This article is the second installment in the “Ask Dr. Kevin” series brought to you by Pfizer Rare Disease in collaboration with the National Newspaper Publishers Association (NNPA) to increase understanding of sickle cell disease. In the United States, sickle cell disease (SCD) is considered rare because it affects only about 100,000 people nationwide. As such, not many people in the U.S. are aware of what SCD is, or if they are aware, they have limited experience with the disease. As with any disease, low awareness can spur myths and misperceptions and make it more difficult for those affected to obtain the care and support they need. Throughout my career, I have been asked a number of questions about SCD – many of which are common myths. In this article, I will share some of the more common myths, in an effort to separate out the facts from fiction. Abstract source

BACKGROUND: Haemopoietic progenitor cell (HPC) transplantation can cure sickle cell disease. Non-myeloablative conditioning typically results in donor-derived erythrocytes and stable mixed chimerism of recipient-derived and donor-derived leucocytes. Exposure to donor antigens from the HPC graft and new red cell antibodies induced by transfusion can lead to immunohaematological complications. We assessed the incidence of such complications among HPC transplant recipients with sickle cell disease. METHODS: The study population was all patients with sickle cell disease enrolled before March 31, 2015, in the three clinical trials of non-myeloablative HPC transplantation at the National Institutes of Health. We assessed formation of new red cell antibodies after transplantation and red cell incompatibility between donors and recipients. FINDINGS: 61 patients were enrolled, 42 were HLA matched and 19 were haploidentical. Nine (15%) had immunohaematological complications. Before HPC transplantation, three patients had antibodies incompatible with their donors. After HPC transplantation, new red cell antibodies were seen in six patients (11 alloantibodies and two autoantibodies), among whom three developed antibodies incompatible with donor or recipient red cells and three developed compatible antibodies. The clinical course of complications was highly variable, from no severe effects attributable to antibodies, to sustained reticulocytopenia, to near-fatal haemolysis. We found no significant correlation between immunohaematological complications and graft failure, graft rejection, or death. Abstract source Full text

Treatment of vaso-occlusive crises (VOC) or events in sickle cell disease (SCD) remains limited to symptom relief with opioids. Animal models support the effectiveness of the pan-selectin inhibitor GMI-1070 in reducing selectin-mediated cell adhesion and abrogating VOC. We studied GMI-1070 in a prospective multicenter, randomized, placebo-controlled, double-blind, phase 2 study of 76 SCD patients with VOC. Study drug (GMI-1070 or placebo) was given every 12 hours for up to 15 doses. Other treatment was per institutional standard of care. All subjects reached the composite primary end point of resolution of VOC. Although time to reach the composite primary end point was not statistically different between the groups, clinically meaningful reductions in mean and median times to VOC resolution of 41 and 63 hours (28% and 48%, P = .19 for both) were observed in the active treatment group vs the placebo group. As a secondary end point, GMI-1070 appeared safe in acute vaso-occlusion, and adverse events were not different in the two arms. Also in secondary analyses, mean cumulative IV opioid analgesic use was reduced by 83% with GMI-1070 vs placebo (P = .010). These results support a phase 3 study of GMI-1070 (now rivipansel) for SCD VOC. This trial was registered at www.clinicaltrials.gov as #NCT01119833. Abstract source Full text Full text (PMC)

Background: Transition from pediatric to adult centered care for emerging adults with sickle cell disease (SCD) has previously been unsuccessful due to lack of connection to adult providers with experience with SCD, physician mistrust, poor patient preparation, and difficulty navigating the adult health care system. The resulting gaps in medical care lead to decreased out-patient visits and increased Emergency Department (ED) visits and hospitalizations, contributing to fragmented care and poor outcomes. Objectives: To assess barriers that adults with SCD face when accessing adult care, satisfaction and trust with medical providers, and health care utilization. Results: Only 62% of the 34 survey participants, ages 22-39 years, identified having an adult PCP and/or hematologist. Patients’ general satisfaction with care increased as their trust increased in both their adult hematologist (p=0.001) and PCP (p<0.001). Patients had greater trust in their hematologist (mean score 79.4 vs 65.1, p = 0.0376) and trended towards improved general satisfaction with care (mean score 3.8 vs 3.2, p=0.128) when compared to their PCP. For complications related to SCD, 62% of all participants had been to the ED and 50% had been hospitalized in the previous 6 months. Of those utilizing the ED, 60% had negative comments regarding their care, including delays and sub-optimal dosing in pain management and lack of provider experience with SCD. Regarding their transition experience, 50% were dissatisfied and more than 50% reported they were not prepared for adult care. Conclusion: Almost 40% of patients are not receiving regular medical care for their SCD with a significant portion relying on emergency departments, which can lead to fragmented medical care. There was a higher level of trust and general satisfaction with adult hematologists, which may reflect patients’ confidence in their specialists’ ability to manage their disease. Based on participant feedback, medical care improved when their adult provider was involved in their hospital care, indicating the importance of the connection with an adult provider familiar with their disease, which can lead to improved long-term outcomes. Abstract source

