non-HU Group Research Articles

Impact of hydroxyurea on follicle density in patients with sickle cell disease

AbstractThe impact of hydroxyurea (HU) on the ovarian reserve of female patients with sickle cell disease (SCD) remains poorly elucidated. Only direct histological analysis of ovarian follicle density can effectively evaluate HU’s effect on ovarian reserve. By analyzing digitized slides of ovarian tissue from girls and young women with SCD who underwent ovarian tissue cryopreservation (OTC) before hematological stem cell transplantation, we meticulously counted follicles and categorized them based on their growth stage. We then calculated the densities of different follicle types and assessed their correlation with patient characteristics, clinical manifestations, and treatments extracted from medical records. Seventy-six patients with SCD participated in the study, with a median age at OTC of 10.2 years (interquartile range [IQR], 7.5-14.6), and 50 (65.8%) were prepubertal. Of these, 35 patients (46.1%) had received HU, with a median daily dosage of 23.0 mg/kg (IQR, 20.0-25.0) and median exposure time of 44 months (IQR, 24.0-54.0). Primordial follicle density was comparable between the HU and non-HU groups (5.8 follicles per mm2 [IQR, 1.0-13.3] vs 4.2 follicles per mm2 [IQR, 1.1-14.4], respectively; P = .95). However, in the HU group, after adjusting for age, the density of growing follicles was marginally lower than that in the non-HU group (P = .09). Notably, other parameters such as vaso-occlusive crisis did not affect follicular density. In conclusion, exposure to HU did not demonstrate a reduction in ovarian reserve in girls or women with SCD. Therefore, fertility preservation measures before initiating HU treatment do not seem necessary.

Urinary Klotho Abnormalities in Children with Sickle Cell Disease

Background: Klotho is a trans membrane protein expressed in the renal tubules and serves as an obligatory co-receptor for fibroblast growth factor 23(FGF23) to aid in phosphorus excretion. Prior studies have shown FGF23 resistance in sickle cell disease (SCD). The purpose of the study is to investigate urinary klotho/creatinine (Ur Kl/Cr) in pediatric SCD with normal traditional markers of renal function (eGFR > 90 ml/min and no micro albuminuria) and to compare it with the healthy control population. Methods: Cross-sectional observational study to compare Ur Kl/Cr in pediatric SCD and controls. To do a subgroup analysis among the study population to assess the effect of hydroxyl urea (HU) on Ur Kl/Cr. Results: 20 controls and 22 pediatric SCD were enrolled. In the SCD group, 13 were on treatment with HU. The baseline characteristics of the study and control group were the same. Wilcoxon rank-sum test was used to compare the levels of Ur Kl/Cr ratio between SCD and control. For P value of 0.05, the levels of Ur Kl/Cr were statistically significantly higher in the sickle cell group (752.7 ± 1101.0) over the control group (216.8 ± 225.3). Subgroup analysis in the SCD group showed high Urinary Kl excretion in the non-HU group (1346.7 ± 1523.4) vs. non HU group (341.4 ± 355.3) but not statistically significant. Conclusion: Children with SCD tend to have increased secretion of Ur Kl/Cr compared to control likely due to tubular receptor resistance. HU may reverse this phenomenon by its effect on preventing tubular damage.

Tolerance and humoral immune response to the yellow fever vaccine in sickle cell disease children treated with hydroxyurea: a multicentre prospective study

