Background: Hydroxyurea is well established as the standard of care for children with sickle cell anemia (SCA) in the US, but current dosing schemes and dose responses for individual patients are highly variable. Traditionally, hydroxyurea is started at a low dose of 15-20 mg/kg/day, then slowly escalated to maximum tolerated dose (MTD) based upon hematological parameters to avoid toxicities. Using this approach, the average hydroxyurea MTD is about 25 mg/kg/day and yields an average HbF induction of 20-25%, but the time to achieve MTD is more than 6 months. We developed and prospectively evaluated a population pharmacokinetics (PK)-based dosing model of hydroxyurea for children with SCA, aiming to initiate hydroxyurea at a personalized dose that achieves MTD quickly and achieves a more robust HbF response. Results: A total of 38 children enrolled in TREAT had PK studies performed to generate an individualized starting dose. Only three participants (7.9%) had incomplete PK studies that did not allow for an individualized starting dose and were started at 20 mg/kg. The enrolled children were young with an average (mean±SD) age of 3.1±4.3 years. Most participants (26/38=68%) were less than two years of age at enrollment, while half (19/38=50%) were less than one year of age. For participants starting with PK-based dosing (n=35), the average starting hydroxyurea dose was 27.5±4.5 mg/kg/day, with 12/35 children (34%) starting hydroxyurea at doses >=30 mg/kg/day. Despite the high starting doses, there were very few hematological toxicities, with only 2/35 participants requiring a dose decrease from the starting dose due to moderate neutropenia. The individualized starting dose was the actual MTD for 73% of participants without the need for a single dose escalation. The mean time to MTD was 6.2 months (median 4 months) compared to a historical baseline of 9 months. Even with high starting HbF (24.9±11.6%), response was excellent with all participants who have completed at least 6 months of hydroxyurea demonstrating an increase in HbF from baseline. The mean maximum achieved HbF is 35.5±9.5% with 74% achieving HbF>30% and 35% achieving HbF>40%. Abstract source

Background: Sickle cell disease (SCD) is an inherited blood disorder characterized by vaso-occlusive crises (VOC). Abnormal hemoglobin-S polymerizes after releasing oxygen to tissue which leads to the formation of sickled red blood cells (RBC) that obstruct the blood flow in the capillary circuit. Any trigger that decreases microvascular perfusion can further promote vaso-occlusion with increased risk of VOC. We used a novel methodology to quantify the regional microvascular blood flow (MBF) as a physiological biomarker of neural response to thermal pain and showed that there was a greater change in MBF due to thermal pain in patients with SCD. Interestingly, we noticed that there was decrease in MBF when subjects were told they were about to experience pain, suggesting that neural induced vasoconstriction might be a physiologic link between common VOC triggers like stress and vaso-occlusion. Objectives: To determine if pain anticipation and mental stress causes decrease in MBF in SCD. Results: When subjects were told that they were about to experience severe pain from heat applied to their arm in the pain anticipation task, there was a significant decrease in MBF compared to baseline(p<0.0001). However, there was no significant difference in MBF compared to baseline when heat pain was applied without verbal instructions. There was a significant decrease in MBF during N-back and Stroop compared to baseline(p<0.01). Conclusion: There was a profound vasoconstriction response (VCR) to anxiety induced by pain anticipation and stress tasks which is congruent with clinical observations that social and mental stress can trigger VOC. Unlike our previous studies, the VCR response during thermal pain was not significant, in the absence of induced anxiety. This could explain objectively how stress may play a role in the initiation of VOC in SCD by enhancing neural mediated vasoconstriction and increasing the likelihood of vaso-occlusion. Importantly, the methodology presented here offers a way to quantify physiological response to mental stress. Abstract source

