Pain screening in youth with sickle cell disease: A quality improvement study.

BACKGROUND: Youth with sickle cell disease (SCD) face several challenges as they age, including increased pain frequency, duration, and interference. The purpose of this study was to (i) determine the feasibility of routine pain screening; (ii) identify and describe various clinical pain presentations; and (iii) understand preferences/resources related to engaging in integrative health and medicine (IHM) modalities within an outpatient pediatric SCD clinic. METHODS: During routine outpatient visits, patients aged 8-18 completed measures of pain frequency, duration, and chronic pain risk (Pediatric Pain Screening Tool [PPST]). Participants screening positive for (i) persistent or chronic pain or (ii) medium or high risk for persistent symptoms and disability on the PPST were asked to complete measures of pain interference, pain catastrophizing, and interest in/resources for engaging in IHM modalities. RESULTS: Between March 2022 and May 2023, 104/141 (73.8%) patients who attended at least one outpatient visit were screened. Of these 104 (mean age 12.46, 53.8% female, 63.5% HbSS), 34 (32.7%) reported persistent or chronic pain, and 48 (46.2%) reported medium or high risk for persistent symptoms and disability. Patients completing subsequent pain screening measures reported a mean pain interference T-score of 53.2 ± 8.8 and a mean pain catastrophizing total score of 24.3 ± 10.2. Patients expressed highest interest in music (55.6%) and art therapy (51.9%) and preferred in-person (81.5%) over virtual programming (22.2%). CONCLUSIONS: Comprehensive pain screening is feasible within pediatric SCD care. Classifying patients by PPST risk may provide a means of triaging patients to appropriate services to address pain-related psychosocial factors.

Biopsychosocial Factors Associated With Pain and Pain-Related Outcomes in Adults and Children With Sickle Cell Disease: A Multivariable Analysis of the GRNDaD Multicenter Registry.

Pain is the primary symptomatic manifestation of sickle cell disease (SCD), an inherited hemoglobinopathy. The characteristics that influence pain experiences and outcomes in SCD are not fully understood. The primary objective of this study was to use multivariable modeling to examine associations of biopsychosocial variables with a disease-specific measure of pain interference known as pain impact. We conducted a secondary analysis of data from the Global Research Network for Data and Discovery national SCD registry. A total of 657 children and adults with SCD were included in the analysis. This sample was 60% female with a median age of 34 (interquartile range 26-42 years) and a chronic pain prevalence of 64%. The model accounted for 58% of the variance in pain impact. Low social (P < .001) and emotional (P < .001) functioning, increasing age (P = .004), low income (P < .001), and high acute painful episodes (P = .007) were most strongly associated with high pain impact in our multivariable model. Additionally, multivariable modeling of pain severity and physical function in 2 comparable samples of registry participants revealed that increasing age and low social functioning were also strongly associated with higher pain severity and low physical functioning. Overall, the results suggest that social and emotional functioning are more strongly associated with pain impact in individuals with SCD than previously studied biological modifiers such as SCD genotype, hemoglobin, and percentage fetal hemoglobin. Future research using longitudinally collected data is needed to confirm these findings. PERSPECTIVE: This study reveals that psychosocial (ie, social and emotional functioning) and demographic (ie, age) variables may play an important role in predicting pain and pain-related outcomes in SCD. Our findings can inform future multicenter prospective longitudinal studies aimed at identifying modifiable psychosocial predictors of adverse pain outcomes in SCD.

Massage therapy for children, adolescents, and young adults: Clinical delivery and effectiveness in hematology and oncology.

