Hydroxyurea Effectiveness in Children and Adolescents with Sickle Cell Anemia: A Large Retrospective, Population-Based Cohort Study

Abstract Background: The clinical efficacy of hydroxyurea (HU) in patients with sickle cell anemia (SCA) is well established. In clinical trials, HU has been demonstrated to alter the clinical course of SCA; HU decreases rates of pain, dactylitis, acute chest syndrome (ACS), transfusions, hospitalizations and improves hemoglobin levels. Other studies have shown that HU improves quality of life and decreases mortality. While evidence of efficacy has been well demonstrated, published data about clinical effectiveness is limited. Additionally, attempts to compare outcomes of patients taking HU to those not taking HU have been limited by the inherent selection bias for greater disease severity in patients on HU. We sought to examine the clinical effectiveness of HU in the large population of patients with sickle cell disease (SCD) at Children's Healthcare of Atlanta (CHOA). The program provides comprehensive care to >1,700 active patients; because they include about 95% of all children and adolescents with SCD in the greater Atlanta Metropolitan Area, the program provides a population-based sample. Currently 57% of the 922 children ≥ 1 yr of age with SCA (SS and Sβ0 thalassemia) who are not on chronic transfusions are receiving HU. Methods: Using a retrospective cohort, pre-post treatment study design to control for disease severity selection bias we evaluated the clinical effectiveness of HU in patients with SCA who received care at CHOA and who first initiated HU in 2009-2011. Children on chronic transfusions, or children with inadequate follow up data and/or who ever took HU in the 3 years prior were excluded. Clinical guidelines for dosing HU have been standardized locally and recommend initial dosage of 20mg/kg/day, followed by dose escalation every 2 months to maximum tolerated dose. For each patient, healthcare utilization, laboratory values and clinical outcomes for the 2-year period prior to HU initiation were compared to those for two years after initiation. Medians were compared using the Wilcoxon Signed Rank test and means using T test. Rate ratios were computed using unadjusted Poisson regression. Interactions testing whether the effect of HU varied by age, sex, or insurance status, were assessed using multivariable Poisson regression. Results: Of 211 children with SCA who initiated HU in 2009-2011, 134 met eligibility criteria. After initiation of HU, the rate of hospitalization was 0.53 the rate before HU, a 47% reduction (Table). The number of inpatient days, emergency room (ER) visits, pain encounters, episodes of acute chest syndrome (ACS), and transfusions were also significantly reduced (Table). The hemoglobin level (mean +/- SD) pre- and post-HU initiation was 7.3+/-2.7 g /dl and 8.1+/- 2.9 respectively; an increase of 0.8+/-1.1, p<0.0001. Similarly, pre-HU mean corpuscular volume increased from 82.9+/-7.5 fl pre-HU to 95.7+/-10.7 post-HU; an increase of 12.8+/-7.2, p <0.0001. There was a statistically significant interaction between the effect of HU and age of initiation of the drug on hospitalization rates; patients < 7 years of age had a greater reduction in hospitalizations than older children (58% vs 33%, p=0.03). The effect of HU on hospitalizations did not vary by sex or insurance type. Table 1. Effect of HU initiation on clinical outcomes using Poisson Regression Rate Ratio (Confidence Limits) P Value Hospitalizations 0.53 (0.43 - 0.66) <0.0001 Inpatient Days 0.50 (0.40 - 0.63) <0.0001 ER visits 0.57 (0.49 - 0.67) <0.0001 Pain Encounters 0.64 (0.51 - 0.81) 0.0001 ACS 0.57 (0.39 - 0.83) 0.0036 Blood Exposure 0.43 (0.29 - 0.64) <0.0001 Conclusions: HU is clinically effective in children and adolescents with SCA. HU decreased hospitalizations, ER visits, pain encounters, ACS, use of transfusions and improved hemoglobin levels. HU effectiveness was similar across gender, insurance types and age, although there was a slightly greater reduction in hospitalizations in younger patients. These results are important as they parallel results obtained from HU efficacy studies, thus demonstrating that in 'real life' settings, even without the additional monitoring and adherence incentives of clinical trials, HU improves short-term outcomes in pediatric SCA. Disclosures Off Label Use: Hydroxyurea use as disease modifying therapy in pediatric patients with sickle cell disease.