Background: Sickle cell disease (SCD) affects approximately 100,000 individuals in the US. Efforts have been directed towards improving the management of complications that individuals with SCD experience: penicillin (PCN) prophylaxis study, the multi-center study of hydroxyurea (HU) and stroke prevention trials. Although the NIH has provided guidelines based on these, there remain significant gaps both in in best clinical practices and community support for children with SCD and a pressing current need to address aspects of health, equity and racial disparity in this population. Objectives: For providers and support staff of children with SCD in the New England area to work together to develop practice guidelines, community based participatory research with an opportunity to share data, to share clinical experiences, and to provide community and provider support for affected children and their families. Results: Over time the NEPSCC has added members, including an American Red Cross staff member, adult primary care and hematology providers, community based organizations, and an institution outside New England: Wyckoff Hospital, Brooklyn, New York. Research from the consortium includes one paper on obesity in SCD and a number of abstracts presented at national meetings. There is currently a study across the consortium on the impact of HU in children. In addition, through public-private partnerships, NEPSCC has held seven, annual, daylong symposia, free of charge, for members and the greater regional SCD community. Topics presented include pain management, describing conventional and alternative approaches, indications for HU therapy, transition from pediatric to adult care, sickle cell trait, clinical trials, and transplantation. NEPSCC has published handbooks for patients and their families and made available social, legal and medical resources for the community both online and in print. Conclusion: With a passion for improving the wellbeing of patients and a willingness to devote time and energy (membership is entirely voluntary), it is possible to bring together a group of likeminded providers and SCD community-based organizations to work at a regional level for the betterment of children and families affected by SCD. Abstract source

Background: Sickle cell disease (SCD) is an inherited condition affecting over 100,000 individuals in the United States with increasing prevalence, with annual healthcare costs of approximately $488 million dollars. Peak rates of healthcare utilization occur in the young adult population, with the highest mortality risk when transitioning to adult care. This has prompted increased efforts to improve the transition process from pediatric to adult care, in addition to optimizing overall care for SCD patients. The impact of these efforts on current healthcare utilization, including reasons for hospitalization, has yet to be explored. This study sought to explore current rates of healthcare utilization in SCD patients, measured by inpatient hospitalizations, as well as the most common reasons for hospitalization to inform continued efforts to improve outcomes in the SCD population. Results: A total of 19,729 patients had at least one hospitalization from 2005-2014 coded for SCD, with a total of 140,779 hospitalizations. The SCD population was 57.6% female and the primary insurance type was Medicaid (49.9%). The mean age at index hospitalization was 26.5 years (SD 19.3, range 0-104) and the mean length of stay was 5.5 days (SD 11.4). At the time of the index hospitalization SCD patients aged18-30 years made up 29% of the population (Table 1). The largest percentage of all hospitalizations also occurred among patients in this age group (33.3% of total encounters). Hospitalization rates per 10 person-years of observation were similar among patients aged 10-17 years (13.2), 18-30 years (13.8), 31-45 years (12.9) and 46-64 years (13.3). Both 30-day and 90-day readmissions after the index hospitalization were highest in the 18-30 year age group (33.9% and 31.1%, respectively, Table 2). The most commonly coded diagnoses were pneumonia (23.3%), vaso-occlusive crisis (22.9%) and respiratory infection (20.1%, Table 3). The most commonly coded principal diagnosis was vaso-occlusive crisis (11.7%). Diagnoses associated with the respiratory system accounted for the largest category of hospitalization reasons, including: pneumonia (23.3%), respiratory infection (20.1%), asthma (14.5%), respiratory failure (11.0%) and chronic lung disease (14.6%). (Table 3) Conclusion: Analysis of 10 years of inpatient data shows that overall rates of hospitalizations in SCD patients have decreased as compared to those previously reported in the literature. Rates per person years were similar across most age groups, but 30-day readmission, a frequently used quality metric, was highest in the young adult age group. This suggests an improvement in utilization patterns, but also reiterates the need for targeted efforts towards improved care in the young adult group. Hospitalizations were frequently due to vaso-occlusive episodes, and a large number of hospitalizations were due to complications of the pulmonary system, both infectious and non-infectious. Directed efforts towards optimizing pulmonary health and aggressive treatment of respiratory infections may further decrease the utilization burden and hasten the improvement of outcomes in the SCD population. Abstract source

