A network model to predict the risk of death in sickle cell disease.
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ABSTRACT:
SUBMITTER: Sebastiani P
PROVIDER: S-EPMC1988954 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundDecreases in direct maternal deaths in Jamaica have been negated by growing indirect deaths. With sickle cell disease (SCD) a consistent underlying cause, we describe the epidemiology of maternal deaths in this population.MethodsDemographic, service delivery and cause specific mortality rates were compared among women with (n = 42) and without SCD (n = 376), and between SCD women who died in 1998-2002 and 2003-7.ResultsWomen with SCD had fewer viable pregnancies (p: 0.02) despite greater access to high risk antenatal care (p: 0.001), and more often died in an intensive care unit (p: 0.002). In the most recent period (2003-7) SCD women achieved more pregnancies (median 2 vs. 3; p: 0.009), made more antenatal visits (mean 3.3 vs. 7.3; p: 0.01) and were more often admitted antenatally (p:<0.0001). The maternal mortality ratio for SCD decedents was 7-11 times higher than the general population, with 41% of deaths attributable to their disorder. Cause specific mortality was higher for cardiovascular complications, gestational hypertension and haemorrhage. Respiratory failure was the leading immediate cause of death.ConclusionsWomen with SCD experience a significant excess risk of dying in pregnancy and childbirth [MMR: (SCD) 719/100,000, (non SCD) 78/100,000]. MDG5 cannot be realised without improving care for women with SCD. Tertiary services (e.g. ventilator support) are needed at regional centres to improve outcomes in this and other high risk populations. Universal SCD screening in pregnancy in populations of African and Mediterranean descent is needed as are guidelines for managing SCD pregnancies and educating families with SCD.
| S-EPMC3200316 | biostudies-literature
Project description:We developed a risk score to predict event-free survival (EFS) after allogeneic hematopoietic cell transplantation for sickle cell disease. The study population (n = 1425) was randomly split into training (n = 1070) and validation (n = 355) cohorts. Risk factors were identified and validated via Cox regression models. Two risk factors of 9 evaluated were predictive for EFS: age at transplantation and donor type. On the basis of the training cohort, patients age 12 years or younger with an HLA-matched sibling donor were at the lowest risk with a 3-year EFS of 92% (score, 0). Patients age 13 years or older with an HLA-matched sibling donor or age 12 years or younger with an HLA-matched unrelated donor were at intermediate risk (3-year EFS, 87%; score, 1). All other groups, including patients of any age with a haploidentical relative or HLA-mismatched unrelated donor and patients age 13 years or older with an HLA-matched unrelated donor were high risk (3-year EFS, 57%; score, 2 or 3). These findings were confirmed in the validation cohort. This simple risk score may guide patients with sickle cell disease and hematologists who are considering allogeneic transplantation as a curative treatment relative to other available contemporary treatments.
| S-EPMC7393258 | biostudies-literature
Project description:Expression profiling using a defined set of iron regulated genes identifies co-regulation of genes and pathways related to inflammatory cytokines In this dataset, we include the whole genome expression data obtained from PBMCs from steady state HbSSs with Sickle Cell Disease and healthy HbAAs . Unsupervised two-way hierarchical clustering using a predefined iron regulated gene list identified 3 groups of subjects with high, low and intermediate expression of iron activated genes.In analysis of these three iron regulated gene clusters, we found 98 genes which were consistently and significantly differentially expressed.
2014-12-31 | GSE53441 | GEO
Project description:RationalePatients with sickle cell disease (SCD) have markers of chronic inflammation, but the mechanism of inflammation and its relevance to patient survival are unknown.ObjectiveTo assess the relationship between iron, inflammation, and early death in SCD.Methods and resultsUsing peripheral blood mononuclear cell transcriptome profile hierarchical clustering, we classified 24 patients and 10 controls in clusters with significantly different expression of genes known to be regulated by iron. Subsequent gene set enrichment analysis showed that many genes associated with the high iron cluster were involved in the toll-like receptor system (TLR4, TLR7, and TLR8) and inflammasome complex pathway (NLRP3, NLRC4, and CASP1). Quantitative PCR confirmed this classification and showed that ferritin light chain, TLR4, and interleukin-6 expression were >100-fold higher in patients than in controls (P<0.001). Further linking intracellular iron and inflammation, 14 SCD patients with a ferroportin Q248H variant that causes intracellular iron accumulation had significantly higher levels of interleukin-6 and C-reactive protein compared with 14 matched SCD patients with the wild-type allele (P<0.05). Finally, in a cohort of 412 patients followed for a median period of 47 months (interquartile range, 24-82), C-reactive protein was strongly and independently associated with early death (hazard ratio, 3.0; 95% confidence interval, 1.7-5.2; P<0.001).ConclusionsGene expression markers of high intracellular iron in patients with SCD are associated with markers of inflammation and mortality. The results support a model in which intracellular iron promotes inflammatory pathways, such as the TLR system and the inflammasome, identifying important new pathways for additional investigation.
