Susan Creary

A pilot study of electronic directly observed therapy to improve hydroxyurea adherence in pediatric patients with sickle‐cell disease

Poor hydroxyurea (HU) adherence limits effective HU use in patients with sickle cell disease (SCD). Electronic directly observed therapy (DOT) may limit costs and achieve high HU adherence in children with SCD. This study aimed to determine if electronic DOT was feasible, acceptable, and could achieve ≥90% HU adherence.

Losartan for the nephropathy of sickle cell anemia: A phase-2, multicenter trial

Nephropathy is a common and progressive complication of sickle cell anemia (SCA). In SCA mice, we found that hyperangiotensinemia in the absence of hypertension underlies nephropathy, and its downregulation by losartan, an angiotensin‐II‐receptor‐1 blocker, reduced albuminuria and progression of nephropathy. Therefore, we performed a phase‐2 trial of oral losartan, given for 6 months, to explore whether it reduced albuminuria in children and adults with SCA. Participants were allocated to groups defined by class of baseline urinary albumin‐to‐creatinine ratio (UACR): no albuminuria (NoA), microalbuminuria (MicroA), and macroalbuminuria (MacroA). The primary endpoint was a ≥25% reduction UACR from baseline. There were 32 evaluable participants (mean age 24 years; NoA = 14, MicroA = 12, MacroA = 6). The primary endpoint was met in 83% of the MacroA group (P < 0.0001) and 58% of the MicroA group (P < 0.0001). Median fold‐change in UACR was −0.74 for MacroA and −0.46 for MicroA. In MacroA and MicroA, UACR classification improved in 50% but worsened in 11%. Urine osmolality and estimated glomerular filtration rate (eGFR) did not change significantly. Losartan was discontinued in three participants [leg cramps, N = 1; decline in eGFR >25% (142➝104 mL/minute/1.73 m2), N = 1; rise in serum creatinine >50% (0.2➝0.3 mg/dL), N = 1]. Albuminuria was associated with diastolic dysfunction and impaired functional capacity, although cardiopulmonary status was unchanged after 6 months of losartan therapy. In summary, losartan decreased urinary albumin excretion in most participants with albuminuria. Those with macroalbuminuria had the greatest benefit. This study forms the basis for a phase‐3, randomized, placebo‐controlled trial of losartan for the nephropathy of SCA.

Hydroxyurea use in Children with Sickle Cell Disease: Do Severely Affected Patients Use It and Does It Impact Hospitalization Outcomes?

Expert guidelines recommend that hydroxyurea (HU) be offered to all children with hemoglobin SS and Sβ0 sickle cell disease (SCD) and be considered for children with clinically severe hemoglobin SC or Sβ+. This study aims to determine the rate of HU use in hospitalized children, if HU is differentially used in children with clinically severe SCD, and if HU users have shorter length of stay (LOS), fewer intensive care unit (ICU) admissions, and fewer inpatient transfusions compared to nonusers.

Secondhand smoke is an important modifiable risk factor in sickle cell disease: A review of the current literature and areas for future research

Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy that causes significant morbidity and mortality related to chronic hemolytic anemia, vaso-occlusion, and resultant end-organ damage. Tobacco smoke exposure (TSE) through secondhand smoke exposure in people with SCD of all ages and through primary smoking in adolescents and adults is associated with significantly increased morbidity, with increased rates of emergency department visits and hospitalizations for painful vaso-occlusive crises and acute chest syndrome (ACS). Secondhand smoke is also associated with pulmonary function abnormalities in children with SCD who are already at risk for pulmonary function abnormalities on the basis of SCD. TSE is emerging as one of the few modifiable risk factors of SCD. This review discusses the current state of the evidence with respect to TSE and SCD morbidity, discusses potential mechanisms, and highlights current gaps in the evidence and future research directions.

Desire for parenthood and reproductive health knowledge in adolescents and young adults with sickle cell disease and their caregivers

Sickle cell disease (SCD) and hydroxyurea have implications for fertility and reproductive health. The goal of this study was to examine desire for parenthood and reproductive health knowledge among a cohort of adolescent and young adult (AYA) with SCD receiving hydroxyurea and their caregivers at a large pediatric academic center.

Prevalence and risk factors for venous thromboembolism in children with sickle cell disease: an administrative database study

A hypercoagulable state resulting in increased venous thromboembolism (VTE) has been described in adults with sickle cell disease (SCD), but similar data for children are lacking. The objective of this retrospective cohort study was to describe the rate of VTE and risk factors associated with VTE in children with SCD across tertiary-care childrens hospitals in the United States between the years 2009 and 2015. We used the Pediatric Health Information System database to investigate all pediatric patients with SCD admitted to 1 of 48 participating institutions between 1 January 2009 and 30 September 2015. International Classification of Disease, Ninth Edition, Clinical Modification codes were used to identify index thromboembolic events and chronic medical conditions known to be associated with VTE. Billing codes were used to identify central venous line (CVL) placement and pharmaceutical billing codes to identify estrogen containing oral-contraceptive use. Logistic regression analysis was used to study the association among unique patient characteristics, VTE, and death. 10 454 eligible subjects with SCD were identified. Median age (±interquartile range) of study cohort was 10 (±11) years. 181 subjects (1.7%) developed an index venous thromboembolic event during the study period. Median age at VTE diagnosis was 15.9 (±7.4) years. On multivariable logistic regression analysis, CVL placement, chronic renal disease, history of stroke, female sex, length of hospitalization, intensive care unit utilization, and older age were associated with VTE. After adjusting for other variables, VTE was independently associated with death. In summary, VTE can occur in pediatric patients with SCD. CVL placement is a modifiable risk factor for VTE development.

