Factors Associated with Overt Stroke in Children and Adolescents with Sickle Cell Disease: A Retrospective Cohort Study.

Sickle cell disease (SCD) is associated with a high occurrence of complications due to vaso-occlusive phenomenon such as stroke. This retrospective cohort study aimed to examine the clinical and laboratory characteristics of 120 children and adolescents with SCD and analyze the factors associated with overt stroke incidence. All relevant data were obtained from patient medical records. Survival analysis was used to compare the demographic, clinical, and laboratory characteristics between patients with and those without overt stroke. The patients were 52.5% female with a mean (SD) age of 11.2 (4.3) years. The incidence of overt stroke in this cohort was nine out of 956.7 patient-years, resulting in an incidence density of 0.94 cases/100 patient-years. Reports of greater than or equal to two previous attacks of dactylitis and greater than or equal to three episodes of acute chest syndrome (ACS)/pneumonia were associated with overt stroke and an increase in reticulocyte count and red blood cell distribution width (RDW). In conclusion, a history of a high number of dactylitis, ACS/pneumonia, increased RDW, and reticulocytosis was associated with overt stroke occurrence in children and adolescents with SCD. Future studies with a higher stroke incidence in the evaluated sample are necessary to confirm this hypothesis.

Managing sickle cell disease and related complications in pregnancy: results of an international Delphi panel.

ABSTRACT: Data to guide evidence-based management of pregnant people with sickle cell disease (SCD) are limited. This international Delphi panel aimed to identify consensus among multidisciplinary experts for SCD management during pregnancy. The 2-round Delphi process used questionnaires exploring 7 topics (antenatal care, hydroxyurea use, transfusion, prevention of complications, treatment of complications, delivery and follow-up, and bottlenecks and knowledge gaps) developed by a steering committee. Thirteen panelists (hematologists, physiologists, obstetricians, maternal fetal medicine, and transfusion medicine physicians) from the United States, the United Kingdom, Turkey, and France completed the first survey; 12 panelists completed the second round. Anonymized responses were collected and summarized by a contract research organization (Akkodis Belgium). Consensus and strong consensus were predefined as 75% to 90% (9-10 of 12) and >90% (≥11 of 12) of panelists, respectively, agreeing or disagreeing on a response to a predefined clinical scenario or statement. In several areas of SCD management, consensus was achieved: experts recommended performing at least monthly multidisciplinary antenatal follow-up, administering prophylactic aspirin for preeclampsia prevention between gestational weeks 12 and 36, initiating prophylactic transfusion therapy in certain cases, or choosing automated red blood cell exchange over other transfusion methods for patients with iron overload or severe acute chest syndrome. No consensus was reached on several topics including the prophylactic aspirin dose, indications for starting infection prophylaxis, routine use of prophylactic transfusions, or use of prophylactic transfusions for preventing fetal complications. These recommendations could inform clinical care for patients with SCD who are pregnant in the absence of large clinical trials involving this population; the identified knowledge gaps can orient future research.

Unique Changes in the Incidence of Acute Chest Syndrome in Children With Sickle Cell Disease Unravel the Role of Respiratory Pathogens: A Time Series Analysis.

BACKGROUND: Acute chest syndrome (ACS) is a life-threatening complication of sickle cell disease (SCD). Although respiratory pathogens are frequently detected in children with ACS, their respective role in triggering the disease is still unclear. We hypothesized that the incidence of ACS followed the unprecedented population-level changes in respiratory pathogen dynamics after COVID-19-related nonpharmaceutical interventions (NPIs). RESEARCH QUESTION: What is the respective role of respiratory pathogens in ACS epidemiology? STUDY DESIGN AND METHODS: This study was an interrupted time series analysis of patient records from a national hospital-based surveillance system. All children aged < 18 years with SCD hospitalized for ACS in France between January 2015 and May 2022 were included. The monthly incidence of ACS per 1,000 children with SCD over time was analyzed by using a quasi-Poisson regression model. The circulation of 12 respiratory pathogens in the general pediatric population over the same period was included in the model to assess the fraction of ACS potentially attributable to each respiratory pathogen. RESULTS: Among the 55,941 hospitalizations of children with SCD, 2,306 episodes of ACS were included (median [interquartile range] age, 9 [5-13] years). A significant decrease was observed in ACS incidence after NPI implementation in March 2020 (-29.5%; 95% CI, -46.8 to -12.2; P = .001) and a significant increase after lifting of the NPIs in April 2021 (24.4%; 95% CI, 7.2 to 41.6; P = .007). Using population-level incidence of several respiratory pathogens, Streptococcus pneumoniae accounted for 30.9% (95% CI, 4.9 to 56.9; P = .02) of ACS incidence over the study period and influenza 6.8% (95% CI, 2.3 to 11.3; P = .004); other respiratory pathogens had only a minor role. INTERPRETATION: NPIs were associated with significant changes in ACS incidence concomitantly with major changes in the circulation of several respiratory pathogens in the general population. This unique epidemiologic situation allowed determination of the contribution of these respiratory pathogens, in particular S pneumoniae and influenza, to the burden of childhood ACS, highlighting the potential benefit of vaccine prevention in this vulnerable population.