BACKGROUND: Children, adolescents, and young adults with hematologic and/or oncologic conditions experience multiple, significant symptoms (e.g., pain, stress, and anxiety), which may be addressed by nonpharmacologic approaches such as massage therapy (MT). The purpose of this study was to describe the clinical delivery of MT provided by a certified pediatric massage therapist and assess effectiveness in two patient groups: those with sickle cell disease (SCD) or hematologic and/or oncologic conditions excluding SCD (HemOnc). METHODS: Investigators conducted a retrospective review of MT sessions provided to patients 0-39 years with hematologic and/or oncologic conditions at a large pediatric academic medical center. RESULTS: Between October 2019 and December 2021, 3015 MT sessions were provided to 243 patients (171 HemOnc; 72 SCD) and documented in the electronic health record. Patients (mean age: 12.21 ± 7.19 years) were generally White (49.4%) or Black/African American (43.2%), non-Hispanic (94.2%), and 52.3% female. Patients in the SCD group (vs. patients in the HemOnc group) reported significantly higher (p < .05) pretreatment pain (6.95 vs. 4.46), stress (6.47 vs. 4.58), and anxiety (6.67 vs. 4.59). All patients reported clinically and statistically significant (p < .001) mean reductions in pain (-2.25 ± 1.87), stress (-2.50 ± 1.73), and anxiety (-2.52 ± 1.69), with patients in the HemOnc group reporting greater mean pain change (-2.54 vs. -1.87) than patients in the SCD group. CONCLUSIONS: This study supports the clinical effectiveness of MT for addressing acute pain, stress, and anxiety among youth with hematologic and/or oncologic conditions. Future research is needed to identify optimal MT utilization.

Case report: Daratumumab treatment in pre-transplant alloimmunization and severe hemolytic anemia.

Daratumumab, a CD38 monoclonal antibody that has been FDA-approved to treat multiple myeloma, has acquired popularity and is used off-label for both auto- and alloantibody mediated disorders, particularly in refractory/resistant circumstances. Much of the published data for its use in pediatric blood disorders has been in post-transplant autoimmune cytopenias. Here we describe three patients in whom daratumumab was used outside of post-transplant autoimmune cytopenias, highlighting further potential uses of this medication.

Multispectral imaging for MicroChip electrophoresis enables point-of-care newborn hemoglobin variant screening.

Hemoglobin (Hb) disorders affect nearly 7% of the world's population. Globally, around 400,000 babies are born annually with sickle cell disease (SCD), primarily in sub-Saharan Africa where morbidity and mortality rates are high. Screening, early diagnosis, and monitoring are not widely accessible due to technical challenges and cost. We hypothesized that multispectral imaging will allow sensitive hemoglobin variant identification in existing affordable paper-based Hb electrophoresis. To test this hypothesis, we developed the first integrated point-of-care multispectral Hb variant test: Gazelle-Multispectral. Here, we evaluated the accuracy of Gazelle-Multispectral for Hb variant newborn screening in 265 newborns with known hemoglobin variants including hemoglobin A (Hb A), hemoglobin F (Hb F), hemoglobin S (Hb S) and hemoglobin C (Hb C). Gazelle-Multispectral detected levels of Hb A, Hb F, Hb S, and Hb C/E/A2, demonstrated high correlations with the results reported by laboratory gold standard high performance liquid chromatography (HPLC) at Pearson Correlation Coefficient = 0.97, 0.97, 0.93, and 0.95. Gazelle-Multispectral demonstrated accuracy of 96.8% in subjects of 0-3 days, and 96.9% in newborns. The ability to obtain accurate results on newborn samples suggest that Gazelle-Multispectral can be suitable for large-scale newborn screening and for diagnosis of SCD in low resource settings.

Antithrombin-III mitigates thrombin-mediated endothelial cell contraction and sickle red blood cell adhesion in microscale flow.

Individuals with sickle cell disease (SCD) have persistently elevated thrombin generation that results in a state of systemic hypercoagulability. Antithrombin-III (ATIII), an endogenous serine protease inhibitor, inhibits several enzymes in the coagulation cascade, including thrombin. Here, we utilize a biomimetic microfluidic device to model the morphology and adhesive properties of endothelial cells (ECs) activated by thrombin and examine the efficacy of ATIII in mitigating the adhesion of SCD patient-derived red blood cells (RBCs) and EC retraction. Microfluidic devices were fabricated, seeded with ECs, and incubated under physiological shear stress. Cells were then activated with thrombin with or without an ATIII pretreatment. Blood samples from subjects with normal haemoglobin (HbAA) and subjects with homozygous SCD (HbSS) were used to examine RBC adhesion to ECs. Endothelial cell surface adhesion molecule expression and confluency in response to thrombin and ATIII treatments were also evaluated. We found that ATIII pretreatment of ECs reduced HbSS RBC adhesion to thrombin-activated endothelium. Furthermore, ATIII mitigated cellular contraction and reduced surface expression of von Willebrand factor and vascular cell adhesion molecule-1 (VCAM-1) mediated by thrombin. Our findings suggest that, by attenuating thrombin-mediated EC damage and RBC adhesion to endothelium, ATIII may alleviate the thromboinflammatory manifestations of SCD.

