advanced disease may be expected to first affect OEF, with decreases in CBF to follow. That may, in part explain why a treatment effect was observed with OEF and not with CBF. Additionally, the proximity of the labeling plane of inflowing arterial blood to the brain tissue being perfused and the high carotid artery flow rate in these animals means that the CBF measure by pCASL MRI is considerably more challenging in mice than in humans. The sensitivity of MRI-derived OEF to therapeutic intervention in mice is similar to what has been reported in SCD patients, where elevated OEF is particularly associated with regions of the brain at highest risk for developing silent infarct. CBF and OEF are currently being evaluating for an approved HbS modifier (NCT05228821). The ability to use the same techniques in both mice and humans to non-invasively and quantitatively demonstrate the amelioration of the cerebrophysiological compensatory measures that precede end CNS organ damage is a valuable step in characterizing potential benefit of novel therapeutics beyond standard regulatory endpoints associated with pain crises.

Perspectives of Adolescents and Young Adults with Sickle Cell Disease and Clinicians on Improving Transition Readiness and a Videogame Intervention

Background Adolescents and young adults with sickle cell disease (AYA-SCD) have higher rates of mortality and the highest rates of healthcare utilization compared with older and younger SCD patients. The transition period between pediatric and adult care for AYA-SCD is well recognized as a critical window because it represents the intersection of normal adolescent development, change in healthcare access and increased clinical manifestations of disease. Interventions that support AYA-SCD during this time are crucial to improving outcomes. Hallmarks of transition readiness amongst AYA-SCD include self-efficacy (i.e., patients' ability to manage their disease), active participation in shared decision-making (SDM), and adequate disease specific knowledge. Although videogames have been shown to positively affect adolescents' behavior and health outcomes, there has been no study evaluating this technology for improving transition readiness in AYA-SCD. Our objective was to learn AYA-SCD patients' and clinicians' experiences with AYA-SCD managing their disease at home and making medical decisions as they transition from pediatric to adult care, including whether a videogame intervention can positively impact these skills. Methods We conducted individual, semi-structured interviews with purposively sampled patients (AYA-SCD ages 15 to 26 with any genotype of SCD) and clinicians who provide care or support to AYA-SCD (pediatric and adult hematology providers, pediatric and general emergency medicine physicians and nurses, child life specialists) at an urban, quaternary care hospital. Interviews elicited patients' and clinicians' experiences with AYA-SCD in the clinic, emergency department, and/or hospital, including the transition from pediatric to adult care, barriers and facilitators to successful home management, and their perspectives on SDM and a videogame intervention. To identify themes related to patients' and clinicians' experiences with AYA-SCD managing their disease at home and making medical decisions, we conducted an inductive analysis following the principles of grounded theory until data saturation was reached for both groups. For patients' and clinicians' perspectives on a videogame intervention, we used a deductive analysis. Three investigators independently coded all transcripts to identify themes, with discrepancies resolved by consensus. Results We interviewed 16 patients and 21 clinicians. Participants identified two main themes: 1) self-efficacy to manage their disease successfully as they transition from pediatric to adult care, and 2) the importance of patient engagement in making medical decisions (Table 1; representative quotations). Sub-themes were environmental, clinician, and patient factors that served as barriers and facilitators to achieving self-efficacy and patient engagement in decision-making. Facilitators including having social support, the importance of education about SCD and SDM before adolescence, clinicians having good communication, building trust, listening, and involving patients in medical decisions, and patient self-advocacy by voicing their needs and being empowered to actively participate in medical decisions. Barriers included lack of support and resources, adolescent behaviors/traits, co-dependency on a parent/caregiver, pediatric vs. adult culture, and stigma/implicit bias/provider judgement (Figure 1; conceptual model). Participants were supportive of a videogame intervention to improve self-efficacy and engagement in decision-making (Table 1), with the primary goal being education and insight into SCD, and the secondary goal being distraction during pain crises. Conclusions AYA-SCD patients and their clinicians identified self-efficacy in successful disease management and patient engagement in medical decision-making as two primary areas of importance in the transition from pediatric to adult care. Several barriers and facilitators to achieving self-efficacy and patient engagement are potential targets for interventions to improve these skills in AYA-SCD. Overall, patients and clinicians supported the concept of a videogame to support self-efficacy and patient engagement to improve transition readiness. Future studies will focus on the design, development, and implementation of a videogame intervention which centers the key themes identified in this study.