Intravenous fluid therapy and hospital outcomes for vaso-occlusive episodes in children, adolescents, and young adults with sickle cell disease.

BACKGROUND: While intravenous fluid (IVF) therapy in patients with sickle cell disease (SCD) admitted for a vaso-occlusive episode (VOE) can help reduce red blood cell sickling, clinical practice varies across institutions. We examined the relationship between IVF therapy and hospital length of stay (HLOS), as well as adverse events, such as acute chest syndrome (ACS), pediatric intensive care unit (PICU) transfer, and 28-day re-admission. METHODS: This is a single-center retrospective analysis of SCD VOE hospitalizations between January 2015 and April 2020. Patients with SCD, age 0-30, with consecutive hospitalizations for VOE were included. For the first 3 days of each admission, an "IVF ratio" was calculated by dividing actual IVF rate administered by weight-based maintenance IVF (mIVF) rate. RESULTS: A total of 617 hospitalizations for 161 patients were included. Mean HLOS was 5.7 days, (SD 3.9), and mean IVF volume over the first 3 days of admission was 139.6 mL/kg/day (SD 57.8). Multivariate analysis showed that for each additional 0.5 times the mIVF rate, HLOS increased by 0.53 day (p < .001; 95% confidence interval [CI]: 0.609-0.989), but there was no significant association between IVF therapy and adverse events. History of chronic pain was associated with increased odds of re-admission (OR 6.4; 95% CI: 3.93-10.52). CONCLUSIONS: Despite the theoretical potential for IVF therapy to slow down the sickling process, our findings suggest that increased IVF therapy was associated with prolonged HLOS, which places a burden on patients, families, and the health system.

Evaluation of a prophylactic transfusion program on obstetric outcomes in pregnant women with sickle cell disease: A single centre retrospective cohort study.

OBJECTIVE: To evaluate the effects of a prophylactic transfusion program (TP) on obstetric and perinatal outcomes in pregnant women with sickle cell disease (SCD). METHODS: This retrospective cohort study included all singleton pregnancies among women with SCD in a French university tertiary care center between 1 January 2004 and 31 December 2017. The TP group included patients selected according to the French guidelines who received regular red blood cell transfusions during pregnancy until delivery. The factors associated with TP indication [year of birth, SCD genotype, history of acute chest syndrome and delayed hemolysis transfusion reaction (DHTR) risk score] were taken into account in a propensity score. A composite obstetric adverse outcome was defined associating birth before 34 gestational weeks and/or pre-eclampsia and/or small for gestational age and/or abruption and/or stillbirth and/or maternal death and/or neonatal death. RESULTS: In total, 246 pregnancies in 173 patients were analyzed. Twenty-two pregnancies with a history of DHTR were excluded. A higher frequency of TP was found before 2013 [119/148 (80.4%) vs 38/76 (50%); p < 0.001]. Rates of preterm birth before 34 gestational weeks (5.6% vs 19.7%; p = 0.001), vaso-occlusive crisis (36.5% vs. 61.8%; p < 0.001), and acute chest syndrome (6.1% vs. 14.5%; p = 0.04) during pregnancy were decreased significantly in the TP group. Among the groups with and without composite obstetric adverse outcomes, the frequency of TP was 52.6% and 74.7%, respectively [odds ratio (OR) 0.30, 95% confidence interval (CI) 0.09-1.02]. The multivariate analysis shows that the TP was associated with a significant reduction in the risk of composite obstetric adverse outcomes (OR 0.28, 95% CI 0.08-0.97; p = 0.04). CONCLUSION: A red blood cell TP may have an independent protective effect on maternal and perinatal adverse outcomes during pregnancy in women with SCD.

Interventions for chronic kidney disease in people with sickle cell disease.