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Inpatient Utilization Among Children and Adolescents with Sickle Cell Disease: Analysis of a Large Populated-Based Retrospective Cohort

Blood ◽

10.1182/blood.v126.23.3262.3262 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3262-3262 ◽

Cited By ~ 1

Author(s):

Rodney Theodore ◽

Vaughn Barry ◽

Maa-Ohui Quarmyne ◽

Carlton Dampier ◽

Peter A. Lane

Keyword(s):

Sickle Cell Disease ◽

Children And Adolescents ◽

Hospital Discharge ◽

Sickle Cell ◽

Hospitalization Rate ◽

Hospital Utilization ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Readmission Rates ◽

Hospitalization Rates

Abstract Background: Sickle cell disease (SCD) is characterized by marked heterogeneity in clinical outcomes, severity and utilization of health care services. This heterogeneity is particularly evident with regards to utilization of inpatient hospital services. Some children with SCD are frequently admitted to the hospital while others are rarely or never admitted. In addition, rates of readmission within 30 days of hospital discharge are high in SCD. The causes of this variable utilization and high rates of readmission are not well understood. Objectives: We sought to determine rates and primary causes of SCD-related hospital utilization among children and adolescents with SCD and to determine whether rates of hospitalization and of 7-, 14- and 30-day readmissions varied by age, SCD genotype, gender and cause of hospitalization. Methods: Children who lived in the 28-county greater metro Atlanta area with a confirmed SCD diagnosis and who received care at the ChildrenÕs Healthcare of Atlanta (CHOA) SCD program between January 1, 2010 through December 31, 2014 were included. The earliest and latest encounter during the five-year period was used to determine total length of observation for each patient. To ensure a substantial period of observation, individuals with two consecutive encounters >18 months apart or with < 2 yr of observation were excluded. SCD genotype (SS, SC, and Sβ0 and Sβ+ thalassemia) was confirmed for each patient by review of hematologic and clinical data, including results of diagnostic hemoglobin electrophoresis; those with rare SCD genotypes (e.g. SD, SE) were excluded. The primary cause for each admission was determined through medical chart review and classified into 4 mutually exclusive hierarchical categories in the following descending order: acute chest syndrome (ACS), pain crisis, fever/infection, and other complications of SCD (i.e. an admission for both pain and ACS was categorized as ACS). Scheduled hospitalizations for elective procedures (e.g. splenectomy, cholecystectomy, venous catheter placement) were excluded. A readmission was defined as a hospitalization occurring within 7, 14, or 30 days of a previous hospital discharge. Results: The analysis included 1,331 individuals with 5,362 person-years of observation; 68% had SS/Sβ0 thal genotypes, 49% were male. Age at the time of the earliest encounter ranged from 2 months to 19 years; average length of observation was 4.02 years (min, max= 2, 5). Total n of hospital admissions was 5,317; 19.4% were never hospitalized, and 44.8% were hospitalized less than once per year. The most common primary cause for hospital admission was pain (53.1% of admissions). Overall and cause-specific hospitalization rates varied by age and genotype (Figure) with overall hospitalization rates lowest among children 4-9 years old compared to other ages (0.68 vs. 1.00 admissions per person-year) and highest among those with SS or Sβ0 thal compared to those with SC or Sβ+ thal (0.97 vs. 0.68 admissions per person-year). Hospitalization rates associated with pain increased with age while rates for fever/infection decreased with age. Of the 1,073 patients who were admitted, 356 were readmitted within 30 days of a previous admission at least once. All-cause 7-, 14- and 30-day readmission rates were 5.6%, 10.0% and 18.2%, respectively. 30-day readmission rates were lower among younger age groups (15.7% for age 1-3 yr, 15.3% for 4-6 yr, 15.8% for 7-9 yr) but higher in older patients (18.3% for 10-12yr, 19.9% for 13-15yr, and 23.3% for 16-18yr). Readmission rates were highest following index admissions for pain (20.4%) and lowest for ACS (11.3%). Gender was not associated with readmission or cause of readmission. Conclusion: SCD-related hospitalization rates were highest in early life and in later adolescence with admissions for fever/infection most common in younger children and admissions for pain crises in older children. Rates of readmission strongly correlated with age and were highest following admissions for pain. These data highlight to need to develop and implement improved strategies prevention and treatment of pain in children and adolescents with SCD. Further studies should also explore individual and/or family factors that may contribute to the high rates of hospital utilization and 30-day readmissions that occur among a relatively small percentage of patients. Figure 1. Hospitalization rate per person-year by type of admission and age Figure 1. Hospitalization rate per person-year by type of admission and age Disclosures No relevant conflicts of interest to declare.

