The evolution of the COVID-19 pandemic in paediatric patients with sickle cell disease: From Alpha to Omicron.

We compare the impact of SARS-CoV-2 variants on healthcare utilization and clinical presentation in paediatric patients with sickle cell disease (SCD). One hundred and ninety-one unique patients with SCD and positive SARS-CoV-2 polymerase chain reactions were identified between March 2020 and January 2022. Hospitalizations, which accounted for 42% (N = 81) of cases, were highest during the Delta dominant era (48%) and lowest during Omicron (36%) (p = 0.285). The most common SCD-related complication was vaso-occlusive pain (37%, N = 71), which accounted for 51% of all hospital admissions (N = 41), and acute chest was highest in the Alpha variant era (N = 15). Overall, COVID-19 remained mild in clinical severity within most paediatric SCD patients.

Neurocognitive and emotional factors predict pain-related healthcare utilization in children with sickle cell disease.

BACKGROUND: Youth with sickle cell disease (SCD) experience increased rates of neurocognitive and emotional difficulties. Cross-sectional studies suggest neurocognitive and emotional functioning are associated with health outcomes in SCD. We investigated whether neurocognitive and emotional factors predicted future pain-related healthcare utilization in children with SCD. PROCEDURE: Total 112 youth with SCD between ages 7 and 16 years reported sociodemographics and completed measures of neurocognitive functioning and emotional well-being. The number of emergency department (ED) visits and hospitalizations for pain 1 and 3 years after enrollment were determined by chart review. RESULTS: The mean age of participants was 10.61 years (standard deviation = 2.91), with most being female (n = 65; 58%). Eighty-three (74%) participants had either HbSS or HbSß0 thalassemia. Regression analyses showed that attention significantly predicted ED visits and hospitalizations for pain at 1 and 3 years after enrollment (all p-values ≤ .017), such that poorer attention was associated with higher healthcare utilization. Lower emotional quality of life also predicted more ED visits for pain at 3 years (b = -.009, p = .013) and hospitalizations for pain at 3 years (b = -.008, p = .020). CONCLUSIONS: Neurocognitive and emotional factors are associated with subsequent healthcare use in youth with SCD. Poor attentional control might limit implementation of strategies to distract from pain or could make disease self-management behaviors more challenging. Results also highlight the potential impact of stress on pain onset, perception, and management. Clinicians should consider neurocognitive and emotional factors when developing strategies to optimize pain-related outcomes in SCD.

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

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

Telemedicine in sickle cell disease: Patient, parent, and provider perspectives.

INTRODUCTION: Patients with sickle cell disease (SCD) need frequent health maintenance visits and may face barriers accessing care. Telemedicine, during COVID pandemic, has provided a unique model of care to improve access; however, potential barriers and satisfaction with its use in SCD have not been fully evaluated. OBJECTIVE: To determine caregiver, patient, and healthcare provider (HCP) perspectives and satisfaction with telemedicine in healthcare delivery. METHODS: We surveyed patients with SCD, caregivers, and HCP, who participated in at least one telemedicine visit from March 2020 to June 2021, using the Telemedicine Usability Questionnaire (TUQ). We also accessed and compared the Press Ganey surveys completed by families who completed a telemedicine or in-person visit. Data were summarized using descriptive statistics. The internal reliability of TUQ was assessed using Cronbach's coefficient alpha. Press Ganey data comparing satisfaction with telemedicine versus in-person visits were analyzed by Mann-Whiney U test. RESULTS: Fifty-two patients/caregivers and 10 HCP completed the survey. Patients/caregivers rated satisfaction "excellent" in the five areas (Usefulness, Ease of use, Effectiveness, Reliability and Satisfaction). HCP rated Usefulness, Ease of use, Effectiveness, Satisfaction as "good," and Reliability as "excellent." Press Ganey scores for satisfaction with care for telemedicine and in-person visits were not statistically different (p > .05). DISCUSSION: We found high satisfaction for caregivers and patients as well as HCP in the delivery of clinical services via telemedicine for SCD. We suggest that telemedicine is a viable option for this population and may help overcome the barriers SCD families often face accessing care.

Spirometric Changes After Initiation of Hydroxyurea in Children With Sickle Cell Anemia.

