Incidence Of Acute Chest Syndrome Research Articles

Impact of hospitalized vaso-occlusive crises in the previous calendar year on mortality and complications in adults with sickle cell disease: a French population-based study

BackgroundHistorically, sickle cell disease (SCD) patients experiencing frequent hospitalized vaso-occlusive crises (HVOC) have been associated with increased mortality, yet recent data reflecting the widespread use of hydroxyurea and advancements in disease management remain limited. Our study aims to assess the association between HVOC and mortality or severe complications in patients with SCD in this new treatment landscape. MethodsThis was a retrospective observational cohort study using the French national health data system. Between 01-01-2012 and 12-31-2018, all SCD patients ≥16 years old (ICD-10 codes D57·0-2) were included and followed until 12-31-2018. HVOC was defined as a hospitalization of ≥1 night with primary diagnosis of SCD with crisis, following an emergency room visit. The association between HVOC and severe complications was assessed with a Cox proportional hazards model. FindingsIn total, 8 018 patients (56·6% females; 4 538/8 018) were included. The 2018 SCD standardized one-year period prevalence was 17·9 cases/100 000 person-years [17·4;18·3]. The mean rate was 0.84 (1·88) HVOC/person-year. In 2018, 70% (5 323/7 605), 22% (1 671/7 605), and 8% (611/7 605) of patients experienced 0, 1–2, or 3+ HVOCs, respectively. The median survival time between HVOCs was 415 days [386;439]. Overall, 312 patients died (3·9%) with a mean age of 49·8 (19·4). Compared to patients without HVOC, the hazard ratios of death in patients with 1–2 or 3+ HVOCs the year prior to death were 1·67 [1·21;2·30] and 3·70 [2·30;5·93], respectively. Incidence of acute chest syndrome, pulmonary embolism, osteonecrosis, and sepsis increased with the HVOCs category, but not stroke. In 2018, 29·5% (180 / 611) of patients with 3+ HVOCs did not take hydroxyurea. InterpretationPatients must be closely monitored during their hospitalizations to intensify treatment and check treatment compliance. Innovative therapies are also required. FundingThe study was funded by Novartis.

Risk factors for acute chest syndrome among children with sickle cell anemia hospitalized for vaso-occlusive crises

Sickle cell anemia (SCA) is a globally prevalent inherited condition, with acute chest syndrome (ACS) being one of its most severe complications. ACS frequently leads to hospitalization, requires intensive care unit (ICU) admission, and can even result in death. This study aimed to discern the early indicators of impending ACS in children with SCA who were initially hospitalized due to painful vaso-occlusive crises (VOC). This was a retrospective, case‒control investigation of 120 patients aged 1–14 years seen at the King Saud Medical City in Riyadh, Saudi Arabia from January 2021 to December 2022. Patients were classified into cases and controls: those who developed and did not develop ACS during hospital stay, respectively. Demographic factors, laboratory results, vital and clinical signs, and treatment protocols were compared between these groups. The following were significant predictors of impending ACS: previous diagnosis of asthma, history of ACS, recent upper respiratory tract symptoms prior to admission, and need for a blood transfusion within the first 24 h of admission due to a drop in hemoglobin levels. Further regression analysis indicated that elevated steady-state mean corpuscular volume, leukocyte count, total bilirubin, and an increased absolute neutrophil count level 24 h after admission also foreshadowed impending ACS among patients admitted for VOC. The location of pain was also significant; the incidence of ACS was higher in patients with back pain, but lower in those with pain confined to the limbs. The ACS group had a longer average duration of hospital stay compared to those with VOC alone, (7.6 vs. 5.8 days). Among patients initially admitted for VOC, 15.7% were diagnosed with ACS. Most ACS cases were managed with transfusions and antibiotics, and nearly one-third of patients needed admission to an ICU or a high-dependency area.