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Prospective Evaluation of the Prevalence of Elevated Tricuspid Regurgitant Jet Velocity and Associated Clinical and Echocardiographic Factors in Children and Adolescents with Sickle Cell Disease.

Blood ◽

10.1182/blood.v110.11.3388.3388 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3388-3388

Author(s):

Andrew D. Campbell ◽

Caterina Minniti ◽

Craig Sable ◽

Greg Ensing ◽

Niti Dham ◽

...

Keyword(s):

Steady State ◽

Sickle Cell Disease ◽

Children And Adolescents ◽

Sickle Cell ◽

Fold Increase ◽

Systemic Hypertension ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Jet Velocity ◽

Minute Walk

Abstract Background: Echocardiography (ECHO)-determined tricuspid regurgitation jet velocity (TRV) ≥2.5 m/s occurs in about 30% of adults with sickle cell disease(SCD)and is associated with increased mortality. The frequency and significance of high TRV in children is not known. We determined the prevalence and risk factors of elevated estimated systolic pulmonary artery pressures in 228 patients with SCD and 39 controls. Methods: Patients with SCD (Hb SS, SC, SB thalassemia or other major sickling phenotypes) aged 3 to 20 years were evaluated clinically and with ECHO and six minute walk tests at their steady state. Healthy, non-SCD controls, matched for ethnicity, sex and age, were also evaluated. Results: A comparison of patients and controls is summarized in Table 1. 184 patients (81%) had hemoglobin SS phenotype and 28 (12%) had hemoglobin SC. TRV was measurable in 214 (94%) of the patients and 34 (87%) of the controls. In a multivariate logistic regression model, each 10 mm Hg increase in systolic blood pressure was associated with an estimated 2.0-fold increase in the odds of TRV≥2.5 m/sec (P = 0.002) and a 10-fold increase in LDH with a 25-fold increase in the odds (P = 0.015). Conclusion: This study of children with SCD who have limited iron overload and limited renal dysfunction compared with the aging SCD population provides a unique window into the early pathogenesis of PH in SCD. TRV and LVMI are significantly higher in children and adolescents with SCD at steady state than age-matched control participants. Among children with SCD, TRV elevation is independently associated with systolic BP and LDH concentration. In this analysis we find a strong association with hemolysis and systemic hypertension and surprisingly no associations with vaso-occlusive events or biomarkers (VOC, ACS, HU use, WBC and platelet counts). Table I. Comparison of SCD and control subjects. Results in mean (SD) unless otherwise stated. SCD(n=228) Control (n=39) p Age in years 12 (5) 12 (5) 0.7 Female (%) 48% 46% 0.8 Systolic BP (mm Hg) 112 (11) 116 (15) 0.1 Diastolic BP (mm Hg) 64 (9) 68 (10) 0.040 Six minute walk in meters 454 (76) 498 (84) 0.006 TRV in m/sec 2.3 (0.3) 2.1 (0.3) 0.003 TRV 2.5 m/sec (%) 21% 3% 0.012 LV intern. diastolic diam Z-score 1.2(1.4) −0.3(1.2) <0.001 LV mass index 88 (25) 59 (13) <0.001 Table II. Comparison of SCD patients according to TRV category. Results in mean (SD) unless otherwise stated. Variables TRV <2.5 (n= 169) TRV ≥2.5 (n=45) p History of acute chest syndrome (%) 20% 40% 0.034 Hydroxyurea therapy 42% 44% 0.8 Hemoglobin in g/dl 9.3 (1.8) 8.9 (1.7) 0.071 LDH in U/L 393 (163) 474 (170) 0.009 Total Bilirubin in mg/dL 2.7 (1.9) 3.8 (2.2) 0.004