Individuals with sickle cell disease (SCD) develop a decline in lung function over time. Hydroxyurea (HU) is the most common disease-modifying therapy used in SCD. We hypothesized that children with SCD treated with HU will have a slower decline in pulmonary function. We performed a retrospective chart review of children with HbSS and HbS-beta zero thalassemia referred to pulmonology for respiratory symptoms. We compared the spirometry results at 2 time points between children on HU (HU group) and not on HU (control group). For the HU group, these endpoints were evaluated before and after being on HU. The mean time interval between 2 spirometry studies was not significantly different between the groups (2.6±1.5 y for HU group vs. 3.0±1.8 y for the control group; P =0.33). The mean age of patients in the HU group was 9.8±3.8 years (55% male) and 10.7±4.9 years (50% male) in the control group. The spirometry data was compared within and between the groups using t test. There was a significant increase in forced vital capacity in HU group during follow-up, while children in the control group showed a decline (7.2±17.1 vs. -3.4±18.2; P <0.01). Our study suggests that HU therapy may help preserve lung function over time in children with SCD.

Sickle cell disease subjects and mouse models have elevated nitrite and cGMP levels in blood compartments.

The hypothesis of decreased nitric oxide (NO) bioavailability in sickle cell disease (SCD) proposes that multiple factors leading to decreased NO production and increased consumption contributes to vaso-occlusion, pulmonary hypertension, and pain. The anion nitrite is central to NO physiology as it is an end product of NO metabolism and serves as a reservoir for NO formation. However, there is little data on nitrite levels in SCD patients and its relationship to pain phenotype. We measured nitrite in SCD subjects and examined its relationship to SCD pain. In SCD subjects, median whole blood, red blood cell and plasma nitrite levels were higher than in controls, and were not associated with pain burden. Similarly, Townes and BERK homozygous SCD mice had elevated blood nitrite. Additionally, in red blood cells and plasma from SCD subjects and in blood and kidney from Townes homozygous mice, levels of cyclic guanosine monophosphate (cGMP) were higher compared to controls. In vitro, hemoglobin concentration, rather than sickle hemoglobin, was responsible for nitrite metabolism rate. In vivo, inhibition of NO synthases and xanthine oxidoreductase decreased nitrite levels in homozygotes but not in control mice. Long-term nitrite treatment in SCD mice further elevated blood nitrite and cGMP, worsened anemia, decreased platelets, and did not change pain response. These data suggest that SCD in humans and animals is associated with increased nitrite/NO availability, which is unrelated to pain phenotype. These findings might explain why multiple clinical trials aimed at increasing NO availability in SCD patients failed to improve pain outcomes.

Bridging the Gap Among Clinical Practice Guidelines for Pain Management in Cancer and Sickle Cell Disease.

Opioids are a critical component of pain relief strategies for the management of patients with cancer and sickle cell disease. The escalation of opioid addiction and overdose in the United States has led to increased scrutiny of opioid prescribing practices. Multiple reports have revealed that regulatory and coverage policies, intended to curb inappropriate opioid use, have created significant barriers for many patients. The Centers for Disease Control and Prevention, National Comprehensive Cancer Network, and American Society of Clinical Oncology each publish clinical practice guidelines for the management of chronic pain. A recent JAMA Oncology article highlighted perceived variability in recommendations among these guidelines. In response, leadership from guideline organizations, government representatives, and authors of the original article met to discuss challenges and solutions. The meeting featured remarks by the Commissioner of Food and Drugs, presentations on each clinical practice guideline, an overview of the pain management needs of patients with sickle cell disease, an overview of perceived differences among guidelines, and a discussion of differences and commonalities among the guidelines. The meeting revealed that although each guideline varies in the intended patient population, target audience, and methodology, there is no disagreement among recommendations when applied to the appropriate patient and clinical situation. It was determined that clarification and education are needed regarding the intent, patient population, and scope of each clinical practice guideline, rather than harmonization of guideline recommendations. Clinical practice guidelines can serve as a resource for policymakers and payers to inform policy and coverage determinations.

The vaso-occlusive pain crisis in sickle cell disease: Definition, pathophysiology, and management.

