Abstract 2303: Prospective Correlation of Echocardiography Findings with Hematologic and Pulmonary Function Parameters in Children with Sickle Cell Disease

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Niti Dham ◽  
Craig Sable ◽  
Caterina P Minnitti ◽  
Andrew Campbell ◽  
Manuel Arteta ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Sickle Cell Disease ◽  
Pulmonary Function ◽  
Diastolic Function ◽  
Sickle Cell ◽  
Linear Regression Analysis ◽  
Cell Disease ◽  
Pulmonary Pressure ◽  
Prospective Comparison ◽  
Lv Mass

Background Adults with sickle cell disease (SCD) have an increased prevalence of pulmonary hypertension (PAH), associated with significant morbidity and mortality. This finding has not been validated in children. We carried out a prospective comparison of echocardiography (echo) data between SCD and control patients and a correlation between echo findings and hematologic and pulmonary function testing (PFT) in SCD patients. Methods Children with SCD and age and gender matched controls were prospectively enrolled during well visits. Each subject underwent a history and examination, echo, hematologic testing, and PFT. Echo data was compared between SCD patients and controls, and regression analysis was performed to assess for correlation between echo parameters and anemia, markers of hemolysis, and PFT in SCD patients. Results Of the 194 SCD patients and 29 controls enrolled, 180 SCD patients and 26 controls had measurable tricuspid valve regurgitation (TR) to estimate systolic pulmonary pressure. TR, left ventricle (LV) size and LV mass were significantly higher in children with SCD (Table 1 ). Linear regression analysis in SCD patients showed that TR, LV size, LV mass, and diastolic function (E/E TDI ) correlated significantly with hemoglobin, markers of hemolysis, and obstructive pulmonary disease (Table 2 ). There was no correlation between echo parameters and age, blood pressure, or measures of restrictive lung disease Conclusion Children with SCD have higher estimated pulmonary pressure, LV size and mass and a trend toward worse diastolic function when compared to controls. TR and LV size and mass correlate with anemia, hemolysis, and obstructive patterns on PFT. Table 1 - Comparative Data Table 2 - Regression Analysis

scholarly journals Echocardiographic phenotypes of patients with sickle cell disease. An unsupervised analysis based on etendard cohort

2021 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
T D"humieres ◽  
J Inamo ◽  
S Deswarte ◽  
T Damy ◽  
G Loko ◽  
...  
Keyword(s):  
Cluster Analysis ◽  
Cardiac Output ◽  
Sickle Cell Disease ◽  
Diastolic Function ◽  
Sickle Cell ◽  
Left Ventricular ◽  
Integrative Approach ◽  
Cell Disease ◽  
Clinical Profiles ◽  
Cluster 2

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): PHRC Backgroung Echocardiography is the cornerstone in the diagnosis of cardiopulmonary involvement in sickle cell disease (SCD). However, given the unique pathophysiology of SCD associating high cardiac output, and various degrees of peripheral vasculopathy, differentiate the pathological from the physiological using echocardiography can be particularly challenging. Purpose This study sought to link cardiac phenotypes in homozygous SCD patients with clinical profiles and outcomes using cluster analysis. Methods We analyzed data of 379 patients with a sufficient echographic dataset included in the French Etendard Cohort, a prospective cohort initially designed to assess the prevalence of pulmonary hypertension. A cluster analysis was performed on echocardiographic variables, and the association between clusters and clinical profiles and outcomes was assessed. Results Three clusters were identified. Cluster 1 (N = 122) patients had the lowest cardiac output, only mild left cavities remodeling, diastolic dysfunction, and high tricuspid regurgitation velocity (TRV). They were predominantly female, as old as cluster 2, and displayed the most severe functional limitation. Cluster 2 (N = 103) patients had the highest cardiac output, left ventricular mass and a severely dilated left atrium. Diastolic function and TRV were similar to cluster 1. These patients had a higher blood pressure and a severe hemolytic anemia. Cluster 3 (N = 154) patients had mild left cavities remodeling, the best diastolic function and the lowest TRV. They were younger patients with the highest hemoglobin and lowest hemolytic markers. Right heart catheterization was performed in 94 patients. Cluster 1 gathered the majority of precapillary PH while cluster 2 gathered postcapillary PH and no PH was found in cluster 3. After a follow-up of 9.9 years (IQR: 9.3 to 10.5 years) death occurred in 38 patients (10%). Clusters 2 had the worst prognosis with 18% mortality rate vs. 12% in cluster 2 and 5% in cluster 1 (P log-rank = 0,02). Results are summarized in the central illustration. Conclusions Cluster analysis of echocardiographic variables identified 3 phenotypes among SCD patients, each associated with different clinical features and outcome. These findings underlines the necessity to rethink echocardiographic evaluation of SCD patients, with an integrative approach based on simultaneous evaluation of TRV along with left cavities remodeling and diastolic parameters. Abstract Figure.