Impact of Srs-CoV2 Infection on Pain Crises and Acute Chest Syndome in Patients with Sickle Cell Anemia: A Retrospective Multi-Cohort Study Based on USA Data from 2020-2022

Objective: To determine the impact of SARS-CoV-2 infection on vaso-occlusive pain crisis (VOC) and acute chest syndrome (ACS), incidence, and outcomes in sickle cell anemia (SCA) patients. Method: This retrospective study used the TriNetX USA health research network database to identify SCA patients (Hb-SS, Sβ0-thal) ages 1-50 with and without concomitant SARS-CoV-2 infection from May 2020 to May 2022. A total of 6 cohorts were created: pain crisis with/without SARS-CoV-2, ACS with/without SARS-CoV-2, and SARS-CoV-2 without pain crisis/ACS. Patients with SARS-CoV-2 and pain crisis/ACS were compared to 2 cohorts (SARS-CoV-2 without pain crisis/ACS) for demographic characteristics, baseline laboratory parameters, disease-modifying drug use, and influenza/COVID-19 vaccination status by t-tests. Pain crisis/ACS patients with SARS-CoV-2 were then compared to 2 cohorts (pain crisis/ACS without concomitant infection) for demographic characteristics, and relative risk for acute settings of care, pain control, laboratory parameters/outcomes (including hemolytic and inflammatory markers), procedures (blood transfusion) and mortality. Results : The incidence of pain crises and ACS in SCA patients following SARS-CoV-2 infection was 34 and 27 per 100 patients, respectively. The risk of developing ACS was significantly increased by SARS-CoV-2 infection (2.57% vs. 1.17%, RR 2.2), but not the risk of developing a pain crisis (RR 1.04). Pain crisis and ACS patients with concomitant SARS-CoV-2 infection had a greater risk for inpatient services, subsequent hospital visits, opioid and non-opioid analgesia, blood transfusions, and concerning hemolytic and inflammatory markers compared to those without the infection. Patients with SARS-CoV-2 who did not develop pain crises/ACS had higher baseline hemoglobin levels prior to infection compared to patients who developed pain crisis/ACS. There was a higher rate of COVID-19 and influenza vaccination in the cohorts who did not develop pain crisis/ACS and might have improved pain crisis rates (but not ACS) following SARS-CoV-2 infection. Conclusions: COVID-19 illness had an impact on the incidence of both pain crises and ACS, significantly increased the risk of developing ACS, and influenced morbidity outcomes for both pain crises and ACS. Prior vaccination against influenza and COVID-19 may represent a protective factor for developing pain crises.

Enhanced Expression of Heme Oxygenase-1 (HO-1) Among Children with Sickle Cell Disease: Results of the Sickle Cell Disease Genomics of Africa (SickleGenAfrica) Study

Sickle cell disease (SCD) is characterized by intense and chronic intravascular hemolysis that generates multiple erythroid danger associated molecular pattern (eDAMP) molecules in the extracellular space. Extracellular heme is a prototypical eDAMP that causes tissue injury and is associated with multiple complications of SCD including vaso-occlusive crisis, acute kidney injury and acute chest syndrome (ACS). Heme-oxygenase-1 (HO-1) is the rate-limiting enzyme that degrades heme to neutralize its deleterious effects on organ function. Raised extracellular heme is associated with 2.5 higher odds ratio of developing ACS, while HO-1 gene promoter allelic variants that drive robust HO-1 expression are associated with lower ACS-related hospitalization rates among children. Young transgenic homozygous SCD (SS) mice have higher survival rates than adult SS mice from a heme-induced ACS model due to their ability to rapidly degrade excess extracellular heme. While these data suggest that HO-1 may be involved in the well-established higher ACS survival among children, and potentially other ameliorating features of SCD in early development, no study had previously studied HO-1 expression in this patient population. The SickleGenAfrica Network enrolled over 2,000 children and adults with SCD from three sites in Ghana from 2018 to 2021, with consent for use of samples in future studies. The SCD status of participants was confirmed using automated capillary hemoglobin electrophoresis, and serum HO-1 level measured using ELISA. Patients were grouped based on age, using five-year intervals. The median HO-1 level comparisons across groups were performed using the pairwise Wilcoxon test, with Bonferroni correction for multiple comparisons. All analyses were performed using R version 4.3.1. The study included 1,971 patients with SCD, with a median age of 13 years (range 0 - 78), of which 1,067 participants (55%) were female. The majority of patients (1149 ;58%) had HbSS, 589 (30%) had HbSC, 171 (9%) sickle-hereditary persistence of fetal hemoglobin, and 62 (3%) HbS-beta(+). We observed an approximately 3-fold drop-off in median HO-1 levels between the 11-15-year-old (73.9 ng/ml) and 16-20-year-old (25.1 ng/ml) age groups (adj. p<0.001). Furthermore, males had higher average HO-1 levels (85.5 ng/ml) relative to females (63.1 ng/ml) (p<0.001). Our data show for the first time that children with SCD have significantly elevated HO-1 levels relative to adults, with a sharp decline in HO-1 levels during adolescence. HO-1 may serve as a protective SCD factor, contributing to enhanced ACS survival rates in children versus adults. To the best of our knowledge, this is the first study of HO-1 levels in patients with SCD at different ages. Our future work aims to establish whether baseline blood HO-1 levels can predict ACS incidence and severity, in addition to further investigating genetic and epigenetic mechanisms controlling HO-1 expression.