Outpatient Costs of Patients with Sickle Cell Disease with or without Hydroxyurea at an Institution in Rio De Janeiro, Brazil

Background Brazil is home to a growing population of patients with sickle cell disease (SCD) with an estimated 100,000 patients having some form of the disease. The use of hydroxyurea (HU) is known to decrease numerous complications, such as pain crises and acute chest syndrome, in SCD. In Brazil, this medication is provided by the Brazilian Ministry of Health through the National Health System. The overall cost of the drug, as well as the cost of patients with SCD visiting a large hematology clinic in Rio de Janeiro, HEMORIO, is not known. This study aimed to determine the landscape of patients visiting the hematology clinic and the cost of each visit as stratified by the use of hydroxyurea. Methodology A retrospective analysis of patients with SCD who were seen at the HEMORIO clinic between January 1, 2018, and June 30, 2018, was conducted. Patients were stratified by age, gender, genotype, and prescription use of HU. The total number of appointments attended, which included primary hematology, chronic transfusion, and other subspecialities, was computed. Absentee rates were determined and stratified as listed above. Cost per each type of appointment - outpatient clinic, transfusion visit, dressing change, and lab check - were then calculated. Finally, the cost of medications, which included HU, pain medications, and iron chelators, was calculated per patient. Data was collected from the Sash System (Hematology Service Attendance System) used in HEMORIO. The tool used for data extraction was Microsoft SQL Server 2014. Data were analyzed using the R software. All calculations converted to US dollars. Results A total of 3000 patients with SCD seen at the outpatient clinic were reviewed. 51.6% of patients were female and the mean (± standard deviation) age was 19.1 (± 14.8). 73% of patients had HbSS, 20% had HbSC, and 5% had HbS-beta thalassemia. 984 patients (32.8%) were prescribed HU. 7 patients (0.2%) died during the time of analysis. Out of 14795 appointments scheduled at the medical facility, the highest number of appointments were made in Hematology (6199, 42%) or Chronic Transfusion (2347, 14.2%). The next most common were Ophthalmology, Dentistry, or Physical Therapy (2098 combined, 14%). Patients with HbSS had the greatest number of appointments overall. 9177 (62%) were attended, making the absenteeism rate 38%. When stratified for genotype, age group, and HU use, the highest rates of absenteeism were in patients with HbSS or Sβ 0 (38%), in those aged 19-25 (45%), and in those not taking HU (41%). Patients with HbSS had a higher average outpatient visit cost of $45.88 (± $40.01) per person as compared to patients with all other genotypes ($33.10 ± $35.14 per person). The highest costs for all patients were associated with transfusion visits, with an average of $390.43 (± $299.02) per patient, followed by dressing changes at an average of $123.68 (± $109.90) per person across all genotypes. Compared to those patients not on HU, patients on HU had a statistically significant higher cost for all types of visits (p<.05), except for dressing changes (Table 1, Figure 1). Similarly, patients on HU had a higher average medication cost of $4438.08 (± $12195.34) per person compared to those not on HU at $778.14 (± $5649.32) per person. Discussion At a medical center in a middle-income country that specializes in treating SCD, patients with the HbSS/Sβ 0 genotypes had notably higher treatment costs compared to those with other genotypes. This is consistent with the fact that these patients often have a more severe form of the disease and require more outpatient visits, specialists, and transfusions. The most expensive aspect of treatment for all patients was transfusion appointments. These appointments are likely more costly because they require blood, supplies, and trained staff. Patients who received HU had higher average costs for each type of clinic visit. This is potentially because those receiving hydroxyurea have a more severe disease course, requiring more outpatient and subspecialty services. In future studies, we hope to demonstrate that these same patients have lower overall costs for inpatient and emergency visits, which would provide a net cost-saving with hydroxyurea treatment and benefit the hospital system. Given the detailed information on cost of each transfusion, medication, and intervention per patient, the Ministry of Health may be able to better allocate funds to the aid of patients with SCD in the future.

Remote Blood Hemoglobin Monitoring with Hyperspectral Color Truthing for Advancing Sickle Cell Care