Thrombocytopenia Pitfalls: Misdiagnosing Type 2B von Willebrand Disease as Ethylenediaminetetraacetic Acid-Dependent Pseudothrombocytopenia.

A 9-month-old boy was referred to our emergency department for extensive bruising. Medical history was relevant for increased bleeding postcircumcision and vaccination. Baseline coagulation laboratory values were normal, and a complete blood count revealed severe thrombocytopenia (Table; available at www.jpeds.com). Review of peripheral smear revealed platelet clumps, presumed to be ethylenediaminetetraacetic acid (EDTA)-dependent pseudothrombocytopenia (PTCP) (Figure). The severity of bruising raised suspicion for nonaccidental trauma, prompting the involvement of child protection services. The hemostasis-thrombosis team was consulted and additional coagulation laboratory values revealed low von Willebrand factor (vWF) antigen (32%) and ristocetin cofactor activity (<8%). vWF multimer analysis showed loss of high-molecular-weight multimers, suggesting a diagnosis of type 2B von Willebrand disease (vWD). Findings of nonaccidental trauma testing (skeletal survey, computed tomography brain scan, and ophthalmology examination) were negative. vWF exon 28 gene sequencing confirmed a sequence variant in the A1 domain, c.3940G>C, p.V1314L, which is associated with type 2B vWD.

Prodromal illness before acute chest syndrome in pediatric patients with sickle cell disease.

Background: Acute chest syndrome (ACS) is associated with morbidity and mortality in children with sickle cell disease. We hypothesize that children with sickle cell disease have a distinct prodromal illness before their ACS episode. Materials and Methods: We performed a chart review of ICD-9-CM identified ACS episodes at a pediatric hospital from 2005 to 2010. Prodromal visits were defined as acute visits that resulted in a discharge from care and occurred within 2 weeks of a hospitalization that included ACS. We reviewed the documented history, examination, laboratory studies, and radiographs for each prodromal visit. Results: We identified 196 ACS episodes. Children received prodromal care in 29% of the ACS episodes. Painful vaso-occlusive crisis was a common reason for seeking this care (61%) and was commonly located in the chest or back (81%). We also observed that patients were hypoxic (53%), tachypneic (29%), had a history of asthma (39%) or ACS (80%), and presented during the winter months (38%). Conclusions: These data suggest that nearly one third of patients who develop ACS seek care for a prodromal illness. Further research is needed to confirm and better define an ACS prodromal illness that may help to identify patients at high risk for developing ACS.

Venous Thromboembolism in Children with Sickle Cell Disease: A Retrospective Cohort Study

Objectives To describe the cumulative incidence of venous thromboembolism (VTE) in children with sickle cell disease (SCD) followed at a single institution and report on the risk factors associated with VTE development. Study design Charts for all patients with SCD, aged 0‐21 years, followed at Nationwide Childrens Hospital over a 6‐year period (January 1, 2009, to January 31, 2015) were reviewed. Data on VTE diagnosis, sex, body mass index/weight‐for‐length, SCD genotype, SCD clinical complications, central venous catheter (CVC) placement, and thrombophilia testing were collected. Results Cumulative incidence of VTE in children with SCD followed at a single tertiary care institution was found to be 2.9% (12/414). Nine of the 12 VTE were CVC‐associated. On univariate analysis, hemoglobin SS genotype (OR 10.7, 95% CI 1.4‐83.5), CVC presence (OR 34.4, 95% CI 8.9‐134.6), central nervous system vasculopathy (OR 19.4, 95% CI 5.6‐63.4), chronic transfusion therapy (OR 30.6, 95% CI 8.9‐122.2), and older age (P = .03) were associated with VTE. However, presence of CVC was the only independent risk factor identified on multivariable logistic regression analysis (OR 33.8, 95% CI 8.7‐130.9). Conclusion In our institution, nearly 3% of children with SCD had a history of VTE. CVC is an independent predictor of VTE in children with SCD.

Diverse manifestations of acute sickle cell hepatopathy in pediatric patients with sickle cell disease: A case series

The hepatic complications of sickle cell disease (SCD) are associated with increased morbidity and mortality in adults; children usually survive but may suffer significant sequelae. Few diagnostic tools differentiate the various hepatic manifestations of SCD. Why patients exhibit one hepatic pathology versus another is unclear. We report four pediatric patients with hemoglobin SS disease with diverse manifestations of acute hepatic involvement including acute sickle hepatic crisis, hepatic sequestration, sickle cell intrahepatic cholestasis, and a non‐SCD cause of hepatopathy in a patient with viral hepatitis. These complications require a systematic approach to extensive evaluation and coordinated multidisciplinary care.