Background: Sickle cell disease is a group of genetic diseases which is especially prevalent in tropical and subtropical regions; however, forced migration and ongoing population movement have spread it throughout the world, with estimated birth rates reaching 0.49 per 1000 in the Americas, 0.07 per 1000 in Europe, 0.68 per 1000 in South and Southeast Asia, and 10.68 per 1000 in Africa. Life for individuals with sickle cell disease can be affected by repeated acute complications and compounded by progressive organ damage. Studies reveal that when people with chronic illness learn self-management, their clinical outcomes and quality of life improves; and they show lower dependence on healthcare services. There are, however, no reviews identifying which interventions improve knowledge and little is known about the impact of patient or care-giver knowledge on clinical and psychosocial outcomes in people with sickle cell disease. Objectives: 1. To determine the effectiveness of patient- and caregiver-centred educational interventions for changing knowledge and understanding of sickle cell disease among patients as well as caregivers of people with the disease.2. To assess the effectiveness and safety of patient- and caregiver-centred educational interventions and programs for the recognition of signs and symptoms of disease-related morbidity, adherence to treatment and healthcare utilization in patients with sickle cell disease. Search Methods: The authors searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Additional trials were sought from the reference lists of the trials and reviews identified by the search strategy.Date of last search: 11 April 2016. Selection Criteria: Randomized and quasi-randomized controlled trials which evaluate the effectiveness of individual- and group-based interventions for either the patient with sickle cell disease or their caregivers, or both. Eligible interventions will aim to change knowledge, attitudes or skills, improve psychosocial aspects of the disease as well as treatment adherence and healthcare utilization. Trials evaluating the intervention versus no program, comparing two interventions and those which are part of a multi-faceted intervention to improve a range of sickle cell-related health outcomes are all eligible for inclusion. Data Collection and Analysis: Two review authors independently selected trials based on stated inclusion criteria and thereafter examined each selected report to extract data using a prepared, piloted, data collection form. A third author assisted in reaching consensus if there were any discrepancies. Similarly, risk of bias was assessed by two authors and verified by a third author. Main Results: A total of 12 trials (11 randomized controlled trials and one quasi-randomized trial) of 563 people with HbSS, HbSC or HbSβthal, aged six to 35 years old, were included in the review; the majority of participants were African-American. Interventions ranged from a total of one hour to weekly sessions for eight weeks and the post-intervention assessments ranged from the end of the intervention period to 12 months after completion. The heterogeneity of the included trials, which encompasses setting, inclusion and exclusion criteria, interventional method and time of assessment, ranged from 'not important' to 'moderate to substantial' for different review outcomes. The overall risk of bias was low for selective reporting, unclear for random sequence generation, allocation concealment, blinding of participants and blinding of outcome assessment. Incomplete outcome reporting and blinding of personnel showed mixed bias representations.Patient knowledge was assessed by four trials (160 participants) with moderate to substantial heterogeneity. There was evidence that educational programs improved patient knowledge, standardised mean difference 0.87 points (95% confidence interval 0.28 to 1.45, moderate quality evidence), which improved further when a trial with high bias was removed in a sensitivity analysis. Caregiver knowledge, reported in a single trial of 20 families, also showed an improvement, standardised mean difference 0.52 points (95% confidence interval 0.03 to 1.00, moderate quality evidence). The effect on patient knowledge was sustained at longer follow-up periods, whereas the effect on caregiver knowledge was not sustained.There were two primary outcomes related to the effectiveness of educational programs on the recognition of signs and symptoms of disease-related morbidity. No comparative data were reported for patients or caregivers (or both) recognising signs and symptoms leading to self-management. Data from two trials were analysed for the utilization of health services and showed no evidence of an effect, mean difference 0.33 (95% confidence interval -0.57 to 1.23, moderate quality evidence).With regard to the review's secondary outcomes, depression showed a statistically significant decline in intervention groups, standardised mean difference -0.66 points (95% confidence interval -1.18, to -0.14, moderate quality evidence). Adherence to treatment was not assessed in any of the identified trials. No effects of interventions were seen on coping, family relationships or health-related quality of life of patients.The quality of evidence was low for positive coping and moderate for child knowledge, healthcare utilization and depression. This suggests that further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimates. Authors' Conclusions: This review identifies important positive effects of educational interventions on improving patient knowledge of sickle cell disease and depression. Effects on patients' knowledge were maintained for longer than for caregivers. The effect on knowledge was significant but small and whether it offers any clinical benefit is uncertain. Significant factors limiting these effects could be trials being under powered as well as attrition rates. Effects were not statistically significant in assessments of secondary outcomes, possibly due to the paucity of the number of trials and patients and caregivers. Trials showed moderate to high heterogeneity which might impact the results. To better study effects on outcomes, further controlled trials are needed with rigorous attention given to improve recruitment and retention and to decrease bias. Predetermined protocols using similar measurements should be used across multiple sites. Abstract source Full text

