Hand Foot Syndrome in Sickle Cell Anemia: II. Epidemiology Often the first vaso-Occlusion crisis finding in young children Occurs in up to 50% of children with Sickle Cell Anemia by the age of 2 years Rare over age 4 years old III. Pathophysiology A. Not to be confused with Hand Foot Syndrome that occurs with certain Chemotherapy agents in non-sickle disease B. Occurs in Sickle Cell Anemia with vaso-Occlusion C. Caused by infarction of Bone Marrow 1. Metacarpal or Metatarsal Bones and phalanges IV. Symptoms Painful swelling and tenderness of either the hand or foot Digits may appear mildly erythematous Abstract source

Introduction: Sickle cell anemia is the most common single gene defect in the United States, affecting approximately 100,000 individuals (Hassel Am J Prev Med 2010). It is characterized by chronic hemolysis, unpredictable vaso-occlusive episodes (VOEs), and chronic organ damage leading to early death in patients affected by the disorder. Hydroxyurea, a small molecule chemotherapeutic agent, has been used to treat patients with severe sickle cell disease since 1984 (Brawley Ann Intern Med 2008). Two randomized controlled trials, the Multicenter Study of Hydroxyurea (Charache N Engl J Med 1995) in adults and the Baby HUG trial (Wang Lancet 2011) in children, showed that hydroxyurea reduced the number of VOEs and hospital admissions, while simultaneously increasing hemoglobin and fetal hemoglobin in patients with sickle cell anemia. The goal of this study was to determine the clinical effectiveness of hydroxyurea in reducing the number VOEs and hospitalizations in unselected patients with sickle cell anemia. Methods: The CASIRE group is an international multi-institutional collaborative group evaluating the clinical severity of patients with sickle cell anemia through a validated questionnaire, chart review and laboratory studies. Patients were enrolled on the CASIRE study after informed consent and assent was obtained from either the parent or patient when appropriate. The study was approved at each participating institution’s IRB. A questionnaire was answered by the parents and/or patient, and baseline and current laboratory studies were collected. Patients were stratified into those who were not on hydroxyurea, and those who were currently on hydroxyurea. Number of VOEs, admissions, baseline and current fetal hemoglobin, and change in hemoglobin and MCV were compared. Results: There were 349 patients in this study (134 on hydroxyurea). Baseline laboratory data are reported in table 1. Hemoglobin level and MCV were not statistically different in patients prior to and after taking hydroxyurea (table 2). Fetal hemoglobin in adults increased 2.7 times baseline, whereas in children it was unchanged. All patients on hydroxyurea had a reduction of VOEs, ED visits and admissions compared to prior to hydroxyurea (see table 3) Abstract source

The clinical hallmark of sickle cell anemia is the vaso-occlusive pain crisis. Although the exact cause for severe vaso-occlusive painful events is unknown, sickle cell microvasculature occlusion is thought to be the proximate cause producing tissue hypoxia, reperfusion injury and acute pain. Endothelial dysfunction is a prominent characteristic of sickle cell anemia, and it is unclear to what extent this abnormal vascular response contributes to vaso-occlusion and pain. We sought to evaluate the effects of hypoxia on sickle cell pain by performing a forearm ischemic pain test as a potential in vivomodel for vaso-occlusion. We hypothesized that sickle cell anemia patients would tolerate a shorter period of ischemia before reaching pain tolerance. We further hypothesized that sickle patients would show more hypoxia and increased vasodilation. Thirty adults with sickle cell anemia were recruited and matched by age and sex to 30 normal volunteers. We first performed a timed ischemic pain test with brachial artery occlusion until subjects first reported pain (pain threshold) and until maximum pain tolerated (pain tolerance). Sickle cell subjects first reported pain at 411 vs. 589 s for normal volunteers (mean, p=0.07). Occlusion time to pain tolerance was significantly shorter for sickle cell patients (637 vs. 918 s, mean, p=0.004). Despite this difference, both groups reported nearly identical pain scores at threshold and tolerance. Stepwise linear regression for all subjects against 8 variables likely to influence pain showed sickle status (p=0.002) and gender (p=0.0008) were independently associated with time to tolerance, supporting our initial hypothesis. Testing with continuous physiological monitoring was next repeated in sub-groups of 7 sickle cell and 9 normal subjects in an effort to understand the association between ischemia and pain progression. Before, during, and after brachial artery occlusion, oxygenated/deoxygenated hemoglobin concentration and tissue oxygen saturation were continuously monitored with near-infrared spectroscopy at the thenar eminence. We also recorded cutaneous blood flow with a Laser Speckle Contrast Imager (FLPI-2) in the volar aspect of forearm and continuous blood pressure and pulse in the contralateral arm. Monitoring was performed during steady state prior to occlusion (15 min), during occlusion until pain tolerance, and during recovery (20 min). Abstract source