BACKGROUND: Sickle cell disease (SCD), one of the commonest severe monogenic disorders, is caused by the inheritance of two abnormal haemoglobin (beta-globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Kidney disease is a frequent and potentially severe complication in people with SCD. Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function present for more than three months. Sickle cell nephropathy refers to the spectrum of kidney complications in SCD. Glomerular damage is a cause of microalbuminuria and can develop at an early age in children with SCD, with increased prevalence in adulthood. In people with sickle cell nephropathy, outcomes are poor as a result of the progression to proteinuria and chronic kidney insufficiency. Up to 12% of people who develop sickle cell nephropathy will develop end-stage renal disease. This is an update of a review first published in 2017. OBJECTIVES: To assess the effectiveness of any intervention for preventing or reducing kidney complications or chronic kidney disease in people with sickle cell disease. Possible interventions include red blood cell transfusions, hydroxyurea, and angiotensin-converting enzyme inhibitors (ACEIs), either alone or in combination. SEARCH METHODS: We searched for relevant trials in the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, CENTRAL, MEDLINE, Embase, seven other databases, and two other trials registers. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing interventions to prevent or reduce kidney complications or CKD in people with SCD. We applied no restrictions related to outcomes examined, language, or publication status. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility, extracted data, assessed the risk of bias, and assessed the certainty of the evidence (GRADE). MAIN RESULTS: We included three RCTs with 385 participants. We rated the certainty of the evidence as low to very low across different outcomes according to GRADE methodology, downgrading for risk of bias concerns, indirectness, and imprecision. Hydroxyurea versus placebo One RCT published in 2011 compared hydroxyurea to placebo in 193 children aged nine to 18 months. We are unsure if hydroxyurea compared to placebo reduces or prevents progression of kidney disease assessed by change in glomerular filtration rate (mean difference (MD) 0.58 mL/min /1.73 m2, 95% confidence interval (CI) -14.60 to 15.76; 142 participants; very low certainty). Hydroxyurea compared to placebo may improve the ability to concentrate urine (MD 42.23 mOsm/kg, 95% CI 12.14 to 72.32; 178 participants; low certainty), and may make little or no difference to SCD-related serious adverse events, including acute chest syndrome (risk ratio (RR) 0.39, 99% CI 0.13 to 1.16; 193 participants; low certainty), painful crisis (RR 0.68, 99% CI 0.45 to 1.02; 193 participants; low certainty); and hospitalisations (RR 0.83, 99% CI 0.68 to 1.01; 193 participants; low certainty). No deaths occurred in either trial arm and the RCT did not report quality of life. Angiotensin-converting enzyme inhibitors versus placebo One RCT published in 1998 compared an ACEI (captopril) to placebo in 22 adults with normal blood pressure and microalbuminuria. We are unsure if captopril compared to placebo reduces proteinuria (MD -49.00 mg/day, 95% CI -124.10 to 26.10; 22 participants; very low certainty). We are unsure if captopril reduces or prevents kidney disease as measured by creatinine clearance; the trial authors stated that creatinine clearance remained constant over six months in both groups, but provided no comparative data (very low certainty). The RCT did not report serious adverse events, all-cause mortality, or quality of life. Angiotensin-converting enzyme inhibitors versus vitamin C One RCT published in 2020 compared an ACEI (lisinopril) with vitamin C in 170 children aged one to 18 years with normal blood pressure and microalbuminuria. It reported no data we could analyse. We are unsure if lisinopril compared to vitamin C reduces proteinuria in this population: the large drop in microalbuminuria in both arms of the trial after only one month on treatment may have been due to an overestimation of microalbuminuria at baseline rather than a true effect. The RCT did not report serious adverse events, all-cause mortality, or quality of life. AUTHORS' CONCLUSIONS: We are unsure if hydroxyurea improves glomerular filtration rate or reduces hyperfiltration in children aged nine to 18 months, but it may improve their ability to concentrate urine and may make little or no difference to the incidence of acute chest syndrome, painful crises, and hospitalisations. We are unsure if ACEI compared to placebo has any effect on preventing or reducing kidney complications in adults with normal blood pressure and microalbuminuria. We are unsure if ACEI compared to vitamin C has any effect on preventing or reducing kidney complications in children with normal blood pressure and microalbuminuria. No RCTs assessed red blood cell transfusions or any combined interventions to prevent or reduce kidney complications. Due to lack of evidence, we cannot comment on the management of children aged over 18 months or adults with any known genotype of SCD. We have identified a lack of adequately designed and powered studies, although we found four ongoing trials since the last version of this review. Only one ongoing trial addresses renal function as a primary outcome in the short term, but such interventions have long-term effects. Trials of hydroxyurea, ACEIs or red blood cell transfusion in older children and adults are urgently needed to determine any effect on prevention or reduction of kidney complications in people with SCD.