Sickle Cell Disease (SCD) children are frequent travellers to countries where Yellow Fever (YF) is endemic, but there are no data regarding the safety and immunogenicity of the vaccine in such children treated with hydroxyurea (HU). The main objective of this study was to compare the tolerance and immune response to YF vaccination in SCD children treated or not with HU. SCD Children < 18years attending the international travel clinics of three large paediatric centres and requiring a first YF vaccination were included in a prospective study. Adverse events were collected 2weeks after vaccination. YF vaccine antibody titres were measured approximately 6months after vaccination. Among the 52 SCD children vaccinated against YF, 17 (33%) were treated with HU. Only mild adverse events, mainly fever and local reaction, were observed in the HU group with a similar frequency in the non-HU group (57% and 35%, respectively, p = 0.30). YF antibody titres were measured in 15/17 patients in the HU group and 23/35 patients in the non-HU group after a median of 6.0months (3.5-8.5) following vaccination. The geometric mean of YF antibody titre was similar in both groups. A protective antibody level was observed in 85% of the children in the HU group versus 100% in the non-HU group (p = 0.14), suggesting a lower effectiveness of the vaccine in patients on HU similarly to what has been described in patients on immune suppressive therapy for other vaccines. YF vaccination seems to be safe and efficient in SCD children treated with HU. Considering the potential risk of severe complications in cases of YF while travelling in Africa for those patients, the benefit-to-risk ratio argues for YF vaccination in all SCD children. Control of a protective antibody titre may also be useful to ascertain an adequate response in those treated with HU.

Red Blood Cell Deformability Demonstrated with the Oxygenscan: Exploring the Association with Hydroxyurea Treatment, Co-Inherited α-Thalassemia, and Frequency of Pain in Children with Sickle Cell Anemia

Background Sickle hemoglobin (hemoglobin S, HbS) is a structural variant of adult hemoglobin. HbS polymerizes when oxygen tensions are low, leading to red blood cell (RBC) deformation, so-called "sickling". In sickle cell anemia (SCA), loss of RBC deformability is considered to be a primary factor responsible for vaso-occlusion and hemolysis. Until recently no laboratory tests to measure RBC deformability in SCA have been readily available. Study Aims In this study we examine RBC deformability, measured with the oxygenscan module of the Laser Optical Rotational Red Cell Analyzer (Lorrca) ektacytometer, in children with SCA treated with or without hydroxyurea (HU). Furthermore, we investigate the relationship between RBC deformability and pain frequency, as well as genetic and laboratory measures known to be associated with disease severity in SCA. Methods We included children aged 0-16 years with a confirmed diagnosis of SCA (HbSS) from the pediatric sickle cell clinic at King's College Hospital in London. Children were excluded if they had received any blood transfusions within 3 months of study inclusion. Children on HU were only included if treatment had been initiated &gt;3 months prior to recruitment and the dose was stable. Children and their parents or guardians reported frequency of pain as: daily, weekly, monthly, yearly, or never. Laboratory measurements, including total hemoglobin (hb), hemoglobin F (HbF), and reticulocyte percentage, were performed on the same day as a sample was taken for oxygenscan analysis. Data on co-inheritance of α-thalassemia was recorded if available. EDTA blood samples were kept at approximately 4°C and transported from King's College London to Copenhagen University Hospital (Herlev and Gentofte Hospital), where they were analyzed within 48 hours of sampling using the Lorrca oxygenscan (RR Mechatronics, the Netherlands). The oxygenscan measures RBC deformability expressed as an elongation index (EI) during deoxygenation and reoxygenation, with EImax expressing RBC deformability at normal oxygen concentrations, EImin expressing RBC deformability after deoxygenation, and the point of sickling (POS) expressing the point at which &gt;5% decrease in EI is observed, representing the pO2 at which sickling begins. All statistical analyses were performed in Stata V16.0 (StataCorp. 2019, USA), using the two-sided t-test, one-way ANOVA, and Pearson's correlation when appropriate. Results We included 47 children aged 0-16 years (mean age 7.9 years) in the study, 24 (51%) receiving HU. Children in the HU group presented with significantly higher HbF percentage compared to the non-HU group (15.6% and 10.9%, p=0.03). Children receiving HU had higher EImax and EImin, and lower POS values, compared to children in the non-HU group, although results were not significant (Table 1). There was a positive correlation between HbF and EImax (r= 0.57, p=0.0001) and HbF and EImin (r= 0.56, p=0.0001), and a negative correlation between HbF and POS (r=-0.37, p=0.01), as well as a positive correlation between total hb and EImax (r=0.35, p=0.02). There was no significant correlation between any oxygenscan parameters and reticulocyte percentage. Data on α-thalassemia was available for 23 children. EImax and EImin values were higher in heterozygous children compared to children without co-inherited α-thalassemia, and POS values were lower, but results were not significant (Table 2). We found no significant association between any oxygenscan parameters and pain frequency (Table 3). Conclusion In this study we identified a strong correlation between all oxygenscan parameters and HbF percentage, as has been reported previously. We found higher EImax and EImin and lower POS values in children receiving HU treatment and children with co-inherited heterozygous α-thalassemia, suggesting increased RBC deformability in these children. These results were not significant, however, which may in part be due to lack of power in the study. Also, it is possible that children in the HU group would have presented with lower EImax and EImin and higher POS values prior to HU initiation, with treatment response leading to results similar to those found in the non-HU group. Finally, our results suggest that there is no association between oxygenscan parameters and self-reported frequency of pain in children with SCA. Disclosures No relevant conflicts of interest to declare.