Introduction: An urgent need exists for a noninvasive telemedicine approach to alleviate the burdensome reliance on frequent invasive blood draws for monitoring blood hemoglobin (Hgb) levels in sickle cell disease (SCD) patients. SCD is the most common genetic blood disorder, impacting over 20 million people worldwide, resulting in frequent emergency healthcare use. A blood Hgb level is pivotal in managing SCD and understanding the pathophysiology of SCD including anemia. Even low blood Hgb levels may indicate painful vaso-occlusion crises (Blood 2021;137:2010). Thus, a remote noninvasive monitoring ability of blood Hgb in at-home settings can potentially enhance SCD management without iatrogenic blood loss. Advanced machine learning and spectroscopic analyses can enable digital colorimetric diagnostics for noninvasive blood Hgb quantification with high fidelity, empowering SCD patients. However, one of the key challenges in diagnostic photography is that clinical photos exhibit significant variations in colors, depending on devices, light conditions, and image file formats, hampering reliable colorimetric diagnostics. Methods: We have developed colorimetric analyses of peripheral tissue perfusion to offer remote monitoring and cost-effective blood Hgb readings for SCD patients. A specially designed diagnostic color reference chart, which is highly sensitive to blood Hgb and peripheral perfusion, allowed us to noninvasively predict blood Hgb levels from digital photos of the palpebral conjunctiva (inner eyelid) across diverse smartphone models, light conditions, and file formats. Specifically, a pilot human study of fifteen SCD patients aged 14 to 73 years generated 156 photos from both left and right eyelids juxtaposed with the diagnostic color reference chart, using Samsung Galaxy S21 and Apple iPhone 12 Pro, taken immediately before or after blood draws. Combining a blood Hgb computation (Optica 2020;7:563), blood Hgb levels were computed involving three primary machine learning algorithms (Figure 1): color recovery of the palpebral conjunctiva, hyperspectral learning to reconstruct a spectrum, and spectroscopic blood Hgb quantification. Results: Using our specially designed color chart (Figure 2a), the linear correlation between the computed blood Hgb levels and venous blood Hgb levels shows a high correlation coefficient of 0.88 and 0.81 for Samsung Galaxy S21 and Apple iPhone 12 Pro, respectively. The Bland-Altman plot as a non-parametric statistical method reveal that the 95% limits of agreement (95% LOA) are [-2.68, 2.10 g dL -1] and [-2.74, 3.19 g dL -1] for the two smartphone models. Conversely, when using a conventional color chart for general photography (Macbeth ColorChecker) (Figure 2b), the computed blood Hgb levels exhibit a low accuracy for both Samsung Galaxy S21 (correlation coefficient of 0.69, 95% LOA = [-5.05, 2.60 g dL -1]) and Apple iPhone 12 Pro (correlation coefficient of 0.57, 95% LOA = [-5.14, 5.87 g dL -1]). Conclusion: This study supports the feasibility of noninvasive blood Hgb assessments as colorimetric diagnostics for SCD patients in telemedical settings. The results correlate significantly with conventional laboratory tests based on venous blood draws and are highly comparable to capillary blood sampling (finger prick) tests (Respiratory Care 2019;64:1343). This study lays the foundation for realizing color accuracy in biological tissue for digital diagnostic colorimetric applications of blood Hgb.The proposed color accuracy-based digital health technology can potentially offer accessible, affordable, and reliable blood Hgb readings via smartphones in at-home or telemedicine settings.

Initial Results in a Phase 1b Trial of PB-04 in Sickle Cell Disease Demonstrate Fetal Hemoglobin Induction, Additive Activity with Hydroxyurea, and Improved Red Blood Cell Sickling Parameters

Extensive evidence has shown fetal hemoglobin (HbF) is a major modulator of sickle cell disease (SCD) phenotype. Clinical benefit with any increment of HbF was shown in the NIH-sponsored Natural History Study and the Multicenter Study of Hydroxyurea (HU), with mean HbF increases of 3.6% above baseline (BL), to improve survival, reduce painful vaso-occlusive crises, and recently stroke prevention and improved cardiac and neurocognitive function with HU are reported. As some patients do not tolerate optimal HU doses due to cytopenias, additional inducers suitable for combined use are desirable. Proportions of F-cells and HbF-quantity/cell have been cited as important. PB-04, a repurposed drug with a well-known safety profile, is an oral fetal globin stimulant identified in high throughput screening, which suppresses 4 repressors of the HMG gene promoter, ( BCL-11A, LSD-1, HDAC-3, KLF-1). PB-04 induces fetal globin in nonhuman primates, transgenic mice, with additive effect when combined with HU in SCD erythroid progenitors, and was shown to reduce infarcts in multiple organs with preserved splenic function in transgenic sickle mice. An ongoing Phase 1b trial in beta thalassemia intermedia (BTI) ( NCT04432623) of 3 doses (1,3, or 5 mg/kg QD) given 3 (TIW) or 5 times/week (Wk) for 12 or 24 Wks in 18 courses in 10 subjects demonstrates a favorable safety profile, dose-proportional PK with 5 >3 mg/kg doses and 5 >3 doses/Wk, Median fold-increases from baseline (BL) in F-cells of 4.4x BL (range 2.3-7x), 2.8x F-reticulocytes (1.6-14.8x), and 6.5x (range 3-11x) increases in mean fluorescence intensity (MFI, representing amount of HbF/RBC). Mean increases in % HbF were 6.5%. Evaluation of PB-04 has now begun in 7 subjects with SCD, 19-51 yrs; 3 were receiving HU with HbF responses (12-22%). Adverse events, F-cells, F-reticulocytes, MFI (amount of HbF/RBC or HbF/reticulocyte) by FACS and ImageStream Analysis and % HbF are assessed Q 4 wks; flow adhesion of whole blood to VCAM-1 (FA-WB-VCAM) and sickling kinetics are assessed q 12 wks. In 4 subjects on 3 mg/kg QD TIW for 24 wks, changes observed from BL values included mean increases of 6% F-cells and 27% F-reticulocytes (2-fold) . In 3 ongoing subjects receiving 5 mg/kg QD TIW for 12 wks mean changes above BL are currently 13% F-cells, 15% F-reticulocytes; HbF/cell or HbF/reticulocyte have increased up to 10-fold. Mean % HbF has increased above HU effects in 2/3 pts on the second dose by 5-12.6% (mean 8.8%), producing 81-95% F-cells, and 35-38% HbF. Decline in FA-WB-VCAM) was observed ± HU and with both doses in 3 subjects. Correlation of HbF quantity/cell with RBC survival and sickling dynamics is being explored. These early results with not-yet-optimized doses of PB-04 suggest additive activity with HU, producing significant HbF and F-cell levels, and support further PK-optimized studies in patients with SCD.

