A microfluidic-informatics assay for quantitative physical occlusion measurement in sickle cell disease.

Sickle cell disease (SCD) is a genetic condition that causes abnormalities in hemoglobin mechanics. Those affected are at high risk of vaso-occlusive crisis (VOC), which can induce life-threatening symptoms. The development of measurements related to vaso-occlusion facilitates the diagnosis of the patient's disease state. To complement existing readouts, we design a microfluidic-informatics analytical system with varied confined geometries for the quantification of sickle cell disease occlusion. We detect an increase in physical occlusion events in the most severe hemoglobin SS group. We use bioinformatics and modeling to quantify the in vitro disease severity score (DSS) of individual patients. We also show the potential effect of hydration, clinically recommended for crisis management, on reducing the disease severity of high-risk patients. Overall, we demonstrate the device as an easy-to-use assay for quick occlusion information extraction with a simple setup and minimal additional instruments. We show the device can provide physical readouts distinct from clinical data. We also show the device sensitivity in separate samples from patients with different disease severity. Finally, we demonstrate the system as a potential platform for testing the effectiveness of therapeutic strategies (e.g. hydration) on reducing sickle cell disease severity.

Hemoglobin level and macular thinning in sickle cell disease.

Purpose: To study the relationship between complete blood count (CBC) indices over time, particularly serum hemoglobin (Hb) levels, and severity of macular thinning on spectral domain optical coherence tomography (SD-OCT) in patients with sickle cell disease (SCD). Methods: This is a single-center, retrospective analysis of 141 consecutive SCD patients over a 10-year period, of which 40 patients (79 eyes) had SD-OCT imaging of the macula and 29 (58 eyes, mean age 17.5 years) were eligible for the study. Investigators reviewed electronic medical records for documentation of retinopathy stage, disease genotype, CBC values, and SD-OCT imaging. SD-OCT parameters and CBC values were compared between different retinopathy stages and disease genotypes. Regression analyses were performed on SD-OCT parameters and CBC values. Results: Of the 58 eligible eyes (34HbSS, 18HbSC, 4HbSß +thal, 2HbS ßthal), 18 had PSR (proliferative sickle retinopathy), 14 had NPSR (nonproliferative sickle retinopathy), and 26 had NSR (no sickle retinopathy). Hb values were higher in SC group compared to SS group. Macular thickness in the temporal inner (Δ=26±33 um, p=0.01) and outer (Δ=21±30 um, p=0.02) subfields was higher in SC compared to SS group. Patients with SD-OCT thinning below the 5th percentile in the temporal outer subfields had lower recorded Hb nadirs (6.0±0.9) compared to those with thickness within the top 95th percentile (9.1±2.3). Regression analysis showed temporal macular thickness to be positively correlated with Hb values in the SS group. Conclusion: Macular thinning observed on SD-OCT in SCD patients with SS genotype may be related to the level of anemia in this population.

Improving Care for Sickle Cell Pain Crisis Using a Multidisciplinary Approach.

OBJECTIVES: Frequent hospitalizations for sickle cell disease (SCD) vaso-occlusive crises (VOCs) are associated with school absenteeism, emotional distress, and financial hardships. Our goal was to decrease hospital days for VOC admissions by 40% over a 5-year period. METHODS: From October 2011 to September 2016, a multidisciplinary quality-improvement project was conducted with a plan-do-study-act methodology. Five key drivers were identified and 9 interventions implemented. Interventions included individualized home pain plans, emergency department and inpatient order sets, an inpatient daily schedule, psychoeducation, and a biofeedback program. High users (≥4 admissions per year) received an individualized SCD plan and assigned mental health provider. We expanded the high-use group to include at-risk patients (3 admissions per year). Data were analyzed for patients ages 0 to 21 years admitted for VOC. Hospital days were the primary measure; the 30-day readmission rate was the balancing measure. RESULTS: A total of 216 SCD pediatric patients were managed in 2011 with a 14% increase over 5 years. A total of 122 patients were admitted for VOC. Hospital days decreased by 61% from 59.6 days per month in the preintervention period to 23.2 days per month in the postintervention period (P < .0001). Length of stay decreased from 4.78 (SD = 4.08) to 3.84 days (SD = 2.10; P = .02). Among high users, hospital days decreased from 35.4 to 15.5 days per month. The thirty-day readmission rate decreased from 33.9% to 19.4%. Overall savings in direct hospital costs per year were $555 120. CONCLUSIONS: A dedicated team effort with simple interventions can have a significant impact on the well-being of a patient population and hospital costs.

Proteinuria is associated with elevated tricuspid regurgitant jet velocity in children with sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) affects multiple organ systems. Complications of SCD such as pulmonary hypertension (PHT) and sickle cell nephropathy (SCN) are associated with an increased mortality. Both PHT and SCN have some common risk factors. In adults, PHT has been found to be associated with albuminuria, a manifestation of SCN. There is no data on this association in children. We conducted a study to determine if elevated pulmonary artery systolic pressures estimated on echocardiogram was associated with proteinuria in children with SCD. METHODS: A detailed retrospective chart review was conducted on a cohort of sickle cell patients screened with echocardiograms from June 2005 to July 2010. Patients who had an initial screening echocardiogram and urine analysis within 1 year were included. Longitudinal data from all subsequent echocardiograms and urine analyses were collected. RESULTS: Eighty-five patients were included. On initial echocardiograms 32.9% had an elevated tricuspid regurgitant jet velocity (TRV) ≥2.5 m/second. On follow up, in the 28 patients with elevated TRV, 49.27% of all repeat echocardiograms showed persistent elevation. In the 57 patients with normal baseline TRV, 73.6% of all repeat echocardiograms continued to have normal TRV. On initial screening 7.14% of patients with elevated TRV had proteinuria compared to 1.75% without elevated TRV. On follow up, 19.08% of repeat urinalysis had proteinuria in patients with elevated baseline TRV compared to 12.35% in patients with normal baseline TRV (P = 0.04). CONCLUSIONS: Elevated TRV ≥ 2.5 m/second is significantly associated with proteinuria on longitudinal follow up in children with SCD.