Characterization of high healthcare utilizer groups using administrative data from an electronic medical record database

BackgroundHigh utilizers (HUs) are a small group of patients who impose a disproportionately high burden on the healthcare system due to their elevated resource use. Identification of persistent HUs is pertinent as interventions have not been effective due to regression to the mean in majority of patients. This study will use cost and utilization metrics to segment a hospital-based patient population into HU groups.MethodsThe index visit for each adult patient to an Academic Medical Centre in Singapore during 2006 to 2012 was identified. Cost, length of stay (LOS) and number of specialist outpatient clinic (SOC) visits within 1 year following the index visit were extracted and aggregated. Patients were HUs if they exceeded the 90th percentile of any metric, and Non-HU otherwise. Seven different HU groups and a Non-HU group were constructed. The groups were described in terms of cost and utilization patterns, socio-demographic information, multi-morbidity scores and medical history. Logistic regression compared the groups’ persistence as a HU in any group into the subsequent year, adjusting for socio-demographic information and diagnosis history.ResultsA total of 388,162 patients above the age of 21 were included in the study. Cost-LOS-SOC HUs had the highest multi-morbidity and persistence into the second year. Common conditions among Cost-LOS and Cost-LOS-SOC HUs were cardiovascular disease, acute cerebrovascular disease and pneumonia, while most LOS and LOS-SOC HUs were diagnosed with at least one mental health condition. Regression analyses revealed that HUs across all groups were more likely to persist compared to Non-HUs, with stronger relationships seen in groups with high SOC utilization. Similar trends remained after further adjustment.ConclusionHUs of healthcare services are a diverse group and can be further segmented into different subgroups based on cost and utilization patterns. Segmentation by these metrics revealed differences in socio-demographic characteristics, disease profile and persistence. Most HUs did not persist in their high utilization, and high SOC users should be prioritized for further longitudinal analyses. Segmentation will enable policy makers to better identify the diverse needs of patients, detect gaps in current care and focus their efforts in delivering care relevant and tailored to each segment.

Nutritional Status and Hydroxyurea Use Among Children with Sickle Cell Disease in Malawi