[Lung manifestations of sickle-cell disease]. / Manifestations respiratoires de la drépanocytose.

Sickle-cell disease is an autosomal recessive genetic disorder of hemoglobin that causes systemic damage. Hypoxia is the main actor of sickle-cell disease. It initiates acutely the pathogenic cascade leading to tissue damages that in turn induce chronic hypoxia. Lung lesions represent the major risk of morbidity and mortality. Management of sickle-cell disease requires a tight collaboration between hematologists, intensivists and chest physicians. Recurrent episodes of thrombosis and hemolysis characterize the disease. New therapeutic protocols, associating hydroxyurea, transfusion program and stem cell transplantation in severe cases allow a prolonged survival until the fifth decade. However, recurrent pain, crisis, frequent hospital admissions due to infection, anemia or acute chest syndrome and chronic complications leading to organ deficiencies degrade the patients' quality of life. In low-income countries where the majority of sickle-cell patients are living, the disease is still associated with a high mortality in childhood. This paper focuses on acute chest syndrome and chronic lung manifestations.

Acute chest syndrome, airway inflammation and lung function in sickle cell disease.

BACKGROUND: Acute chest syndrome (ACS) is an acute complication in SCD but its effects on lung function are not well understood. Inflammation is a key component of SCD pathophysiology but with an unclear association with lung function. We hypothesized that children with ACS had worse lung function than children without ACS and aimed to investigate the association of lung function deficits with inflammatory cytokines. METHODS: Patients enrolled in a previous 2-year randomized clinical trial who had consented to future data use, were enrolled for the present exploratory study. Patients were categorized into ACS and non-ACS groups. Demographic and clinical information were collected. Serum samples were used for quantification of serum cytokines and leukotriene B4 levels and pulmonary function tests (PFTs) were assessed. RESULTS: Children with ACS had lower total lung capacity (TLC) at baseline and at 2 years, with a significant decline in forced expiratory volume in 1 sec (FEV1) and mid-maximal expiratory flow rate (FEF25-75%) in the 2 year period (p = 0.015 and p = 0.039 respectively). For children with ACS, serum cytokines IL-5, and IL-13 were higher at baseline and at 2 years compared to children with no ACS. IP-10 and IL-6 were negatively correlated with PFT markers. In multivariable regression using generalized estimating equation approach for factors predicting lung function, age was significantly associated FEV1 (p = 0.047) and ratio of FEV1 and forced vital capacity (FVC)- FEV1/FVC ratio (p = 0.006); males had lower FEV1/FVC (p = 0.035) and higher TLC (p = 0.031). Asthma status was associated with FEV1 (p = 0.017) and FVC (p = 0.022); history of ACS was significantly associated with TLC (p = 0.027). CONCLUSION: Pulmonary function abnormalities were more common and inflammatory markers were elevated in patients with ACS, compared with those without ACS. These findings suggest airway inflammation is present in children with SCD and ACS, which could be contributing to impaired pulmonary function.

Acute chest syndrome in adult patients with sickle cell disease: The relationship with the time to onset after hospital admission.

Data on acute chest syndrome (ACS) in adult sickle cell disease patients are scarce. In this study, we describe 105 consecutive ACS episodes in 81 adult patients during a 32-month period and compare the characteristics as a function of the time to onset after hospital admission for a vaso-occlusive crisis (VOC), that is early-onset episodes (time to onset ≤24 h, 42%) versus secondary episodes (>24 h, 58%; median [interquartile range] time to onset: 2 [2-3] days). The median age was 27 [22-34] years, 89% of the patients had an S/S or S/ß0 -thalassaemia genotype; 81% of the patients had a history of ACS (median: 3 [2-5] per patient), only 61% were taking a disease-modifying treatment at the time of the ACS. Fever and chest pain were noted in respectively 54% and 73% of the episodes. Crackles (64%) and bronchial breathing (32%) were the main abnormal auscultatory findings. A positive microbiological test was found for 20% of episodes. Fifty percent of the episodes required a blood transfusion; ICU transfer and mortality rates were respectively 29% and 1%. Secondary and early-onset forms of ACS did not differ significantly. Disease-modifying treatments should be revaluated after each ACS episode because the recurrence rate is high.

How does sickle cell disease affect the peri-operative outcome in patients undergoing total knee arthroplasty? A large-scale, National Inpatient Sample-based study.

