Promise of Composite Pain Index as a single pain outcome for sickle cell disease across the lifespan.

BACKGROUND: This study aimed to validate a Composite Pain Index (CPI) as a single pain outcome measure for sickle cell disease (SCD) across the lifespan from 8 years of age. PROCEDURE: This prospective, cross-sectional study included 55 participants with SCD who completed the PAINReportIt tool and Adolescent Pediatric Pain Tool (APPT) in random order during outpatient visits to derive respective CPI scores for comparison. RESULTS: Of the 55 participants with SCD, 46 (84%) had HgbSS, eight (15%) HgbSC, and one (2%) HgbSß0+. The mean age of all participants was 17.5 ± 2.6 years, and 28 (51%) were female, 52 (95%) were Black, 42 (98%) were non-Hispanic, and 39 (71%) had a ninth grade or higher education. Correlation analyses between the APPT and PAINReportIt revealed positive associations for the number of pain sites (r = .57, p < .001), pain intensity (r = .46, p < .001), pain quality (r = .74, p < .001), and pain pattern (r = .34, p = .01). Patients' mean CPI scores derived from the PAINReportIt was slightly higher than the APPT; 34.2 (SD = 14.7) and 30.0 (SD = 19.0), respectively. Regression analyses showed that the APPT CPI significantly predicted the PAINReportIt CPI (B = .497, t(53) = 6.051, p < .001). This finding holds true even when accounting for the order of measurement or patient's age. CONCLUSION: The initial validation of CPI as a single pain outcome measure represents a significant advancement in pain assessment for SCD. Further validation is warranted for the CPI as a measure is for both clinicians and researchers to enable longitudinal pain assessment from age 8 years across the lifespan as children age into adult care.

Quantification of Patient-Reported Pain Locations: Development of an Automated Measurement Method.

Patient-reported pain locations are critical for comprehensive pain assessment. Our study aim was to introduce an automated process for measuring the location and distribution of pain collected during a routine outpatient clinic visit. In a cross-sectional study, 116 adults with sickle cell disease-associated pain completed PAIN Report It Ⓡ . This computer-based instrument includes a two-dimensional, digital body outline on which patients mark their pain location. Using the ImageJ software, we calculated the percentage of the body surface area marked as painful and summarized data with descriptive statistics and a pain frequency map. The painful body areas most frequently marked were the left leg-front (73%), right leg-front (72%), upper back (72%), and lower back (70%). The frequency of pain marks in each of the 48 body segments ranged from 3 to 79 (mean, 33.2 ± 21.9). The mean percentage of painful body surface area per segment was 10.8% ± 7.5% (ranging from 1.3% to 33.1%). Patient-reported pain locations can be easily analyzed from digital drawings using an algorithm created via the free ImageJ software. This method may enhance comprehensive pain assessment, facilitating research and personalized care over time for patients with various pain conditions.

A Novel Measure of Pain Location in Adults with Sickle Cell Disease.

BACKGROUND: Pain intensity remains a primary focus clinically for sickle cell disease pain assessment despite the fact that pain quality and pain location and distribution are critical for clinical diagnosis and treatment of its etiology. However, in part because of measurement issues, scant evidence is available about pain location or its relationship to intensity and quality in adults with SCD. AIM: Our study aim was to examine sickle cell disease pain location for relationships with pain quality and intensity measured in outpatient and inpatient settings. METHODS: We used an existing longitudinal dataset prospectively collected with the valid and reliable tablet-based PAINReportItⓇ. Adults with sickle cell disease (n = 99) reported pain location, intensity, and quality during a routine outpatient clinic visit and again during a subsequent hospitalization. From their digital body outline drawings and using the ImageJ software, we computed the pain-affected body surface area. With Pearson's correlations and paired t tests, we examined relationships between pain-affected body surface area and other pain variables across outpatient and inpatient visits. RESULTS: The mean pain-affected body surface area was 14.4% ± 15.0% of the total body surface area for outpatient visits (min-max: 0.0%-90.2%) and 13.5% ± 14.7% (min-max: 0.0%-73.0%) for inpatient stay. Pain-affected body surface area was positively correlated with pain quality scores for both visits but not significantly correlated with pain intensity at either visit. Compared with the outpatient visit, mean pain intensity for inpatient stay was higher (p < .001); pain quality (p = .12) and pain-affected body surface area (p = .60) did not differ significantly between visits. CONCLUSIONS: Unknown is the explanation for pain-affected body surface area association with SCD pain quality but not pain intensity at outpatient and inpatient visits. Additional research is warranted to explore these findings and examine the clinical utility of pain-affected body surface area for chronic sickle cell disease pain and acute sickle cell disease crisis pain.