| S-EPMC4297524 | biostudies-literature
Project description:Pulmonary hypertension is a common complication of sickle cell disease (SCD) and a risk factor for early death. Hemolysis may participate in its pathogenesis by limiting nitric oxide (NO) bioavailability and producing vasculopathy. We hypothesized that hemoglobin mutations that diminish hemolysis in SCD would influence pulmonary hypertension susceptibility. Surprisingly, coincident alpha-thalassemia (Odds Ratio [OR]=0.95, 95% CI=0.46-1.94, P=NS) was not associated with pulmonary hypertension susceptibility in homozygous SCD. However, pulmonary hypertension cases were less likely to have hemoglobin SC (OR=0.18, 95% confidence interval [CI]=0.06-0.51, P=0.0005) or Sbeta(+) thalassemia (OR=0.25, 95% CI=0.06-1.16, P=0.10). These compound heterozygotes may be protected from pulmonary hypertension because of reduced levels of intravascular hemolysis, but develop this complication at a lower rate possibly due to the presence of non-hemolytic risk factors such as renal dysfunction, iron overload and advancing age. Despite this protective association, patients with SC who did develop pulmonary hypertension remained at significant risk for death during 49 months of follow-up (Hazard Ratio=8.20, P=0.0057).
| S-EPMC3509176 | biostudies-literature
Project description:BackgroundThe role of pulmonary hypertension as a cause of mortality in sickle cell disease (SCD) is controversial.Methods and resultsWe evaluated the relationship between an elevated estimated pulmonary artery systolic pressure and mortality in patients with SCD. We followed patients from the walk-PHaSST screening cohort for a median of 29 months. A tricuspid regurgitation velocity (TRV)≥ 3.0 m/s cuttof, which has a 67-75% positive predictive value for mean pulmonary artery pressure ≥ 25 mm Hg was used. Among 572 subjects, 11.2% had TRV ≥ 3.0 m/sec. Among 582 with a measured NT-proBNP, 24.1% had values ≥ 160 pg/mL. Of 22 deaths during follow-up, 50% had a TRV ≥ 3.0 m/sec. At 24 months the cumulative survival was 83% with TRV ≥ 3.0 m/sec and 98% with TRV < 3.0 m/sec (p < 0.0001). The hazard ratios for death were 11.1 (95% CI 4.1-30.1; p < 0.0001) for TRV ≥ 3.0 m/sec, 4.6 (1.8-11.3; p = 0.001) for NT-proBNP ≥ 160 pg/mL, and 14.9 (5.5-39.9; p < 0.0001) for both TRV ≥ 3.0 m/sec and NT-proBNP ≥ 160 pg/mL. Age > 47 years, male gender, chronic transfusions, WHO class III-IV, increased hemolytic markers, ferritin and creatinine were also associated with increased risk of death.ConclusionsA TRV ≥ 3.0 m/sec occurs in approximately 10% of individuals and has the highest risk for death of any measured variable. The study is registered in ClinicalTrials.gov with identifier: NCT00492531.
| S-EPMC4079316 | biostudies-literature
Project description:Sickle cell disease (SCD) is a genetic disorder causing painful and unpredictable Vaso-occlusive crises (VOCs) through blood vessel blockages. In this study, we propose explosive synchronization (ES) as a novel approach to comprehend the hypersensitivity and occurrence of VOCs in the SCD brain network. We hypothesized that the accumulated disruptions in the brain network induced by SCD might lead to strengthened ES and hypersensitivity. We explored ES's relationship with patient reported outcome measures (PROMs) as well as VOCs by analyzing EEG data from 25 SCD patients and 18 matched controls. SCD patients exhibited lower alpha frequency than controls. SCD patients showed correlation between frequency disassortativity (FDA), an ES condition, and three important PROMs. Furthermore, stronger FDA was observed in SCD patients with a higher frequency of VOCs and EEG recording near VOC. We also conducted computational modeling on SCD brain network to study FDA's role in network sensitivity. Our model demonstrated that a stronger FDA could be linked to increased sensitivity and frequency of VOCs. This study establishes connections between SCD pain and the universal network mechanism, ES, offering a strong theoretical foundation. This understanding will aid predicting VOCs and refining pain management for SCD patients.
