COVID-19 mRNA Vaccination Responses in Individuals With Sickle Cell Disease: ASH RC Sickle Cell Research Network Study.

Children and adults with sickle cell disease (SCD) have increases in morbidity and mortality with COVID-19 infections. The ASH Research Collaborative Sickle Cell Disease Research Network performed a prospective COVID-19 vaccine study to assess antibody responses and analyze whether mRNA vaccination precipitated any adverse effects unique to individuals with SCD. Forty-one participants received two doses of the Pfizer-BioNTech vaccine and provided baseline blood samples prior to vaccination and 2 months after the initial vaccination for analysis of IgG reactivity against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Six month IgG reactivity against the viral RBD was also available in 37 patients. Post-vaccination reactogenicity was common and similar to the general population. There were no fevers that required inpatient admission. Vaso-occlusive pain within 2-3 days of 1st or 2nd vaccination was reported by 5 (12%) participants including 4 (10%) who sought medical care. Twenty-seven participants (66%) were seropositive at baseline, and all 14 (34%) initially seronegative participants converted to seropositive post vaccination. Overall, mRNA vaccination had a good risk benefit-profile in individuals with sickle cell disease.This mRNA vaccine study also marks the first evaluation of vaccine safety and antibody response in very young children with sickle cell disease. NCT05139992.

Acute care utilization among individuals with sickle cell disease and related cardiopulmonary and renal complications.

Cardiopulmonary and renal end organ (CPR) complications are associated with early mortality among individuals with sickle cell disease (SCD). However, there is limited knowledge regarding acute care utilization for individuals with SCD and CPR complications. Our objective was to determine the prevalence of CPR complications in a state specific SCD population and compare acute care utilization among individuals with and without CPR complications. We leveraged 2017-2020 data for individuals with SCD identified by the Sickle Cell Data Collection program in Wisconsin. The prevalence of CPR complications is determined for distinct age groups. Generalized linear models adjusted for age compared the rate of acute care visits/person/year among individuals who had cardiopulmonary only, renal only, both cardiopulmonary and renal, or no CPR complications. There were 1378 individuals with SCD, 52% females, mean (SD) age 28.3 (18.5) years; 48% had at least one CPR complication during the study period. The prevalence of CPR complications was higher in adults (69%) compared to pediatric (15%) and transition (51%) groups. Individuals with SCD and cardiopulmonary complications had higher acute visit rates than those without CPR complications (5.4 (IQR 5.0-5.8) vs 2.4 (IQR 2.1-2.5), p <0.001)). Acute care visit rates were similar between individuals with SCD who had renal only complications and no CPR complications (2.7 (IQR 2.5-3.0) vs 2.4 (2.1-2.5), p = 0.24). The high acute care visit rates, especially for those with cardiopulmonary complications, warrant further investigation to understand risk factors for CPR complications, the underlying reasons and identify effective disease management strategies.

Sickle cell disease iPSC-derived sensory neurons exhibit increased excitability and sensitization to patient plasma.

ABSTRACT: Individuals living with sickle cell disease (SCD) experience severe recurrent acute and chronic pain. Challenges to gaining mechanistic insight into pathogenic SCD pain processes include differential gene expression and function of sensory neurons between humans and mice with SCD, and extremely limited availability of neuronal tissues from patients with SCD. Here, we used induced pluripotent stem cells (iPSCs), derived from patients with SCD, differentiated into sensory neurons (SCD iSNs) to begin to overcome these challenges. We characterize key gene expression and function of SCD iSNs to establish a model to investigate intrinsic and extrinsic factors that may contribute to SCD pain. Despite similarities in receptor gene expression, SCD iSNs show pronounced excitability using patch clamp electrophysiology. Furthermore, we find that plasma taken from patients with SCD during acute pain associated with a vaso-occlusive event increases the calcium responses to the nociceptive stimulus capsaicin in SCD iSNs compared with those treated with paired plasma from patients with SCD at steady state baseline or healthy control plasma samples. We identified high levels of the polyamine spermine in baseline and acute pain states of plasma from patients with SCD, which sensitizes SCD iSNs to subthreshold concentrations of capsaicin. Together, these data identify potential intrinsic mechanisms within SCD iSNs that may extend beyond a blood-based pathology.

Gastrointestinal symptoms, diagnostic evaluations, and abdominal pathology in children with sickle cell disease.