INTRODUCTION: In view of the vaso-occlusive pathophysiology affecting osseous micro-circulation, sickle cell disease (SCD) is well known to present with diverse skeletal and arthritic manifestations. With prolonged life-expectancy over the past decades, there has been a progressive increase in the proportion of SCD patients requiring joint reconstructions. Owing to the paucity of evidence in the literature, the post-operative complication rates and outcome in these patients following total knee arthroplasty (TKA) are still largely unknown. METHODS: Based on the National Inpatient Sample (NIS) database (using ICD-10 CMP code), patients who underwent TKA between 2016 and 2019 were identified. The cohort were classified into two groups: A-those with SCD; and B-those without. The data on patients' demographics, co-morbidities, details regarding hospital stay including expenditure incurred, and complications were analyzed and compared. RESULTS: Overall, 558,361 patients underwent unilateral, primary TKA; among whom, 493 (0.1%) were known cases of SCD (group A). Group A included a significantly greater proportion of younger (60.14 ± 10.87 vs 66.72 ± 9.50 years; p < 0.001), male (77.3 vs 61.5%; p < 0.001); and African-American (88.2 vs 8.3%B; p < 0.001) patients, in comparison with group B. Group A patients were also at a significantly higher risk for longer duration of peri-operative hospital stay (p < 0.001), greater health-care costs incurred (p < 0.001), and greater need for alternative step-down health-care facilities (p < 0.001) following discharge. Among the SCD patients, 24.7%, 20.9% and 24.9% developed acute chest syndrome, pain crisis and splenic sequestration crisis, respectively during the peri-operative period. Group A patients had a statistically greater incidence of acute renal failure (ARF; p = 0.014), need for blood transfusion (p < 0.001) and deep vein thrombosis (DVT; p = 0.03) during the early admission period. CONCLUSION: The presence of SCD substantially lengthens the duration of hospital stay and enhances health care-associated expenditure in patients undergoing TKA. SCD patients are at significantly higher risk for systemic complications including acute chest syndrome, pain crisis, splenic sequestration crisis, acute renal failure, higher need for blood transfusions and deep venous thrombosis during the initial peri-operative period following TKA.

Outcomes before and after providing interdisciplinary hematology and pulmonary care for children with sickle cell disease.

People with sickle cell disease (pwSCD) are at risk of developing lung conditions that complicate their SCD but often face health care access barriers. An interdisciplinary clinic providing pulmonary care for pwSCD was created in 2014 at the Nationwide Children's Hospital (NCH) to address access barriers that may prevent optimized treatment. We hypothesize that pwSCD and pulmonary disease would have fewer hospitalizations for acute chest syndrome (ACS), asthma, and vaso-occlusive episodes in the 2 years after their initial SCD-pulmonary clinic visit compared with the 2 years before. From 2014 to 2020, 119 pwSCD were evaluated in the SCD-pulmonary clinic and followed up at the NCH for at least 2 years before and after this initial visit. Acute care outcomes, pulmonary function, polysomnography, echocardiogram, laboratory, and medication prescribing data were collected and analyzed using the Wilcoxon signed ranked and McNemar tests. The median number of acute care visits for ACS (P < .001) and asthma (P = .006) were significantly lower during the 2 years after pwSCD's initial SCD-pulmonary clinic evaluation compared with the 2 years before. Asthma and allergic rhinitis were more frequently diagnosed and prescriptions for hydroxyurea (P = .005) and inhaled corticosteroids (P = .005) were more common in the post-SCD-pulmonary clinic period. The median number of prescribed systemic corticosteroids was lower in the 2 years after SCD-pulmonary clinic evaluation (P < .0001). Lactate dehydrogenase and white blood cell counts also significantly decreased. Implementing a multidisciplinary SCD-pulmonary clinic is feasible and may allow improved management of pulmonary problems and lead to improvements in the usage of health and acute care.

Hydroxyurea (hydroxycarbamide) for sickle cell disease.

