Background: Patients with sickle cell disease (SCD) are at increased risk for Osteomyelitis (OM). Diagnosis of OM in this population is challenging and there is limited pediatric data on the characteristics and outcomes of OM in this population. Objectives: To report characteristics and outcomes of OM in children with SCD treated at our center over the last 10 years. Results: Thirty children with SCD (18 males, median age 12 years) were treated for OM at our institution during the study period. The genotype was SS in 27 patients, SC in 2, and SF in 1. Sites of involvement included lower extremity (11), upper extremity (10), pelvis (2), vertebrae (2), scapula (1), clavicle (1), hand (1), ribs (1) and mandible (1). Leukocytosis (>15,000/mm3) was observed in 13 patients (43%) at presentation. Baseline erythrocyte sedimentation rate was elevated (>20 mm/hour) in 29 patients (97%) but marked elevation (>100 mm/hour) was present in 3 patients (10%). Baseline C-reactive protein was elevated (>10 mg/L) in 13 patients (43%). Bacteremia was present in 6 patients (20%). Magnetic resonance imaging (MRI) findings were suggestive of OM in 18 patients (60%) and indeterminate in the remaining patients. The diagnosis of OM was confirmed in 3 patients (bone biopsy), probable in 6 patients (organism isolated from blood or abscess), and presumed in the remaining cases based on clinical, laboratory, and MRI findings. Non-typhoidal Salmonella was isolated from cultures in 9 (30%) patients [bone biopsy (3), abscess (3), and blood (6)] while no organism was found in the remaining 21 (70%) patients. All patients were treated with prolonged antibiotic therapy. Six patients required surgical drainage/debridement. Two patients developed chronic OM. There were no mortalities and complete resolution of OM was achieved in all patients. Conclusion: Despite improvements in the management of SCD over the past decade, OM continues to be a serious infection in children with SCD associated with significant morbidity. The majority of patients are treated for presumed diagnosis of OM without definitive confirmation. Non-typhoidal Salmonella was the only organism identified in our patient cohort. Abstract source

Patients suffering from sickle cell disease (SCD) commonly have varying degrees of chronic debilitating pain and episodic acute pain. The variability is broad even between individuals with the same genotype. In this study, the AVPR1A polymorphism was explored to investigate the contribution of gene polymorphisms to variations in pain for individuals with SCD. The sample of 115 individuals (mean age 34.1 +/- 12.3 [range 15-70 years], 68% female) was 97% African American with SCD (81% SS, 10% SC, 9% other). From electronic health record review and bi-weekly telephone calls with subjects, we determined each patient’s utilization of emergency and acute care services (mean 4.4, SD 5.4 [range from 0 to 38 visits]) as an indicator for acute SCD pain. At a routine clinic visit, patients completed PAINReportIt to obtain the Composite Pain Index (CPI) as an indicator of chronic pain (mean 40.7, SD 13.6, [ranged 14.8 to 86.5]) and we obtained blood samples. We performed genotyping on SNP rs10877969 and found that there were 35 with CC genotype, 45 with CT genotype, and 34 with TT genotype (1 subject’s genotype was unknown). Negative binomial regression of patient utilization found that, controlling for age, sex, and SCD type, subjects with either CC or CT genotype had significantly higher utilization than those with TT genotype (p=0.026). This SNP was not a significant predictor for CPI in this study. In previous studies of SNPs related to AVPR1a, analgesia effects were found to be dependent on both stress and sex. This is the first study to show that this SNP (rs10877969) is significantly related to acute SCD pain, a pain condition also associated with stress and inconsistent findings related to sex. Additional research is needed to further examine the influence of the SNP rs10877969 on pain outcomes. Abstract source