The impact of emergency department (ED) treatment on outcomes of sickle cell disease (SCD) acute pain hospitalizations is not well described. We investigated whether length of stay (LOS) and change in health-related quality of life (HRQL) are affected by initial opioid dose and time to administration. We conducted secondary analyses of data from the randomized-controlled Magnesium for children in Crisis (MAGiC) trial. The primary outcome was LOS. Secondary outcome was change in HRQL, assessed using PedsQL SCD Pain and Hurt and Pain Impact Domains measured in ED and at discharge. Independent variables were (1) time to first IV opioid, (2) total initial opioid dose (mg/kg/hr of morphine equivalents administered between ED and first study drug), and (3) Time to first oral opioid. Spearman correlations determined the associations with LOS. Using two-sample t-tests, we compared mean change in HRQL scores between IV opioid initiated within 60 and >60 min, opioid doses in the highest and lowest tertiles, and oral opioid initiated within 24 and >24 hr. Two hundred and four patients participated at 8 sites. Mean (SD) age was 13.6 (4.7) years. Earlier initiation of oral opioids was strongly correlated with shorter LOS (r = 0.61, P < 0.01). Higher initial opioid dose was weakly correlated with longer LOS (r = 0.34, P < 0.01). Higher initial opioid doses (6 vs -2.2; P = 0.01) and oral opioids initiated within 24 hr (5.7 vs -1.7, P = 0.04) were associated with larger mean change in HRQL at discharge. Prospective trials evaluating the impact of ED care on outcomes of pain hospitalizations could improve SCD pain treatment. Abstract source Full text

BACKGROUND: Immunogenicity, safety and reactogenicity of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) were evaluated in children with sickle cell disease (SCD), who are at increased risk for infections. METHODS: In this phase III, open-label, single-center, controlled study in Burkina Faso (NCT01175083), children with SCD (S) or without SCD (NS) were assigned to 6 groups (N = 300): children 8-11 weeks of age ( RESULTS: One month postprimary vaccination, for each vaccine serotype ≥98% of infants in the CONCLUSIONS: PHiD-CV was immunogenic with an acceptable safety profile in children with and without SCD starting vaccination at 8 weeks to 23 months of age. Abstract source Full text