Background: Sickle cell trait (SCT) is an inherited blood disorder that affects 1 to 3 million people in the United States and more than 100 million people worldwide. Previous studies have suggested that having sickle cell trait increases one’s risk of exertional rhabdomyolysis and subsequent death. A number of these cases highlighting several high-profile deaths have been reported in both television and newspaper media and attributed death to SCT. A recent study published in the New England Journal of Medicine reported that SCT was not associated with a higher risk of death than absence of the trait. None of the medical experts in the National Institutes of Health (NIH), American Academy of Pediatrics (AAP), or Centers for Disease Control and Prevention (CDC) advise against participation in competitive sports. We performed a retrospective review of both newspaper and television media to determine if television and newspaper media opinion used evidence-based guidelines in accurately depicting the risks associated with SCT. Objectives: To highlight the discrepancy between the evidence-based guidelines in the medical community with the depiction of SCT-associated risks in national television and newspaper media. Results: Three of the 6 television networks and 9 of the 10 newspaper outlets reported stories relating to SCT, however 1 of the 6 television networks and 3 of the 10 newspaper outlets referenced evidence-based guidelines. Additionally just 1 of the 6 television networks and 2 of the 10 newspaper outlets quoted the NCAA policy pertaining to athletic participation. Conclusion: The absolute risks of SCT are known to be low, but not well described by the mainstream media. More accurate risk estimates are needed, as well as continued research into contributing factors. Widespread dissemination of universal precautions for exertion-related illness and a consistent positive message of SCT participation in athletics may lead to less discrimination of SCT individuals and an overall reduction morbidity and mortality. Abstract source

Background: Chronic transfusion therapy (CTT) for sickle cell anemia (SCA) reduces the risk of stroke by diluting hemoglobin S (HbS) with HbA red blood cells and suppressing erythropoiesis. The goal of a CTT regimen is to maintain pre-transfusion HbS <30% while avoiding hyperviscosity; however established protocols for transfusion volumes are lacking. Objectives: To compare HbS, reticulocytosis, and total blood transfusion volumes between 2 CTT protocols that use higher vs. lower transfusion volume parameters for pediatric SCA patients. Results: There were 82 patients (63 HV, 19 LV protocol, 1 LV/HV) who were followed for 1042 transfusion episodes. Excluding 167 PME and transfusions with TI >40 days, there were 571 HV and 205 LV transfusions. For HV transfusions, there was higher mean transfusion volume (13.3 vs. 12.1 ml/kg, p<0.0001), longer TI (29.9 vs. 27.7 days, p<0.0001), higher Hb (9.74 vs. 9.38 g/dL, p<0.0001), but higher mean HbS (22.4 vs. 20.6%, p=0.034). There was no significant difference in reticulocytes (9.64 vs. 9.09%, p=0.11) or frequency of HbS >30% (21.5% of HV vs. 17.1% of LV transfusions, p=0.18). Including all transfusions, the mean total blood volume per 365 days was 172.4 ml/kg for HV and 168.6 ml/kg for LV transfusions (p=0.58). Conclusion: The HV transfusion protocol allowed higher Hb and did not increase the total blood volume received per year; however HbS suppression was greater with the LV protocol. This study did not examine hyperviscosity, which may be a potential concern with higher transfusion volumes. Abstract source

Background: A hypercoagulable state resulting in increased VTE has been described in adults with SCD. Similar data for children is lacking. Previously, in a single-institution, retrospective study of 414 pediatric patients with SCD followed at Nationwide Children’s Hospital, we identified central venous catheters (CVC) as an independent risk factor for VTE [OR (± 95%CI): 10.3 (1.1-92.2)]. 12/414 (2.9%) subjects developed VTE over the course of the study. Objectives: The objective of this retrospective, multicenter cohort study was to describe risk factors associated with VTE in children with SCD across children’s hospitals in the United States (US). Results: A total of 8966 unique subjects (4359 female) met inclusion criteria with a mean age (±SD) of 10.3 (±6.4) years. 160 subjects (96 female) developed VTE during the study period. Mean age (±95%CI) at VTE diagnosis was 14.8 (±5.9) years. On multivariate analysis, CRD [OR (±95%CI): 5.2 (2.5-11.1)], any CVC placement [4.2 (3.1-5.9)]; history of stroke [2.5 (1.5-4.1)]; female gender [1.6 (1.1-2.2); and older age at admission [1.1 (1.06-1.12)] were identified as risk factors associated with VTE diagnosis. There was a positive correlation between the number of CVCs placed/1000 patients and the number of VTE diagnosed/1000 patients (p=0.02). Conclusion: Rate of VTE in children with SCD admitted to children’s hospital in the US is around 1.8%. CVC use is associated with a nearly 4-fold increased risk of VTE diagnosis. Additionally, CRD, history of stroke, female gender and older age at admission were also associated with VTE diagnosis. Prospective cohort studies are needed to confirm these findings and develop risk prediction models for VTE in children with SCD. Abstract source