scholarly journals Adenosine A2A receptors induced on iNKT and NK cells reduce pulmonary inflammation and injury in mice with sickle cell disease

Blood ◽  
2010 ◽  
Vol 116 (23) ◽  
pp. 5010-5020 ◽  
Author(s):  
Kori L. Wallace ◽  
Joel Linden
Keyword(s):  
Sickle Cell Disease ◽  
Pulmonary Function ◽  
Nk Cells ◽  
Natural Killer ◽  
Sickle Cell ◽  
Pulmonary Injury ◽  
Cell Disease ◽  
Inkt Cells ◽  
Adenosine A2a ◽  
Hypoxia Reoxygenation

Abstract We showed previously that pulmonary function and arterial oxygen saturation in NY1DD mice with sickle cell disease (SCD) are improved by depletion of invariant natural killer T (iNKT) cells or blockade of their activation. Here we demonstrate that SCD causes a 9- and 6-fold induction of adenosine A2A receptor (A2AR) mRNA in mouse pulmonary iNKT and natural killer (NK) cells, respectively. Treating SCD mice with the A2AR agonist ATL146e produced a dose-dependent reversal of pulmonary dysfunction with maximal efficacy at 10 ng/kg/minute that peaked within 3 days and persisted throughout 7 days of continuous infusion. Crossing NY1DD mice with Rag1−/− mice reduced pulmonary injury that was restored by adoptive transfer of 106 purified iNKT cells. Reconstituted injury was reversed by ATL146e unless the adoptively transferred iNKT cells were pretreated with the A2AR alkylating antagonist, FSPTP (5-amino-7-[2-(4-fluorosulfonyl)phenylethyl]-2-(2-furyl)-pryazolo[4,3-ϵ]-1,2,4-triazolo[1,5-c]pyrimidine), which completely prevented pro-tection. In NY1DD mice exposed to hypoxia-reoxygenation, treatment with ATL146e at the start of reoxygenation prevented further lung injury. Together, these data indicate that activation of induced A2ARs on iNKT and NK cells in SCD mice is sufficient to improve baseline pulmonary function and prevent hypoxia-reoxygenation–induced exacerbation of pulmonary injury. A2A agonists have promise for treating diseases associated with iNKT or NK cell activation.

scholarly journals Pulmonary function in sickle cell disease with or without acute chest syndrome

1998 ◽  
Vol 12 (5) ◽  
pp. 1124-1129 ◽  
Author(s):  
F. Santoli ◽  
F. Zerah ◽  
N. Vasile ◽  
D. Bachir ◽  
F. Galacteros ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Pulmonary Function ◽  
Sickle Cell ◽  
Acute Chest Syndrome ◽  
Cell Disease

PULMONARY FUNCTION TESTING IS MORE SENSITIVE THAN RADIOLOGY AND ECHOCARDIOGRAPHY IN EVALUATING THE SICKLE CELL DISEASE PATIENTS WITH DYSPNEA

CHEST Journal ◽  
2007 ◽  
Vol 132 (4) ◽  
pp. 614A
Author(s):  
Fayez Bader ◽  
Olumayowa Abe ◽  
Mohammad-Ali El-Harakeh ◽  
Marvin Korot ◽  
Gary T. Kinasewitz ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Pulmonary Function ◽  
Sickle Cell ◽  
Pulmonary Function Testing ◽  
Cell Disease ◽  
Function Testing