Introduction:The global distribution of sickle cell disease (SCD) overlaps with that of food scarcity and nutritional deficiencies. Chronic anemia secondary to SCD contributes to nutritional deficiencies, for example folic acid. Few studies have evaluated associations between malnutrition and SCD, nor effects of malnutrition on SCD outcomes. Moreover,hydroxyurea(HU), a disease modifying agent for SCD, has not been specifically evaluated in malnourished children although it is known to bind pharmacologically to human serum albumin.Methods:We conducted a cross-sectional nutritional assessment of children receiving chronic SCD care at a referral hospital in the capital city of Malawi, Lilongwe, between January and June 2016. Participants were measured for height, weight, and mid-upper arm circumference. Z-scores and percentiles for anthropomorphic indices were calculated using WHOAnthroSoftware. Nutritional measures of interest were BMI-for-age Z-score to assess wasting and height-for-age Z-score to assess stunting. We examined associations between nutritional status and clinical and laboratory data collected longitudinally at six-month intervals during routine care. Differences based on HU use were examined.Results:Fourteen of 99 (14.1%) participants had moderate-to-severe wasting and 36 of 101 (35.6%) moderate-to-severe stunting. The wasted group was significantly older than the non-wasted group but there was no significant difference in age between the stunted and non-stunted groups (Table 1). We observed significantly lower white blood cell (WBC) and lymphocyte counts in the wasted group when compared to the non-wasted group. The stunted group had significantly lower hemoglobin (Hb) than the non-stunted group. There was also a significantly higher prevalence of fevers in the stunted group than the non-stunted group. Forty-four of 151 (29.1%) participants were receiving HU for a median duration of 126 days (IQR 29 - 196 days). There were no significant differences in age or sex between the HU group and the non-HU group. We observed significantly lower Hb in the HU group when compared to the non-HU group, as expected as HU is typically prescribed for children with more severe SCD in Lilongwe. We also observed higher WBC, absolute neutrophil (ANC), and lymphocyte counts in the HU group. Again reflecting greater SCD severity, we observed a significantly more frequent history of fevers, upper respiratory tract infections, and splenomegaly in the HU group. There were no significant differences in the proportions of wasted participants by HU status [5/33 (15.2%) HUvs20/68 (29.4%) non-HU, p=0.84], and a trend toward more frequent stunting among HU users again likely reflecting growth effects of greater chronic SCD severity [16/33 (48.5%) HUvs9/66 (13.6%) non-HU, p=0.061]. Among HU users, peripheral blood counts were not significantly different in wastedvsnon-wasted children, nor stuntedvsnon-stunted children (Table 2).Conclusion:In a pediatric SCD cohort in Malawi we observed 14.1% of children with significant wasting and 35.6% with significant stunting, highlighting growth effects of chronic illness in this population even among children receiving regular SCD care. Among children prescribed HU, nutritional status did not seem to be associated with HU tolerability. Notably, HU was not associated with significantmyelosuppressionin our cohort including those children with wasting or stunting. More studies are needed to clarify interactions between nutritional status, SCD, and HU, but our data suggests wasting or stunting should not be contraindications to HU use when indicated for pediatric SCD in sub-Saharan Africa. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

G306 Hydroxyurea lowers transcranial Doppler flow velocities in Nigerian children with sickle cell anaemia

BackgroundTranscranial Doppler (TCD) flow velocities predict stroke risk in children with sickle cell disease (SCD) and give a chance for primary stroke prevention. Elevated velocities ≥ 170 cm/sec are present...

G149(P) Stroke-Recurrence in Nigerian Children with Sickle Cell Anaemia Treated with Hydroxyurea After a First Clinical Stroke

BackgroundChronic blood transfusion is the standard treatment for secondary stroke prevention in sickle cell anaemia (SCA) but this treatment option poses major challenges in resource-poor countries of the world, especially...

Stroke recurrence in Nigerian children with sickle cell disease treated with hydroxyurea

To compare the outcome after a first clinical stroke, following treatment with and without hydroxyurea (HU).A retrospective review of a cohort of Nigerian children with SCD, who had suffered a first stroke, was carried out. Outcomes in the group of children who received and did not receive HU were compared.Thirty two children presented with stroke and one died of haemorrhagic stroke at presentation. All the children had haemoglobin SS phenotype, and ischaemic stroke was the predominant form seen. Mean age at first clinical stroke was 7 years, 7 months (SD=2 years, 4 months). Thirteen children received HU while 18 declined HU therapy. Maximum dose of HU ranged from 20-25 mg/kg/ day. The secondary stroke incidence of 7/100 person years in the HU group was significantly lower than the 28/100 person years in the non-HU group (P=0.001, OR 3.808, 95% CI 1.556, 9.317). Children who did not receive HU were more likely to drop out of school and to have moderate-severe motor disabilities requiring caregiver assistance for daily living.In settings where facilities for chronic blood transfusion are not accessible or feasible, HU therapy should be considered for secondary stroke prevention in children with SCD.

