A systematic review and meta-analysis of observational studies were conducted to quantify the association between sickle cell disease in pregnancy and adverse maternal and perinatal outcomes. Data sources (Medline, Embase, Maternity and Infant care, Cochrane, Web of Science, Popline) were searched for publications to June 2014. Eligibility criteria included observational studies reporting maternal and perinatal health outcomes in pregnant women with sickle cell disease against a comparative group of pregnant women without sickle cell disease. Twenty-one studies (including 26,349 women with sickle cell disease; 26,151,746 women without sickle cell disease) were eligible for inclusion. Pregnancies in women with HbSS genotype, compared with women without sickle cell disease, were at increased risk of maternal mortality (relative risk [RR], 5.98; 95% confidence interval [CI], 1.94-18.44), preeclampsia (RR, 2.43; 95% CI, 1.75-3.39), stillbirth (RR, 3.94; 95% CI, 2.60-5.96), preterm delivery (RR, 2.21; 95% CI, 1.47-3.31), and small for gestational age infants (RR, 3.72; 95% CI, 2.32-5.98). Meta-regression demonstrated that genotype (HbSS vs HbSC), low gross national income, and high study quality were associated with increased RRs. Despite advances in the management of sickle cell disease, obstetrics, and neonatal medicine, pregnancies complicated by the disease remain associated with increased risk of adverse maternal and perinatal outcomes. Abstract source Full text

BACKGROUND: The pathogenesis of albuminuria in SCD remains incompletely understood. We evaluated the association of albuminuria with measures of endothelial function, and explored associations of both albuminuria and measures of endothelial function with selected biological variables (vascular endothelial growth factor [VEGF], endothelin-1 [ET-1], soluble fms-like tyrosine kinase-1 [sFLT-1], soluble vascular cell adhesion molecule-1 [soluble VCAM-1] and plasma hemoglobin). METHODS: Spot urine measurements for albumin-creatinine ratio (UACR) and 24-hour urine protein were obtained. Endothelial function was assessed using brachial artery ultrasound with measurements of flow-mediated dilation (FMD), nitroglycerin-mediated dilation (NTMD) and hyperemic velocity. RESULTS: Twenty three subjects with varying degrees of albuminuria were evaluated. UACR was significantly correlated with FMD (ρ = -0.45, p = 0.031). In univariate analysis, UACR was correlated with VEGF (ρ = -0.49; 95% CI: -0.75 --0.1, p = 0.015), plasma hemoglobin (ρ = 0.50; 95% CI: 0.11-0.75, p = 0.013) and ET-1 (ρ = 0.40; 95% CI: -0.03-0.69, p = 0.06). Multivariable analysis showed significant associations of ET-1 (estimate: 455.1 [SE: 198.3], p = 0.02), VEGF (estimate: -1.1 [SE: 0.53], p = 0.04) and sFLT-1 (estimate: -1.14 [SE: 0.49], p = 0.02) with UACR. Only ET-1 (estimate: -8.03 [SE: 3.87], p = 0.04) was significantly associated with FMD in multivariable analyses. Finally, UACR was correlated with both 24-hour urine protein (ρ = 0.90, p < 0.0001) and urine aliquots for albumin-creatinine ratio obtained from the 24-hour urine collection (ρ = 0.97, p < 0.0001). CONCLUSION: This study provides more definitive evidence for the association of albuminuria with endothelial dysfunction in SCD. Elevated circulating levels of ET-1 may contribute to SCD-related glomerulopathy by mediating endothelial dysfunction. Abstract source Full text Full text (PMC)

STUDY OBJECTIVE: To review five cases of severe adverse reactions after vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in pediatric and adolescent patients with sickle cell disease (SCD), and to evaluate the prevalence of adverse reactions to PPSV23 in patients with SCD by analyzing data from the Vaccine Adverse Event Reporting System (VAERS). DESIGN: Case series and retrospective analysis of data from the VAERS. DATA SOURCES: Medical records from a tertiary care hospital and the VAERS database. MEASUREMENTS AND MAIN RESULTS: Five cases of severe adverse reactions after vaccination with PPSV23 in pediatric and adolescent patients with SCD (aged 2-22 years) were reviewed. The adverse reactions occurred within 24 hours after immunization, and all five patients required medical attention. Analysis of data from the VAERS found that PPSV23 was the most commonly reported vaccine causing adverse events in patients with SCD, accounting for 62% of all vaccine-induced adverse events. This rate is significantly higher than the rate of adverse events related to PPSV23 in patients with human immunodeficiency virus (HIV) or asthma (62% vs 16%, p<0.0001). The reported number of adverse reactions in pediatric patients (< 18 years old) with SCD was 4 times higher than that reported in adult patients (18-39 years old) with SCD. CONCLUSION: The risk of developing severe adverse reactions to PPSV23 is greater in patients with SCD than in patients with HIV or asthma, and especially in pediatric and adolescent patients with SCD compared with their adult counterparts. Health care professionals should closely monitor for potential adverse events after PPSV23 vaccination or revaccination in patients with SCD, adhere to the recommended time interval between PCV13 and PPSV23 administration, and possibly consider avoiding simultaneous administration of other vaccines with PPSV23. Abstract source Full text