PUM1 mediates the posttranscriptional regulation of human fetal hemoglobin.

The fetal-to-adult hemoglobin switching at about the time of birth involves a shift in expression from γ-globin to ß-globin in erythroid cells. Effective re-expression of fetal γ-globin can ameliorate sickle cell anemia and ß-thalassemia. Despite the physiological and clinical relevance of this switch, its posttranscriptional regulation is poorly understood. Here, we identify Pumilo 1 (PUM1), an RNA-binding protein with no previously reported functions in erythropoiesis, as a direct posttranscriptional regulator of ß-globin switching. PUM1, whose expression is regulated by the erythroid master transcription factor erythroid Krüppel-like factor (EKLF/KLF1), peaks during erythroid differentiation, binds γ-globin messenger RNA (mRNA), and reduces γ-globin (HBG1) mRNA stability and translational efficiency, which culminates in reduced γ-globin protein levels. Knockdown of PUM1 leads to a robust increase in fetal hemoglobin (∼22% HbF) without affecting ß-globin levels in human erythroid cells. Importantly, targeting PUM1 does not limit the progression of erythropoiesis, which provides a potentially safe and effective treatment strategy for sickle cell anemia and ß-thalassemia. In support of this idea, we report elevated levels of HbF in the absence of anemia in an individual with a novel heterozygous PUM1 mutation in the RNA-binding domain (p.(His1090Profs∗16); c.3267_3270delTCAC), which suggests that PUM1-mediated posttranscriptional regulation is a critical player during human hemoglobin switching.

Emerging point-of-care technologies for anemia detection.

Anemia, characterized by low blood hemoglobin level, affects about 25% of the world's population with the heaviest burden borne by women and children. Anemia leads to impaired cognitive development in children, as well as high morbidity and early mortality among sufferers. Anemia can be caused by nutritional deficiencies, oncologic treatments and diseases, and infections such as malaria, as well as inherited hemoglobin or red cell disorders. Effective treatments are available for anemia upon early detection and the treatment method is highly dependent on the cause of anemia. There is a need for point-of-care (POC) screening, early diagnosis, and monitoring of anemia, which is currently not widely accessible due to technical challenges and cost, especially in low- and middle-income countries where anemia is most prevalent. This review first introduces the evolution of anemia detection methods followed by their implementation in current commercially available POC anemia diagnostic devices. Then, emerging POC anemia detection technologies leveraging new methods are reviewed. Finally, we highlight the future trends of integrating anemia detection with the diagnosis of relevant underlying disorders to accurately identify specific root causes and to facilitate personalized treatment and care.

Prevalence of relative systemic hypertension in adults with sickle cell disease in Ghana.

Individuals with sickle cell disease particularly with the homozygous (SS) genotype historically have relatively low blood pressure. Nonetheless, they develop vasculopathy-associated organ dysfunction and the risk of organ dysfunction increases at blood pressures that are normal in the general population. This phenomenon is termed relative systemic hypertension (RSH) with a systolic blood pressure range of 120-139 mmHg, and diastolic blood pressure range of 70-89 mmHg. The significance of RSH lies in its association with renal insufficiency, pulmonary hypertension, stroke and propensity to progress to systemic hypertension. We conducted a retrospective chart review of 1,000 adults with sickle cell disease at the Ghana Institute of Clinical Genetics, to determine the prevalence of RSH in sickle cell disease in Ghana and associated complications. We found a high prevalence of RSH and hypertension with a relatively low frequency of renal insufficiency. Pulse pressure, a predictor of mortality, was higher in males of all ages. We anticipate that providing an estimate of the burden of RSH will heighten its recognition and clinical management among health care providers.