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 foetal haemoglobin (HbF). This is an update of a previously published Cochrane Review. OBJECTIVES: The aims of this review are to determine through a review of randomised or quasi-randomised studies whether the use of hydroxyurea in people with SCD alters the pattern of acute events, including pain; prevents, delays or reverses organ dysfunction; alters mortality and quality of life; or is associated with adverse effects. In addition, we hoped to assess whether the response to hydroxyurea in SCD varies with the type of SCD, age of the individual, duration and dose of treatment, and healthcare setting. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Haemoglobinopathies Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. The date of the most recent search was 17 February 2022. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials (RCTs and quasi-RCTs), of one month or longer, comparing hydroxyurea with placebo or standard therapy in people  with SCD. DATA COLLECTION AND ANALYSIS: Authors independently assessed studies for inclusion, carried out data extraction, assessed the risk of bias and assessed the quality of the evidence using GRADE. MAIN RESULTS: We included nine RCTs recruiting 1104 adults and children with SCD (haemoglobin SS (HbSS), haemoglobin SC (HbSC) or haemoglobin Sߺthalassaemia (HbSߺthal) genotypes). Studies lasted from six to 30 months. We judged the quality of the evidence for the first two comparisons below as moderate to low as the studies contributing to these comparisons were mostly large and well-designed (and at low risk of bias); however, the evidence was limited and imprecise for some outcomes such as quality of life, deaths during the studies and adverse events, and the results are applicable only to individuals with HbSS and HbSߺthal genotypes. We judged the quality of the evidence for the third and fourth comparisons to be very low due to the limited number of participants, the lack of statistical power (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. Hydroxyurea versus placebo Five studies (784 adults and children with HbSS or HbSߺthal) compared hydroxyurea to placebo; four recruited individuals with only severe disease and one recruited individuals with all disease severities. Hydroxyurea probably improves pain alteration (using measures such as pain crisis frequency, duration, intensity, hospital admissions and opoid use) and life-threatening illness, but we found no difference in death rates (10 deaths occurred during the studies, but the rates did not differ by treatment group) (all moderate-quality evidence). Hydroxyurea may improve measures of HbF (low-quality evidence) and probably decreases neutrophil counts (moderate-quality evidence). There were no consistent differences in terms of quality of life and adverse events (including serious or life-threatening events) (low-quality evidence). There were fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups.  Hydroxyurea and phlebotomy versus transfusion and chelation Two studies (254 children with HbSS or HbSߺthal also with risk of primary or secondary stroke) contributed to this comparison. There were no consistent differences in terms of pain alteration, death or adverse events (low-quality evidence) or life-threatening illness (moderate-quality evidence). Hydroxyurea with phlebotomy probably increased HbF and decreased neutrophil counts (moderate-quality evidence), but there were more occurrences of acute chest syndrome and infections. Quality of life was not reported. 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.  Hydroxyurea versus observation One study (22 children with HbSS or HbSߺthal also at risk of stoke) compared hydroxyurea to observation. Pain alteration and quality of life were not reported. There were no differences in life-threatening illness, death (no deaths reported in either group) or adverse events (very low-quality evidence). We are uncertain if hydroxyurea improves HbF or decreases neutrophil counts (very low-quality evidence). Treatment regimens with and without hydroxyurea One study (44 adults and children with HbSC) compared treatment regimens with and without hydroxyurea. Pain alteration, life-threatening illness and quality of life were not reported. There were no differences in death rates (no deaths reported in either group), adverse events or neutrophil levels (very low-quality evidence). We are uncertain if hydroxyurea improves HbF (very low-quality evidence). AUTHORS' CONCLUSIONS: There is evidence to suggest that hydroxyurea may be effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSߺthal 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 with regard to preventing chronic complications of SCD, or 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 the HbSC genotype. Future studies should be designed to address such uncertainties.

Haptoglobin 1 allele predicts higher serum haptoglobin concentration and lower multiorgan failure risk in sickle cell disease.

Haptoglobin (HP) is an acute-phase protein and the main scavenger of cell-free hemoglobin. When HP is depleted, as observed in hemolytic conditions such as sickle cell disease (SCD), cell-free hemoglobin can lead to acute organ damage. The impact of the HP 1-1, 2-1, and 2-2 isoforms on HP and cell-free hemoglobin concentrations and SCD-related complications is unclear. In a longitudinal cohort of patients with SCD, the HP 1 allele was associated with higher HP and lower cell-free hemoglobin concentrations at a routine clinic visit as well as during hospitalization for a vaso-occlusive episode or acute chest syndrome. With a median follow-up of 6.8 years, acute chest syndrome occurred in 42% (n = 163) and multiorgan failure in 14% (n = 53) of 391 patients with SCD with a minimum follow-up of 6 months. The HP 1 allele was independently associated with lower risk of developing multiorgan failure during acute chest syndrome (additive model hazard ratio, 0.5; P < .001). Future studies assessing the regulation of HP concentrations and ability to bind cell-free hemoglobin according to the HP genotype may help to identify patients with SCD at high risk for multiorgan failure and to guide interventions, such as rapid initiation of exchange transfusion or HP replacement therapy.

Incidence of Acute Chest Syndrome in Children With Sickle Cell Disease Following Implementation of the 13-Valent Pneumococcal Conjugate Vaccine in France.