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Population-Based Analysis Of High Hospital Utilization (HHU) Among Children and Adolescents With Sickle Cell Disease (SCD)

Blood ◽

10.1182/blood.v122.21.1740.1740 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1740-1740

Author(s):

Rodney S Theodore ◽

Maa-Ohui Quarmyne ◽

James Bost ◽

Carlton Dampier ◽

Peter A. Lane

Keyword(s):

Health Care ◽

Sickle Cell Disease ◽

Children And Adolescents ◽

Sickle Cell ◽

Insurance Coverage ◽

Population Based ◽

Hospital Utilization ◽

Cell Disease ◽

Relationship Of ◽

The Relationship

Abstract Background Sickle cell disease (SCD) is characterized by marked heterogeneity in clinical manifestations, severity and utilization of health care services. This heterogeneity is particularly evident with regards to utilization of inpatient services, which account for a large percentage of total health care costs and significant absence from school and work. Previous studies of utilization, based on analysis of administrative datasets, have been limited by inaccuracies in ICD-coding, inability to differentiate among SCD genotypes, and/or inability to capture individuals never hospitalized. Single center studies have been limited by potential disease severity referral bias, inability to capture service utilization at outside facilities, and relatively small numbers. Objectives We sought to identify children and adolescents with SCD with high hospital utilization (HHU) and to determine the relationship of HHU with age, SCD genotype, and insurance coverage. We also sought to examine trends over a three year period (2010-2012) and explore the relationship of any trends in hospital utilization over time. Methods The clinical database of the SCD Program at Children's Healthcare of Atlanta (CHOA) was used to identify all patients with SCD, ages ≥ 5 years, who received comprehensive outpatient, acute care, and inpatient services at three CHOA facilities in metro Atlanta during 2010-2012. SCD genotype was confirmed for each patient by review of hematologic and clinical data, including results of diagnostic hemoglobin electrophoresis. All outpatient clinic, emergency department, and inpatient utilization was captured as well as insurance (payer) status at each encounter. HHU was defined as ≥3 admissions during a calendar year. Data were analyzed for significance by Chi-square. The extent to which the data were population-based was determined from the Georgia Hospital Association database with includes DRG-level data for all inpatient hospitalizations in Georgia. Results Hospitalizations at CHOA accounted for 96.1% of all SCD admissions for children within the 28-county greater metro Atlanta area. During 2010-2012, 1348 individual children and adolescents ≥ 5yr of age with SCD received comprehensive care at CHOA (1076 in 2010, 1112 in 2011, 1159 in 2012): 928 (68.8%) had SS/S β°thal, 334 (24.8%) SC, 86 (6.4%) S β+thal. Of 1159 active patients in 2012, 441 (38.1%) were 5-9 yr of age, 419 (36.2%) 10-14 yr, 299 (25.8%) ≥ 15 yr; 474 (40.9%) had traditional medicaid (MC), 205 (17.7%) managed-care medicaid (MMC), 374 (32.3%) private payer (PP), and 105 (9.1%) multiple payers (MP). HHU (≥ 3 admissions/yr) decreased from 119 of 1076 (11.1%) in 2010 to 96 of 1112 (8.6%) in 2011 and 95 of 1159 (8.2%) in 2012 (p <.01). The Table shows percentage HHU for each year by age, genotype, and payer. Conclusions For children and adolescents with SCD, HHU decreased during the three year period. HHU was significantly associated with older age and with MC and MP insurance coverage during all three years. HHU was significantly associated with the SS/S β°thal genotype in 2010, but not in 2011-12. The extent to which the decline of HHU among patients with SS/S β°thal genotype was related to increasing use of hydroxyurea is being investigated. Disclosures: Off Label Use: Hydroxyurea is not FDA approved for use in children.