Impact of COVID-19 on incidence, clinical presentation, and prognosis of acute chest syndrome in patients with sickle cell disease.

Acute chest syndrome (ACS) is a frequent complication of sickle cell disease (SCD). Because coronavirus disease 2019 (COVID-19) increases mortality and morbidity in many diseases, we retrospectively analyzed the impact of SARS-CoV-2 infection on the incidence, the clinical presentation, and the prognosis of ACS in patients with SCD by comparing ACS episode before and during COVID-19 pandemic. Ninety-nine episodes of ACS were registered over 24 months before pandemic versus 81 episodes over 24 months during the pandemic period. The number of ACS episodes varies among children regarding the two period of time: 26 episodes (26%) for the pre-pandemic period versus 11 episodes (13%) for the pandemic period (p=0.03). Comparisons between adults and children showed a higher incidence of initial VOC (45%vs. 24%; p=0.04) in adults, and a higher incidence of initial pneumonia (35%vs. 15%; p=0.01) and documented infection (35%vs. 7%; p<0.001) in children. One patient died during the pandemic period but without any relationship with ACS or COVID-19. During this pandemic period, 13 episodes of ACS (16%) were found related to coronavirus infection. These ACS episodes did not show any significant differences in terms of outcome when compared to the other ACS episodes observed during this period. Overall, coronavirus infection did not demonstrate a negative impact on incidence, clinical presentation, and outcome of ACS in patients with SCD. Early management, chronic treatment with HU, and exchange transfusions could likely explain the low morbidity and mortality rates.

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

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). What is the respective role of respiratory pathogens in ACS epidemiology? This study was an interrupted time series analysis of patient records from a national hospital-based surveillance system. All childrenaged < 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. 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. 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.

Is Hydroxyurea Treatment Changing the Life of Children with Sickle Cell Disease?

Background: Sickle cell disease (SCD) is a prevalent hemoglobinopathy involving sickled hemoglobin that causes multiorgan disease due to chronic recurrent vaso-occlusion and hemolysis. Fetal hemoglobin (HbF) being present showed reduction in disease severity, owing to which hydroxyurea has gained significant recognition. The latter’s exact mechanism of action is yet unknown, but it has been demonstrated that the resulting rise in HbF raises hemoglobin levels and lessens the incidence of acute chest syndrome and vaso-occlusive crises. In the United Arab Emirates, our study is the first to assess the effects of hydroxyurea therapy in pediatric SCD patients. Methods: We conducted a retrospective cross-sectional study on 100 patients aged 2–13 years who were diagnosed with SCD, under regular outpatient follow-up with pediatric hematology clinic and receiving hydroxyurea therapy for at least 2 years. Basic hematologic parameters, frequency of SCD complications, and need for blood transfusions were studied. Results: Our analysis has shown a statistically significant (p < 0.05) correlation between hydroxyurea therapy and improved baseline hemoglobin and HbF levels; it decreased the incidence of painful crises and acute chest syndrome episodes; reduced the demand for blood transfusions; and recorded no side effects (pancytopenia or liver function disturbance). Conclusions: This study is the first of its kind in the UAE, and our findings support those of international data. The use of hydroxyurea therapy in SCD significantly improved hematologic and clinical parameters, thus markedly improving the patient’s quality of life. The side-effect profile is also limited, which further supports the fact that hydroxyurea is a relatively safe drug.

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

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. To assess the association of PCV13 implementation in the general pediatric population with the incidence of ACS in children with SCD. 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. PCV13 implementation. 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. 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. 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.