BACKGROUND: Alloimmunization remains a significant complication of transfusion and has been associated with multiple factors, including inflammation, an important pathophysiologic mechanism in sickle cell disease (SCD). We explored whether alloimmunization is associated with disease severity in SCD. STUDY DESIGN AND METHODS: Adult SCD patients were enrolled in a study of outcome-modifying genes in SCD. Historical records of patients with SCD at two participating institutions were reviewed for data on antigen phenotype and alloimmunization. Differences in demographic, clinical, and laboratory findings; end-organ damage; and overall disease severity were then compared between alloimmunized and nonalloimmunized patients. RESULTS: Of 319 patients, 87 (27%) were alloimmunized. Alloantibody specificities differed from those previously described, especially due to the significantly higher frequency of anti-S. Although alloimmunization was not associated with frequency of vasoocclusive episodes, a higher percentage of alloimmunized patients had chronic pain, as defined by daily use of short-acting narcotics (p = 0.006), long-acting narcotics (p = 0.013), or both (p = 0.03). Additionally, alloimmunized patients had poorer survival (hazard ratio, 1.92; p = 0.01) and were more likely to have avascular necrosis (p = 0.024), end-organ damage (p = 0.049), and red blood cell autoantibodies (p < 0.001), even after controlling for the effects of age, sex, and hemoglobin diagnosis. Alloimmunization was not associated with other SCD-related complications, such as acute chest syndrome or stroke. CONCLUSION: Alloimmunization in SCD may be associated with chronic pain, risk of end-organ damage, and shorter survival. These novel findings suggest new directions for the investigation of immune response-mediated pathways common to alloimmunization and chronic pain. Abstract source Full text Full text (PMC)

PURPOSE OF REVIEW: As the safety and availability of allogeneic hematopoietic stem cell transplantation (HSCT) have improved, this procedure is becoming a viable option for nonmalignant conditions such as sickle cell disease (SCD). There are very few treatment options available for SCD, and even with optimal care SCD patients still suffer from a myriad of comorbidities to multiple organ systems and have a decreased life span. In this review, we will summarize results from trials of HSCT for children or adults with SCD using a variety of graft sources as well as conditioning and graft-versus-host disease prophylaxis regimens, and discuss the unique challenges that arise in these patients. RECENT FINDINGS: AlloHSCT for SCD has been performed on small numbers of patients at multiple centers around the world using several different transplant platforms, and early outcomes are encouraging. Overall survival is excellent, although graft failure remains a challenge. SUMMARY: As alloHSCT becomes safer and more widely available, the procedure should be considered for patients with severe disease phenotypes in whom the potential benefits of transplantation outweigh the complications from the disease. AlloHSCT has been shown to reverse or at least halt the progression of end-organ damage secondary to SCD. More research is needed to understand the mechanisms underlying graft failure in SCD recipients, as well as to understand the biopsychosocial underpinnings of persistent pain in the posttransplant period to maximize the benefit from the transplant procedure. Abstract source Full text

BACKGROUND: Oxidative stress is thought to be involved in the pathogenesis of microalbuminuria in Sickle cell anemia (SCA). Antioxidant enzymes such as glutathione peroxidase (GPx) and Cu-Zn superoxide dismutase (SOD) may play an important protective role. This study aimed to evaluate the association between albuminuria and these two antioxidant enzymes. METHODS: We consecutively recruited Steady state children aged between 2 and 18 years old with established diagnosis of homozygous SCA in two hospitals of Kinshasa/DR Congo. The relationship between Urinary Albumin Creatinine Ratio (UACR) and other variables of interest (age, systolic blood pressure, diastolic blood pressure, plasma GPx and Cu-Zn SOD, free plasmatic hemoglobin, LDH, indirect bilirubin, white blood cells (WBC), percentage of fetal hemoglobin, serum iron, ferritin, CRP) was analyzed by Bivariate correlation (Pearson's correlation coefficient). Microalbuminuria was defined by urine albumin/creatinine ratio between 30 and 299 mg/g. RESULTS: Seventy Steady state Black African children with SCA (56% boys; average age 9.9 ± 4.3 years; 53% receiving hydroxyurea) were selected. Prevalence of microalbuminuria was 11.8%. LDH (r = 0.260; p = 0.033) and WBC count (r = 0.264; p = 0.033) were positively correlated with UACR whereas GPx (- 0.328; p = 0.007) and Cu-Zn SOD (- 0.210; p = 0.091) were negatively correlated with UACR. CONCLUSIONS: Albuminuria is associated with decreased antioxidant capacity and increased levels of markers of hemolysis and inflammation. Therefore, strategies targeting the reduction of sickling and subsequent hemolysis, oxidative stress and inflammation could help preventing or at least delaying the progression of kidney disease in SCA children. Abstract source Full text Full text (PMC)