Background: Sickle cell disease (SCD) can lead to multiple complications, including bone complications and pain crisis. Vitamin D has been reported to have multiple skeletal and extra-skeletal effects, which might help prevent those complications. Objectives: The objectives of our study were to 1) evaluate the clinical practice at the Sainte-Justine University Hospital Center (UHC) regarding the assessment of vitamin D status in children with SCD, and 2) document the prevalence of vitamin D deficiency, vitamin D intakes and compliance to vitamin D supplementation in our cohort. A secondary objective of our study was to determine if vitamin D deficiency is associated with SCD complications. Results: Our study population included 116 SCD patients, 53% girls; median age at the time of the evaluation of 11.2 years (range 1.3 to 18.4); 49% were Haitians, 49% Africans and 2% of other ethnicities, genotype was 65% HbSS, 27% HbSC and 8% other genotypes. Characteristics of the study population were representative of the entire cohort followed up at our center. Vitamin D status was then assessed in 38% of SCD children followed up in our clinic. Amongst those, 67% of children were vitamin D insufficient while 33% were deficient. Vitamin D intakes were also insufficient (352.59 +/- 234 IU) and were correlated to serum 25-OH-vitamin D levels (p = 0.005). Moreover, 17% of patients took vitamin D supplements, but only 50% were adherent to their supplementation. Finally, 28.6% of insufficient patients had renal complications, compared to 8.3% for non-insufficient patients (p=0.025) while 18.9% of deficient patients tended to have gall-bladder complications compared to 7.2% for non-deficient patients (p= 0.071). Conclusion: Given the high prevalence of vitamin D deficiency and its potential association with SCD complications, vitamin D supplementation and effective compliance strategies should be considered in Canadian children with SCD. These results highlight the need for randomized double blind placebo controlled trials to test the impact of optimal vitamin D supplementation on clinically important outcomes in children with SCD. Abstract source

Background: Children with Sickle Cell Disease (SCD) often experience pain, fatigue, and a host of other stressors that could affect their quality of life. A subset of the population will also manage a second chronic illness; the most prevalent comorbid chronic disease is asthma (15-28% of youth with SCD). Objectives: We compared children with SCD only to children with comorbid SCD and asthma to explore differences in quality of life and academic disruption. Results: Nineteen children (30%) had SCD and asthma. When comparing caregiver-rated PedsQL-SCD Total Scores, the SCD and asthma group demonstrated lower quality of life (M=55.04, SD=21.34) than the SCD-only group (M=71.00, SD=20.54), t(46)=2.47, p=0.017. The SCD and asthma group had more problems with pain-related functional impairment, pain management, anxiety, and communication with medical providers (p’s=0.010-0.030). The SCD and asthma group also missed significantly more days of school (M=20.42, SD=26.89) than the SCD-only group (M=10.52, SD=10.76), t(57)=-2.03, p= 0.047. Higher IQ was associated with better child-rated quality of life for children with SCD and asthma (r=0.467, p=0.019) but not for those with SCD only. Better parent-rated child quality of life was also correlated with having more material resources in the SCD and asthma group (r=0.463, p=0.035) but not in the SCD-only group. Conclusion: Caregivers of children with SCD and asthma feel their children experience poorer quality of life compared to children with SCD only. Adding to evidence of increased functional impairment, children with SCD and asthma also missed more days of school. Child IQ and family resources were associated with quality of life for children with SCD and asthma but not for children with SCD only, suggesting that cognitive and family resources may have a heightened role in moderating disease outcomes on quality of life among children with multiple chronic conditions. Results highlight the increased complexity of managing multiple chronic conditions, but could also reflect cumulative physiological factors influencing disease severity. Youth with SCD and asthma may benefit from disease self-management interventions. Abstract source

Background: Sickle cell disease (SCD), which affects the red blood cell, is the most common genetic disorder in the United States. There are approximately 100,000 patients with SCD in the United States and approximately 15,000 in the Midwest. Sickle Cell Treatment and Outcomes Research in the Midwest (STORM) is a six-state regional learning network funded by Health Resources and Services Administration (HRSA) to improve outcomes for individuals with SCD in Indiana, Illinois, Ohio, Michigan, Minnesota and Wisconsin. Led by the Cincinnati Comprehensive Sickle Cell Center in collaboration with the James M. Anderson Center for Health Systems Excellence, STORM brings together pediatric and adult providers to collaborate with patients and families to 1) address the lack of providers knowledgeable evidence-based management of SCD and 2) improve under-utilization of hydroxyurea by using provider education strategies and quality improvement methods. Objectives: STORM’s global aim is to build a sustainable network to improve outcomes and care for patients with SCD in the Midwest. Our current smart aim is to improve health for patients with SCD, as measured by a 20% increase in the eligible number of patients prescribed hydroxyurea, based on recommendations in the NHLBI Evidence-Based Management of SCD guidelines. Results: Sites received training in QI methods and are now conducting site-specific QI projects to address local needs. Regional data collection efforts are ongoing; currently, there have been over 300 patients and 1700 patient encountered entered into REDCap. Preliminary results show that the number of eligible patients prescribed hydroxyurea has increased 20% over time, and 100% of eligible patients have been offered hydroxyurea in the STORM network. Conclusion: Preliminary data suggests that improvements will continue as sites become more experienced in QI methods. More regional patient-level data will also become useful in guiding future regional quality improvement efforts. Abstract source