Antimicrobial resistance is a risk factor for mortality in adults with sickle cell disease.

Not available.

A QST-based Pain Phenotype in Adults With Sickle Cell Disease: Sensitivity and Specificity of Quality Descriptors.

BACKGROUND: We sought to refine a screening measure for discriminating a sensitized or normal sensation pain phenotype among African American adults with sickle cell disease (SCD). OBJECTIVE: To develop scoring schemes based on sensory pain quality descriptors; evaluate their performance on classifying patients with SCD who had sensitization or normal sensation, and compare with scores on the Self-report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) and the Neuropathic Pain Symptom Inventory (NPSI). METHODS: Participants completed PAINReportIt, quantitative sensory testing (QST), S-LANSS, and NPSI. Conventional binary logistic regression and least absolute shrinkage and selection operator (lasso) regression were used to obtain 2 sets of weights resulting in 2 scores: the PR-Logistic (PAINReportIt score weighted by conventional binary logistic regression coefficients) and PR-Lasso (PAINReportIt score weighted by lasso regression coefficients). Performance of the proposed scores and the existing scores were evaluated. RESULTS: Lasso regression resulted in a parsimonious model with non-zero weights assigned to 2 neuropathic descriptors, cold and spreading. We found positive correlations between the PR-Lasso and other scores: S-LANSS (r = 0.22, P < 0.01), NPSI (r = 0.22, P < 0.01), and PR-Logistic (r = 0.35, P < 0.01). The NPSI and PR-Lasso performed similarly at different levels of required specificity and outperformed the S-LANSS and PR-Logistic at the various specificity points. CONCLUSION: The PR-Lasso offers a way to discriminate a SCD pain phenotype.

Dendrimer-Based Platform for Effective Capture of Tumor Cells after TGFß1-Induced Epithelial-Mesenchymal Transition.

Detection of circulating tumor cells (CTCs) relying on their expression of epithelial cell markers, such as epithelial cell adhesion molecule (EpCAM), has been commonly used. However, this approach unlikely captures CTCs that have undergone the process of epithelial-mesenchymal transition (EMT). In this study, we have induced EMT of in vitro prostate (PCa) and breast cancer (BCa) cell lines by treatment of transforming growth factor ß 1 (TGFß1), a pleiotropic cytokine with transition-regulating activities. We found that the TGFß1-treated, post-EMT cells exhibited up to a 45% reduction in binding affinity to antibodies against EpCAM (aEpCAM). To overcome this limitation, we designed our capture platform that integrates a unique combination of biomimetic cell rolling, dendrimer-mediated multivalent binding, and antibody cocktails of aEpCAM/aEGFR/aHER-2. Our capture surfaces resulted in up to 98% capture efficiency of post-EMT cells from mixtures of TGFß1-treated and untreated cancer cells spiked in culture media and human blood. In a clinical pilot study, our CTC device was also able to capture rare CTCs from PCa patients with significantly enhanced capture sensitivity and purity compared to the control surface with aEpCAM only, demonstrating its potential to provide a reliable detection solution for CTCs regardless of their EMT status.

Relationship of Pain Quality Descriptors and Quantitative Sensory Testing: Sickle Cell Disease.

BACKGROUND: Chronic pain in adults with sickle cell disease (SCD) may be the result of altered processing in the central nervous system, as indicated by quantitative sensory testing (QST). Sensory pain quality descriptors on the McGill Pain Questionnaire (MPQ) are indicators of typical or altered pain mechanisms but have not been validated with QST-derived classifications. OBJECTIVES: The specific aim of this study was to identify the sensory pain quality descriptors that are associated with the QST-derived normal or sensitized classifications. We expected to find that sets of sensory pain quality descriptors would discriminate the classifications. METHODS: A cross-sectional quantitative study of existing data from 186 adults of African ancestry with SCD. Variables included MPQ descriptors, patient demographic data, and QST-derived classifications. RESULTS: The participants were classified as central sensitization (n = 33), mixed sensitization (n = 23), and normal sensation. Sensory pain quality descriptors that differed statistically between mixed sensitization and central sensation compared to normal sensitization included cold (p = .01) and spreading (p = .01). Aching (p = .01) and throbbing (p = .01) differed statistically between central sensitization compared with mixed sensitization and normal sensation. Beating (p = .01) differed statistically between mixed sensitization compared with central sensitization and normal sensation. No set of sensory pain quality descriptors differed statistically between QST classifications. DISCUSSION: Our study is the first to examine the association between MPQ sensory pain quality descriptors and QST-derived classifications in adults with SCD. Our findings provide the basis for the development of a MPQ subscale with potential as a mechanism-based screening tool for neuropathic pain.

Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease.

We report on the screening and development of haploidentical hematopoietic stem cell transplantation (HSCT) for adult patients with clinically aggressive sickle cell disease (SCD) at our institution. Of 50 adult SCD patients referred for HSCT between January 2014 and March 2017, 20% were denied by insurance. Of 41 patients initially screened, 10% lacked an available haploidentical donor, 29% had elevated donor-specific antibodies (DSAs), and 34% declined to proceed to HSCT. All 10 patients who were transplanted received peripheral blood stem cells. The initial 2 were conditioned with alemtuzumab/total body irradiation (TBI) 3 Gy followed by post-transplant cyclophosphamide and failed to engraft. The next 8 patients received the regimen developed at Johns Hopkins University with TBI 3 Gy. Granulocyte colony-stimulating factor was administered from day +12 in those with HbS < 30%. All 8 patients engrafted with a median time to neutrophil >.5 × 109/L of 22 days (range, 18 to 23). One patient subsequently lost the graft, and 7 (87.5%) maintained >95% donor cell chimerism at 1-year post-HSCT. Two patients developed acute graft-versus-host disease (GVHD) of at least grade II. One had chronic GVHD and died >1 year after HSCT of unknown causes. With a median follow-up of 16 months (range, 11 to 29), 7 patients (87.5%) are alive. Our findings suggest that limited insurance coverage, high rate of DSAs, and patient declining HSCT may limit the availability of haploidentical HSCT in adult SCD patients. The modified Hopkins regimen used here demonstrates high engraftment and low morbidity rates and should be tested in larger, multicenter, prospective clinical trials.

Risk factors for vitamin D deficiency in sickle cell disease.

Vitamin D deficiency (VDD), 25-OHD levels <20 ng/ml, is prevalent among patients with sickle cell disease (SCD) and is linked to acute and chronic pain and bone fracture in this population. There is limited literature regarding VDD-associated risk factors for SCD. We examined potential clinical and genomic parameters associated with VDD in 335 adults with SCD in a cross-sectional study. VDD was present in 65% of adult SCD patients, and 25-OHD levels independently and positively correlated with older age (P < 0·001) and vitamin D supplementation (P < 0·001). 25-OHD levels were higher in SCD patients over 40 years of age compared to the general African-American population. Both lower 25-OHD levels and increased pain frequency were associated with increased expression of SLC6A5 encoding glycine transporter-2 (GlyT2), a protein involved in neuronal pain pathways. Lower 25-OHD levels were also associated with increased expression of CYP3A4, and with decreased expression of GC (also termed DBP) and VDR, three genes involved in vitamin D metabolism. We conclude that vitamin D supplementation should be an almost universal feature of the care of young adults with SCD, and that further research is warranted into genomic factors that regulate vitamin D metabolism in SCD.

Opioid doses and acute care utilization outcomes for adults with sickle cell disease: ED versus acute care unit.

BACKGROUND: Acute care units (ACUs) with focused sickle cell disease (SCD) care have been shown to effectively address pain and limit hospitalizations compared to emergency departments (ED), the reason for differences in admission rates is understudied. Our aim was compare effects of usual care for adult SCD pain in ACU and ED on opioid doses and discharge pain ratings, hospital admission rates and lengths of stay. METHODS: In a retrospective, comparative cohort, single academic tertiary center study, 148 adults with sickle cell pain received care in the ED, ACU or both. From the medical records we documented opioid doses, unit discharge pain ratings, hospital admission rates, and lengths of stay. FINDINGS: Pain on admission to the ED averaged 8.7±1.5 and to the ACU averaged 8.0±1.6. The average pain on discharge from the ED was 6.4±3.0 and for the ACU was 4.5±2.5. 70% of the 144 ED visits resulted in hospital admissions as compared to 37% of the 73 ACU visits. Admissions from the ED or ACU had similar inpatient lengths of stay. Significant differences between ED and ACU in first opioid dose and hourly opioid dose were noted. CONCLUSIONS: Applying guidelines for higher dosing of opioids for acute painful episodes in adults with SCD in ACU was associated with improved pain outcomes and decreased hospitalizations, compared to ED. Adoption of this approach for SCD pain in ED may result in improved outcomes, including a decrease in hospital admissions.

The AVPR1A Gene and Its Single Nucleotide Polymorphism rs10877969: A Literature Review of Associations with Health Conditions and Pain.