BACKGROUND: Sickle cell anemia (SCA) is characterized by chronic hemolytic anemia. Worsening of anemia after red blood cell (RBC) transfusion has been reported and is often referred to as hyperhemolysis syndrome (HS). HS is a severe transfusion reaction characterized by destruction of both donor and host RBCs. CASE REPORTS: In this study we report the clinical findings and treatment of three adolescent patients with SCA who presented with HS. HS occurred after exchange transfusion in two cases and after RBC transfusion during vasoocclusive crises in one. A decrease of serum hemoglobin (Hb) levels was observed 5 to 7 days after transfusions and ranged from 2.5 to 5.7 g/dL. The direct antiglobulin test was positive in two patients who also presented with alloantibodies. Patient 3 received 2 additional RBC units after the onset of HS and experienced the lowest Hb values (2.5 g/dL) shortly after. Patients received intravenous steroids as the main specific treatment and also immunoglobulin and erythropoietin. Resolution of hemolysis was observed in all cases. Of note, spleen lesions were detected in two patients, one had a normal spleen size, and the other presented with enlarged spleen. Pathophysiologic implications of these findings were discussed. CONCLUSIONS: HS must be a well-recognized complication of SCA after RBC transfusion. Prompt initiation of treatment and avoiding further transfusions may contribute to reduce the mortality associated with HS. The presence of functional spleen on the pathophysiology of HS deserves further evaluation. Abstract source Full text

The clinical efficacy of hydroxyurea in patients with sickle cell anemia (SCA) has been well established. However, data about its clinical effectiveness in practice is limited. We evaluated the clinical effectiveness of hydroxyurea in a large pediatric population using a retrospective cohort, pre-post treatment study design to control for disease severity selection bias. The cohort included children with SCA (SS, Sβ0 thalassemia) who received care at Children's Healthcare of Atlanta (CHOA) and who initiated hydroxyurea in 2009-2011. Children on chronic transfusions, or children with inadequate follow up data and/or children who had taken hydroxyurea in the 3 years prior were excluded. For each patient healthcare utilization, laboratory values, and clinical outcomes for the 2-year period prior to hydroxyurea initiation were compared to those 2 years after initiation. Of 211 children with SCA who initiated hydroxyurea in 2009-2011, 134 met eligibility criteria. After initiation of hydroxyurea, rates of hospitalizations, pain encounters, and emergency department visits were reduced by 47% (<0.0001), 36% (P = 0.0001) and 43% (P < 0.0001), respectively. Average hemoglobin levels increased by 0.7 g/dl (P < 0.0001). Hydroxyurea effectiveness was similar across gender, insurance types and age, although there was a slightly greater reduction in hospitalizations in younger children. Abstract source Full text

PURPOSE: Previous clinical trials suggested that inhaled nitric oxide (iNO) could have beneficial effects in sickle cell disease (SCD) patients with acute chest syndrome (ACS). METHODS: To determine whether iNO reduces treatment failure rate in adult patients with ACS, we conducted a prospective, double-blind, randomized, placebo-controlled clinical trial. iNO (80 ppm, N = 50) gas or inhaled nitrogen placebo (N = 50) was delivered for 3 days. The primary end point was the number of patients with treatment failure at day 3, defined as any one of the following: (1) death from any cause, (2) need for endotracheal intubation, (3) decrease of PaO2/FiO2 ≥ 15 mmHg between days 1 and 3, (4) augmented therapy defined as new transfusion or phlebotomy. RESULTS: The two groups did not differ in age, gender, genotype, or baseline characteristics and biological parameters. iNO was well tolerated, although a transient decrease in nitric oxide concentration was mandated in one patient. There was no significant difference in the primary end point between the iNO and placebo groups [23 (46 %) and 29 (58 %); odds ratio (OR), 0.8; 95 % CI, 0.54-1.16; p = 0.23]. A post hoc analysis of the 45 patients with hypoxemia showed that those in the iNO group were less likely to experience treatment failure at day 3 [7 (33.3 %) vs 18 (72 %); OR = 0.19; 95 % CI, 0.06-0.68; p = 0.009]. CONCLUSIONS: iNO did not reduce the rate of treatment failure in adult SCD patients with mild to moderate ACS. Future trials should target more severely ill ACS patients with hypoxemia. Abstract source Full text