Use of Race and Ethnicity in Sickle Cell Disease Research

Introduction Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by chronic hemolytic anemia, devastating ischemic pain crises and chronic organ damage, resulting in shortened lifespan. Ethnicity and race are often mentioned in SCD research. Possibly, since SCD is particularly prevalent amongst people who originate from sub-Saharan Africa. In research studies, ethno racial categories (ERCs) are frequently considered confounding variables. However, these ERCs are often large aggregate categories and include individuals with a diversity in phenotype, exposures and genetic make-up. Recent journal submission guidelines urge researchers, when applicable, to declare the relevance of the use of ERCs to the study as well as the modality through which an ERC is determined (e.g. self-identification, country of birth, visual identification by the observer). Providing such detailed information is important because true confounders with a specific feature might distort study results. However, when operationalizing ERCs in SCD research, there exists a risk of reification of already marginalized populations as both a social and a biological group. Therefore, contextualization is essential when deciding to use ERCs in SCD research. This study aims to provide an overview of how ethnicity and race are applied in SCD research. Methods We systematically searched the literature to explore the current practice of ERCs in SCD research across world regions. Embase and Medline were systematically searched in November 2022 for all published articles on SCD published from 2011 onwards. Studies were considered eligible when cases defined as individuals with SCD and controls individuals without SCD. A total of 1,105 articles in SCD research were included. Of these articles, 1,085 were domestic studies and 20 international studies. Statistical tests and models implemented in R included chi-square tests and univariate linear regression. Results In 27% (298/1,085) of all studies, ERC confounder adjustment occurred. This methodological practice was dependent on geographical region the research subjects were sourced from (p<0.05), as made visible in Figure 1. In 175/302 (57%) of studies with a North American study population ERC confounder adjustment took place, as well as in 45% [58/129]) of the studies reporting on a European study population. In contrast, in 6% (14/239) of sub-Saharan African study populations, ERC confounder adjustment was performed (Table 1). Of the twenty international studies, six operationalized ERCs as confounders. In five publications, the control group was sourced from the same country as the SCD cases. One study used a healthy Congolese reference population as a control cohort whilst the SCD patients were from France. ERC confounder adjustment also varied with the biomedical discipline in which the article was published. Compared to Hematological journals, articles published in journals with categories “Medicine, General & Internal medicine” (OR=0.30, 95% CI -1.76 - -0.67, p<0.0001), were less likely to adjust for ERCs as confounders whereas articles in Ophthalmological journals (OR= 3.36, 95% CI 0.27 - 2.23, p=0.01) were more likely to do so. Of the studies that used ERC confounder adjustment, 80% (239/298) did not explain why this was relevant. Furthermore, in 70% (209/298) of these ERC-adjusted studies, it was unclear through which modality ERCs were determined. In the papers that described modalities, 49% (44/89) used ERCs from pre-existing databases, 18%(16/89) used sibling/relative recruitment, 30% (27/89) used self-reporting ERCs and 2% (2/89) used multiple ways to classify ethnicity or race. Moreover, in 28% (83/298) of the ERC-adjusted studies, it was not clear which specific categories were used. Conclusion ERC confounder adjustment is a common occurrence in SCD case-control studies in the United States and Europe. Furthermore, contrary to current author guideline recommendations, reporting on ethnicity and race in SCD studies is frequently inconsistent and incomplete. This confuses the possible relevance of ERCs to the study and inadvertently reinforces reification of these constructs. Moving forward, we recommend the promotion of global guidelines around the use of ERCs in case-control studies to stimulate further research into uncovering specific relevant mechanisms that create differences in health outcomes.