Pain in sickle cell disease (SCD) is a heterogeneous and severe phenotype that requires thorough characterization for precision therapy. The beta 2 adrenergic receptor (ADRB2) is an intronless gene in the monoamine neurotransmitter system that plays an important role in pain perception and modulation; however, its contribution to SCD pain has not been previously examined. In this study, we investigated 16 ADRB2 candidate SNPs that are located in 5’-intergenic/UTR and coding regions on chronic non-crisis pain variability in SCD. Subjects provided informed consent and recorded their pain experience on the tablet-based PAINReportIt system, from which we obtained comprehensive pain phenotypes. The Composite Pain Index (CPI) was used as a measurement for chronic pain. Using the additive multiple linear regression model adjusted for covariates, a single rs17778257 T allele was found to shift CPI by -4.39 (p=0.032). The A allele of rs12654778 caused a 4.52 decrease in the CPI (p=0.019), whereas rs11168070 G allele led to a 5.99 increase in CPI (p=0.016). Rs11959427 C allele caused a 5.69 increase in CPI (p=0.023), and 5’UTR rs1042711 C allele and rs1801704 C allele caused a 10.86 (p=0.000494) and 5.26 (p=0.031) increase, respectively. The coding SNP rs1042713 A allele (Arg16) caused a 5.73 decrease in CPI (p=0.002). Collectively, these SNPs accounted for 2-15% of the variance in CPI. Moreover, we found these SNPs are in linkage disequilibrium showing 3 LD blocks in our cohort. Haplotype analyses reveal association of CPI with a 10-marker haplotype from block 1 leading to a 10.60 increase in CPI (p=0.000341). A 2-marker haplotype from block 2 was associated with a 5.94 decrease in CPI (p=0.001). Data from this study strongly implicated significant influences of ADRB2 polymorphisms and haplotypes on chronic pain in SCD. Abstract source

Introduction: Transition to adult care is a high-risk period with increased health care utilization and death in Sickle Cell Disease (SCD) patients (Brousseau 2010, Hemker BG 2011, Paulukonis ST 2016), as in other chronic illnesses. Lack of transition planning may result in poor quality of care; low patient satisfaction; and avoidable morbidity, ED visits, hospitalizations and mortality. The American Academy of Pediatrics (AAP), American Academy of Family Physicians (AAFP) and American College of Physicians (ACP) issued joint recommendations describing steps to assure effective transition, however, few pediatric hematology practices follow these recommendations. Use of a dedicated transition navigator (TN) from pediatric to adult care has been successful in other chronic illnesses such as congenital heart disease and diabetes. (Mackie 2016) We report on changes in transition readiness following an intensive TN intervention delivered to youth 17-20 years old over a period of 6-12 months at an urban academic medical center. Methods: We developed and implemented a protocolized intervention for young adults with SCD, aged 17-20 years, delivered by a trained TN with 5 goals: (1) an individualized transition plan; (2) a portable medical summary (Transition Passport); (3) improve patient knowledge and skills for self-management of SCD to address quality of care, adherence, and proper use of the ED; (4) address family members’ roles in transition; and (5) facilitate transfer to an adult provider. Youth completed self-administered surveys at enrollment and program completion including the 20-item Transition Readiness Assessment Questionnaire (TRAQ) and measures of SCD knowledge, confidence in disease management, and use of an appropriate pain management plan. Pre/post scores were compared using paired t-tests. Satisfaction with the TN intervention was assessed at program completion. Conclusion: A TN program is acceptable to youth with SCD and feasible to implement at an urban academic medical center. Our data demonstrate that participation in the TN program is associated with improved transition readiness and disease knowledge for youth with SCD. Further study is needed to determine if this intervention improves transfer to adult care and reduces morbidity. Abstract source

Interindividual variability in analgesic effects of opioids prescribed for sickle cell disease (SCD) pain is attributed to polymorphisms in drug metabolizing enzymes and transporters (DMET). We describe UGT2B7, CYP3A4, CYP3A5, and CYP2B6 allelic variants characterized in opioid pharmacokinetic and pharmacodynamic pathways for determination of potential suboptimal opioid exposure in SCD patients. DNA from 165 unrelated SCD patients was genotyped for 2 UGT2B7 alleles, 4 CYP3A4 alleles, 6 CYP3A5 alleles, and 7 CYP2B6 alleles using the iPLEX ADME PGx multiplexed panel. We reported genotype frequencies as homozygous wild-type, heterozygous, and homozygous variant/compound heterozygous; and predicted phenotypes as extensive, intermediate, ultra-rapid, and poor metabolizers. Four CYP2B6 alleles were detected in the cohort. The most common alleles were *1 (0.482) and *6 (0.442). Phenotypes were distributed into EM (21.8%), IM (72%), and UNK (6%).The CYP3A4 *1 frequency was 0.994 and the *20 was 0.006. The phenotypes were distributed as EM (98.8) and IM (1.2%). For the CYP3A5*1, allelic frequency was 0.461. The combined frequency for the *3, *6 & *7 was 0.539. Phenotypically, 23% of the cohort were EM, 30% were PM, and 46.1% were IM. The UGT2BT*1 frequency was 0.785 and the *2 was 0.215. The phenotypes were EM (64.2%), UM/EM (28.5%), and UM (7.3%) respectively. Our study provides important data on the pattern of the UGT2B7, CYP3A4, CYP3A5, and CYP2B6 allelic variants for the first time in an African American SCD cohort. For SCD pain, preemptive genotyping of selected DMETs variants could empower clinicians to communicate pharmacologic risk and drug response prediction with SCD patients using biological evidence as opposed to explaining statistical risk without biological significance. Additional pharmacokinetic studies are necessary to determine the genotype - metabolic phenotype concordance in SCD patients due to the influence of disease state on DMETs expression. Abstract source