BACKGROUND: Pain is the quintessential symptom for individuals suffering from sickle cell disease (SCD). Although the degree of suffering and the cost of treatment are staggering, SCD continues to be grossly understudied, including a lack of data for pain-related genes and prevalence of polymorphisms in this population. This lack of data adds to the inadequacy of pain therapy in this population. Pain genetics investigators have recently examined allele frequencies of single-nucleotide polymorphisms from candidate genes in people who have SCD. One of the genes identified was the arginine vasopressin receptor 1A gene (AVPR1A) and its associated single-nucleotide polymorphism (SNP) rs10877969. Progress in explaining pain-related polymorphisms associated with SCD can be facilitated by understanding the literature. Aim/Design: The purpose of this literature review was to describe mechanisms of the polymorphic gene AVPR1A and the phenotypic variations associated with its SNPs relative to health conditions and pain. METHODS: Published studies were included if the research addressed AVPR1A and was a full article in a peer-reviewed journal, in the English language, a human or animal study, and published 2009 to present. Abstracts were included if they were in English and provided information not found in a full article. RESULTS: The results of this review revealed that AVPR1A is associated with behavioral phenotypes, which include pair bonding, autism spectrum disorder, musical aptitude, infidelity, altruism, monogamy, mating, substance abuse, and alcohol preference. In addition, there were associations with pain, stress pain by sex, and sickle cell pain. CONCLUSION: Summary of this literature could provide insights into future pain research of this SNP in people with SCD.

Differences in Sensory Pain, Expectation, and Satisfaction Reported by Outpatients with Cancer or Sickle Cell Disease.

BACKGROUND: Patients with sickle cell disease (SCD) report pain scores that appear greater than those reported in a meta-analysis for patients with cancer, but statistical comparisons of the pain scores from both populations have not been published. AIMS: The goal of the study described here was to compare pain outcomes reported by outpatients with cancer or SCD. DESIGN: Descriptive comparative study. SETTING: Outpatient oncology or sickle cell clinics. SUBJECTS: The participants were outpatients (N = 415) from three studies: (1) 106 patients with SCD, 93% African-American (referent group); (2) 140 patients with cancer, 90% Caucasian (race discordant); (3) 169 patients with cancer, 20% Caucasian, 65% African-American (race concordant). METHODS: Patients completed the PAINReportIt including pain location, quality, pattern, intensity, expectation, satisfaction, and demographic questions. Analyses included the χ2 test, analysis of variance, and regression. RESULTS: Outpatients with SCD reported more pain location sites than the race-discordant (p < .001) and race-concordant (p < .001) cancer groups; higher pain quality than the race-discordant (p < .001) and race-concordant (p < .001) groups; and greater pain pattern scores than the race-discordant (p < .001) and race-concordant (p < .001) groups. The race-concordant group reported higher worst pain intensity than the SCD (p < .001) and race-discordant (p = .002) groups. The three groups did not differ significantly on pain expectation (p = .06). Regarding satisfaction with pain level, there was a significant difference between the race-concordant and SCD (p = .006) groups, but not between the race-discordant and SCD (p = .12) groups or between the race-discordant and race-concordant (p = .49) groups. CONCLUSIONS: Outpatients with SCD reported three of four sensory pain parameters that were greater than those reported by outpatients with cancer. A better understanding of these differences is pertinent to improving pain outcomes.

Management of Sickle Cell Pain Using Pregabalin: A Pilot Study.

Sickle cell disease (SCD) pain may have a neuropathic component. Adjuvant drugs used to treat neuropathic pain have not been studied for the treatment of adults with SCD. To determine the safety and feasibility of using pregabalin for chronic SCD pain. A randomized, controlled, double-blind pilot study. Based on random assignment, participants were treated with pregabalin or placebo control for 3 months with monthly follow-up visits. Participants were recruited from the University of Illinois Hospital and Health Sciences System outpatient SCD clinic. Participants/Subjects: A total of 22 participants with SCD (21 African American, 1 other) were included 16 women aged 18-82 (mean age 33.1 ± 9.9). PAINReportIt, Leeds Assessment of Neuropathic Signs and Symptoms, Neuropathic Pain Symptom Inventory, and Short Form 36 Health Survey were completed. Adverse effects were minimal. Mean scores for average pain intensity, composite pain index, and neuropathic pain revealed a reduction for pregabalin and placebo control groups. Although the between-group differences were not significant, sustained reduction in pain over time within the pregabalin group indicated promising effects of pregabalin for SCD pain. Mean quality-of-life scores increased slightly over time (representing better quality of life) in 7 of 8 domains for the pregabalin group and decreased in 4 of 8 domains for the placebo control group. Small sample size made it difficult to interpret quality-of-life findings. This pilot study provided sufficient evidence that further investigation of pregabalin's potential efficacy for treatment of chronic SCD pain in adults is warranted.