Hydroxyurea Treatment of Young Children with Sickle Cell Anemia: Safety and Efficacy of Continued Treatment – the BABY HUG Follow-up Study

Abstract 7▪BABY HUG [Clinical Trials #NCT00006400], an NIH-NICHD sponsored randomized placebo-controlled trial showed that hydroxyurea (HU) administered to 9–18 month old children with sickle cell anemia (SCA) provides substantial clinical benefit. Benefits include a decrease in pain crises, acute chest syndrome events, need for transfusion and hospital admission; hematologic improvement include higher total and fetal hemoglobin concentration, larger red cell size, and lower WBC counts with toxicity limited to transient reduction in absolute neutrophil count (ANC) [Lancet 2011; 377:1663–72]. The parent or guardian of all 176 children who completed at least 18 months of randomized treatment were offered participation in an initial observational BABY HUG Follow-Up Study and 163 (93%) consented to participate. Clinical and laboratory data were collected every 6 months by structured abstraction of the medical record regarding use of clinically prescribed HU (dose escalation recommended), blood counts, clinical imaging, and sickle cell-related events. At the time of enrollment the family did not know their child’s randomized study treatment assignment; 133 (82%) initially chose clinical prescription of open-label HU. Acceptance of HU has remained high through 36 months of follow-up; during each 6 month data collection period 68–75% of participants reported having taken HU.Only 2 patients have left the study (due to relocation) and more than 93% of expected data have been collected. Preliminary analyses as of May 2011, including 417 patient years (pt-yrs) of follow up, demonstrate that in comparison to participants not taking HU, children who continue to take HU have statistically lower rates of pain crises requiring emergency department (ED) visits, episodic transfusions, and hospital admissions for any reason, including acute chest syndrome or febrile illness (see table). The substantial decrease in acute chest syndrome episodes is similar to the effect demonstrated with HU use in the randomized BABY HUG trial in younger infants and consistent with published trials detailing the benefit of HU therapy in older children and adults. The decrease in the rate of admission for febrile events in HU-treated patients is also comparable to that in the randomized trial, but the reason for this benefit is uncertain. There was no difference in hospitalization rates for painful events including dactylitis. Two patients in the non-HU group had a stroke. There were no differences between groups in the frequency of a palpable spleen or rate of acute splenic sequestration crises. Through 36 months of follow up children taking HU had persistently higher hemoglobin and MCV, and lower WBC and ANC than those not taking HU.Event Rate per 100 pt-yrsHUNo HUp valueED visit for Pain Crisis28.853.60.004Episodic Transfusion18.334.00.010Hospital Admission (any cause)74.9133.20.001Acute Chest Syndrome (admission)9.522.30.0001Febrile Illness (admission)30.764.3<.001Pain Crisis (admission)18.630.40.102Results of these analyses including growth and development assessments will enhance our understanding of the impact of HU use in children with SCA starting at a very young age. The accruing data from the BABY HUG Follow-Up Study demonstrate a continuation of the substantial benefits of early HU therapy with no discernable additional toxicities. Ongoing follow up of this cohort is essential to fully define these benefits as children grow, and to observe for late toxicity. Disclosures:Off Label Use: Hydroxyurea is not indicated for treatment of children with sickle cell disease. Use of this medication was for clinical indications and not mandated by this observational study.

Stroke recurrence in children with sickle cell disease treated with hydroxyurea following first clinical stroke

Chronic transfusion therapy is the treatment of choice for preventing stroke recurrence in children with sickle cell disease (SCD). The majority of children affected by this devastating complication live in the developing world where access to regular blood transfusions may be impractical. Since 2000, in the absence of regular blood supplies, all children at the Sickle Cell Unit who had experienced a first clinical stroke were offered hydroxyurea (HU) as the only intervention to prevent stroke recurrence. Forty-four children were identified as having experienced a first clinical stroke between January 1, 2000 and September 30, 2009; one died at that presentation. Forty-three children were therefore followed for 111 person-years, of whom 10 (23.3%) agreed to start HU. Only one child in the HU group, incidence rate 2/100 person-years, had clinical stroke recurrence, compared to 20/33 in the non-HU group, incidence rate 29/100 person-years (Hazard ratio (HR) 9.4 [95% Confidence interval (CI): 1.3-70.6]; P = 0.03). When the groups were compared, in the non-HU group, four died (vs. zero), 13 (53% vs. 10%) had moderate-severe physical disability (P = 0.017), and 12 (44% vs. 20%) required special education or were too disabled to attend school. Our data support the role of HU as a useful intervention for prevention of stroke recurrence in SCD when transfusion programs are not available or practical.