Submandibular TCD approach detects post-bulb ICA stenosis in children with sickle cell anemia.

BACKGROUND: Transcranial Doppler (TCD) ultrasound is a procedure commonly used to screen individuals with the major hemoglobin S diseases, Hb SS and Hb S-beta(0), for significant stenoses in the circle of Willis. Flow velocities above 200 cm/s have been shown to identify patients at elevated risk for cerebral infarction. Among TCD's limitations is the inability to insonate the distal extracranial, petrous, and cavernous internal carotid artery (ICA) through the standard transtemporal approach. METHODS: We extended the submandibular approach to include infra-siphon portions of the ICA. RESULTS: Using the extended submandibular approach to evaluate these portions of the ICA, we identified stenotic lesions in 4 patients with Hb SS disease out of a population of 131 children with Hb SS. Three of the 4 patients had no history of overt stroke or stroke-like symptoms. Neuroimaging confirmed the stenotic lesions, and also revealed watershed infarction as well as discrete areas of silent infarction. All 4 children had neuropsychological impairment. CONCLUSIONS: The submandibular approach, when added to a standard transcranial Doppler examination, may increase the sensitivity of this technique to identify important potential sources of cerebral infarction.

Longitudinal follow up of elevated pulmonary artery pressures in children with sickle cell disease.

Elevated pulmonary artery pressures (PAP) occur in approximately 30% of children with sickle cell disease. In adults, pulmonary hypertension is significantly associated with mortality. There are no data on the long term significance in children. Nineteen children with SS/Sbeta(0) thalassaemia had elevated PAP, defined as tricuspid regurgitant jet velocity (TRV) > or =2.5 m/s on screening echocardiograms. They were prospectively followed for 23 months (range 19-31 months). Patients with initial TRV > or = 3 or TRV > or = 2.5 m/s on repeat echocardiogram had cardiopulmonary evaluation and were offered treatment with hydroxyurea. Associated conditions like asthma and obstructive sleep apnea were treated. 18/19 patients had follow-up echocardiograms. These showed normalization of TRV in 8 patients. Risk factors associated with persistent elevation were higher TRV on initial echocardiogram (P = 0.01), lower haemoglobin (P = 0.003) and lower oxygen saturation (P = 0.03). Five patients with persistently elevated PAP were treated with hydroxyurea. Mean right ventricular pressure dropped from 40.16 to 29.26 (P = 0.017) after 3-6 months and to 23.6 mmHg (P = 0.002) after 9-12 months on treatment. In conclusion (i) At borderline elevation of TRV there is intrapatient variability and echocardiograms should be repeated for confirmation. (ii) Elevated PAP are reversible in children with early detection and treatment with hydroxyurea.

Prevalence and risk factors of elevated pulmonary artery pressures in children with sickle cell disease.

OBJECTIVES: The objectives of this study were (1) to determine the prevalence and risk factors of elevated pulmonary artery pressures in children with homozygous SS or Sbeta(0) thalassemia using Doppler echocardiography and (2) to determine a correlation between abnormal transcranial Doppler examinations and elevated pulmonary artery pressures. METHODS: Screening echocardiograms were prospectively performed during an annual comprehensive clinic visit on children who were older than 6 years and had homozygous SS or Sbeta(0) thalassemia. Detailed history, examination, and laboratory tests were done, and transcranial Doppler examinations were obtained in children 2 to 14 years of age. Pulmonary hypertension was defined as pulmonary artery systolic pressure of at least 30 mmHg corresponding to a peak tricuspid regurgitant jet velocity of > or = 2.5 m/second. Mild pulmonary hypertension was defined as tricuspid regurgitant jet velocity > or = 2.5 to 2.9 m/second. Moderate pulmonary hypertension was defined as tricuspid regurgitant jet velocity > or = 3 m/second. Patients with pulmonary stenosis or right outflow obstruction were excluded. Characteristics were compared between patients with mild, moderate, and no pulmonary hypertension using 1-way analysis of variance for continuous variable and Fisher's exact test for categorical variables. RESULTS: Of the 75 patients who had homozygous SS/Sbeta(0) thalassemia and were older than 6 years, echocardiograms were obtained for 62 (82.6%). Thirty percent (19 of 62) of patients had elevated tricuspid regurgitant jet velocity > or = 2.5 m/second. One third of these patients had tricuspid regurgitant jet velocity > or = 3 m/second. All patients with elevated tricuspid regurgitant jet velocity had SS disease. A high reticulocyte count, low oxygen saturation, and a high platelet count were significantly associated with elevated pulmonary artery pressures. There was no difference in age, gender, history of acute chest syndrome, hydroxyurea therapy, chronic blood transfusion, stroke, hemoglobin, and bilirubin between patients with and without elevated pulmonary artery pressures. A total of 47% patients with elevated tricuspid regurgitant jet velocity and 57% without elevated tricuspid regurgitant jet velocity had screening transcranial Doppler examinations. Transcranial Doppler examinations were normal for all patients. CONCLUSIONS: High pulmonary artery pressures do occur in children with sickle cell disease. Screening by echocardiography can lead to early detection and intervention that may potentially reverse this disease process. There was no correlation between elevated pulmonary artery pressures and abnormal transcranial Doppler examination in our study.