Nocturnal Autonomic and Vasoconstriction Parameters By Wearable Wrist Photoplethysmography Predict Intensity of Imminent Pain in Subjects with Sickle Cell Disease

Introduction: Sudden and unpredictable onset of pain is one of the biggest contributors to the morbidity of sickle cell disease (SCD), thought to occur due to obstruction of microvascular blood flow by rigid sickle-shaped red blood cells. Autonomic mediated vasoconstriction in the peripheral vasculature, with resulting decrease in tissue perfusion, is likely a triggering mechanism for the onset of vaso-occlusive pain, while the autonomic nervous system is also implicated in the pathogenesis of chronic neuropathic pain. Our analysis of 212 polysomnograms in SCD subjects showed that greater magnitude of nocturnal vasoconstriction (Mvasoc) is predictive of increased frequency of hospitalizations for vaso-occlusive pain crises (VOC) in the subsequent years (Chalacheva et al., Am J Hematol, 2020). In order to further develop this finding into a biomarker of more imminent pain, we monitored nocturnal photoplethysmography (PPG) at home with a wearable wristband device to measure vasoconstriction activity and heart rate variability, along with a daily electronic pain survey. Methods: 10 subjects with SCD were consented and underwent autonomic monitoring with a wristband device (Biostrap Inc) that uses an optical sensor to measure continuous PPG during sleep, with the raw PPG waveforms available from a cloud-based server. A unique biomarker (Mvasoc) was used to quantify the magnitude of vasoconstriction from the raw PPG signal, considering the frequency, magnitude, and duration of autonomic mediated spontaneous vasoconstrictions each night. Heart rate variability was derived from the pulse-to-pulse interval (PPI) of the PPG signal. Spectral indices of the PPI represent parasympathetic activity (high frequency power; HFP) and sympatho-vagal balance (Low to high Ratio; LHR = low frequency power(LFP)/HFP). Subjects concurrently documented daily pain incidence using an electronic text-based REDCap survey, with pain intensity measured on a scale of 1-10 if experiencing pain. Daily stress levels were also recorded on a scale of 1-10. Multivariate regression analysis was performed. Results: The subjects had a mean age of 25 years (range 14- 40 years) with an average hemoglobin of 8.8 g/dl . A total of 68 usable nocturnal PPG recordings were made (3-16 nights per subject). Therewere 25 incidents of pain on the day following autonomic monitoring with Biostrap, with the pain intensity ranging from 3-8. Multivariate analysis of nocturnal autonomic and vasoconstriction parameters revealed that a lower HFP ( p =0.0002) and a higher Mvasoc ( p=0.02) both preceded a higher intensity of pain the following day (Table 1). These results are consistent with a greater parasympathetic withdrawal and a higher magnitude of peripheral vasoconstriction predicting higher intensity of imminent pain. Age, gender, hemoglobin, stress levels and LHR were not predictive of pain the following day. Conclusion: Augmented nocturnal vasoconstriction and parasympathetic withdrawal noted prior to high intensity of pain imply that dysautonomia, with attendant changes in peripheral perfusion, has a significant role in pathogenesis of pain in SCD. Furthermore, autonomic vasoreactivity parameters were not significantly altered on the night after pain onset suggesting that the dysautonomia precedes pain. These results support the possibility of employing indices of nocturnal autonomic vasoreactivity as a predictive biomarker for imminent pain in SCD and provides a potential window for therapeutic intervention. This pilot study demonstrates the successful use of a wearable device PPG to remotely monitor nocturnal autonomic vasoreactivity and the ability to objectively quantify peripheral vasoconstriction responses. These findings will need to be applied in a larger cohort of SCD subjects with longer term monitoring for further validation and development of autonomic vasoreactivity as a predictive tool for pain in SCD.

Emergency Admissions and the Prescribing of Buprenorphine, Methadone, and Psychotropic Medications in People with Sickle Cell Disease: An Analysis of National Insurance Claims