Organ damage in sickle cell disease study (ORDISS): protocol for a longitudinal cohort study based in Ghana.

INTRODUCTION: Sickle cell disease is highly prevalent in Africa with a significant public health burden. Nonetheless, morbidity and mortality in sickle cell disease that result from the progression of organ damage is not well understood. The Organ Damage in Sickle Cell Disease Study (ORDISS) is designed as a longitudinal cohort study to provide critical insight into cellular and molecular pathogenesis of chronic organ damage for the development of future innovative treatment. METHODS AND ANALYSIS: ORDISS aims to recruit children aged 0-15 years who attend the Kumasi Centre for Sickle Cell Disease based at the Komfo Anokye Teaching Hospital in Kumasi, Ghana. Consent is obtained to collect blood and urine samples from the children during specified clinic visits and hospitalisations for acute events, to identify candidate and genetic markers of specific organ dysfunction and end-organ damage, over a 3 year period. In addition, data concerning clinical history and complications associated with sickle cell disease are collected. Samples are stored in biorepositories and analysed at the Kumasi Centre for Collaborative Research in Tropical Medicine, Ghana and the Centre for Translational and International Haematology, University of Pittsburgh, USA. Appropriate statistical analyses will be performed on the data acquired. ETHICS AND DISSEMINATION: Research ethics approval was obtained at all participating sites. Results of the study will be submitted for publication in peer-reviewed journals, and the key findings presented at national and international conferences.

Assessment of Transition Readiness in Adolescents with Sickle Cell Disease and their Caretakers, A single institution experience.

AIM: Sickle Cell Disease (SCD) is associated with high child mortality and birth incidence in sub-Saharan Africa. Improved SCD medical services in Ghana aims to enhance survival into adulthood, creating emerging need for transition from pediatric to adult care. Anticipating transition for adolescents with SCD, we sought to understand patient and caretaker perspectives on transition to adult care within Ghana. MATERIALS AND METHODS: Structured interviews were conducted with a sample of patients ages 12-15 years and accompanying adults at Ghana's Komfo Anokye Teaching Hospital Sickle Cell Clinic (KATH SCC) covering four areas: SCD medical knowledge, symptom self-management, psychosocial impact, and transition preparation. RESULTS: In total, 46 children (mean age 13 years) paired with 46 adults were interviewed. Most children and caretakers had some knowledge about SCD and disease management. At least one-third lacked knowledge about SCD as an inherited condition. Youth were significantly more concerned about family burden and social stigmatization than adults. Most were unaware that patients are expected to switch care to adult medical providers by age 15 years, but were willing to transfer if needed. CONCLUSIONS: Our clinic-based assessment at KATH SCC identified needs of adolescents and caretakers for education and counseling about disease, self-management, transition, family burden, and stigmatization. These findings provide insights into perspectives and educational gaps of families treated for SCD. Results suggest consideration of transition planning for adolescents with SCD and their caretakers in Ghana. Generalizability of our findings and practical methods to address needs for transition within Africa remain to be tested.

Nonhematopoietic Nrf2 dominantly impedes adult progression of sickle cell anemia in mice.

The prevention of organ damage and early death in young adults is a major clinical concern in sickle cell disease (SCD). However, mechanisms that control adult progression of SCD during the transition from adolescence are poorly defined with no cognate prophylaxis. Here, we demonstrate in a longitudinal cohort of homozygous SCD (SS) mice a link between intravascular hemolysis, vascular inflammation, lung injury, and early death. Prophylactic Nrf2 activation in young SS mice stabilized intravascular hemolysis, reversed vascular inflammation, and attenuated lung edema in adulthood. Enhanced Nrf2 activation in endothelial cells in vitro concurred with the dramatic effect on vascular inflammation in the mice. BM chimeric SS mice lacking Nrf2 expression in nonhematopoietic tissues were created to dissect the role of nonerythroid Nrf2 in SCD progression. The SS chimeras developed severe intravascular hemolysis despite having erythroid Nrf2. In addition, they developed premature vascular inflammation and pulmonary edema and died younger than donor littermates with intact nonhematopoietic Nrf2. Our results reveal a dominant protective role for nonhematopoietic Nrf2 against tissue damage in both erythroid and nonerythroid tissues in SCD. Furthermore, we show that prophylactic augmentation of Nrf2-coordinated cytoprotection effectively impedes onset of the severe adult phenotype of SCD in mice.