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Comprehensive Handbook of Childhood Cancer and Sickle Cell Disease

10.1093/oso/9780195169850.001.0001 ◽

2006 ◽

Keyword(s):

Quality Of Life ◽

Sickle Cell Disease ◽

Childhood Cancer ◽

Children And Adolescents ◽

Peer Relationships ◽

Sickle Cell ◽

Cell Disease ◽

Life Issues ◽

Art Research

Over recent decades, tremendous advances in the prevention, medical treatment, and quality of life issues in children and adolescents surviving cancer have spawned a host of research on pediatric psychosocial oncology. This important volume fulfills the clear need for an up-to-date, comprehensive handbook for practitioners that delineates the most recent research in the field--the first of its kind in over a decade. Over 60 renowned authors have been assembled to provide a thorough presentation of the state-of-the art research and literature, with topics including: -Neuropsychological effects of chemotherapy and radiation therapy -Bone marrow transplantation -Important issues about quality of life during and following treatment -Collaborative research among child-focused psychologists -Standards of psychological care for children and adolescents -Stress and coping in the pediatric cancer experience -The role of family and peer relationships The Comprehensive Handbook of Childhood Cancer and Sickle Cell Disease represents both multidisciplinary and international efforts, an alliance between physicians and parents, and a combination of research and service. With a wealth of information of great interest to patients and their families, this volume will also be a welcome resource to the psychologists, psychiatrists, pediatricians, oncologists, nurses, and social workers who confront these issues as they help children and their families through the treatment, recovery, and grieving processes.

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ECMO Therapy in Acute Chest Syndrome for Patients with Sickle Cell Disease: a Case Report and Literature Review

SN Comprehensive Clinical Medicine ◽

10.1007/s42399-021-00987-0 ◽

2021 ◽

Author(s):

Soi Avgeridou ◽

Ilija Djordjevic ◽

Anton Sabashnikov ◽

Kaveh Eghbalzadeh ◽

Laura Suhr ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Scientific Data ◽

Acute Chest Syndrome ◽

Data Sets ◽

Limited Data ◽

Cell Disease ◽

Life Saving ◽

Institutional Experience ◽

Ecmo Therapy

AbstractExtracorporeal membrane oxygenation (ECMO) plays an important role as a life-saving tool for patients with therapy-refractory cardio-respiratory failure. Especially, for rare and infrequent indications, scientific data is scarce. The conducted paper focuses primarily on our institutional experience with a 19-year-old patient suffering an acute chest syndrome, a pathognomonic pulmonary condition presented by patients with sickle cell disease. After implementation of awake ECMO therapy, the patient was successfully weaned off support and discharged home 22 days after initiation of the extracorporeal circulation. In addition to limited data and current literature, further and larger data sets are necessary to determine the outcome after ECMO therapy for this rare indication.