| S-EPMC10973361 | biostudies-literature
Project description:The nature and development of cardiorespiratory impairments associated with sickle cell disease are poorly understood. Given that the mechanisms of these impairments cannot be addressed adequately in clinical studies, we characterized cardiorespiratory pathophysiology from birth to maturity in the sickle cell disease SAD mouse model. We identified two critical phases of respiratory dysfunction in SAD mice; the first prior to weaning and the second in adulthood. At postnatal day 3, 43% of SAD mice showed marked apneas, anemia, and pulmonary vascular congestion typical of acute chest syndrome; none of these mice survived to maturity. The remaining SAD mice had mild lung histological changes in room air with an altered respiratory pattern, seizures, and a high rate of death in response to hypoxia. Approximately half the SAD mice that survived to adulthood had an identifiable respiratory phenotype including baseline tachypnea at 7-8 months of age, restrictive lung disease, pulmonary hypertension, cardiac enlargement, lower total lung capacity, and pulmonary vascular congestion. All adult SAD mice demonstrated impairments in exercise capacity and response to hypoxia, with a more severe phenotype in the tachypneic mice. The model revealed distinguishable subgroups of SAD mice with cardiorespiratory pathophysiology mimicking the complications of human sickle cell disease.
| S-EPMC5561125 | biostudies-other
Project description:BackgroundSickle cell retinopathy (SCR) is one of the most important ocular manifestations of sickle cell disease (SCD). This study aims to assess the prevalence of SCR in SCD, identify risk factors for its development and progression to proliferative sickle cell retinopathy (PSCR), and evaluate the potential implications of these results on clinical practice.MethodsThis research is a secondary analysis of patients diagnosed with SCD from the epidemiological, multicenter Cooperative Study of Sickle Cell Disease (CSSCD). We included all patients who completed a full ophthalmic evaluation. We identified clinical and laboratory SCD characteristics associated with SCR using multivariate logistic regression models. Proliferative sickle cell retinopathy (PSCR) was diagnosed according to the Goldberg classification system.ResultsOf the 1904 study participants with SCD who met the inclusion criteria, 953 (50.1%) had retinopathy; of which 642 (67.3%) had bilateral disease. SCR was associated with older age (p < 0.001), history of smoking (p = 0.001), hematuria (p = 0.050), and a lower hemoglobin F (HbF) level (p < 0.001). PSCR risk increased with smoking (p = 0.005), older age (p < 0.001) higher hemoglobin level (p < 0.001) and higher white blood cell count (p = 0.011). Previous blood transfusion (p = 0.050), higher reticulocyte count (p = 0.019) and higher HbF level (p < 0.001) were protective factors against the development of PSCR. Ocular symptoms were associated with progression to PSCR in patients with SCR (p = 0.021).ConclusionIn this cohort of individuals with SCD, half of the participants had signs of SCR. Smoking and blood hemoglobin level were the two modifiable risk factors associated with increased retinopathy progression. Screening to identify the different stages of retinopathy, actively promoting smoking cessation, and optimizing the hematological profile of patients with SCD should guide treatment protocols designed to prevent the vision-threatening complications of the disease.
| S-EPMC9502612 | biostudies-literature
Project description:Vitamin D deficiency (VDD), 25-OHD levels <20 ng/ml, is prevalent among patients with sickle cell disease (SCD) and is linked to acute and chronic pain and bone fracture in this population. There is limited literature regarding VDD-associated risk factors for SCD. We examined potential clinical and genomic parameters associated with VDD in 335 adults with SCD in a cross-sectional study. VDD was present in 65% of adult SCD patients, and 25-OHD levels independently and positively correlated with older age (P < 0·001) and vitamin D supplementation (P < 0·001). 25-OHD levels were higher in SCD patients over 40 years of age compared to the general African-American population. Both lower 25-OHD levels and increased pain frequency were associated with increased expression of SLC6A5 encoding glycine transporter-2 (GlyT2), a protein involved in neuronal pain pathways. Lower 25-OHD levels were also associated with increased expression of CYP3A4, and with decreased expression of GC (also termed DBP) and VDR, three genes involved in vitamin D metabolism. We conclude that vitamin D supplementation should be an almost universal feature of the care of young adults with SCD, and that further research is warranted into genomic factors that regulate vitamin D metabolism in SCD.
| S-EPMC6002929 | biostudies-literature