Inflammatory targets of therapy in sickle cell disease.

Sickle cell disease (SCD) is a monogenic globin disorder characterized by the production of a structurally abnormal hemoglobin (Hb) variant Hb S, which causes severe hemolytic anemia, episodic painful vaso-occlusion, and ultimately end-organ damage. The primary disease pathophysiology is intracellular Hb S polymerization and consequent sickling of erythrocytes. It has become evident for more than several decades that a more complex disease process contributes to the myriad of clinical complications seen in patients with SCD with inflammation playing a central role. Drugs targeting specific inflammatory pathways therefore offer an attractive therapeutic strategy to ameliorate many of the clinical events in SCD. In addition, they are useful tools to dissect the molecular and cellular mechanisms that promote individual clinical events and for developing improved therapeutics to address more challenging clinical dilemmas such as refractoriness to opioids or hyperalgesia. Here, we discuss the prospect of targeting multiple inflammatory pathways implicated in the pathogenesis of SCD with a focus on new therapeutics, striving to link the actions of the anti-inflammatory agents to a defined pathobiology, and specific clinical manifestations of SCD. We also review the anti-inflammatory attributes and the cognate inflammatory targets of hydroxyurea, the only Food and Drug Administration-approved drug for SCD.

Triterpenoid inducers of Nrf2 signaling as potential therapeutic agents in sickle cell disease: a review.

Sickle cell disease (SCD) is an inherited disorder of hemoglobin in which the abnormal hemoglobin S polymerizes when deoxygenated. This polymerization of hemoglobin S not only results in hemolysis and vasoocclusion but also precipitates inflammation, oxidative stress and chronic organ dysfunction. Oxidative stress is increasingly recognized as an important intermediate in these pathophysiological processes and is therefore an important target for therapeutic intervention. The transcription factor nuclear erythroid derived-2 related factor 2 (Nrf2) controls the expression of anti-oxidant enzymes and is emerging as a protein whose function can be exploited with therapeutic intent. This review article is focused on triterpenoids that activate Nrf2, and their potential for reducing oxidative stress in SCD as an approach to prevent organ dysfunction associated with this disease. A brief overview of oxidative stress in the clinical context of SCD is accompanied by a discussion of several pathophysiological mechanisms contributing to oxidative stress. Finally, these mechanisms are then related to current management strategies in SCD that are either utilized currently or under evaluation. The article concludes with a perspective on the potential of the various therapeutic interventions to reduce oxidative stress and morbidity associated with SCD.

Complications associated with sickle cell trait: a brief narrative review.

Sickle cell trait occurs in approximately 300 million people worldwide, with the highest prevalence of approximately 30% to 40% in sub-Saharan Africa. Long considered a benign carrier state with relative protection against severe malaria, sickle cell trait occasionally can be associated with significant morbidity and mortality. Sickle cell trait is exclusively associated with rare but often fatal renal medullary cancer. Current cumulative evidence is convincing for associations with hematuria, renal papillary necrosis, hyposthenuria, splenic infarction, exertional rhabdomyolysis, and exercise-related sudden death. Sickle cell trait is probably associated with complicated hyphema, venous thromboembolic events, fetal loss, neonatal deaths, and preeclampsia, and possibly associated with acute chest syndrome, asymptomatic bacteriuria, and anemia in pregnancy. There is insufficient evidence to suggest an independent association with retinopathy, cholelithiasis, priapism, leg ulcers, liver necrosis, avascular necrosis of the femoral head, and stroke. Despite these associations, the average life span of individuals with sickle cell trait is similar to that of the general population. Nonetheless, given the large number of people with sickle cell trait, it is important that physicians be aware of these associations.