Background Although there have been efforts to address overdose risks and treatment gaps in general populations receiving opioids, there is has been little research examining potential drug-related poisoning risks in some of the highest-need and complex populations, including those with sickle cell disease (SCD). Chronic opioid medications are necessary and well-tolerated for the treatment of chronic pain, diffuse inflammation, chronic organ damage, and vaso-occlusive pain crises for people with SCD. Previous studies have found that patients with SCD are not more likely to develop addiction to opioids than the general population. However, amid the ongoing endemic of drug-related poisonings in the U.S., epidemiological data is scarce regarding the clinical characteristics of people who have SCD and physiologic opioid tolerance and dependence. There has been particularly limited work on the intersection of sociodemographic characteristics, substance use, and other mental health conditions in the SCD population. Concern has also been raised about the ongoing opioid epidemic contributing to increased stigma, and greater barriers to the management of acute and chronic pain in SCD. Studies have shown that preoccupation with opioid prescription monitoring hindered the ability of physicians to provide comprehensive SCD care. People with SCD often face more restrictive utilization management policies for opioids than peers with other forms of chronic pain (i.e., cancer-related pain). In order for us to develop better interventions for people with SCD, real-world data is urgently needed to describe the current treatment landscape and identify gaps in care for people with SCD and physiologic opioid dependence or tolerance. Using administrative claims data in the US, we aim to: 1) quantify the burden of hospitalization and emergency room admission for medication-related poisoning events, 2) describe the prevalence of opioid prescriptions, such as buprenorphine and methadone, in people with SCD and physiologic opioid dependence or misuse. Methods In this retrospective cohort study of people with physiologic opioid dependence or opioid use disorder (OUD), we analyzed ten years (1/2006-12/2016) of data from the Merative™ MarketScan® Commercial and Multi-State Medicaid Databases. The predictor variable was SCD (versus a comparator group of people with chronic pain) with diagnoses identified using ICD-9/10 codes. The outcome variables were 1) emergency admissions or hospitalization for non-fatal drug/medication-related poisoning events during enrollment, and 2) prescriptions for buprenorphine, methadone, and other opioids, identified via procedure codes and linked pharmacy records respectively. We used multivariable cox regression to estimate the relationship between SCD diagnosis and time until poisoning events. Multivariable poisson regression models were used to assess the relationship between SCD and buprenorphine, methadone, and other opioid prescriptions. Results Our overall cohort consisted of 25,448 people with ICD9-10 opioid dependence or misuse, including 313 with SCD and 25,135 with non-SCD chronic pain. In the SCD cohort, the median age was 30.8 years, and 82% were enrolled in Medicaid. Compared to the non-SCD chronic pain cohort, the SCD cohort had more hospitalizations or emergency admission for iatrogenic events (37.4% vs 9.8%, aHR=2.21[2.12-2.31]). With regards to medication receipt compared to peers with non-SCD chronic pain, the SCD cohort had a lower prevalence of buprenorphine prescriptions (8% vs 30.1%, aRR=0.20[0.18-0.21]) and a higher prevalence of methadone prescriptions for chronic pain (63.6% vs 6.8%, aRR=5.36[5.21-5.51]) and non-methadone/non-buprenorphine opioid prescriptions (80.5% vs 33.7%, aRR=2.20[2.15-2.25]). Conclusions We observed an elevated rate of emergency admission and/or hospitalization for drug/medication-related poisoning, as well as a significant burden of psychiatric comorbidity in a cohort of people with SCD and physiologic opioid dependence or OUD. The prescribing of potentially safer opioids, such as buprenorphine, was uncommon in the cohort. Further research is urgently needed to optimize opioid treatment strategies, combat stigma, and improve the comprehensive management of pain and co-occurring disorders in the SCD population.

Use of Apple Watch to Acquire Baseline Wearable Biometric Data for Patients with Sickle Cell Disease and Correlations to Symptoms Such As Pain and Fatigue