P1471: CURRENT INDICATIONS AND RISKS OF SPLENECTOMY IN A LARGE MODERN COHORT OF CHILDREN WITH SCA

Background: In children with sickle cell anemia (SCA), the spleen is altered early in life and may be the site of serious complications such as acute splenic sequestration (ASS) or hypersplenism. Surgical splenectomy may be necessary in those who experience such complications, but both the consequent infectious and thrombo-embolic risks, and the age at which splenectomy may be safely performed, remain unclear. Aims: The objective of our study was to determine the post-splenectomy incidence of invasive bacterial infections and thrombo-embolic complications in a large cohort of children with SCA. The secondary objective was to analyze the effect of age at splenectomy on these risks. Methods: Retrospective review of children with SCA (SS or SB0-thalassemia) splenectomized during the 2000-2018 period at Robert Debré University Hospital (Paris, France) was undertaken. The study received ethical approval. The main clinical characteristics of patients, indications for splenectomy and outcomes were analyzed. Results: A total of 188 children were included, with 164 (87.2%) SS children. Median (Q1-Q3) age at splenectomy was 4.1 yrs (2.5-7.3). Median duration of post splenectomy follow-up (FU) was 5.9 yrs (2.7-9.2) yielding 1192.6 patients-years (PY) of observation. One death (0.5%) occurred during FU, unrelated to splenectomy. Indications for splenectomy were ASS in 101 (53.7%) cases, hypersplenism in 75 (39.9%) and diverse reasons in the remaining children (splenomegaly n=5; delayed hemolytic post transfusion reaction n=5, other n=2). Pneumococcal immunization coverage was good with 166 (95.9%) eligible children immunized with polysaccharidic pneumococcal vaccination at the time of splenectomy and 7 (4.0%) after the procedure. Regarding the conjugated pneumococcal vaccination, 158 (91.9%) of eligible patients had received at least one injection at the time of splenectomy. All patients received penicillin prophylaxis. Overall incidence of invasive bacterial infection was 0.005 /PY (n=6 in 5 patients, no pneumococcal infections). Overall incidence of thrombo-embolic events was 0.003 /PY (n= 4 in 4 patients). In this cohort, 123 (65.4%) and 65 (34.6%) children were splenectomized > or < 3 years of age, respectively. Overall incidence of invasive bacterial infection and thrombo-embolic events was not different according to the age at splenectomy (0.005/ PY in both groups) and 0.004/ PY versus 0.003/ PY (p= 0.7), respectively. Likewise, there was no difference between these groups in the incidence of acute chest syndrome or vaso-occlusive events. Conversely, a significant increase in the overall incidence of cerebral vasculopathy (including abnormal TCD, stroke and cerebral stenosis) was found in children splenectomized before 3 (0.037/PY) versus after 3 (0.011/ PY), p<0.01). Patients who presented with ASS (n=101) were splenectomized at a median age of 3.3 yrs (2.4-5.4), following a median number of 3 (2-4) episodes of ASS and therefore contributed to a large proportion of patients splenectomized under 3 (n=44/65, 67.7 %). Summary/Conclusion: To date this is the largest pediatric cohort study of splenectomized patients with SCA. We show that surgical splenectomy does not result in a significant increased risk of complications, notably invasive bacterial infections or thrombo-embolic complication. Splenectomy should not be delayed in patients once there is an indication for surgical removal, and the children have received recommended vaccines and prophylactic penicillin therapy. The relationship between ASS, splenectomy and cerebral vasculopathy needs to be further assessed.

In Africa, a High Proportion of Adults with HbSC Meet American Society of Hematology's Eligibility Criteria for Severe Sickle Cell Disease and Starting Hydroxyurea Therapy in a Clinical Trial Setting