Myocardial Ischemia without Coronary Artery Obstruction in Patients with Sickle Cell Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3180-3180
Author(s):  
Subha V. Raman ◽  
Orlando P. Simonetti ◽  
Spero R. Cataland ◽  
William J. Hicks ◽  
Eric H. Kraut
Keyword(s):  
Sickle Cell Disease ◽  
Myocardial Ischemia ◽  
Sickle Cell ◽  
Single Gene ◽  
Blood Pool ◽  
Microvascular Perfusion ◽  
Cell Disease ◽  
Dark Blood ◽  
Lv Mass ◽  
Artery Obstruction

Abstract Objectives. Sickle cell disease (SCD) is the most common single gene disorder in black Americans, with poorly described cardiovascular sequelae partly due to insensitive techniques to identify microvascular perfusion abnormalities. We employed cardiac magnetic resonance (CMR) and computed tomography (CTA) to assess myocardium, microvascular perfusion and coronary arteries in SCD patients. Methods. Twelve adult patients with SCD (10 HbSS, 1 HbSC and 1 S-thal) age 20–45 years were enrolled. CMR protocol included: dark blood multiecho imaging, rest and stress myocardial perfusion, multiplane cines, and delayed post-gadolinium imaging (DME) for infarct imaging. Myocardial T2*, reflecting iron content, was calculated and verified using a T2* phantom. Left and right ventricular volumes and ejection fractions were quantified from short axis cines. Coronary CTA was performed in patients and five controls using a 64-slice scanner and 70cc of isotonic, isoosmolar contrast, with vessel review in multiple planes. Results. Three subjects, all SS genotype, had striking subendocardial ischemia (top image, arrows) with vasodilator stress that was not present at rest (signal intensity-vs-time curves, solid line=abnormal subendocardium, dotted and dashed=normal myocardium, dot-dash=blood pool). Myocardial T2* was normal in all subjects (25 to 33ms) as were DME, LV mass and LVEF. One subject with pulmonary hypertension had marked RV dysfunction (RVEF 26%). No subject had obstructive epicardial coronary disease, though proximal coronary diameters were significantly larger for SCD patients compared to controls (2.7mm/m2 versus 1.9mm/m2, p<0.001). Conclusions. A subset of SCD patients has quantifiable myocardial ischemia with coronary dilatation and absence of infarcted myocardium. Further studies are ongoing to correlate perfusion abnormalities with episodic chest pain and ischemia-based therapies. Figure Figure Figure Figure

Abnormal Pulmonary Function in Adults with Sickle Cell Disease: Association of Decreased DLCO with Systemic Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 316-316 ◽  
Author(s):  
Elizabeth S. Klings ◽  
Diego F. Wyszynski ◽  
Vikki G. Nolan ◽  
Martin H. Steinberg
Keyword(s):  
Sickle Cell Disease ◽  
Pulmonary Function ◽  
Sickle Cell ◽  
Pulmonary Function Tests ◽  
Systemic Disease ◽  
The United States ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Restrictive Physiology ◽  
Abnormal Pulmonary Function

Abstract Pulmonary complications of sickle cell disease (SCD), including acute chest syndrome, pulmonary hypertension (PH) and pulmonary fibrosis, are common. Dyspnea and hypoxemia are equally common in this population. It is likely that pulmonary function tests (PFT) are abnormal in the SCD population, however, no extensive study has been reported to date. Moreover, the relationship between abnormal pulmonary function and other manifestations of SCD, such as PH, is unclear. We hypothesized that abnormalities of pulmonary function, particularly a low diffusion capacity for carbon monoxide (DLCO), may be associated with other complications of SCD. The Cooperative Study of Sickle Cell Disease (CSSCD) enrolled and followed more than 4,000 SCD patients who had visited one of 23 participating clinical centers across the United States between 1978 and 1998. Data were collected on many complications of the disease, and standardized collection of PFTs were part of the protocol. From the more than 1300 CSSCD patients who had the results of PFTs recorded, 310 adults (age≥ 20 years of age) homozygous for the Hb S gene without coincident α thalassemia and with sufficient data were identified. Predicted values for FEV1, FVC, FEV1/FVC, TLC, RV and DLCO were calculated using algorithms that accounted for gender, age, and height in the African American population (using STATA, version 9); data are presented as percent predicted. Based on criteria established by the American Thoracic Society, subjects were sub-classified into 7 groups: obstructive physiology; restrictive physiology; mixed obstructive/restrictive disease; low lung volumes with normal spirometry (LLV); LLV with a low DLCO, isolated low DLCO, or normal. The association of blood counts and serum chemistries between patients with low DLCO compared with those with a normal DLCO was assessed by multivariate linear regression (using SAS software version 8.2). Normal PFTs were present in only 31 of 310 (10 %) SCD patients. Overall, the adult SCD population was characterized by decreased total lung capacities (70.2 + 14.7% predicted) and DLCO (64.5 + 19.9 % predicted adjusted for hemoglobin concentration). The most common PFT patterns observed were restrictive physiology (35.8%), LLV with normal spirometry (34.2% of patients), and an isolated low DLCO (12.9%). The presence of a low DLCO was associated with an elevated platelet count (p=0.05), hepatic dysfunction [elevated ALT (p=0.07) with elevated AST (p=0.01)] and renal dysfunction [elevated BUN and creatinine (p=0.05, 0.07)]. Restrictive disease is marginally associated with a decrease in hematocrit (p=0.07) and Hb F levels (p=0.07). Pulmonary function is abnormal in 90% of adult SCD patients. Common abnormalities include restrictive physiology, LLV with normal spirometry and a decreased DLCO. The presence of a decreased DLCO may be a marker of more severe systemic disease that includes impaired renal and hepatic function and possibly complications of hemolytic anemia such as PH.