Background: Pain, the hallmark complication of sickle cell disease (SCD), is largely managed with opioid analgesics in the United States (1, 2). There is a common perception that SCD patients tend to use high dose of opioids chronically (3, 4), but comprehensive data regarding the long-term use of opioids in this patient population is lacking. Methods: A cohort of 359 adults (age ≥ 18 years old) with the diagnosis of SCD followed at University of Illinois Hospital in FY 2010-2013 was enrolled in a prospective natural history study. An outpatient clinic visit with comprehensive laboratory closest to the enrollment date was selected as the focal point of this report. A total of 140 patients had consistent outpatient follow-up defined as ³4 visits between 6 months prior to and 6 months after this clinic visit (the study period). Pain medication prescribing records, number of hospital admissions, and other clinical variables during the study period were collected and evaluated with descriptive statistics and Spearman correlation. Results: Among the 140 patients analyzed, 74% took short-acting opioid medications and 31% took long-acting opioid medications (Table 1). The median daily opioid dose was 4.8 mg oral morphine equivalents (OME) with an interquartile range (IQR) of 0 to 14.7 mg. Sixty-six percent of patients used less than 10 mg OME daily whereas 11% used more than 50 mg OME daily (Figure 1). Among the short-acting opioids, acetaminophen-hydrocodone was the most commonly used medication (34% of patients) followed by immediate-release morphine (23%) and acetaminophen-codeine (20%) (Table 2). Extended-release morphine was used by 24% of the patients. Twelve patients (8.6%) were prescribed with nonsteroidal anti-inflammatory drugs (NSAIDs), and 16% used medications treating neuropathic pain. The Spearman correlation test with Bonferroni correction showed that the dose of opioid usage was significantly associated with the number of hospital admissions due to vaso-occlusive crisis (VOC) (p<0.0001) (Table 3). Hydroxyurea use, hemoglobin genotype, history of avascular necrosis (AVN) and 25-OHD levels did not correlate with opioid dose. Summary: The doses and types of opioid medications used by adult SCD patients vary widely. The majority of patients use a relatively low dose ( Abstract source

Maternal mortality results among women with sickle cell disease (SCD) from recent population-based studies using US hospital discharge data range from 72 (Villers, 2008) to 160 per 100,000 (Alayed, 2014). Researchers use hospital discharge or death certificate data to examine maternal death, as no national SCD surveillance system exists. We analyze California’s surveillance data to describe the in-hospital maternal mortality rate among women meeting a stringent case definition for SCD, compare that rate to rates for all women and for Black women, and describe cases of SCD maternal demise. The CDC has developed the Sickle Cell Data Collection (SCDC) program to conduct state level surveillance in this disease. SCDC uses a validated case definition: confirmed SCD with known genotype (via newborn screening or clinical case reports) or three or more healthcare encounters in administrative or claims data with SCD ICD-9 codes. California SCDC collected hospitalization data for years 2004-2014 on 1,829 women with SCD. We queried hospitalization data for women ages 15-45 at time of admission for ICD-9 codes for delivery (V27.X) with disposition codes indicating death during the same admission. We used the same query for all women and for Black women to calculate comparable in-hospital maternal mortality rates. We reviewed death records for ICD-10-CM underlying cause of death (COD) codes, and prior ED and inpatient records, and describe the history of the women with SCD who died. We found 636 delivery hospitalizations among 441 of the 1,829 eligible women with SCD during the 11-year period. The maternal death rate for SCD was 629 per 100,000 (n = 4 of 636 deliveries), compared to 6 per 100,000 deliveries in the general population and 12 per 100,000 among Black women. There was an additional death (#5) among the women with SCD that occurred shortly after discharge; we include this death in the case descriptions, but not in the mortality rates. All of the women with SCD who died were Black. All births were live, singleton deliveries by cesarean surgery. Abstract source