▪Introduction: Sickle cell disease (SCD), HbSC, is the second most frequent hemoglobinopathy after HbSS. Worldwide, an estimated 54,736 babies are delivered annually with HbSC disease, with the highest HbC gene frequency in West Africa (Piel et al.2013). A retrospective study at the Ghana Institute of Clinical Genetics [(GICG), a sickle cell clinic] reported that 40% of the 3,000 SCD patients attending the clinic yearly are HbSC (Asare et al.2018). HbSC disease usually results in a comparatively milder form of SCD. However, rates of maternal-fetal morbidity, retinopathy, avascular necrosis (AVN) of the hip, priapism, and chronic kidney disease are increased (Powars et al.2002; Oppong et al.2018). While microalbuminuria is lower in HbSC than HbSS, it still occurs in >23% of adults (Drawz et al.2016). In addition, thrombosis, silent cerebral infarction, sensorineural hearing loss, and pulmonary hypertension may be higher than previously suspected (Sathi et al.2019). Unlike HbSS, hydroxyurea is not routinely recommended for HbSC patients because they are all perceived to have a milder phenotype, with improved life expectancy. Thus, HbSC individuals are often excluded from randomized controlled trials in children and adults with SCD (Luchtman-Jones et al.2016).Given the high proportion of adults with HbSC in Ghana, who may benefit from hydroxyurea therapy, we tested the hypothesis that at least 5% of adults with HbSC will meet the ASH criteria for severe disease and treatment. Data indicating that a significant proportion of adults with HbSC are eligible for hydroxyurea could potentially support pilot safety trials to determine the optimal hydroxyurea dose to ameliorate symptoms while limiting toxicity. Data can also facilitate government health policy decisions to subsidize hydroxyurea costs.Methodology: We conducted a medical chart review of all adults with HbSC disease (total: 639; 18-45years) who attended the SCD clinic, GICG (January 1, 2019, to December 31, 2019). We identified a comparison group of 639 adults with HbSS, age, and gender-matched to the HbSC patients from the same clinic. Severe complications were defined as a history of ≥3 sickle cell-associated moderate to severe pain episodes/year, a history of severe acute chest syndrome (ACS), and severe symptomatic chronic anemia that interferes with daily activities or quality of life (Hydroxyurea and Transfusion Therapy for the Treatment of Sickle Cell Disease.2014). We defined acute pain episode as new onset of pain that lasts at least 4 hours, for which there is no explanation other than vaso-occlusion, which requires therapy with parenteral opioids in a medical setting (Ballas et al.2010). Severe symptomatic chronic anemia was defined as a drop in hemoglobin by ≥2g/dL below the steady state. Data were analyzed using SPSS version 23 and summarized as simple descriptive statistics. Study endpoints were the proportion of individuals with SCD who met the definition of severe disease and were eligible for hydroxyurea. We also calculated the pain and ACS incidence rates.Results: The 639 HbSC participants had a mean age of 30.8years during the one-year study period, which was identical to that of the HbSS group. At least 8.5% of HbSC adults had ≥three acute pain episodes/ year, while 1.6% had ACS. No HbSC patient had severe symptomatic chronic anemia . In total, 10.0%(64/639) of patients with HbSC disease met the eligibility criteria for hydroxyurea therapy, compared to 24.1%(154/639) of patients with HbSS, p=<0.001. The pain and ACS incidence rates for the HbSC and HbSS individuals were [74.6; 95% CI(67.9-81.3) and 2.3; 95% CI(1.2-3.5)] events per 100 patient-years vs. [123.0; 95% CI(114.4-131.6) and 5.6; 95% CI(3.8-7.5)] events per 100 patient-years respectively. Also, 1.1%(7/639), 7.7%(49/639), 0.5%(4/639), and 4.4%(11/252) of patients with HbSC had papillary necrosis, AVN, stroke, and priapism, respectively while 8.5%(54/639) of patients with HbSS had proteinuria, Table 1. Only 0.9%(HbSC) and 2.3%(HbSS) took hydroxyurea during the study period.Conclusion: Based on ASH's evidence-based guidelines, in a large SCD clinic at an academic medical center in Ghana, 10.0% of HbSC adults meet the criteria for shared decision-making to consider starting hydroxyurea therapy in a clinical trial setting. The optimal dose of hydroxyurea that maximizes benefit and minimizes toxicity in adults with HbSC is yet to be determined. [Display omitted] DisclosuresAsare: ASH Global Research Award: Research Funding.

Benefits of a Disease Management Program for Sickle Cell Disease in Germany 2011-2019: The Increased Use of Hydroxyurea Correlates with a Reduced Frequency of Acute Chest Syndrome.