Early diagnosis, treatment, and prevention of a vaso-occlusive crisis (VOC) are critical to the management of patients with sickle cell disease. It is essential to differentiate between VOC-associated pain and chronic pain, hyperalgesia, neuropathy, and neuropathic pain. The pathophysiology of VOCs includes polymerization of abnormal sickle hemoglobin, inflammation, and adhesion. Hydroxyurea, L-glutamine, crizanlizumab, and voxelotor have been approved by the US Food and Drug Administration for reducing the frequency of VOCs; the European Medicines Agency has approved only hydroxyurea. Other novel treatments are in late-stage clinical development in both the United States and the European Union. The development of agents for prevention and treatment of VOCs should be driven by our understanding of its pathophysiology.

Tricuspid regurgitation velocity and other biomarkers of mortality in children, adolescents and young adults with sickle cell disease in the United States: The PUSH study.

In the US, mortality in sickle cell disease (SCD) increases after age 18-20 years. Biomarkers of mortality risk can identify patients who need intensive follow-up and early or novel interventions. We prospectively enrolled 510 SCD patients aged 3-20 years into an observational study in 2006-2010 and followed 497 patients for a median of 88 months (range 1-105). We hypothesized that elevated pulmonary artery systolic pressure as reflected in tricuspid regurgitation velocity (TRV) would be associated with mortality. Estimated survival to 18 years was 99% and to 25 years, 94%. Causes of death were known in seven of 10 patients: stroke in four (hemorrhagic two, infarctive one, unspecified one), multiorgan failure one, parvovirus B19 infection one, sudden death one. Baseline TRV ≥2.7 m/second (>2 SD above the mean in age-matched and gender-matched non-SCD controls) was observed in 20.0% of patients who died vs 4.6% of those who survived (P = .012 by the log rank test for equality of survival). The baseline variable most strongly associated with an elevated TRV was a high hemolytic rate. Additional biomarkers associated with mortality were ferritin ≥2000 µg/L (observed in 60% of patients who died vs 7.8% of survivors, P < .001), forced expiratory volume in 1 minute to forced vital capacity ratio (FEV1/FVC) <0.80 (71.4% of patients who died vs 18.8% of survivors, P < .001), and neutrophil count ≥10x109 /L (30.0% of patients who died vs 7.9% of survivors, P = .018). In SCD children, adolescents and young adults, steady-state elevations of TRV, ferritin and neutrophils and a low FEV1/FVC ratio may be biomarkers associated with increased risk of death.

The CYB5R3c .350C>G and G6PD A alleles modify severity of anemia in malaria and sickle cell disease.

Genetic modifiers of anemia in Plasmodium falciparum infection and sickle cell disease (SCD) are not fully known. Both conditions are associated with oxidative stress, hemolysis and anemia. The CYB5R3 gene encodes cytochrome b5 reductase 3, which converts methemoglobin to hemoglobin through oxidation of NADH. CYB5R3c.350C > G encoding CYB5R3T117S , the most frequent recognized African-specific polymorphism, does not have known functional significance, but its high allele frequency (23% in African Americans) suggests a selection advantage. Glucose-6-phosphate dehydrogenase (G6PD) is essential for protection from oxidants; its African-polymorphic X-linked A+ and A- alleles, and other variants with reduced activity, coincide with endemic malaria distribution, suggesting protection from lethal infection. We examined the association of CYB5R3c.350C > G with severe anemia (hemoglobin <5 g/dL) in the context of G6PD A+ and A- status among 165 Zambian children with malaria. CYB5R3c.350C > G offered protection against severe malarial anemia in children without G6PD deficiency (G6PD wild type or A+/A- heterozygotes) (odds ratio 0.29, P = .022) but not in G6PD A+ or A- hemizygotes/homozygotes. We also examined the relationship of CYB5R3c.350C > G with hemoglobin concentration among 267 children and 321 adults and adolescents with SCD in the US and UK and found higher hemoglobin in SCD patients without G6PD deficiency (ß = 0.29, P = .022 children; ß = 0.33, P = .004 adults). Functional studies in SCD erythrocytes revealed mildly lower activity of native CYB5R3T117S compared to wildtype CYB5R3 and higher NADH/NAD+ ratios. In conclusion, CYB5R3c.350C > G appears to ameliorate anemia severity in malaria and SCD patients without G6PD deficiency, possibly accounting for CYB5R3c.350C > G selection and its high prevalence.