Background: Sickle cell disease (SCD) is an inherited blood disorder that impacts the structure of red blood cells. The most common complication of SCD are vaso-occlusive crises (VOCs), commonly called pain crisis. Frequency and intensity of VOCs can differ among individuals. The unpredictable nature of VOCs increases risk of further complications, limits daily activities, affects mental well-being, and decreases health related quality of life. The use of mHealth and wearables for those living with SCD allows the opportunity to better understand pain and general wellbeing through real time data and analysis. Objectives: We aimed to: 1) Establish a comprehensive baseline health profile for individuals with SCD; and 2) determine potential relationships between patient reported symptoms and biometric data. Methods: Following IRB approval, patients entering the SCD clinic or the SCD Day Hospital at Duke University were approached, consented, and provided with the Nanbar Health app. Participants were instructed to make entries at least once daily and wear an Apple Watch throughout the day for 6 months. If a participant did not have Apple devices, an iOS Apple smartphone and/or Apple Watch series SE were provided. Self-reported general symptoms were recorded in the Nanbar Health app on scales from 0 (none) to 10 (most severe). General wellbeing was rated on an emoji scale, converted to 1 (worst/'frowny face') to 5 (best/'smiley face'). The biometric data from wearable collected included heart rate, step count, heart rate variability (HRV), resting heart rate (RHR), respiratory rate, and O2 saturation. For participants that had their own Apple Watch, 3 months of retroactive data was acquired. Statistical and network analysis was performed to analyze the correlations between symptoms, biometric data, and the general wellbeing of the participant. Results: Over 3 months, 18 participants were enrolled in the study. Median age of participant was 25 (IQR 21-33), 10 females, all Black/African American, and most either HgbSS (72%) or HgbSC (16%). Participants logged symptoms in the app 597 times over 93 days with a median of 0.33 entries/day/patient (IQR 0.22-0.44). The average pain score participants reported was 5.9 (SD 2.4, n=220). The three most reported symptoms, besides pain, were tiredness (22.1%), headache (5.2%), and priapism (5%). The patient-reported general feeling average was 3.3 (n=597, SD 1.6). Heart rate (n=74646), HRV (n=1277), and step count (n=1566) were the most recorded biometrics from the wearables. The average heart rate, HRV, and step count were 105.1 bpm (SD 26.8), 31.9 ms (SD 13.3), and 4100 steps/day (SD 5960), respectively. Significant expected correlations include between pain and priapism (r=0.85, p<0.01), aching and pain (r=0.78, p<0.01), and feeling bad and aching (r= -0.74, p<0.01). We also found feeling well correlated positively to back pain and tired correlated negatively with aching (see Table 1). Using network analysis of biometrics, RHR and HRV had a higher expected influence on patient feeling compared to the other biometrics collected. Conclusion: Baseline biometric characteristics for patients were similar to other diseases with chronic pain and as expected, pain is the most common symptom reported. Our data reflected lower HRV compared to healthy individuals and consistent with other disorders characterized by chronic pain. However, compared to other chronic pain disorders, patients with SCD appeared to have lower HRV values. There was no strong correlation (>0.7) between biometrics obtained by the watch and SCD patient-reported pain scores. Our study found a strong significant correlation between priapism and feeling cold. The strongest correlation was between feeling tired and feeling cold, however, tired/fatigue was also significantly correlated with priapism and feeling cold, although negatively correlated with aching. Limitations to conducting comprehensive analyses and making direct comparisons with other conditions include discrepancies in biometrics due to high variability and participant adherence. These limitations underscore the need to enroll more patients and improve patient adherence to improve the reliability of biometric data in future studies. Future efforts will compare the use of other mHealth devices besides the Apple Watch and expand to patients outside our institution.

Perception of Nutrition in Adults with Sickle Cell Disease: Concept Elicitation of Nutritional Status and the Mini Nutrition Assessment

Introduction Sickle Cell Disease (SCD) is a genetic disorder that causes recurrent vaso-occlusive pain events, functional impairment, and nutritional deficiencies due to increased metabolic demands. Prior studies have highlighted nutritional issues in people with SCD, such as micronutrient and macronutrient deficiencies, low body mass index (BMI), and a recent rise in obese adults with SCD. In older adults in the general population, evaluation and management of nutritional status is essential since malnutrition can weaken the immune system and increase the risk of hospitalization and death. Despite the importance of nutrition, little is known about the best way to evaluate nutritional status in older adults with SCD. To identify a relevant yet efficient method to evaluate nutritional status, we conducted content elicitation interviews to describe how younger and older adults conceptualized nutrition. Based on the content of the interviews, we piloted a brief nutritional survey called the Mini Nutritional Assessment (MNA); a common nutritional measure in geriatric assessments. Methods As standard practice for concept elicitation, we conducted semi-structured interviews with adults SCD in 4 separate focus groups: two groups of young adults age 18-39 and two groups of older adults age ≥ 40 years. Participants were asked about their perception of the construct of nutrition as part of a longer concept elicitation interview assessing the content validity of the Sickle Cell Disease Functional Assessment (SCD-FA), which is the geriatric assessment for adults with SCD. After focus group transcripts were analyzed using rapid qualitative analysis, we administered the MNA to a separate cohort of adults with SCD, since its content on macronutrients and hydration was consistent with how adults with SCD conceptualized nutrition. The scores on the 6-item MNA-Short Form (MNA-SF) range from 0 to 14 with higher scores indicating better nutritional status. Scores 12-14 indicate a normal nutritional status, 8-11 indicate at risk for malnutrition, and 0-7 indicate a malnourished state. Results The 4 focus group interviews included 6 younger adults (age 18-39) and 8 older adults (age ≥ 40 years) with SCD. Participants were 57% females and 79% had severe SCD genotype (HbSS or HbSβnull-thalassemia). In the focus groups, participants described a healthy diet as one that included the major food groups, which were generally defined as protein, fruits and vegetables, and starches/carbs. The majority discussed the importance of adequate hydration to reduce the risk of pain crises. Additionally, participants reported trying to substitute water for soda, juice, and caffeine containing beverages. Many participants stated that a healthy diet involved limited processed foods and sugars. Despite knowledge of the characteristics of a “healthy” diet, some participants expressed difficulty maintaining this diet. Based on these qualitative results, we selected the MNA to evaluate nutrition since it included items on hydration and assessed intake of various food groups as described by focus group participants. We administered the MNA-SF to a cohort of 88 adults with SCD and 81 had complete data to score the MNA-SF. The mean score for the MNA-SF for all participants was 11.7 ± 1.8 (younger adults 11.6 ± 1.9 and older adults 11.9 ± 1.8; p= 0.44). The MNA-SF identified 40% (n=34) as being at risk of malnutrition [36% of older adults and 46% younger adults]. Two participants were identified as being malnourished (1 younger and 1 older adult). On remaining MNA items (Table 1), 25% of participants reported decreased food intake with 17% having only 1 meal/day. Most participants (85%) consumed ≥ 1 serving of protein/day and 75% had ≥ 2 servings of fruits or vegetables/day. Most participants (68%) drank > 5 cups of water/day. Results were similar for younger and older adults with SCD. Conclusion Data from the focus group interviews revealed that BMI and unintentional weight loss measures alone did not comprehensively capture how people with SCD perceived the concept of nutrition. Incorporating the MNA-SF enhanced measurement of the nutritional domain in the SCD-FA by capturing data on food intake and hydration. In future studies we will assess the construct validity of the full MNA in a larger sample to identify older adults with SCD who would benefit most from nutritional interventions.