Pain is prevalent in sickle cell disease (SCD) patients who display great heterogeneity in pain severity and frequency. Studying the contribution of relevant candidate gene polymorphisms may shed light on the etiology of the pain heterogeneity, allowing for precision pain medicine in SCD. We hypothesize that inflammatory factors are involved in the pathogenesis of sickle cell pain. In this study, we focused on the IL1A C/T polymorphism rs1800587 that is a single nucleotide polymorphism (SNP) located at position -889. The SNP came to our attention because our bioinformatic analysis predicted that this SNP is located in a cis-transcriptional regulatory region modulating the protein expression level. Pain phenotype data were gathered from PAINReportIt, a pain assessment tool for multidimensional pain experience. The composite pain index (CPI) was used as a measurement for the baseline pain. Utilization of urgent or emergency care due to sickling pain crisis was used as a surrogate for acute pain crisis in SCD. We found the T allele was associated with increased CPI. In our SCD cohort, each T allele was associated with a 3.9 increase in CPI (p=0.04), accounting for 3% of variability in CPI as determined by the additive multiple linear regression. We did not find significant association between this SNP and the patient utilization due to acute pain. These results represent the first indication that IL1A rs1800587 may influence the chronic non-crisis pain in SCD. Abstract source

Chronic pain in sickle cell disease (SCD) often begins during adolescence, affecting approximately 23% of youth and up to 37% of adults. Youth with chronic SCD pain report moderate-severe levels of functional disability and reduced quality of life. Protective parenting and parent pain catastrophizing are known to contribute to poor functional outcomes among youth with chronic pain; however, little is known about parent influences that contribute to the persistence of chronic pain and disability in SCD. This study examined the interplay between protective parenting and parent catastrophizing and its impact on functional disability among youth with chronic SCD pain. Adolescents with SCD (n=40, Mage = 14.4, SD = 2.6) characterized as having chronic pain (i.e., pain ≥ 3 days/week/month, persisting for ≥ 3 months) completed measures of pain characteristics and disability (Functional Disability Inventory). Parents completed measures of catastrophizing (Pain Catastrophizing Scale) and parenting behaviors in response to pain (Adult Responses to Children’s Symptoms). As predicted, controlling for pain intensity, a significant two-way interaction emerged between protective parenting and parent catastrophizing in predicting adolescent disability (t=2.88, p<.01). For parents who reported high levels of pain catastrophizing, high engagement in protective parenting behaviors was associated with severe levels of child disability. In contrast, for parents reporting low levels of catastrophizing, protective parenting was not predictive of disability. Youth with chronic SCD pain are most adversely affected in their disability by both high parent catastrophizing and high engagement in protective parenting. Parents’ increased anxiety about pain combined with solicitous parenting responses likely results in adolescents’ restricted engagement in daily activities and fewer opportunities to gain independence; these patterns may limit adolescents’ ability to improve function despite chronic pain. More targeted parent training during behavioral pain treatment may promote more robust functional improvements in pediatric SCD. Abstract source