Background: Sickle cell anemia (SCA) is an inherited hemoglobinopathy characterized by episodic painful crises, progressive multi-organ injury, and early death. Hydroxyurea (HU) is the only FDA-approved disease modifying medicine for SCA. Recent NHLBI guidelines recommend offering HU to all children with SCA. Despite this, many eligible children are not on this treatment. Novel strategies to increase HU use in children with SCA are needed. Objectives: To evaluate the effectiveness of an intervention to start HU in children with SCA soon after a disease complication. Results: Over 9 months (2/17/2016 – 12/1/2016), 69 eligible patients presented to our ED. 68% (n=47) attended a Q-SHIP session a median of 5 days (IQR 1.5-15.5) after ED or hospital discharge. Median patient age was 8.1 years (IQR 5.0-16.5). Nearly half of participants (parents or patients >18 years old), reported no previous HU offer (49%, n=23/47), but documentation in 69% (n=15/23) of these patients’ charts stated that HU had been offered and declined. Patients/parents who reported a previous HU offer (n=24) had not previously accepted HU due to concern for treatment side effects (n=8), infrequent SCA complications (n=6), and wanting more information (n=6). Post-intervention, 51% of patients (n=24/47) started HU. The intervention was equally effective for participants who reported a previous HU offer compared to those who reported no previous offer (13/24, 54%, vs. 11/23, 48%, p=0.66). At follow-up (median 5.5 months, IQR 1.9-7.6), 91% of patients (n=22/24) who started HU after Q-SHIP continued taking it. Conclusion: Targeted HU education for patients who recently suffered a SCA complication led to HU initiation in over half of participants. This raises the intriguing possibility that intervention after an acute SCA complication will increase parent/patient HU acceptance. Surprisingly, many parents/patients reported no prior HU offer despite documentation to the contrary. This may reflect an unappreciated communication barrier between parents/patients and providers that requires further study. Abstract source

We recently showed that in Sickle Cell Disease (SCD), activation of anti-viral restriction factor SAMHD1 and NF-κB inhibitor, IkBα prevented ex vivo HIV-1 infection. SAMHD1 activation was due to its reduced phosphorylation by CDK2, whose activity was inhibited by reduced intracellular iron levels in SCD peripheral blood mononuclear cells (PBMC). We also found that a hazard ratio associated with HIV infection among 11,412 SCD trait subjects was 1.0% comparing to >2% HIV-1 infection among African-Americans in USA. We compared 9 HbAS HIV-1 infected individuals with 107 HbAA or HbAC HIV-1 infected individuals who were enrolled at Howard University clinic. While hemoglobin levels in these two groups were not significantly different, HIV-1 viral load was significantly lower in HbAS group as well the number of HIV-1 associated complications (Hospitalization) were reduced. In the present study, we analyzed ex vivo HIV-1 infection of SCD trait PBMC and determined the expression of iron and hypoxia-regulated host factors including HO-1, NFκB, IKK, IKBα that are implicated in HIV-1 replication. We also analyzed CDK2 activity, SAMHD1 phosphorylation and RNR2 expression in SCD trait PBMCs. One round HIV-1 infection was significantly reduced in in SCD trait PBMC. Expression of HO-1 and IKBα was upregulated in SCD trait whereas IKK and NF-κB expression was downregulated. While CDK2 activity and SAMHD1 phosphorylation were not changed, RNR2 expression was reduced. Expression levels of HIV-1 env and gag mRNA were significantly lower in HIV-1 infected SCD trait subjects. In the same patients, HO-1 and IKBα mRNA levels were upregulated comparing to HIV-1+ HbAA or HbAC subjects. Our findings suggest that HIV-1 infection might be deregulation in SCD trait and that iron metabolism and hypoxia might play a role in this deregulation. Abstract source