Characteristics and outcomes of osteomyelitis in children with sickle cell disease: A 10-year single-center experience.

BACKGROUND: Patients with sickle cell disease (SCD) are at increased risk for osteomyelitis (OM). Diagnosis of OM in SCD is challenging as the clinical presentation is similar to a vasoocclusive crisis (VOC) with no diagnostic gold standard. We report characteristics and outcomes of OM in SCD patients treated at our center over 10-year period. DESIGN/METHOD: We conducted a retrospective analysis of patients with SCD who were treated for OM at our center over a 10-year period (2006-2016). Cases were identified utilizing radiology data mining software. Radiology reports and medical charts of potential OM cases were reviewed. RESULTS: Twenty-eight children with SCD were treated for OM at our institution. Patients treated for OM were largely similar to patients treated for a VOC. However, patients treated for OM had significantly higher C-reactive protein (10 mg/dL vs 5.58 mg/dL, P = 0.03) and erythrocyte sedimentation rate (60 mm/h vs 47 mm/h, P = 0.02). Magnetic resonance imaging (MRI) findings were consistent with OM in 18 (64%) patients and indeterminate in the remaining. Based on clinical, laboratory, and radiological findings, the diagnosis of OM was considered confirmed in 3 patients, probable in 6 patients, and presumed in 19 patients. Nontyphoidal Salmonella was isolated from cultures in 9 (32%) patients, while no organism was identified in 19 (67%) patients. All patients were treated with antibiotics. Six patients (21%) required surgical interventions. CONCLUSIONS: OM continues to pose diagnostic challenges. Most patients are treated for OM without definitive confirmation. Nontyphoidal Salmonella was the only organism identified in our cohort.

Identification of red blood cell antibodies in maternal breast milk implicated in prolonged hemolytic disease of the fetus and newborn.

BACKGROUND: Alloantibodies against more than 50 non-ABO blood group antigens have been implicated in hemolytic disease of the fetus and newborn (HDFN) and are expected to wane within weeks after delivery. Persistent anemia leads to the hypothesis of continued exposure to red blood cell (RBC) alloantibodies via breast milk, which has been shown in a murine model and suggested in rare case reports. CASE REPORT: We report three cases of prolonged HDFN in two neonates with anti-D HDFN and one with anti-Jka HDFN. Patient 1 demonstrated 4+ anti-D serologic testing beyond 2 months; therefore, antibody testing was performed on maternal breast milk. METHODS: Maternal serum samples were tested for the presence of unexpected antibodies using standard Ortho gel card and 37 °C 60 minutes with anti-human globulin (AHG) tube saline methods. Antibody titrations were performed using the standard 37 °C 60 minutes to AHG tube saline method. Fresh breast milk samples were tested using the standard 37 °C 60 minutes to AHG tube saline method for both unexpected antibodies and titration study. Fresh breast milk from an O-positive, antibody-negative donor was used as control for any reactivity that may have been due to milk solids or proteins alone. RESULTS: Using a known methodology applied in a novel way to test breast milk for RBC alloantibodies, antibodies against fetal RBCs were identified in the maternal breast milk of three patients. CONCLUSION: Maternal RBC alloantibodies are present in breast milk and may be clinically significant in patients with prolonged recovery from HDFN.

Targeted Hydroxyurea Education after an Emergency Department Visit Increases Hydroxyurea Use in Children with Sickle Cell Anemia.