BACKGROUND: Children with sickle cell disease (SCD) frequently present with acute pain. The abdomen, a common site of acute SCD-related pain, may be present in a variety of gastrointestinal (GI) pathologies. Limited data exist on prevalence and workup of abdominal pain in patients with SCD during acute pain events. OBJECTIVES: Determine prevalence of GI symptoms, GI-specific evaluation and risks of hospitalization in children with SCD presenting to the emergency department (ED) or hospitalized with abdominal pain. METHODS: Retrospective study of children less than 21 years presenting to the ED or hospitalized with pain in our center over 2 years. Descriptive statistics were used to report clinical characteristics, frequency of GI symptoms, workup by age (<5 vs. ≥5 years), and genotype (sickle cell anemia [SCA] vs. non-SCA). Logistic regression models were used to identify risks associated with hospitalization. RESULTS: A total of 1279 encounters in 378 patients were analyzed; 23% (n = 291) encounters were associated with abdominal pain. More abdominal pain-associated hospitalizations occurred in older children, SCA, children with lower mean hemoglobin (8.7 ± 1.9 vs. 9.6 ± 1.6 g/dL, p < .001) and higher mean white blood cell (WBC) count (14.9 ± 6.6 vs. 13.2 ± 5.3 × 103 /µL, p = .02). We identified that less than 50% of patients presenting to the ED with abdominal pain received a GI-specific evaluation. CONCLUSION: Children with SCD frequently present with abdominal pain and other GI symptoms, with limited GI evaluations performed. GI-specific evaluation may increase diagnosis of GI pathologies, rule out GI pathologies, and contribute to the limited knowledge of the abdomen as a primary site of SCD pain.

Return visit rates after an emergency department discharge for children with sickle cell pain episodes.

BACKGROUND: High return visit rates after hospitalization for people with sickle cell disease (SCD) have been previously established. Due to a lack of multicenter emergency department (ED) return visit rate data, the return visit rate following ED discharge for pediatric SCD pain treatment is currently unknown. PROCEDURE: A seven-site retrospective cohort study of discharged ED visits for pain by children with SCD was conducted using the Pediatric Emergency Care Applied Research Network Registry. Visits between January 2017 and November 2021 were identified using previously validated criteria. The primary outcome was the 14-day return visit rate, with 3- and 7-day rates also calculated. Modified Poisson regression was used to analyze associations for age, sex, initial hospitalization rate, and a visit during the COVID-19 pandemic with return visit rates. RESULTS: Of 2548 eligible ED visits, approximately 52% were patients less than 12 years old, 50% were female, and over 95% were non-Hispanic Black. The overall 14-day return visit rate was 29.1% (95% confidence interval [CI]: 27.4%-30.9%; site range 22.7%-31.7%); the 7- and 3-day return visit rates were 23.0% (95% CI: 21.3%-24.6%) and 16.7% (95% CI: 15.3%-18.2%), respectively. Younger children had slightly lower 14-day return visit rates (27.3% vs. 31.1%); there were no associations for site hospitalization rate, sex, and a visit occurring during the pandemic with 14-day returns. CONCLUSION: Nearly 30% of ED discharged visits after SCD pain treatment had a return visit within 14 days. Increased efforts are needed to identify causes for high ED return visit rates and ensure optimal ED and post-ED care.

Evaluating the Discriminatory Ability of the Sickle Cell Data Collection Program's Administrative Claims Case Definition in Identifying Adults With Sickle Cell Disease: Validation Study.