Importance: Acute chest syndrome (ACS) is one of the leading acute severe complications of sickle-cell disease (SCD). Although Streptococcus pneumoniae (S pneumoniae) is highly prevalent in children with SCD, its precise role in ACS is unclear. The efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) implementation on ACS is still unknown. Objective: To assess the association of PCV13 implementation in the general pediatric population with the incidence of ACS in children with SCD. Design, Setting, and Participants: This cohort study used an interrupted time-series analysis of patient records from a national hospital-based French surveillance system. All children younger than 18 years with SCD (based on the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision definition) hospitalized in France between January 2007 and December 2019 were included. Exposures: PCV13 implementation. Main Outcomes and Measures: Monthly incidence of ACS per 1000 children with SCD over time as analyzed by segmented linear regression with autoregressive error; monthly incidence of hospitalization for vaso-occlusive crisis, asthma crisis, and acute pyelonephritis per 1000 children with SCD over the same period as the control outcomes. Results: Among the 107 694 hospitalizations of children with SCD, 4007 episodes of ACS were included (median [IQR] age, 8 [4-12] years; 2228 [55.6%] boys). PCV13 implementation in 2010 was followed by a significant decrease in the incidence of ACS (-0.9% per month; 95% CI, -1.4% to -0.4%; P < .001), with an estimated cumulative change of -41.8% (95% CI, -70.8% to -12.7%) by 2019. Sensitivity analyses yielded the same results, including the incidence of ACS adjusted for that of vaso-occlusive crisis over time. The results were similar among different age groups. By contrast, no change was found for the 3 control outcomes over the study period. Conclusions and Relevance: PCV13 implementation was associated with an important reduction in the incidence of ACS in children with SCD. This vaccine benefit provides new evidence of the key role of S pneumoniae in ACS and should be considered when estimating outcomes associated with current PCVs and the potential benefit of next-generation PCVs in children.

[Gallstone complications in sickle cell patients]. / Complications lithiasiques chez les patients drépanocytaires.

Chronic haemolysis exposes patients with sickle cell disease (SCD) to the development of black pigment gallstones, which can trigger biliary complications. In order to avoid these complications, elective cholecystectomy is recommended in France for all SCD patients with detected gallstones. However, all surgeries, and especially abdominal surgeries, entail an increased risk of vaso-occlusive complications in the peri- and post-operative periods, the most dreadful one being the acute chest syndrome. Preoperative transfusion has been shown in several studies to reduce acute postoperative complications, but exposes the patient to definitive alloimmunization, or even delayed post- transfusion haemolysis, justifying a recent trend towards transfusion sparing. The conditions for avoiding transfusion for a simple and frequent surgery such as cholecystectomy are based on a benefit- risk balance, and must be discussed on a case-by-case basis by the SCD specialist. In particular, it seems fully justified to perform prophylactic preoperative transfusion in patients with a history of recent vaso-occlusive crisis or acute chest syndrome (within 6 months preoperatively), and those operated on in an emergency setting, who are particularly at risk of postoperative events.

A case of autopsy discovery of acute chest syndrome triggered by pulmonary embolism in a sickle cell patient.

This is a case report about a 7-year-old male child with sickle cell anemia (S/ß+) who died unexpectedly during hospitalization, justifying the performance of a forensic autopsy completed by histological examination of organ fragments and toxicological analyses of biological fluids. The diagnosis retained was pulmonary thromboembolism as the cause of death occurring in the context of an acute chest syndrome (ACS). The mechanism of occurrence of this pulmonary embolism was vascular stasis caused by sickle cell disease. The search for etiologies of ACS complicating sickle cell disease should not exclude pulmonary embolism with red cell dense fibrin clot..

Demand-only patient-controlled analgesia for treatment of acute vaso-occlusive pain in sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is a chronic illness that is associated with frequent admissions for vaso-occlusive episodes (VOE). Opioids are frequently utilized in pain management, but dosing is often provider dependent. Opioids cause both short-term and long-term side effects, so the minimal effective dose is desired. This study examined demand-only patient-controlled analgesia (PCA) in pediatric patients. METHODS: A new clinical practice guideline (CPG) for a single institution was implemented, which eliminated basal infusion dosing for PCAs on hospital admission. The primary aim of this retrospective study was to evaluate length of stay (LOS) before and after implementation of a CPG of demand-only PCA and, in a selected subpopulation, addition of short-term methadone. Secondary aims included opioid utilization, acute chest syndrome (ACS), and hypoxia. Inclusion criteria included SCD, ≤21 years of age, uncomplicated VOE admission, and ≥ 3 and ≤ 8 hospital admissions for SCD pain control within one calendar year. RESULTS: LOS decreased postintervention (7.2 ± 5.1 vs 4.5 ± 3.8 days, P < 0.001). Mean total opioid utilization in morphine equivalents mg/kg markedly decreased between the cohorts (13.3 ± 33.8 vs 3.6 ± 3.0, P < 0.001). ACS (21.9% vs 2.8%, P = 0.004) and hypoxia (28% vs 6.9%, P< 0.001) decreased significantly as well. CONCLUSION: Bolus PCA dosing of opioids resulted in decreased LOS and reductions in opioid utilization, hypoxia, and ACS.