Sickle Cell Disease (SCD) is the most common monogenic disorder globally but qualifies as a rare disease in Germany. In 2012, the German Society for Paediatric Oncology and Haematology (GPOH) mandated a consortium of five university hospitals to develop a disease management program for patients with SCD. Besides other activities, this consortium issued treatment guidelines for SCD that strongly favour the use of hydroxyurea and propagated these guidelines in physician and patient education events. In order to quantify the effect of these recommendations, we made use of claims data that were collected by the research institute (WIdO) of the major German insurance company, the Allgemeine Ortskrankenkasse (AOK), and of publicly accessible data collected by the Federal Statistical Office (Statistisches Bundesamt, Destatis). While the number of patients with SCD in Germany increased from approximately 2200 in 2011 to approximately 3200 in 2019, important components of the recently issued treatment guidelines have been largely implemented. Specifically, the use of hydroxyurea has more than doubled, resulting in a proportion of approximately 44% of all patients with SCD being treated with hydroxyurea in 2019. In strong negative correlation with the use of hydroxyurea, the frequency of acute chest syndromes decreased. Similarly, the proportion of patients who required analgesics and hospitals admissions declined. In sum, these data demonstrate an association between the dissemination of treatment guidelines and changes in clinical practice. The close temporal relationship between the increased use of hydroxyurea and the reduction in the incidence of acute chest syndrome in a representative population-based analysis implies that these changes in clinical practice contributed to an improvement in key measures of disease activity.

A non-injected opioid analgesia protocol for acute pain crisis in adolescents and adults with sickle cell disease.

Initial management of the acute pain crisis (APC) of sickle cell disease (SCD) is often unsatisfactory, and might be improved by developing a standardised analgesia protocol. Here, we report the first stages in developing a standard oral protocol for adolescents and adults. Initially, we performed a dose finding study to determine the maximal tolerated dose of sublingual fentanyl (MTD SLF) given on arrival in the acute care facility, when combined with repeated doses of oral oxycodone. We used a dose escalation algorithm with two dosing ranges based on patient’s weight (<50 kg or >50 kg). We also made a preliminary evaluation of the safety and efficacy of the protocol. The study took place in a large tertiary centre in London, UK. Ninety patients in the age range 14–60 years were pre-consented and 31 treatment episodes were evaluated. The first 21 episodes constituted the dose escalation study, establishing the MTD SLF at 600 mcg (>50 kg) or 400 mcg (<50 kg). Further evaluation of the protocol indicated no evidence of severe opioid toxicity, nor increased incidence of acute chest syndrome (ACS). Between 0 and 6 hours, the overall gradient of reduction of visual analogue pain score (visual analogue scale (VAS)) was 0.32 centimetres (cm) per hour (95% confidence interval (CI) = 0.20 to 0.44, p < 0.001). For episodes on MTD SLF, there was median (interquartile range (IQR)) reduction in VAS score of 2.8 cm (0–4.2) and 59% had at least a 2.6-cm reduction. These results are supportive of further evaluation of this protocol for acute analgesia of APC in a hospital setting and potentially for supervised home management.

Outcome of Severe Vaso Occlusive Crisis in Sickle Cell Disease Adults Admitted to Referral Centers in Africa and Europe. Preliminary Results from the Presev 2 Study

▪Introduction : Vaso-Occlusive Crisis (VOC), the most common manifestation of sickle cell disease (SCD), is the first cause of death, particularly when complicated by an acute chest syndrome (ACS).In the PRESEV1 study, we developed a predictive score of secondary ACS in SCD patient admitted in the hospital for VOC (AUC = 0.840 [95% CI: 0.780 - 0.900]), with a negative predictive value of 98.8% for the low level risk and a positive predictive value of 39.5%. The aim of the PRESEV-2 study is to validate the predictive score of ACS on adults and children with SCD in Europe and Africa. Herein we present preliminary data on 235 adults with a severe VOC included in 11 referral centers from 4 countries.Patients and Methods: We conduct an international multicenter prospective observational study. The primary outcome measure is the occurrence of an ACS. The ACS is defined as a new auscultatory abnormality (crepitation or bronchial breathing) OR the association of a new radiologic infiltrate AND chest pain or decreased breath sounds. Secondary outcome measures are length of hospitalization, transfusion, morphine consumption, mortality and hospitalization in intensive care unit. Inclusion criteria are: SS or S-b0 thalassemia patients, VOC admitted at the emergency unit (VOC is defined as pain or tenderness affecting at least one part of the body not attributable to other causes) that required hospitalization and opioids (level 3). Exclusion criteria are: no inaugural ACS, homeless patients, pregnancy, deprived of their liberty or under guardianship, unable to understand the purpose and conditions of carrying out the study, unable to give consent.Results : From march 2016 to june 2017, 112 adult patients were included in Africa and 122 adults in Europe. Patients in Africa were younger than in Europe with a mean age, respectively, of 26 ± 7 yrs and 29 ± 8 yrs (p=0.008). Sex ratio (M/F) in Africa was 0.84 and 0.95 in Europe. Use of hydroxyurea was significantly higher in Europe (65%) than in Africa (6%) (p<0.0001). The ACS incidence was significantly higher in Africa than in Europe, respectively 22% and 11% (OR=2.24; p=0.03), in both areas the time for ACS appearance was the second day. Transfusion was performed in 27% in Africa and 6% in Europe (p<0.001), ACS was the main cause of transfusion (53.3% in Africa and 62.5% in Europe). Patients with ACS were more transfused in Africa than in Europe, respectively 64% and 35.7% but the difference was not significant. Mortality was 3.6% in Africa and was not observed in Europe; circumstances of death were stroke (1), profound anemia (1), kidney failure (1) and VOC (1).Discussion and conclusion: Our preliminary results provide epidemiologic insights about VOC and ACS incidence in Europe and Africa. A better availability of HU treatment in Africa is a health care priority. DisclosuresGalactéros:Addmedica: Membership on an entity's Board of Directors or advisory committees. Bartolucci:GBT: Membership on an entity's Board of Directors or advisory committees; Fondation Fabre: Research Funding; Addmedica: Research Funding; Novartis US: Membership on an entity's Board of Directors or advisory committees.