BACKGROUND: Sickle cell disease (SCD) was first recognized in 1910 and identified as a genetic condition in 1949. However, there is not a universal clinical registry that can be used currently to estimate its prevalence. The Sickle Cell Data Collection (SCDC) program, funded by the Centers for Disease Control and Prevention, funds state-level grantees to compile data within their states from various sources including administrative claims to identify individuals with SCD. The performance of the SCDC administrative claims case definition has been validated in a pediatric population with SCD, but it has not been tested in adults. OBJECTIVE: The objective of our study is to evaluate the discriminatory ability of the SCDC administrative claims case definition to accurately identify adults with SCD using Medicaid insurance claims data. METHODS: Our study used Medicaid claims data in combination with hospital-based medical record data from the Alabama, Georgia, and Wisconsin SCDC programs to identify individuals aged 18 years or older meeting the SCDC administrative claims case definition. In order to validate this definition, our study included only those individuals who were identified in both Medicaid's and the partnering clinical institution's records. We used clinical laboratory tests and diagnostic algorithms to determine the true SCD status of this subset of patients. Positive predictive values (PPV) are reported overall and by state under several scenarios. RESULTS: There were 1219 individuals (354 from Alabama and 865 from Georgia) who were identified through a 5-year time period. The 5-year time period yielded a PPV of 88.4% (91% for data from Alabama and 87% for data from Georgia), when only using data with laboratory-confirmed (gold standard) cases as true positives. With a narrower time period (3-year period) and data from 3 states (Alabama, Georgia, and Wisconsin), a total of 1432 individuals from these states were included in our study. The overall 3-year PPV was 89.4% (92%, 93%, and 81% for data from Alabama, Georgia, and Wisconsin, respectively) when only considering laboratory-confirmed cases as true cases. CONCLUSIONS: Adults identified as having SCD from administrative claims data based on the SCDC case definition have a high probability of truly having the disease, especially if those hospitals have active SCD programs. Administrative claims are thus a valuable data source to identify adults with SCD in a state and understand their epidemiology and health care service usage.

Gut microbiota and metabolites drive chronic sickle cell disease pain.

Pain is a debilitating symptom and leading reason for hospitalization of individuals with sickle cell disease. Chronic sickle cell pain is poorly managed because the biological basis is not fully understood. Using transgenic sickle cell mice and fecal material transplant, we determined that the gut microbiome drives persistent sickle cell pain. In parallel patient and mouse analyses, we identified bilirubin as one metabolite that induces sickle cell pain by altering vagus nerve activity. Furthermore, we determined that decreased abundance of the gut bacteria Akkermansia mucinophila is a critical driver of chronic sickle cell pain. These experiments demonstrate that the sickle cell gut microbiome drives chronic widespread pain and identify bacterial species and metabolites that should be targeted for chronic sickle cell disease pain management.

Preliminary construct validity of patient-reported outcomes to assess chronic pain in adults with sickle cell disease.

Chronic pain affects 30% to 40% of individuals with sickle cell disease (SCD) and impairs patient functioning. Clinically meaningful, practical, and valid assessment tools for investigation, evaluation, and management of chronic pain are limited, representing a barrier for advancing SCD care. We sought to determine whether patient-reported outcomes (PROs) show preliminary construct validity in identifying individuals with SCD who were a priori defined as suggestive of having chronic pain based on previously published criteria. All individuals completed the Patient-Reported Outcomes Measurement Information System (PROMIS) domains: pain interference, pain behavior, pain quality (nociceptive, neuropathic), fatigue, sleep disturbance, depression, and anxiety; the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) domains: pain impact and emotional impact; and the painDETECT questionnaire. Thirty-three adults living with SCD were enrolled, and 42.4% had chronic pain. Pain-related PROs scores distinctly differentiated individuals with chronic pain from those without. Individuals with chronic pain had significantly worse pain-related PROs scores: PROMIS pain interference (64.2 vs 54.3), PROMIS pain behavior (63.2 vs 50), and ASCQ-Me pain impact (42.9 vs 53.2). According to published PROMIS clinical cut scores for the pain-related domains, individuals with chronic pain were categorized as having moderate impairment, whereas those without chronic pain had mild or no impairment. Individuals with chronic pain had PRO pain features consistent with neuropathic pain and worse scores in fatigue, depression, sleep disturbance, and emotional impact. Pain-related PROs show preliminary construct validity in differentiating individuals with and without chronic SCD pain and could be used as valuable tools for research and clinical monitoring of chronic pain.

Sickle cell disease patient plasma sensitizes iPSC-derived sensory neurons from sickle cell disease patients.

Individuals living with sickle cell disease (SCD) experience severe recurrent acute and chronic pain. In order to develop novel therapies, it is necessary to better understand the neurobiological mechanisms underlying SCD pain. There are many barriers to gaining mechanistic insight into pathogenic SCD pain processes, such as differential gene expression and function of sensory neurons between humans and mice with SCD, as well as the limited availability of patient samples. These can be overcome by utilizing SCD patient-derived induced pluripotent stem cells (iPSCs) differentiated into sensory neurons (SCD iSNs). Here, we characterize the key gene expression and function of SCD iSNs to establish a model for higher-throughput investigation of intrinsic and extrinsic factors that may contribute to increased SCD patient pain. Importantly, identified roles for C-C Motif Chemokine Ligand 2 (CCL2) and endothelin 1 (ET1) in SCD pain can be recapitulated in SCD iSNs. Further, we find that plasma taken from SCD patients during acute pain increases SCD iSN calcium response to the nociceptive stimulus capsaicin compared to those treated with paired SCD patient plasma at baseline or healthy control plasma samples. Together, these data provide the framework necessary to utilize iSNs as a powerful tool to investigate the neurobiology of SCD and identify potential intrinsic mechanisms of SCD pain which may extend beyond a blood-based pathology.