Patients and families seek treatment in Emergency Departments (ED) for chronic pain when in crisis. The purpose of this study was to describe the prevalence of ED visits for pediatric chronic pain conditions and pain treatments used during these visits. Data for this secondary analysis were obtained from the Pediatric Health Information System (PHIS) administrative database of inpatient, ED, ambulatory surgery and observation encounter-level data from 49 US children’s hospitals. Data from ED visits coded for chronic pain (excluding sickle cell disease) from January 1, 2012 to December 31, 2015 were analyzed. During the 4-year study period, 24 hospitals had data reported for the entire study period. Included hospitals reported a total of 531 ED visits for 512 patients < 18 years of age with chronic pain. The 4-year trend shows visits have increased over time, few patients (n=6) have >1 visit to the same ED each year, and hospital admission from the ED for chronic pain is rare. Analgesic administration steadily increased from 80 to 90% of visits. However, opioid administration decreased, with < 30% of pediatric patients diagnosed with chronic pain receiving opioids in the ED. The CDC reports increasing use of opioids to treat adults with chronic pain conditions; whereas these data indicate decreasing use of opioids to treat pediatric chronic pain conditions in the ED. PHIS data does not include non-pharmacologic pain treatments used in the ED or what was prescribed for patients upon ED discharge. Despite these limitations, we conclude that pediatric patients with chronic pain are likely to receive a non-opioid analgesic when pain crisis leads them to seek treatment in the ED. Increasing use of the ED for treatment of pediatric chronic pain conditions suggests the need to increase the availability of multidisciplinary pediatric chronic programs in the US. Abstract source

Stigma is associated with adverse health outcomes. Patients with sickle cell disease (SCD) experience stigma because of their minority status, frequency of their acute healthcare utilization, and chronic use of opioids for pain management. There is minimal research on the association of sickle cell-related stigma (stigma) with physical and emotional symptoms in adult patients with SCD. This descriptive comparative study was conducted to determine the association of stigma with physical (pain and fatigue) and emotional (anger, anxiety, and depression) symptoms in patients with SCD. Patients (N=52, mean age 36.1±10.9 years [ranged from 22-74 years], 96% African-American, 56% female) recruited between March-November 2015 completed PAINReportIt, a computerized pain measure, demographic questions, the Sickle Cell Stigma Scale, and the PROMIS measures (anger, anxiety, and depression). Data were analyzed using the statistical software R. The mean scores for the study variables were: Stigma (2.3±1.0); average pain intensity (4.0±2.3); fatigue (56.3±9.5); anger (51.1±12.6); anxiety (52.8±9.3); and depression (51.8±10.2). Our comparative analysis results indicated that there were statistically significant differences between Low Stigma (<=2, n=26) and High Stigma (>2, n=26) groups on study variables. Patients who reported high stigma were more likely to report increased: fatigue (p<.001); anger (p<.001); anxiety (p<.001); and depression (p<.001) than patients who reported low stigma. Patient who reported high stigma and those who reported low stigma did not differ on average pain intensity (p=.07). Findings provide preliminary evidence of the association of stigma with fatigue, anger, anxiety, and depression in patients with SCD. Results from future studies will provide additional evidence to better understand the influence of stigma on physical and emotional symptoms in patients with SCD, and likely inform future intervention studies to decrease stigma in this vulnerable pain patient population. Abstract source

One of the major and most encumbering complications of sickle cell disease (SCD) are recurrent episodes of acute pain crises, which are often superimposed on chronic pain and managed with high opiate dosages. Consequently, recurrent acute painful episodes may lead to opioid tolerance, transition to chronic pain, and in some cases, opioid-induced hyperalgesia (OIH). A review of the literature reveals anecdotal case reports of ketamine infusion for patients whose SCD pain crises were refractory to opioids, resulting in reduced pain scores and opioid use, and suggesting that ketamine may serve as a useful adjunct in the management of severe SCD-induced pain. We present our experience with 10 opioid-tolerant adult patients with SCD who were admitted to the University of Colorado Hospital for acute exacerbation of pain refractory to opioid therapy. These patients received a total of 72 continuous ketamine infusions, representing the largest reported experience to date. Sixty-six (91.7%) of the administrations led to reduced pain intensity scores (from an average of 7.88 to 4.25 out of 10) and reduced opioid intake. Only a total of 8 administrations (11.1%) caused side effects, including hallucinations and vomiting, that led to discontinuation. Ongoing analysis will determine if there is a subsequent sustained reduction in chronic opioid dosing. These data suggest ketamine infusion may be beneficial as an analgesic adjunct in the management of severe acute pain in patients with SCD. However, a randomized trial will be necessary to cultivate an evidence-based protocol for the use of ketamine infusion as a therapeutic option for patients with SCD whose pain become severe and refractory to opioids. Abstract source