In an article recently published in Pediatric Nephrology, Baddam and colleagues discuss the relatively underreported clinical problem of repeated episodes of acute kidney injury (AKI) in children with sickle cell disease (SCD). Their report is a cautionary note about the importance of repeated kidney injury on the background of underlying chronic kidney injury and its potential implications on long-term kidney outcome. In children and adults with SCD, this includes the effects of repeated vaso-occlusive crises and the management of these painful episodes with non-steroidal anti-inflammatory drugs. Here we review the scope of kidney involvement in SCD in children and discuss the potential short- and long-term consequences of AKI in children with SCD. Abstract source Full text

OBJECTIVES: The objective was to determine the test performance characteristics for point-of-care lung ultrasonography (LUS) performed by pediatric emergency medicine (PEM) physicians compared with radiographic diagnosis of acute chest syndrome (ACS) in patients with sickle cell disease (SCD) and fever. METHODS: This was a prospective study of patients up to 21 years with SCD and fever requiring chest X-ray (CXR) evaluation for ACS. Before obtaining CXR, a blinded PEM physician performed LUS using a standardized scanning protocol. Positive LUS for ACS was defined as lung consolidation. All patients received CXR and follow-up. The criterion standard for ACS was consolidation on CXR as determined by a blinded radiologist. LUS clips were reviewed by a blinded expert PEM sonologist. RESULTS: A total of 116 febrile events from 91 patients with a median age of 5.7 years were enrolled by 15 PEM sonologists. CXR was positive for ACS in 15 (13%) patients, and LUS was positive for ACS in 19 (16%) patients. Positive LUS had a sensitivity of 87% (95% confidence interval [CI] = 62% to 96%), specificity of 94% (95% CI = 88% to 97%), positive likelihood ratio of 14.6 (95% CI = 6.5 to 32.5), and negative likelihood ratio of 0.14 (95% CI = 0.04 to 0.52) for ACS. The interobserver agreement (kappa) was 0.77. There were two missed cases of ACS on LUS. CONCLUSIONS: LUS may be sensitive and specific for diagnosis of ACS in pediatric patients with SCD and fever. LUS may reduce the need for routine CXR and associated ionizing radiation exposure in this population. Abstract source Full text

BACKGROUND: In utero hematopoietic cell transplantation (IUHCT) has curative potential for sickle cell disease (SCD) but carries a risk of fetal demise. METHODS: We assessed the conditions under which parents of children with SCD and young adults with SCD would consider IUHCT in a future pregnancy, given a 5% fixed risk of fetal demise. Participants were randomized to consider a hypothetical cure rate (20%, 40%, or 70%). Subsequently, cure rate was either increased or decreased depending on the previous answer to reveal the lowest acceptable rate. Participants also completed the Pediatric Research Participation Questionnaire (PRPQ) and an omission scale. RESULTS: Overall, 74 of 79 (94%) participants were willing to consider IUHCT, and 52 (66%) participants accepted IUHCT at a cure rate of 40%, the estimated rate of therapeutic mixed chimerism. Participants with higher scores on the PRPQ perceived benefits scale were more likely to participate at lower cure rates (OR 1.08, p=0.007) and participants with a greater degree of omission bias were less likely to participate at lower cure rates (OR 0.83, p=0.04). Demographics and SCD severity were not significantly associated with acceptability of IUHCT. CONCLUSION: This study suggests that the majority of parents >and young adults would consider IUHCT under expected therapeutic conditions. Abstract source Full text

All patients with HbSS (SCA) share the same genetic mutation but the clinical phenotype is variable and difficult to predict early in life. A reliable severity predictor would be invaluable toward directing therapeutic decisions in those patients at highest risk of SCA complications. A search of PubMed, Cochrane Clinical Trials Register, and Scopus was performed to determine which SCA severity predictors have been validated in pediatric patients. The full text of 94 of the 590 references identified was reviewed based on the title/abstract. Fifty-four articles were included in the analysis. Alpha globin gene number was the most commonly studied severity predictor, followed by fetal hemoglobin (HbF) and reticulocyte count. Alpha thalassemia trait was protective against overt stroke and abnormal transcranial Doppler (TCD) in all but one study, but not frequency of painful crisis or silent cerebral infarct. Two thirds of the HbF studies reported beneficial effects with increasing HbF levels; however, increased HbF levels were not associated with lower hospitalization or stroke rates in others. The ability to predict SCA complications was mixed for all variables, except TCD and absolute reticulocyte count. More reliable predictors are urgently needed to guide therapeutic decisions in children with SCA. Abstract source Full text