A perspective on the sickle cell disease international COVID-19 registry.

To understand the risks and outcomes of COVID-19 in the sickle cell disease (SCD) population, our team established a rapid reporting registry to collect data on the course of COVID-19 illness in individuals with SCD. The registry includes cases reported voluntarily by providers. All data are collected through an online case report form available at covidsicklecell.org. The registry helped to recognize patients with SCD as a population at risk of severe COVID-19 illness and to identify comorbidities that put them at higher risk. In this report, we present data on 1045 reported COVID-19 cases based during a two-year long data collection period. Data include 590 (56.5%) children and 455 (43.5%) adults; 51.2% of total population were female. Most individuals (63.1%) had HbSS genotype. Majority of individuals experienced mild symptoms (62.2% of children, 55.6% of adults). We also present a perspective on setting up the registry and experiences through its growth.

Chronic Pain: Prevalence and Management.

Chronic pain is a distinct complication that profoundly affects the lives of individuals with sickle cell disease (SCD). Chronic SCD pain emerges with increasing age and is very prevalent in adults. The pathophysiology of chronic SCD pain is likely distinct from acute SCD pain and therefore needs a different treatment approach. Clinical trials evaluating the treatment of chronic SCD pain are lacking and treatment currently relies on evidence from other chronic pain conditions. Continued investigations into the underlying causes of chronic SCD pain are needed, and clinical trials focused on chronic pain therapy are imperative.

COVID-19 and venous thromboembolism risk in patients with sickle cell disease.

Venous thromboembolism (VTE) is a life-threatening complication observed among patients with sickle cell disease (SCD) and also among those with severe COVID-19 infection. Although prior studies show that patients with SCD are at risk of severe COVID-19 illness, it remains unclear if COVID-19 infection further increases VTE risk for this population. We hypothesized that patients with SCD hospitalized for COVID-19 would have higher VTE rates than those hospitalized for other causes. Using electronic health record data from a multisite research network, TriNetX, we identified 2 groups of patients with SCD hospitalized during 2020: (1) with COVID-19 and (2) without COVID-19. We compared VTE rates using risk ratios estimated based on adjusted Poisson regression model with log link and robust error variances. Of the 281 SCD patients hospitalized with COVID-19 and 4873 SCD patients hospitalized without COVID-19 , 35 (12.46%) and 418 (8.58%) had incident VTE within 6 months of the index hospitalization respectively. After adjusting for differences in baseline characteristics, no significant differences in VTE rates within 6 months were found between the 2 groups (adjusted relative risk, 1.06 [95% confidence interval, 0.79-1.41]). These data suggest that hospitalization with COVID-19 does not further increase VTE risk in patients with SCD.

Non-crisis related pain occurs in adult patients with sickle cell disease despite chronic red blood cell exchange transfusion therapy.

BACKGROUND: Chronic red blood cell transfusions reduce acute care utilization for sickle cell disease (SCD) pain. However, little is known about whether chronic transfusions treat or prevent the development of non-crisis pain. We investigated patient-report of pain in adults with SCD receiving chronic exchange transfusions (CET) compared to adults not on CET with similar disease characteristics. STUDY METHOD AND DESIGN: Eleven participants receiving chronic exchange transfusion (CET) for at least one year were compared to 33 participants not receiving CET. Participants completed validated patient-reported outcomes regarding pain impact and quality of life at regularly scheduled visits or before CET. One year of health care utilization and opioid prescriptions were examined. RESULTS: After 1:1 propensity matching was performed for age, genotype, WBC and neutrophil counts, patients on CET had lower Pain Impact scores (-5.1, p = 0.03) and higher Neuropathic (7.4, p < 0.001) and Nociceptive Pain Quality (3.7, p < 0.001) scores, all indicating worse pain. However, CET was associated with a reduction in annual all cause admissions (-3.1, p < 0.001), length of stay (-2.1 days, p < 0.001) and ED visits (-2.7, p < 0.001). CET was not associated with differences in opioids dispensed. CONCLUSIONS: After adjusting for disease characteristics, CET was associated with worse pain impact and neuropathic and nociceptive pain quality, lower health care utilization and with similar levels of opioids dispensed. This data suggest that CET may reduce hospitalizations for acute pain but may not adequately treat nociceptive or neuropathic pain in SCD.