Hydroxyurea Induces Hepcidin Expression In Monocytes In Sickle Cell Anemia Patients

AbstractAbstract 2653The antimicrobial peptide hormone hepcidin is a key regulator of iron metabolism. Although mainly produced in the liver, hepcidin is also known to be synthesized by monocytic-macrophagic cells. We have previously shown that hepcidin is overexpressed in mononuclear cells in patients with sickle cell anemia (SCA), but whether monocyte-derived hepcidin production is related to iron metabolism remains unknown.To gather further insight into the role of hepcidin in monocytes, we collected peripheral blood samples from adult SCA patients (n=54) and normal age- and race-matched controls (CTRL, n=13) for assessment of hematological parameters, biochemical markers of iron status (serum iron and transferrin saturation - TfSat), hemolysis (lactate dehydrogenase-LDH) and inflammation (C reactive protein - CRP), and separation of peripheral blood monocytes by Ficoll-Hypaque and Percoll gradients for gene expression analyses of genes involved in iron metabolism signaling (HAMP encoding hepcidin, and three genes belonging to different pathways known to influence hepcidin expression, STAT3, SMAD4 and TLR4). Plasma GDF-15 levels were also measured, as this protein has been shown to be a potent downregulator of hepcidin. SCA patients were further stratified according to the number of previous blood transfusions and to treatment with hydroxyurea (HU). All patients were in steady-state, had no history of iron chelation treatment and were not enrolled in a regular transfusion program. 18 patients were receiving HU and 15 from the non-HU group had received over 20 blood transfusions during their lifetime.As expected, SCA patients had elevated LDH levels, but no differences were found between control and SCA groups regarding serum iron, TfSat or CRP levels. Except for a higher red cell mean corpuscular volume, patients on HU did not differ significantly from patients not using HU. Plasma GDF-15 levels were higher in SCA patients (2146±506.4pg/mL) than in control individuals (228.5±21.0pg/mL, p<0.0001). Among the genes studied, HAMP expression was significantly increased in the SCA group as a whole compared to the CTRL group, but SCA patients on HU had higher levels of monocytic hepcidin expression when compared to the remaining individuals (CTRL 0.043±0.030, SCA on HU 1.240±0.426, remaining SCA 0.332±0.093, p=0.0196). There were no significant correlations between monocytic hepcidin expression and hemoglobin levels, hematocrit, leucocyte or reticulocyte counts, serum iron, LDH or CRP levels, TfSat or transfusion history. STAT3, SMAD4 and TLR4 gene expressions did not differ significantly, suggesting that a possible alternative cause for hepcidin upregulation unrelated to known mechanisms by IL-6, BMP6, LPS or GDF-15 could be an unexpected effect of hydroxyurea. To further investigate if HU was able to modulate hepcidin expression, we performed experiments with THP-1, a human monocytic lineage, since in vitro analysis would allow us to exclude the influence of circulating cytokines elevated in SCA patients. THP-1 cells were cultured in RPMI medium enriched with 10% fetal bovine serum at 37°C and 5% CO2 atmosphere, and were submitted to treatment with water as control, or HU dissolved in water in increasing concentrations (100μM, 400μM and 1600μM) for 6 hours (n≥4). Cell viability was not affected by treatment (>90% viable cells at all experiments), and HAMP gene expression was increased up to four times in the cell cultures exposed to HU (p=0.03), while STAT3 and SMAD4 expressions remained unchanged.We have shown that hepcidin expression is upregulated in monocytes in SCA patients, particularly in those receiving HU, and that HU is capable of inducing this expression in an in vitro model, independently from inflammatory cytokine-mediated stimulation. Our data suggest that, although liver-derived hepcidin has been shown to have a major role in iron metabolism, its monocyte-derived counterpart does not seem to be directly influenced by iron status and may have other functions. Some studies have demonstrated that hepcidin in other species has anti-inflammatory effects in vitro, and that patients with SCA on HU shift to a lower inflammatory status. Thus, monocytic hepcidin overexpression might be a response against the chronic inflammatory state in SCA, and HU treatment may enhance this response. This is the first description of monocyte-derived hepcidin in SCA and the influence of HU on its expression. Disclosures:No relevant conflicts of interest to declare.