OBJECTIVE: To evaluate the impact of an initiative to increase hydroxyurea use among children with sickle cell anemia (SCA) who presented to the emergency department (ED). STUDY DESIGN: This observational cohort study included children with SCA not taking hydroxyurea who presented to the ED with pain or acute chest syndrome and then attended a Quick-Start Hydroxyurea Initiation Project (Q-SHIP) session. A Q-SHIP session includes a hematologist-led discussion on hydroxyurea, a video of patients talking about hydroxyurea, and a direct offer to start hydroxyurea. RESULTS: Over 64 weeks, 112 eligible patients presented to the ED and 59% (n = 66) participated in a Q-SHIP session a median of 6 days (IQR 2, 20 days) after ED or hospital discharge; 55% of participants (n = 36) started hydroxyurea. After a median follow-up of 49 weeks, 83% (n = 30) of these participants continued hydroxyurea. Laboratory markers of hydroxyurea adherence were significantly increased from baseline: median mean corpuscular volume +8.6 fL (IQR 5.0, 17.7, P < .0001) and median hemoglobin F +5.7% (IQR 2.5, 9.8, P = .0001). Comparing Q-SHIP participants to nonparticipants, 12 weeks after ED visit, participants were more likely to have started hydroxyurea than nonparticipants (53% vs 20%, P = .0004) and to be taking hydroxyurea at last follow-up (50% vs 20%, P = .001). Two years after the implementation of Q-SHIP the overall proportion of eligible patients on hydroxyurea presenting to our ED increased from 56% to 80%, P = .0069. CONCLUSIONS: Participation in a clinic to specifically address starting hydroxyurea after a SCA complication increases hydroxyurea use.

Diverse manifestations of acute sickle cell hepatopathy in pediatric patients with sickle cell disease: A case series.

The hepatic complications of sickle cell disease (SCD) are associated with increased morbidity and mortality in adults; children usually survive but may suffer significant sequelae. Few diagnostic tools differentiate the various hepatic manifestations of SCD. Why patients exhibit one hepatic pathology versus another is unclear. We report four pediatric patients with hemoglobin SS disease with diverse manifestations of acute hepatic involvement including acute sickle hepatic crisis, hepatic sequestration, sickle cell intrahepatic cholestasis, and a non-SCD cause of hepatopathy in a patient with viral hepatitis. These complications require a systematic approach to extensive evaluation and coordinated multidisciplinary care.

Views of parents of children with sickle cell disease on pre-implantation genetic diagnosis.

Pre-implantation genetic diagnosis (PGD) is an option for parents who have a child with sickle cell disease (SCD) to have another child without SCD. We conducted a survey of 19 parents with at least one child with SCD to investigate views on PGD. Before education, 44% of parents were aware of PGD. All parents rated PGD education as important. All parents considering another child also reported interest in using PGD if insurance covered its costs. Parents who have a child with SCD appear to be interested in PGD and educational tools informing this group about PGD should be developed.

A multicenter randomized controlled trial of intravenous magnesium for sickle cell pain crisis in children.

Magnesium, a vasodilator, anti-inflammatory, and pain reliever, could alter the pathophysiology of sickle cell pain crises. We hypothesized that intravenous magnesium would shorten length of stay, decrease opioid use, and improve health-related quality of life (HRQL) for pediatric patients hospitalized with sickle cell pain crises. The Magnesium for Children in Crisis (MAGiC) study was a randomized, double-blind, placebo-controlled trial of intravenous magnesium vs normal saline placebo conducted at 8 sites within the Pediatric Emergency Care Applied Research Network (PECARN). Children 4 to 21 years old with hemoglobin SS or Sß(0) thalassemia requiring hospitalization for pain were eligible. Children received 40 mg/kg of magnesium or placebo every 8 hours for up to 6 doses plus standard therapy. The primary outcome was length of stay in hours from the time of first study drug infusion, compared using a Van Elteren test. Secondary outcomes included opioid use and HRQL. Of 208 children enrolled, 204 received the study drug (101 magnesium, 103 placebo). Between-group demographics and prerandomization treatment were similar. The median interquartile range (IQR) length of stay was 56.0 (27.0-109.0) hours for magnesium vs 47.0 (24.0-99.0) hours for placebo (P = .24). Magnesium patients received 1.46 mg/kg morphine equivalents vs 1.28 mg/kg for placebo (P = .12). Changes in HRQL before discharge and 1 week after discharge were similar (P > .05 for all comparisons). The addition of intravenous magnesium did not shorten length of stay, reduce opioid use, or improve quality of life in children hospitalized for sickle cell pain crisis. This trial was registered at www.clinicaltrials.gov as #NCT01197417.