Surveillance for the Rare Condition of Sickle Cell Disease in Wisconsin.

INTRODUCTION: Despite universal newborn screening, there is no comprehensive surveillance system to understand the sickle cell disease population in Wisconsin. METHODS: We initiated the development of a sickle cell disease surveillance system by linking newborn screening data and electronic health records from 2 large tertiary health care institutions in Wisconsin: Children's Wisconsin and Froedtert Hospital. RESULTS: There were 1478 individuals within the 3 data sources. One hundred thirty-two (82%) of 159 identified by newborn screening from 2013 through 2019 received care at Children's Wisconsin. The majority of individuals with sickle cell disease at Children's Wisconsin and Froedtert Hospital resided in Milwaukee County. DISCUSSION: The new surveillance program will increase our understanding of the sickle cell disease population in Wisconsin and help improve quality of care and health outcomes.

A polygenic score for acute vaso-occlusive pain in pediatric sickle cell disease.

Individuals with monogenic disorders can experience variable phenotypes that are influenced by genetic variation. To investigate this in sickle cell disease (SCD), we performed whole-genome sequencing (WGS) of 722 individuals with hemoglobin HbSS or HbSß0-thalassemia from Baylor College of Medicine and from the St. Jude Children's Research Hospital Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort study. We developed pipelines to identify genetic variants that modulate sickle hemoglobin polymerization in red blood cells and combined these with pain-associated variants to build a polygenic score (PGS) for acute vaso-occlusive pain (VOP). Overall, we interrogated the α-thalassemia deletion -α3.7 and 133 candidate single-nucleotide polymorphisms (SNPs) across 66 genes for associations with VOP in 327 SCCRIP participants followed longitudinally over 6 years. Twenty-one SNPs in 9 loci were associated with VOP, including 3 (BCL11A, MYB, and the ß-like globin gene cluster) that regulate erythrocyte fetal hemoglobin (HbF) levels and 6 (COMT, TBC1D1, KCNJ6, FAAH, NR3C1, and IL1A) that were associated previously with various pain syndromes. An unweighted PGS integrating all 21 SNPs was associated with the VOP event rate (estimate, 0.35; standard error, 0.04; P = 5.9 × 10-14) and VOP event occurrence (estimate, 0.42; standard error, 0.06; P = 4.1 × 10-13). These associations were stronger than those of any single locus. Our findings provide insights into the genetic modulation of VOP in children with SCD. More generally, we demonstrate the utility of WGS for investigating genetic contributions to the variable expression of SCD-associated morbidities.

Comorbidities are risk factors for hospitalization and serious COVID-19 illness in children and adults with sickle cell disease.

Patients with sickle cell disease (SCD) are at high risk of developing serious infections, therefore, understanding the impact that severe acute respiratory syndrome coronavirus 2 infection has on this population is important. We sought to identify factors associated with hospitalization and serious COVID-19 illness in children and adults with SCD.We established the international SECURE-SCD Registry to collect data on patients with SCD and COVID-19 illness. We used multivariable logistic models to estimate the independent effects of age, sex, genotype, hydroxyurea, and SCD-related and -nonrelated comorbidities on hospitalization, serious COVID-19 illness, and pain as a presenting symptom during COVID-19 illness. As of 23 March 2021, 750 COVID-19 illness cases in patients with SCD were reported to the registry. We identified history of pain (relative risk [RR], 2.15; P < .0001) and SCD heart/lung comorbidities (RR, 1.61; P = .0001) as risk factors for hospitalization in children. History of pain (RR, 1.78; P = .002) was also a risk factor for hospitalization in adults. Children with history of pain (RR, 3.09; P = .009), SCD heart/lung comorbidities (RR, 1.76; P = .03), and SCD renal comorbidities (RR, 3.67; P < .0001) and adults with history of pain (RR 1.94, P = .02) were at higher risk of developing serious COVID-19 illness. History of pain and SCD renal comorbidities also increased risk of pain during COVID-19 in children; history of pain, SCD heart/lung comorbidities, and female sex increased risk of pain during COVID-19 in adults. Hydroxyurea showed no effect on hospitalization and COVID-19 severity, but it lowered the risk of presenting with pain in adults during COVID-19.