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Streptococcus pneumoniae and Its Virulence Factors H2O2 and Pneumolysin Are Potent Mediators of the Acute Chest Syndrome in Sickle Cell Disease

Toxins ◽

10.3390/toxins13020157 ◽

2021 ◽

Vol 13 (2) ◽

pp. 157

Author(s):

Joyce Gonzales ◽

Trinad Chakraborty ◽

Maritza Romero ◽

Mobarak Abu Mraheil ◽

Abdullah Kutlar ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Sickle Cell Disease ◽

Virulence Factors ◽

Sickle Cell ◽

Biological Activities ◽

Acute Chest Syndrome ◽

Antibiotics Resistance ◽

Cell Disease ◽

Antibiotic Drug ◽

Tract Infections

Sickle cell disease (SCD) is one of the most common autosomal recessive disorders in the world. Due to functional asplenia, a dysfunctional antibody response, antibiotic drug resistance and poor response to immunization, SCD patients have impaired immunity. A leading cause of hospitalization and death in SCD patients is the acute chest syndrome (ACS). This complication is especially manifested upon infection of SCD patients with Streptococcus pneumoniae (Spn)—a facultative anaerobic Gram-positive bacterium that causes lower respiratory tract infections. Spn has developed increased rates of antibiotics resistance and is particularly virulent in SCD patients. The primary defense against Spn is the generation of reactive oxygen species (ROS) during the oxidative burst of neutrophils and macrophages. Paradoxically, Spn itself produces high levels of the ROS hydrogen peroxide (H2O2) as a virulence strategy. Apart from H2O2, Spn also secretes another virulence factor, i.e., the pore-forming exotoxin pneumolysin (PLY), a potent mediator of lung injury in patients with pneumonia in general and particularly in those with SCD. PLY is released early on in infection either by autolysis or bacterial lysis following the treatment with antibiotics and has a broad range of biological activities. This review will discuss recent findings on the role of pneumococci in ACS pathogenesis and on strategies to counteract the devastating effects of its virulence factors on the lungs in SCD patients.

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To Give or Not to Give: RhD Immunoglobulin for an RHD*39 Pregnant Woman with Sickle Cell Disease

Transfusion Medicine and Hemotherapy ◽

10.1159/000512644 ◽

2021 ◽

pp. 1-5

Author(s):

Justin E. Juskewitch ◽

Craig D. Tauscher ◽

Sheila K. Moldenhauer ◽

Jennifer E. Schieber ◽

Eapen K. Jacob ◽

...

Keyword(s):

Pregnant Woman ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Pregnancy Termination ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Childbearing Age ◽

Procedural Complications ◽

History Of ◽

Chronic Hemolysis

Introduction: Patients with sickle cell disease (SCD) have repeated episodes of red blood cell (RBC) sickling and microvascular occlusion that manifest as pain crises, acute chest syndrome, and chronic hemolysis. These clinical sequelae usually increase during pregnancy. Given the racial distribution of SCD, patients with SCD are also more likely to have rarer RBC antigen genotypes than RBC donor populations. We present the management and clinical outcome of a 21-year-old pregnant woman with SCD and an RHD*39 (RhD[S103P], G-negative) variant. Case Presentation: Ms. S is B positive with a reported history of anti-D, anti-C, and anti-E alloantibodies (anti-G testing unknown). Genetic testing revealed both an RHD*39 and homozygous partial RHCE*ceVS.02 genotype. Absorption/elution testing confirmed the presence of anti-G, anti-C, and anti-E alloantibodies but could not definitively determine the presence/absence of an anti-D alloantibody. Ms. S desired to undergo elective pregnancy termination and the need for postprocedural RhD immunoglobulin (RhIG) was posed. Given that only the G antigen site is changed in an RHD*39 genotype and the potential risk of RhIG triggering a hyperhemolytic episode in an SCD patient, RhIG was not administered. There were no procedural complications. Follow-up testing at 10 weeks showed no increase in RBC alloantibody strength. Discussion/Conclusion: Ms. S represents a rare RHD*39 and partial RHCE*ceVS.02 genotype which did not further alloimmunize in the absence of RhIG administration. Her case also highlights the importance of routine anti-G alloantibody testing in women of childbearing age with apparent anti-D and anti-C alloantibodies.

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