BACKGROUND: Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and a reduced life expectancy. Hydroxyurea (hydroxycarbamide), an oral chemotherapeutic drug, ameliorates some of the clinical problems of SCD, in particular that of pain, by raising fetal haemoglobin. This is an update of a previously published Cochrane Review.   OBJECTIVES: To assess the effects of hydroxyurea therapy in people with SCD (all genotypes), of any age, regardless of setting.   SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Register, comprising of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries.Date of the most recent search: 16 January 2017.   SELECTION CRITERIA: Randomised and quasi-randomised controlled trials, of one month or longer, comparing hydroxyurea with placebo, standard therapy or other interventions for people with SCD.   DATA COLLECTION AND ANALYSIS: Authors independently assessed studies for inclusion, carried out data extraction and assessed the risk of bias.   MAIN RESULTS: Seventeen studies were identified in the searches; eight randomised controlled trials were included, recruiting 899 adults and children with SCD (haemoglobin SS (HbSS), haemoglobin SC (HbSC) or haemoglobin Sβºthalassaemia (HbSβºthal) genotypes). Studies lasted from six to 30 months.Four studies (577 adults and children with HbSS or HbSβºthal) compared hydroxyurea to placebo; three recruited individuals with only severe disease and one recruited individuals with all disease severities. There were statistically significant improvements in terms of pain alteration (using measures such as pain crisis frequency, duration, intensity, hospital admissions and opoid use), measures of fetal haemoglobin and neutrophil counts and fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups. There were no consistent statistically significant differences in terms of quality of life and adverse events (including serious or life-threatening events). Seven deaths occurred during the studies, but the rates by treatment group were not statistically significantly different.Two studies (254 children with HbSS or HbSβºthal also with risk of primary or secondary stroke) compared hydroxyurea and phlebotomy to transfusion and chelation; there were statistically significant improvements in terms of measures of fetal haemoglobin and neutrophil counts, but more occurrences of acute chest syndrome and infections in the hydroxyurea and phlebotomy group. There were no consistent statistically significant differences in terms of pain alteration and adverse events (including serious or life-threatening events). Two deaths occurred during the studies (one in a the hydroxyurea treatment arm and one in the control arm), but the rates by treatment group were not statistically significantly different. In the primary prevention study, no strokes occurred in either treatment group but in the secondary prevention study, seven strokes occurred in the hydroxyurea and phlebotomy group (none in the transfusion and chelation group) and the study was terminated early.The quality of the evidence for the above two comparisons was judged as moderate to low as the studies contributing to these comparisons were mostly large and well designed (and at low risk of bias); however evidence was limited and imprecise for some outcomes such as quality of life, deaths during the studies and adverse events and results are applicable only to individuals with HbSS and HbSβºthal genotypes.Of the remaining two studies, one (22 children with HbSS or HbSβºthal also at risk of stoke) compared hydroxyurea to observation; there were statistically significant improvements in terms of measures of fetal haemoglobin and neutrophil counts but no statistically significant differences in terms of adverse events (including serious or life-threatening events).The final study (44 adults and children with HbSC) compared treatment regimens with and without hydroxyurea - there was statistically significant improvement in terms of measures of fetal haemoglobin, but no statistically significant differences in terms of adverse events (including serious or life-threatening events). No participants died in either of these studies and other outcomes relevant to the review were not reported.The quality of the evidence for the above two comparisons was judged to be very low due to the limited number of participants, the lack of statistical power (as both studies were terminated early with approximately only 20% of their target sample size recruited) and the lack of applicability to all age groups and genotypes.   AUTHORS' CONCLUSIONS: There is evidence to suggest that hydroxyurea is effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSβºthal genotypes and in preventing life-threatening neurological events in those with sickle cell anaemia at risk of primary stroke by maintaining transcranial doppler velocities. However, there is still insufficient evidence on the long-term benefits of hydroxyurea, particularly in preventing chronic complications of SCD, recommending a standard dose or dose escalation to maximum tolerated dose. There is also insufficient evidence about the long-term risks of hydroxyurea, including its effects on fertility and reproduction. Evidence is also limited on the effects of hydroxyurea on individuals with HbSC genotype. Future studies should be designed to address such uncertainties. Abstract source Full text