COVID-19 in individuals with sickle cell disease/trait compared with other Black individuals.

In the United States, COVID-19 has disproportionately affected Black persons. Sickle cell disease (SCD) and sickle cell trait (SCT) are genetic conditions that occur predominantly among Black individuals. It is unknown if individuals with SCD/SCT are at higher risk of severe COVID-19 illness compared with Black individuals who do not have SCD/SCT. The objective of our study was to compare COVID-19 outcomes, including the disease manifestations, hospitalization, and death, among individuals with SCD/SCT vs Black individuals who do not have SCD/SCT. We leveraged electronic health record data from a multisite research network to identify Black patients with COVID-19 who have SCD/SCT and those who do not have SCD/SCT. During the study period of 20 January 2020 to 20 September 2020, there were 312 patients with COVID-19 and SCD and 449 patients with COVID-19 and SCT. There were 45 517 Black persons who were diagnosed with COVID-19 but who did not have SCD/SCT. After 1:1 propensity score matching (based on age, sex, and other preexisting comorbidities), patients with COVID-19 and SCD remained at a higher risk of hospitalization (relative risk [RR], 2.0; 95% CI, 1.5-2.7) and development of pneumonia (RR, 2.4; 95% CI, 1.6-3.4) and pain (RR, 3.4; 95% CI, 2.5-4.8) compared with Black persons without SCD/SCT. The case fatality rates for those with SCD compared with Black persons without SCD/SCT were not significantly different. There also were no significant differences in COVID-19 outcomes between individuals with SCT and Black persons without SCD/SCT within the matched cohorts.

Recommendation to reality: Closing the transcranial Doppler screening gap for children with sickle cell anemia.

BACKGROUND: Although annual transcranial Doppler (TCD) screening is recommended for children with sickle cell anemia (SCA), compliance is low and variable. Our objective was to utilize an electronic health record (EHR)-based registry to improve TCD adherence among children with SCA, 2-16 years of age, at our institution. METHODS: We developed an in-EPIC real time registry for children with sickle cell disease in year 2016. Since end of year 2016, we have been extracting data quarterly to examine TCD rates and share the list of children who have not received a TCD screen in the past 18 months with the clinical team. The registry also includes a TCD risk score to enhance point of care. We also added Child Life support to increase TCD compliance among children <7 years. Control charts are used to examine TCD rates. RESULTS: At baseline, prior to and start of quarterly data audit and feedback, 63% of children received the recommended annual TCD screen. TCD rates steadily increased to 80% by the third quarter of 2017. We observed a dip in TCD rates, driven by failure of screening young children. Since the initiation of Child Life support for children <7 years, we have sustained TCD screen rates >70%. Overall, our data meet criteria for special cause variation, indicating improvement in TCD rates since 2015. CONCLUSIONS: Regular tracking and identification of patients overdue for a TCD screen using an EHR-based registry resulted in sustained improvement in TCD screening rates. Involvement of Child Life support further improved TCD rates.

Neuropathic pain in sickle cell disease: measurement and management.

The identification of chronic pain and neuropathic pain as common contributors to the overall pain experience of patients with sickle cell disease (SCD) has altered the way we should evaluate difficult-to-treat pain. The recognition of these 2 entities is not generally routine among various medical specialties and provider levels that treat SCD. Due to the relative recency with which neuropathic pain was first described in SCD, validated assessment tools and evidence-based treatments remain lacking. Although clinical assessment and judgment must continue to inform all decision making in this understudied area of SCD pain management, a number of validated neuropathic pain assessment tools exist that can make possible a standardized evaluation process. Similarly, investigation of available neuropathic pain treatments for the uniquely complex pain phenotypes of SCD has only just begun and is better established in pain conditions other than SCD. The aim of this review is to briefly summarize the proposed basic pathophysiology, assessment, and treatment of neuropathic pain in patients with SCD. Furthermore, the aim of this review is to encourage an expanded framework for the assessment and treatment of SCD pain that appreciates the hidden complexities of this common complication of SCD.