Therapeutic plasma exchange in the management of acute complications of sickle cell disease: A single centre experience.

Sickle cell disease results in systemic inflammation even at steady state and this is accentuated during acute crises. The plasma of affected patients contains several proinflammatory cytokines as well as adhesion molecules and prothrombotic factors. This environment promotes further red cell sickling while many of these substances can cause direct tissue toxicity and end-organ damage. Even though red cell transfusion, whether simple or exchange, is the mainstay of treatment of severe acute complications, addition of therapeutic plasma exchange could potentially provide additional benefit by removing such harmful substances. Here, we describe two cases where therapeutic plasma exchange was used. The first involved a patient with the acute chest syndrome who despite adequate red cell exchange remained significantly hypoxic and in severe pain. We therefore proceeded to perform plasma exchange; this led to rapid clinical improvement and resolution of his symptoms. The second case involved a patient with intractable chest wall pain and impending acute chest syndrome; this patient also had a past history of hyperhaemolysis. The patient underwent therapeutic plasma exchange with very rapid resolution of the pain, avoidance of any respiratory deterioration and full recovery. We also give a brief summary of our previous experience using plasma exchange in patients with sickle cell disease. Plasma exchange was well tolerated with no adverse events in all cases we have treated, led to rapid resolution of pain irrespective of primary indication and in the majority of cases to a favourable clinical outcome.

Successful use of veno-venous extracorporeal membrane oxygenation for acute chest syndrome in a child with sickle cell disease and SARS-CoV-2.

Children with sickle cell disease (SCD) are at increased risk for severe illness due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We describe the successful native lung recovery of a child with SCD referred for lung transplant (LTx) evaluation who was on prolonged veno-venous extracorporeal membrane oxygenation (VV-ECMO). He initially presented with acute chest syndrome complicated by SARS-CoV-2 infection that ultimately required dual-lumen, single bicaval VV-ECMO cannulation for respiratory support. Despite the increased risk of hemolysis and thrombosis from SCD and SARS-CoV-2 infection, he was successfully supported on VV-ECMO for 71 days without complications leading to native lung recovery with meticulous management of his SCD therapy. This report provides new insight on our approach to VV-ECMO support in a child with SCD and SARS-CoV-2 infection. With a successful outcome, the patient has returned home but still on mechanical ventilation with LTx still an option if he is not eventually liberated from invasive respiratory support.

Evaluation of the relationship between intravascular hemolysis and clinical manifestations in sickle cell disease: decreased hemopexin during vaso-occlusive crises and increased inflammation in acute chest syndrome.

The aims of this study were to determine the possible relationships between the levels of hemin, hemopexin, acid sphingomyelinase, nitrite/nitrate (NOx), and other parameters in patients with SCD and to assess whether they were associated with vaso-occlusive crises (VOCs) or acute chest syndrome (ACS). Patients with SCD (homozygous or sickle beta-thalassemia) who were confirmed to have VOC or ACS were included. Blood samples were obtained at admission, on the third day of hospitalization, and at steady state. Demographic characteristics, pain (visual analog scale), complication history, complete blood count, lactate dehydrogenase, and C-reactive protein levels were recorded. Hemin, hemopexin, acid sphingomyelinase, and NOx were measured via ELISA. A total of 31 patients (22 VOC, 9 ACS) were included. Mean age was 16.4 ± 4.7 years. Admission white blood cell count and C-reactive protein levels were significantly higher in the ACS group. Patients with ACS also demonstrated a significant decreasing trend of LDH and an increasing trend of NOx values from admission to steady state. Notably, hemopexin levels were significantly lower on the third day of hospitalization compared to steady-state levels. Despite limited patient count in the ACS group, these patients appear to have strikingly greater inflammatory activation at admission, and the progression of ACS may be associated with LDH and NOx levels. Lower hemopexin levels during hospitalization versus steady state appear to support a role for the administration of hemopexin therapy during crises.