Silent cerebral infarction (SCI) is the most common neurological abnormality among children with sickle cell anaemia (SCA). The effect of hydroxycarbamide (also termed hydroxyurea) on the development and progression of SCI is unclear. We evaluated brain magnetic resonance imaging/angiography (MRI/MRA) in children with SCA receiving long-term hydroxycarbamide therapy. Fifty participants (median 9·4 years, range 1·1-17·3) enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE; NCT00305175) underwent brain MRI/MRA and laboratory evaluations before hydroxycarbamide initiation and after 3 and 6 years of treatment to maximum tolerated dose. SCI and vascular stenosis were evaluated. At baseline, 3 and 6 years, SCI were present in 19/50 (38%), 20/49 (41%), and 7/17 (41%), respectively. At 3 years, one child developed a SCI lesion, and another progressed (single lesion to multiple). Lower haemoglobin (Hb) (80 g/l vs. 86 g/l, P = 0·049), fetal Hb (5·0% vs. 10·4%, P < 0·001) and oxygen saturation (97% vs. 98%, P = 0·027) before hydroxycarbamide initiation were associated with SCI. No patients had vascular stenosis identified on MRA, transient ischaemic attack or stroke. Our data indicate that children receiving hydroxycarbamide over a 3- to 6-year period have a low rate of new or worsening cerebrovascular disease. Further studies are needed to confirm that hydroxycarbamide can prevent the onset and progression of SCI. Abstract source Full text

Transfusion therapy is effective in the prevention and treatment of many complications of sickle cell disease (SCD). However, its benefits must be balanced against its risks, including delayed haemolytic transfusion reactions (DHTR). Not only is the relative rate of alloimmunization higher in patients with SCD than in other patient populations, but attendant risks associated with DHTR are even greater in SCD. Clinicians' awareness of DHTR events is poor because symptoms of DHTR mimic acute vaso-occlusive pain and immunohaematology findings are often negative. Transfusions delivered in the acute rather than elective setting appear to confer a higher risk of DHTR. Management of DHTR in SCD depends on the clinical severity, ranging from supportive care to immunosuppression, and optimization of erythropoiesis. DHTR must be considered in any recently transfused patient presenting with acute sickle cell pain. Meticulous documentation of transfusion and immunohaematology history is key. We anticipate an increase in DHTR events in SCD patients with the increasing use of red blood cell transfusion therapy. Abstract source Full text

OBJECTIVE: The aim of this study was to identify the factors associated with delays in treatment of sickle pain crisis in the pediatric emergency department with the goal of discerning whether earlier pain management is correlated with better clinical outcome. METHODS: This retrospective study examined data collected from clinical records of patients, aged 21 years or younger, who was treated for sickle cell pain crisis between January and June 2012. Demographic and clinical characteristics were extracted from electronic records, as well as time of registration, triage, initial pain assessment, analgesic administration, and pain reassessment. RESULT: A total of 160 sickle cell pain crises visits by 67 unique patients were identified. Opiates were the most common initial pain medication prescribed and administered. The mean time to initial analgesic administration and pain reassessment was 89 and 60 minutes, respectively. Patients with orders for imaging studies experienced significant delays in time to initial analgesic medication and pain reassessment. In addition, higher triage pain score correlated with shorter time to first dose of pain medication. However, age, sex, and final disposition did not affect time to administration of analgesic medications.Earlier pain management resulted in shorter ED length of stay for all patients regardless of disposition. However, earlier pain management did not affect the total length of hospitalization for patients admitted to the inpatient services. CONCLUSIONS: Pediatric patients with sickle cell pain crises experienced significant delays to initial analgesic medication. A standardized approach to pain management may improve ED management of SCD crises. Abstract source Full text