Beneficial effects of adenotonsillectomy in children with sickle cell disease.

Tonsillectomy and adenoidectomy (T&A) is frequently performed in children with sickle cell disease (SCD). Our aim was to evaluate the impact of this surgery on overnight oxygenation and rates of complications in these patients.Children with SCD who underwent T&A between 2008 and 2014 in two tertiary hospitals were retrospectively evaluated. Overnight oximetry and admission rates due to vaso-occlusive pain episodes (VOEs) and acute chest syndrome (ACS) in the year preceding and following the surgery were compared.19 patients (10 males, 53%) with a median age of 6 years (range 3.5–8) were included. A significant increase of mean overnight arterial oxygen saturation measured by pulse oximetry (SpO2) (from 93±3.6% to 95.3±2.8%, p=0.001), nadir SpO2 (from 83.0±7.1% to 88±4.1%, p=0.004) and a reduction of 3% oxygen desaturation index (from a median value of 5.7 to 1.8, p=0.003) were shown. The mean annual rate of ACS decreased from 0.6±1.22 to 0.1±0.2 events per patient-year (p=0.003), while the mean cumulative rate of hospitalisations for all causes and the incidence of VOEs were not affected.T&A improved nocturnal oxygenation and was also associated with a reduction in the incidence of ACS at 1-year follow-up after surgery.

Salbutamol Worsens the Autonomic Nervous System Dysfunction of Children With Sickle Cell Disease.

BackgroundSickle cell disease (SCD) patients with asthma have an increased rate of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) episodes when compared to those without asthma. We hypothesized that either asthma diagnosis or bronchodilator treatment might aggravate SCD via their modulating effect on the autonomic nervous system (ANS).MethodsCross-sectional evaluation of heart rate variability (HRV) during pulmonary function tests, including salbutamol administration, in children with SCD receiving asthma treatment or not when compared to asthmatic children without SCD matched for ethnicity.ResultsSCD children with asthma (n = 30, median age of 12.9 years old) were characterized by a reduced FEV1/FVC ratio, an increased bronchodilator response, and a greater incidence of VOC and ACS when compared to SCD children without asthma (n = 30, 12.7 years). Children with asthma without SCD (n = 29, 11.4 years) were characterized by a higher exhaled NO fraction than SCD children. SCD children when compared to non-SCD children showed reduced HRV [total power, low (LF) and high (HF, vagal tone) frequencies], which was further worsened by salbutamol administration in all the groups: reduction in total power and HF with an increase in LF/HF ratio. After salbutamol, the LF/HF ratio of the SCD children was higher than that of the non-SCD children. The two groups of SCD children were similar, suggesting that asthma diagnosis per se did not modify ANS functions.ConclusionSCD children are characterized by impaired parasympathetic control and sympathetic overactivity that is worsened by salbutamol administration.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT04062409.

Blood transfusions for treating acute chest syndrome in people with sickle cell disease.