Background: Sickle cell disease (SCD) is characterized by continuous oxidative stress through various mechanisms contributing to the pathophysiology and clinical course of sickle cell crises (SCC) and organ damage. L-glutamine is a precursor for the synthesis of essential metabolic redox cofactors including Nicotinamide Adenine Dinucleotide (NAD). Early studies have demonstrated that altered erythrocyte NAD redox potential was improved by oral L-glutamine therapy, suggesting that higher L-glutamine utilization in SCD exceeded de novo synthesis and its depletion played a role in oxidative stress. A Phase 2 study of Pharmaceutical Grade L-glutamine (L-glutamine) versus placebo showed promising results on clinical endpoints. In a Phase 3 study with 230 SCD patients, randomized 2:1 to L-glutamine or placebo, the median number of SCCs was 25% lower for L-glutamine than placebo (L-glutamine 3.0 vs. placebo 4.0). An analysis of SCC events showed significant differences between groups (p < 0.01). Categories for pre-specified subgroups for Age, Gender and Hydroxyurea (HU) use were defined in the statistical plan. HU use was also a randomization stratification factor since HU is the only FDA-approved drug for SCD treatment. Examination of the HU subgroup for differences in L-glutamine effect across categories (HU vs. no HU) was appropriate since approximately 66% of patients remained on HU throughout the Phase 3 study. To investigate the subgroup treatment effect size, treatment by subgroup interaction and consistency of the primary endpoint across the categories of the subgroups, an examination was performed following the guidelines for reporting subgroup analysis. Methods: The Negative Binomial Regression (NBR) model was utilized to generate an estimate of treatment effect and treatment by subgroup interactions of the three pre-specified subgroups. SCC events are most accurately described as counts and NBR is specifically intended for modeling count variables, usually for over-dispersed counts as seen in SCD studies. Rates of SCC for each treatment arm in a subgroup (Rate L-glutamine per 48 weeks / Rate placebo per 48 weeks) provide rate ratios, and an estimate of effect size, with 95% confidence intervals. A rate ratio Abstract source

Introduction: Previous sickle cell disease (SCD) studies found that patients who have anxiety and depression have worse pain control compared to patients without these mental health problems. The purpose of this study was to assess SCD patient demographics, education level, literacy, employment and pain characteristics related to anxiety and depression. Methods: A descriptive study was conducted with a convenience sample of 100 SCD patients at an academic medical system hematology clinic. A research assistant administered a structured interview which included demographic questions (age, gender, type of SCD, employment, marital status, education), amount of opioid pain medication needed in a 24-hour period for chronic pain, and the PROMIS (Patient-Reported Outcomes Measurement Information System) Pain Intensity, Pain Interference, Depression and Anxiety surveys. Cognitive ability was screened for using the Callahan 6-Item Screener. Literacy was assessed using the REALM-SF. PROMIS anxiety and depression surveys consist of eight questions each which are scored on a 5 point Likert scale ranging from 1 (never) to 5 (always). The tests are scored on a T-score metric and normed to the adult U.S. population with a mean of 50 and a standard deviation of 10. Interpretation of scores: Mild range (T scores 55-60), moderate (T scores 60-70), and severe (T scores>70). Analysis of variance (ANOVA) was conducted to investigate the relationship between anxiety, depression, pain intensity and interference to age, gender, type of SCD, education, employment and marital status. Results: Patient age ranged from 19 to 66 years with a mean of 33 years. All patients were African Americans, 52% were female. Despite the fact that over half were at least high school graduates (37% were high school graduates while an additional 14% graduated from college), none were reading or above a 9th grade level. Abstract source