Background: Pain during Vaso-Occlusive Crisis (VOC) is a hallmark of sickle cell disease (SCD) as deoxygenated (sickled) red blood cells (RBC) aggregate in the microvasculature due to Hemoglobin S (HbS) polymerization. PEGylated carboxyhemoglobin bovine (PEG-COHb; SANGUINATE®) was designed as a gas transfer agent to depolymerize HbS resulting from hypoxia. Prior in vitro studies have shown PEG-COHb capability to transfer carbon monoxide (CO) and oxygen (O2) to SCD hypoxic RBCs, reversing sickling. A prospective, randomized, single-dose Phase II clinical study is in progress (NCT02411708) evaluating the safety and efficacy of PEG-COHb in the treatment of severe VOC including pain reduction in the ambulatory setting. This study is also evaluating the levels of RBC sickling following treatment and association with pain scoring. Methods: Participants were randomized to a PEG-COHb (320 mg/kg) or saline (placebo) arm, in addition to standard treatment and IV opioid per institutional practice. Pain was assessed using a 10-point pain scale at screening, pre-infusion, hourly until discharge, 24-hours, 72-hours, and Day 7 post-infusion. Blood was collected at pre-infusion, time for readiness to discharge and 72 hours post-infusion to assess RBC shape morphology changes using image-based flow cytometry. Results: Interim results showed PEG-COHb treated subjects experienced significant reduction at discharge in pain score of 4.3 (±0.3) compared to 2.4 (±0.6) reduction in the placebo arm (p<0.01) (Fig 1). All PEG-COHb participants exhibited RBC morphology changes consistent with unsickling shortly after administration (Fig 2). There were no drug-related severe adverse events. Conclusions: PEG-COHb appeared to be safe, well tolerated, and associated with significantly reduced pain scores. The flow cytometry analysis of blood samples revealed PEG-COHb treatment reverted RBC to a more normal round morphology when compared to the placebo group. Individual patient data showed a trend between RBC unsickling (roundness) and pain score reductions. These results are consistent with depolymerization of HbS resulting from transfer of CO and/or O2 to sickled RBCs and O2 delivery to hypoxic tissue. This study supports advanced clinical trials of PEG-COHb as a potential therapy to reduce the pain associated with VOC. Abstract source

Clinical trials in sickle cell disease (SCD) continue to have challenges achieving clinical endpoints. Most SCD clinical trials have focused on painful vaso-occlusive crisis (VOC) episodes because they are prevalent, debilitating and often lead to medical contact. However with VOC as a clinical endpoint: there are no objective, quantifiable biomarkers of pain; pain may not be specific to VOC; the threshold for medical contact varies between patients; VOCs occurring at home without medical contact are not captured; other components of VOC (e.g., fatigue, functioning) are poorly assessed. We therefore undertook the present non-interventional, longitudinal study to test novel tools for the identification of VOCs occurring in SCD patients with varying degrees of medical contact. During 6 months of evaluation, longitudinal measures of pain, fatigue, function, activity (by actigraphy), clinical laboratory and biomarker samples from SCD patients (+/- hydroxyurea therapy) in steady state to VOC were studied. A novel electronic patient-reported outcome tool (ePRO) enabled patients to self-report daily pain, fatigue, function, and medication use. It was also used to report VOC in real time, triggering an alert to a mobile phlebotomy team. Blood collections were taken within 24 and 48 hours of self-reported VOC onset (either at home, emergency department [ED], or hospital). Follow-up blood samples were collected 2 days after resolution of the VOC. Baseline blood samples were drawn at home every 3 weeks during stable, non-VOC periods. Biomarker assays included leukocyte-platelet aggregates and circulating microparticles measured by flow cytometry, cell adhesion in microfluidic flow-based assays to immobilized vascular cell adhesion molecule or P-selectin, and a panel of soluble adhesion molecules, cytokines, inflammatory mediators and coagulation factors. Patients wore a Phillips Actiwatch Spectrum™ actigraphy device to track sleep and activity. Patient-reported outcomes, activity, and biomarkers on non-VOC days were compared to those on VOC days using a mixed model approach and results are reported as means with 95% confidence intervals (95%CI). Abstract source