Genetics of HbF and HbF Response to Hydroxyurea In Pediatric Sickle Cell Disease: A Multi-Site Pilot Analysis of Candidate SNP Variants

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2641-2641
Author(s):  
Nancy S. Green ◽  
Katherine Ender ◽  
Farzana Pashankar ◽  
Catherine Driscoll ◽  
Patricia Giardina ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Multiple Testing ◽  
Linear Regression Analysis ◽  
Minor Allele ◽  
Candidate Snps ◽  
Genetic Associations ◽  
Cell Disease ◽  
Bonferroni Adjustment ◽  
Snp Association

Abstract Abstract 2641 Abstract: Only few genes appear to strongly regulate HbF levels in adults with sickle cell disease (SCD). We aim to: (1) Extend these observations to children with SCD, who likely have better preserved marrow capacity; (2) Assess whether these same genes and other previously identified candidates (Ma et al., 2007) associate with HbF response to HU. Methods: We performed a retrospective analysis from 6 sites (see author affiliations) of children age 5–21 with HbSS or HbS-B thalassemia, untreated with HU or treated for > 6 months at comparable indications and dosing, using %HbF at steady state (baseline) and on HU at or near maximal tolerated dose (MTD), defined as >20mg/kg/day. Subject adherence to HU was assessed by report to their hematology clinician. Siblings were excluded to ensure genetic independence. Candidate 36 SNPs from 2 groups of genes were genotyped: 1) those from reported GWAS: 15 SNPs in BCL11A, 3 in HBS1L-MYB intron, 5' site in B globin, plus sar1; and 2) 15 candidate SNPs exhibiting the largest effect size on HbF with HU treatment (Ma, 2007). SNP genotyping (minor allele frequency (MAF) ranging from 0.10 to 0.50) was performed on the Sequenom MassArray iPLEX platform. (SNP sequences are available.) Duplicate samples assured genotype concordance. Genotype frequency distribution at each SNP was tested for deviations from Hardy-Weinberg equilibrium. MAFs were comparable across our 6 sites, to allele frequencies in HapMap for CEU populations, and CSSCD (Lettre et al., 2008), confirming validity of pooling SNP genotype data from the sites. Using HbF as a continuous trait, genetic associations were assessed from a total of 80 children, 29 of whom are on HU, between each of the 36 SNPs and: a) baseline %HbF; b) %HbF on HU treatment; c) delta %HbF (HU treatment - baseline). For each model, linear regression analysis was used to test quantitative trait and disease trait SNP associations assuming an additive effect for each copy of the minor allele on the phenotype. Resultant p-values were assessed for significance using Bonferroni adjustment for multiple testing. Results: Of the 80 children, comparing the 51 not on HU to those 29 on HU, no significance differences were seen in the distribution and average of baseline %HbF (9.2 vs. 8.9, p=0.820). SNP analyses are summarized in Table 1. 8 SNPs were nominally significantly associated with baseline %HbF. Direction of SNP association differed among these SNPs; some MAF may be reversed in this population compared to those previously reported. For %HbF on HU, the B globin SNP was significantly associated. The delta %HbF on HU is significantly associated with the B globin SNP and nominally so with BCLA11 and SAR1A gene. Our preliminary data begin to extend findings of specific genetic variants regulating HbF to children with SCD. Early data suggest that HbF in response to HU may share some of the mechanisms governing baseline HbF in SCD, not surprising given the commonality of enhanced erythropoiesis. Subject recruitment and analyses are on-going. Disclosure: Off Label Use: Hydroxyurea has not been FDA approved for use in children with sickle cell disease, a topic of the submitted abstract.