Patients, Parents and Providers Perspectives Toward Treatment Options for Sickle Cell Disease

Introduction Sickle cell disease (SCD) is the most common hemoglobinopathies in the world. It is more prevalent in malaria endemic areas where most low-and-middle-income countries (LMIC) are found. Because of challenges in accessing care, persons with SCD (PWSCD) in these settings have a poor outcome and up to 50% die before the age of five years in some places. Those who survive early childhood develop complications at a young age causing their families significant emotional and socioeconomic distress. Effort in LMIC is being directed toward screening for SCD and early initiation of treatment which has improved overall survival and quality of life of PWSCD. However, there are concerns about adherence to treatment due to pill fatigue, persistent SCD symptoms, end organ damage despite available treatment, and side effects of medications. With improved care, SCD is evolving into a chronic illness even in LMIC and PWSCD are surviving into adulthood. These countries will soon face the challenge of handling lifestyle and health demands of an emerging adult and aging PWSCD. There have been significant advances in disease modifying (DM) and curative treatment for SCD in high-income-countries (HIC) and the two promising treatment modalities for cure are bone marrow transplant and gene therapy which can be life changing for PWSCD and their families despite treatment related adverse events. Curing SCD may help prevent long-term complications. It is therefore important to explore the perspectives of PWSCD, their parents and SCD providers toward traditional and novel therapies for SCD as the initial step in planning for improved access to SCD treatment in LMIC. Objective To explore the attitudes of PWSCD, Parents (caregivers) of PWSCD and SCD care providers toward traditional and novel therapies for SCD in a LMIC setting. Methodology This was a mixed methods study conducted at a referral facility for PWSCD in western Kenya. It included 5 focused group discussions (FGD) of 6 - 7 consented participants; 2 with patients, 2 with parents and 2 with SCD providers. FGDs were conducted by trained clinicians and lasted 2 hours. A discussion guide which included information on novel therapies was applied to direct the audio-recorded sessions conducted in local dialect. FGD and analysis were iterative with each thematic content analyzed independent of the others and key concepts arising from these sessions explored. Necessary adjustments were made to the discussion guide for subsequent sessions based on emerging themes. The recorded material was then transcribed in verbatim and translated for analysis using a qualitative analysis tool. Results and Discussion This study enrolled 13 PWSCD, 13 parents of PWSCD and 6 SCD providers (n=32). Participants had similar attitudes towards SCD barriers and novel treatments. 96.9% of participants reported using hydroxyurea and folic acid for themselves, their loved one, or their PWSCD. Over the past year, 83.1% of PWSCD reported painful crisis while 33.% had been hospitalized despite adherence to treatment (table 1). Most participants (65.4%) would consider using novel SCD treatments with hesitations being cost, treatment adverse effect, and distance to treatment location. After the educational intervention, participants were more likely to opt for gene therapy (65.4%) than stem cell transplant (19.2%) or remaining on their current regimen (15.6%) (Table 2). Only one SCD providers' FGD was conducted due to their limited availability from competing clinical duties. Some patients who reported being on recommended treatment continued to have health events and complications that made them, their parents or providers want an alternative treatment. Most participants preferred a curative treatment option for their disease despite the challenges mentioned, which highlighted their willingness to participate in clinical trials. While there are infrastructural challenges in LMIC, they have the highest number of PWSCD that would benefit from new DM and curative treatment for SCD despite being underrepresented in clinical trials. They are the most impacted by complications associated with SCD due to sub-optimal care thus need for action to reverse this. Conclusion This study highlights the importance of involving population in LMIC in efforts to find better treatment for PWSCD. There is a need to conduct a similar study involving a larger cohort in future to further explore more perspectives.