Introduction: Pain in sickle cell disease (SCD) starts as episodes of recurrent pain and progresses to chronic pain with age. Pain is typically treated with opioids which are often insufficient. One reason for this may be that opioids likely do not effectively treat neuropathic or inflammatory pain in SCD. Cannabinoids, such as marijuana, alleviate neuropathic pain and reduce inflammation. Our SCD patients report marijuana improves their pain and studies in murine models of SCD show cannabinoids reduce mast cell activation, inflammation, and hyperalgesia. Medical marijuana is now legal in 28 states and 4 of them list SCD as a qualifying condition. However, there are minimal data on the use of marijuana in SCD. Thus, we performed a pilot study of adults with SCD who use daily marijuana. Our hypothesis was that daily marijuana users would have worse pain scores from non-daily users which drives their drug use. Our secondary hypotheses were that daily marijuana users may have decreased levels of opioid use, hospital utilization, quality of life measures (QoL) or inflammation. Results: We enrolled 29 subjects,16 (55%) of whom reported marijuana use in the past 30 days and of those 6 (21%) reported daily marijuana use. Pain relief was endorsed as a reason for marijuana use in 93% of users and 100% of daily users. There was no difference in mean age (32.0 SD 8.6 vs 32.4 SD 12.6 years p=1.0) or gender (% female: 67 vs 52% p=0.7) between groups. Daily marijuana users had higher pain crisis severity scores (61.7 vs 50.0 p=0.03). There was no significant difference in scores for pain crisis frequency, pain interference, or other QoL measures (Table). Daily users had similar median annual admissions and emergency room visits to non-daily users (1.0 (IQR 0.25-1.0) vs 2.0 (IQR 0 - 5.0) admissions p=0.3; 1.0 (IQR 0.25-1.75) vs 0 (IQR 0-1.5) ED visits p=0.6) and used similar doses of weekly opioids (274.5 [IQR 91.5-3447.9] vs 28.6 [IQR 3.03-135.6] mg weekly po morphine equivalents p=0.5). There were no differences in CRP, CBC, CECs or EPCs, or in levels of all neutrophils and monocytes types. Conclusion: In our pilot study, we found daily marijuana users reported more severe pain crisis, but had similar rates of hospital utilization and similar amounts of opioids dispensed. We posit that patients with more severe pain crisis may use daily marijuana to effectively treat their pain allowing them to have similar hospital and opioid utilization to those with less severe pain. Larger prospective studies should be performed to test these hypotheses. Abstract source

Introduction: In 2005 the life expectancy for adults with sickle cell disease (SCD) in Los Angeles (LA) county was 35-38 years (Powars 2005), lower than the national average. Lack of access to care was a significant factor in these early deaths. By comparison, the lifespan of patients in the UK National Health Service is much longer (Gardner 2016). In 2009 the only comprehensive adult sickle cell program in LA outside the Kaiser system closed. The California Department of Public Health found that 51% of the adults in CA with SCD live in LA county (Paulukonis 2014). Thus the majority of the 1500 adults living in the largest county in the US have had no access to comprehensive care for over 7 years. The problem is especially acute in southern LA county where many of the adults reside. The dearth of programs for adults drives them to seek recurrent care in emergency departments. Recognizing this as a county-wide public health issue, the LA Department of Health partnered with the Pacific Sickle Cell Regional Collaborative (PSCRC) in 2015 to establish an advanced practice medical home at the Martin Luther King Jr. Outpatient Center to fill this important gap in services. Results: After intense and focused planning, including a PR campaign, the clinic opened August 2016. The staff includes a hematologist with expertise in SCD, a primary care provider, a nurse educator and two community health workers trained by the Foundation. In the first 10 months we have cared for 23 patients. All but two of these patients are from the south LA county area. The age range of the patients is 20-62 years of age. The majority of the patients are genotype SS. All patients were on Medicaid or Medicare insurance. This first cohort of patients is notable for health complications due to lack of coordinated, preventive services. This was measured by a number of indicators: outpatient visits in the 12 months prior to coming to MLK, immunizations, iron overload, and use of Hydroxyurea (HU) (Table 1). One quarter of the patients had no care other than ED or inpatient care for the 12 months preceeding their first visit to our clinic. 100% of the patients had were missing one or more adult immunizations (hepatitis B, tetanus, pneumococcal disease, meningitis, seasonal flu, HPV).Three patients are severely iron overloaded due to multiple transfusions as inpatients with no hematology follow up to address chelation issues. One of those patients required a liver transplant. 39% of the patients (9 patients) seen were eligible for HU but were not on the drug. 17% (4 patients) were on the drug but were noncompliant or poorly managed with episodes of neutropenia. Of those 13 total patients, 11 are now on HU with good compliance and excellent monitoring of drug. Abstract source