Impact of Hydroxyurea On Peri-Operative Management and Outcomes in Children with Sickle Cell Anemia.

Abstract 2567Poster Board II-544Surgical procedures in children with sickle cell anemia (SCA) can be complicated by vasoocclusive events (VOE) such as acute chest syndrome (ACS) and pain. Peri-operative management requires a multidisciplinary approach to provide appropriate pre-operative intravenous hydration and intra- and post-operative monitoring. Transfusion therapy has been controversial. Our institution previously described a low incidence of complications in children who received serial transfusions over 3-4 weeks prior to surgery. Subsequently, an increasing number of children have been prescribed hydroxyurea (HU) to prevent SCA complications. In general, children on HU at our institution only receive a single top-off transfusion the day prior to surgery if their hemoglobin is less than 10 g/dL. We hypothesized that children in the HU group would have a lower number of serial transfusion compared to the non-HU group and that there would be no difference in complications or days to discharge between the two groups. We conducted a single-institution retrospective cohort study of children with SCA, who were age less than 18 years and underwent at least one surgical procedure at Duke University Medical Center between January 1, 2003 and April 30, 2008. Data were abstracted from electronic and written medical records. Descriptive statistics were used to characterize the cohort. Wilcoxon test was used to compare continuous variables and Pearson test was used to compare categorical variables between the non-HU and HU groups. Fifty-three subjects were included (Table 1). The non-HU group was significantly younger than the HU group, but children in the non-HU group were significantly more likely to be transfused pre-operatively, primarily with serial transfusions or erythrocytopheresis, compared to the HU group. One subject in the non-HU group developed a pre-operative delayed hyperhemolytic transfusion reaction. Post-operative complications are detailed in Table 1; the overall rate was low. Two subjects in the HU group developed acute chest syndrome despite pre-operative transfusion; one episode was likely related to underlying asthma and poor response to hydroxyurea; the second was likely related to pain and hypoventilation after laparoscopic splenectomy and tonsillectomy/adenoidectomy. Overall, there were no significant differences in complications and no significant difference in days to discharge between the two groups. In summary, children with SCA on HU may safely undergo surgery without significantly reducing their percent HbS. Nonetheless, attention should still be made towards multidisciplinary effort to reduce intra- and post-operative complications, and clinicians should consider response to HU, pulmonary status and type of surgery when planning peri-operative management in children with SCA on HU.Table 1Comparison of HU and non-HU groups.non-HUHUPN2330Age, years; mean±SD8.0±4.511.8±4.20.001Males, N (%)12 (52)18 (60)NSProcedures, N (%)..NSCholecystectomy6 (26.1)8 (26.7)Splenectomy1 (4.3)1 (3.3)Ears, Nose, Throat12 (52.2)8 (26.7)Orthopedic07 (23.3)Central Lines2 (8.7)1 (3.3)Other2 (8.7)5 (16.7)Procedure characteristics, N (%)..NSEmergency2 (8.7)1 (3.3)Multiple procedures3 (13)7 (23)Peri-op transfusions, N (%)..0.006No transfusion2 (8.7)8 (26.7)Serial transfusions*19 (82.6)11 (36.7)Top-off transfusion2 (8.7)11 (36.7)Transfusion complications, N (%)1, 4.30Time to discharge, days; mean±SD1.4±11.8±1.5NSPost-op complications, N(%)..NSACS02 (6.7)Isolated fever02 (6.7)Vaso-occlusive pain00Bleeding at incision site01 (3.3)*including erythrocytopheresis Disclosures:Off Label Use: hydroxyurea in young children.