Determining the longitudinal validity and meaningful differences in HRQL of the PedsQL™ Sickle Cell Disease Module.

BACKGROUND: Detecting change in health status over time and ascertaining meaningful changes are critical elements when using health-related quality of life (HRQL) instruments to measure patient-centered outcomes. The PedsQL™ Sickle Cell Disease module, a disease specific HRQL instrument, has previously been shown to be valid and reliable. Our objectives were to determine the longitudinal validity of the PedsQL™ Sickle Cell Disease module and the change in HRQL that is meaningful to patients. METHODS: An ancillary study was conducted utilizing a multi-center prospective trial design. Children ages 4-21 years with sickle cell disease admitted to the hospital for an acute painful vaso-oclusive crisis were eligible. Children completed HRQL assessments at three time points (in the Emergency Department, one week post-discharge, and at return to baseline (One to three months post-discharge). The primary outcome was change in HRQL score. Both distribution (effect size, standard error of measurement (SEM)) and anchor (global change assessment) based methods were used to determine the longitudinal validity and meaningful change in HRQL. Changes in HRQL meaningful to patients were identified by anchoring the change scores to the patient's perception of global improvement in pain. RESULTS: Moderate effect sizes (0.20-0.80) were determined for all domains except the Communication I and Cognitive Fatigue domains. The value of 1 SEM varied from 3.8-14.6 across all domains. Over 50% of patients improved by at least 1 SEM in Total HRQL score. A HRQL change score of 7-10 in the pain domains represented minimal perceived improvement in HRQL and a HRQL change score of 18 or greater represented moderate to large improvement. CONCLUSIONS: The PedsQL™ Sickle Cell Disease Module is responsive to changes in HRQL in patients experiencing acute painful vaso-occlusive crises. The study data establish longitudinal validity and meaningful change parameters for the PedsQL™ Sickle Cell Disease Module. TRIAL REGISTRATION: ClinicalTrials.gov (study identifier: NCT01197417 ). Date of registration: 08/30/2010.

Dexmedetomidine as an Adjuvant to Analgesic Strategy During Vaso-Occlusive Episodes in Adolescents with Sickle-Cell Disease.

Patients with sickle-cell disease (SCD) can experience recurrent vaso-occlusive episodes (VOEs), which are associated with severe pain. While opioids are the mainstay of analgesic therapy, in some patients with SCD, increasing opioid use is associated with continued and increasing pain. Dexmedetomidine, an α2 -adrenoreceptor agonist with sedative and analgesic properties, has been increasingly used in the perioperative and intensive care settings and has been shown to reduce opioid requirement and to facilitate opioid weaning. Therefore, there might be a role for dexmedetomidine in pain management during VOEs in patients with SCD. Here, we present the hospital course of 3 patients who during the course of VOEs had severe pain unresponsive to opioids and ketamine and were treated with dexmedetomidine. Dexmedetomidine infusions that lasted for 3 to 6 days were associated with marked reduction in daily oral morphine-equivalent intake and decreases in pain scores (numeric rating scale). There were no hemodynamic changes that required treatment with vasoactive or anticholinergic agents. These preliminary findings of possible beneficial effects of dexmedetomidine in decreasing opioid requirements support the hypothesis that dexmedetomidine may have a role as a possible analgesic adjuvant to mitigate VOE-associated pain in patients with SCD.

Thinking beyond sickling to better understand pain in sickle cell disease.

Painful vaso-occlusive crises (VOCs) are the hallmark of sickle cell disease (SCD); however, many patients experience frequent daily pain that does not follow the pattern of typical VOCs. This pain of variable severity, also referred as persistent pain in the SCD literature, contributes to significant morbidity and poor quality of life and often fails to respond adequately to standard SCD therapies. In this article, we briefly describe types of pain encountered in SCD with a special emphasis on persistent pain. We discuss altered pain processing as a potential contributing mechanism, which may lead to development and maintenance of persistent pain. We describe the advances in the non-SCD pain field that may help improve the understanding of SCD pain. We highlight the need for further investigation in this area because some of these patients with persistent pain may benefit from receiving adjuvant mechanism-based therapies used successfully in other non-SCD chronic pain conditions.