Nonmyeloablative Stem Cell Transplantation with Alemtuzumab/Low-Dose Irradiation to Cure and Improve the Quality of Life of Adults with Sickle Cell Disease.

Allogeneic hematopoietic stem cell transplantation (HSCT) is rarely performed in adult patients with sickle cell disease (SCD). We utilized the chemotherapy-free, alemtuzumab/total body irradiation 300 cGy regimen with sirolimus as post-transplantation immunosuppression in 13 high-risk SCD adult patients between November 2011 and June 2014. Patients received matched related donor (MRD) granulocyte colony-stimulating factor-mobilized peripheral blood stem cells, including 2 cases that were ABO incompatible. Quality-of-life (QoL) measurements were performed at different time points after HSCT. All 13 patients initially engrafted. A stable mixed donor/recipient chimerism was maintained in 12 patients (92%), whereas 1 patient not compliant with sirolimus experienced secondary graft failure. With a median follow-up of 22 months (range, 12 to 44 months) there was no mortality, no acute or chronic graft-versus-host disease (GVHD), and no grades 3 or 4 extramedullary toxicities. At 1 year after transplantation, patients with stable donor chimerism have normalized hemoglobin concentrations and improved cardiopulmonary and QoL parameters including bodily pain, general health, and vitality. In 4 patients, sirolimus was stopped without rejection or SCD-related complications. These results underscore the successful use of a chemotherapy-free regimen in MRD HSCT for high-risk adult SCD patients and demonstrates a high cure rate, absence of GVHD or mortality, and improvement in QoL including the applicability of this regimen in ABO mismatched cases (NCT number 01499888).

Patterns of opioid use in sickle cell disease.

Pain, the hallmark complication of sickle cell disease (SCD), is largely managed with opioid analgesics in the United States, but comprehensive data regarding the long-term use of opioids in this patient population is lacking. The pain medication prescription records from a cohort of 203 SCD patients were analyzed. Twenty-five percent were not prescribed opioid medications while 47% took only short-acting opioids, 1% took only long-acting opioids, and 27% took a combination of short-acting and long-acting opioids. The median (interquartile range) daily opioid dose was 6.1 mg (1.7-26.3 mg) of oral morphine equivalents, which is lower than the published opioid use among patients with other pain syndromes. The dose of opioids correlated with the number of admissions due to vaso-occlusive crisis (VOC) (r = 0.53, P < 0.001). When the patients were grouped into quartiles based on daily dose opioid use, a logistic regression model showed that history of avascular necrosis (AVN) (OR: 2.87, 95% CI: 1.37-6.02, P = 0.005), 25-OHD levels (OR: 0.59, 95% CI: 0.38-0.93, P = 0.024) and total bilirubin concentration (OR: 0.64, 95% CI: 0.42-0.99, P = 0.043) were independently associated with opioid use quartiles. In conclusion, doses and types of opioid medications used by adult SCD patients vary widely. Our findings implicate AVN and lower vitamin D levels as factors associated with higher opioid use. They also suggest an association of higher bilirubin levels, possibly suggesting higher hemolytic rate, with lower opioid use. Am. J. Hematol. 91:1102-1106, 2016. © 2016 Wiley Periodicals, Inc.

Reproductive Health CHOICES for Young Adults with Sickle Cell Disease or Trait: Randomized Controlled Trial Outcomes over Two Years.

Interventions to assist reproductive health decision-making in populations affected by sickle cell disease (SCD) or trait (SCT) lack proven efficacy over time. Our aim was to compare effects of CHOICES, a Web-based multimedia education program on implementing informed reproductive plans, and usual care education (e-Book) on reproductive knowledge, intention, and behavior over 24 months. We randomized 234 participants with SCD (n = 138) or SCT (n = 96) (age 18-35 years, 35 % male, 94 % African American) to CHOICES and e-Book groups. Participants completed a sickle cell-specific reproductive measure before and four times after the intervention (6, 12, 18 and 24 months). Compared to the e-Book group the CHOICES group had significantly more improvement in knowledge over time (p = .004) but not intention (p = .18) or behavior (p = .69). At baseline, 114 (48.7 %) participants reported having partners who would not put the couple at risk for their children inheriting SCD. Of the 116 (49.6 %) at-risk participants, a higher poroportion of those who were in the CHOICES group chose partners that reduced their risk by the last visit than the e-Book group (p = .04). Study findings provide important insights for designing a national trial of the CHOICES intervention focusing on subjects whose partner status puts them at risk for having a child with SCD.