Are There True Non-Responders to Hydroxyurea in Sickle Cell Disease? a Multiparameter Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4073-4073 ◽  
Author(s):  
Arati Rani Chand ◽  
Hongyan Xu ◽  
Leigh G Wells ◽  
Betsy Clair ◽  
Cindy Neunert ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Response Rate ◽  
Treatment Time ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Average Dose ◽  
Cell Disease ◽  
Laboratory Parameters

Abstract Hydroxyurea (HU) is the only FDA approved anti-switching agent for the management of sickle cell disease (SCD). The non-response rate to HU (inadequate increase in fetal hemoglobin (HbF)) has been reported to be as high as 30%. However, the role of patient non-compliance as a cause of sub-optimal response to HU has not been studied. Establishing the rate of non-response to HU despite adequate dose and compliance would help in ascertaining patients who might benefit from alternate treatment strategies in SCD. The primary objective of this study was to differentiate between non-compliance and lack of response in patients using laboratory parameters other than HbF. We conducted a retrospective review of 137 adult SCD patients from GRU's Sickle Cell Center that were reportedly taking HU for ≥ 6 months. Data included weight, dose, HbF, Hb, RBC, RDW, retic, MCV, MCH, WBC, ANC, platelets, bilirubin, prior to initiation of HU therapy and at the time of maximal HbF response. Dose of HU/Kg required to achieve that response and time to response was calculated. We defined response as an absolute HbF value of ≥20% or a ≥5% increase in HbF from baseline. The anticipated direction of change in laboratory parameters indicative of compliance was an increase in MCV, MCH, Hb, PCV, and a decrease in RDW, retic count, WBC, neutrophils, platelets, and bilirubin. Patients without a change in HbF but with response from the additional parameters were classified as inadequate-responders. Patients without response in HbF as well as additional parameters were classified as non-compliant. We performed a regression analysis to study the effect of dose and patient age on the response (change in HbF). To model dosage, a new variable called HU exposure was calculated as the product of dose (mg/kg/day) and treatment time (days). The HU exposure and age was used as the predictors for change in HBF. Our results showed that of the 137 patients, 82(59.9%) were responders to HU (mean dose of 18.8mg/kg) with an expected increase in HbF and 36(26.3%) were non-compliant (mean dose of 18.48mg/kg) based on the fact that the aforementioned laboratory values did not change significantly. Only 19(13.9%) were non-responders (mean dose of 16.84 mg/kg) based on a lack of HbF response despite other laboratory parameters being indicative of compliance with HU. Out of the 19 patients who were non-responders only 2 patients were on HU doses more than 20mg/kg. In the overall sample, we found that both age and HU exposure were positively associated with HbF change, which was highly statistically significant (p=2.55E-08 and 7.03E-10, respectively). When we performed regression analysis in the responders, non-responders and non-compliant groups separately we found that in the responder group both age and HU exposure were positively associated with HbF change, with high statistical significance. In the non-responder group however, age and HU exposure were not statistically significant. Patients with SCD on HU who fail to show an adequate increase in HbF are more likely to be non-compliant with medication than actually being truly resistant to it. We have shown that laboratory measurements beside HbF help make the distinction between true HU non-responders and non-compliant patients. We believe a non-response rate of 13.9% may still be too high based on the fact that the average dose of HU was 16.97mg/kg, barely over the recommended starting dose of 15 mg/kg/day. These data suggest that among adult patients on HU, the rates of the non-responders are very low when given adequate doses of HU for sufficient periods of time. Disclosures No relevant conflicts of interest to declare.

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