Hyper-use of the ED

Objectives This study aims to describe the population that averages one or more emergency department (ED) visits per month and compare them to the general ED population to determine if there are associated characteristics. Methods A retrospective cohort study conducted in a teaching hospital between January 1, 2001, and December 31, 2004, identified all patients with more than 35 visits. This hyper-user (HU) cohort (n = 49) was compared to a randomly selected group of non-HU patients (n = 50) on the following measures: age, sex, insurance coverage, primary medical doctor (PMD), dwelling location, chief complaint, comorbidities, and disposition. Results The HU group was significantly older (mean, 49.45 years) than the non-HU group (37.32 years) with a P < .0001. There was no difference between the groups in sex, insurance coverage, PMD, dwelling location, and disposition. A univariant logistical regression found that previous cardiovascular, genitourinary, or psychiatric disease were predictors of hyper-use. Conclusions The HU group is older and more likely to have a history of cardiovascular, genitourinary, and psychiatric disease but is similar to the non-HU group in other measured parameters. The HU group appears to have equal access to a PMD and is not more likely to be admitted to the hospital than the non-HU group.

T-cell receptor excision circles (TREC) in SHIV 89.6p and SIVmac251 models of HIV-1 infection.

T-cell receptor excision circles (TREC) may be a useful surrogate marker in HIV-1 infection for evaluating the likelihood of continued clinical stability and/or the response to therapeutics, including vaccines. Analysis of TREC in SHIV and SIV models of HIV-1 infection may provide additional information concerning the utility of TREC as a marker. We measured TREC in peripheral blood mononuclear cells (PBMC) from rhesus macaques in SHIV89.6p (n = 20) and SIVmac251 (n = 11) models of HIV-1 infection. TREC were also evaluated in tissues in the SIVmac251 model at end-point. In the SHIV89.6p model, TREC in PBMC were significantly lower at 12 weeks postinfection compared to preinfection levels. The decrease in TREC correlated with the decline in CD4+ T cells (r(s) = 0.496; P = 0.026), which in turn correlated inversely with serum viral loads at end-point (r(s) = -0.517; P = 0.019). Macaques that controlled SHIV89.6p infection to some degree (n = 6) had higher TREC at study end-point (P = 0.017). In the SIVmac251 model, TREC in PBMC were significantly reduced after 17 months of infection (P = 0.012) despite receiving highly active antiretroviral therapy (HAART) consisting of didanosine (ddI) and (R)-9-(2-phosphonylmethoxypropyl)-adenine (PMPA) when not cycling off therapy during scheduled treatment interruptions (STI). However, macaques that received continuous hydroxyurea (HU) in addition to the HAART regimen had higher end-point TREC compared to the non-HU group (P = 0.041), and the reduction in TREC observed at end-point within the HU group was not significant. In the SIVmac251 model, TREC correlated with the percentage of CD4+ T cells (r(s) = 0.426; P = 0.048) and CD4+CD28+ T cells (r(s) = 0.624; P = 0.002), and inversely with CD8+ T cells (r(s) = -0.622; P = 0.002), CD8+CD28- T cells (r(s) = -0.516; P = 0.014), and serum viral loads (r(s) = -0.627; P = 0.039). High levels of TREC were observed in the thymus, levels comparable to PBMC were seen in the lymph node, and low but detectable levels of TREC were present in bone marrow. The use of correlates of TREC as covariates in ANCOVA revealed that the decline in TREC in the SHIV 89.6p model reflected the decline in the percentage of CD4+ T-cells due to viral cytopathogenicity. In the SIVmac251 model, the decline in TREC was related to increased immune activation and proliferation due to viral replication, as reflected by decreases in percentages of CD4+CD28+ T cells and increases in CD8+ and CD8+CD28- T cells.