Sickle cell disease is an inherited autosomal recessive blood condition and is one of the most prevalent genetic blood diseases worldwide. Acute chest syndrome is a frequent complication of sickle cell disease, as well as a major cause of morbidity and the greatest single cause of mortality in children with sickle cell disease. Standard treatment may include intravenous hydration, oxygen as treatment for hypoxia, antibiotics to treat the infectious cause and blood transfusions may be given. This is an update of a Cochrane Review first published in 2010 and updated in 2016. To assess the effectiveness of blood transfusions, simple and exchange, for treating acute chest syndrome by comparing improvement in symptoms and clinical outcomes against standard care. We searched The Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. Date of the most recent search: 30 May 2019. Randomised controlled trials and quasi-randomised controlled trials comparing either simple or exchange transfusion versus standard care (no transfusion) in people with sickle cell disease suffering from acute chest syndrome. Both authors independently selected trials and assessed the risk of bias, no data could be extracted. One trial was eligible for inclusion in the review. While in the multicentre trial 237 people were enrolled (169 SCC, 42 SC, 15 Sβ⁰-thalassaemia, 11Sβ+-thalassaemia); the majority were recruited to an observational arm and only ten participants met the inclusion criteria for randomisation. Of these, four were randomised to the transfusion arm and received a single transfusion of 7 to 13 mL/kg packed red blood cells, and six were randomised to standard care. None of the four participants who received packed red blood cells developed acute chest syndrome, while 33% (two participants) developed acute chest syndrome in standard care arm. No data for any pre-defined outcomes were available. We found only one very small randomised controlled trial; this is not enough to make any reliable conclusion to support the use of blood transfusion. Whilst there appears to be some indication that chronic blood transfusion may play a roll in reducing the incidence of acute chest syndrome in people with sickle cell disease and albeit offering transfusions may be a widely accepted clinical practice, there is currently no reliable evidence to support or refute the perceived benefits of these as treatment options; very limited information about any of the potential harms associated with these interventions or indeed guidance that can be used to aid clinical decision making. Clinicians should therefore base any treatment decisions on a combination of; their clinical experience, individual circumstances and the unique characteristics and preferences of adequately informed people with sickle cell disease who are suffering with acute chest syndrome. This review highlights the need of further high quality research to provide reliable evidence for the effectiveness of these interventions for the relief of the symptoms of acute chest syndrome in people with sickle cell disease.

Impact of Asthma on Inpatient Outcome of Sickle Cell Crisis: A Population-Based Study

Introduction: Sickle cell disease (SCD) is one of the most common inherited hematological disorder in the United States. Sickle cell crisis is a common complication caused by excessive sickling of red blood cells, resulting in tissue ischemia. The frequency of such pain crisis, however, varies greatly among patients depending on disease control and other patient characteristics. Asthma is a common comorbidity in SCD patients which is associated with higher incidence of acute chest syndrome (ACS). However, the impact of asthma on short term outcome of acute sickle cell crisis remains unclear. Methods: We analyzed data from the National Inpatient Sample database. Data entries from year 2005 through 2014 were included. The presence of SCD, sickle cell crisis, ACS, asthma are identified using corresponding ICD codes. Data regarding demographic information, performed procedures, inpatient mortality, and length of stay are extracted and analyzed accordingly. Results: A total of 247,266 records were identified. The median age at admission was 26 years (interquartile range 18 - 37), with most patients being of African American origin (91.8%). A total of 16,828 (6.8%) patients presented with ACS, whereas 173,869 (70.3%) presented with non-ACS crisis. The remaining 56,569 (22.9%) patients were admitted for reasons other than sickle cell crisis, most commonly infection. Overall, 34,609 patients (14.0%) had asthma. Compared to patients without ACS, the incidence of asthma was significantly higher in patients with ACS (19.0% vs 13.6%, P&lt;0.001), whereas patients with non-ACS crisis had a similar incidence of asthma compared to those without sickle cell crisis (13.7% vs 13.5%, P=0.42). Asthma patients who presented with ACS exhibited a lower inpatient mortality (0.4% vs 1.1%, P&lt;0.001), as well as lower use of invasive mechanical ventilation (3.0% vs 4.1%, P=0.006). Similarly, in patients with non-ACS sickle cell crisis, asthma was associated with lower mortality (0.4% vs 0.2%, P&lt;0.001), lower use of invasive mechanical ventilation (0.4% vs 0.7%, P&lt;0.001), and lower frequency of transfusion (27.5% vs 31.9%, P&lt;0.001). Conclusion: Our study again demonstrated the association between asthma and ACS in SCD patients. Furthermore, asthma appears to be associated with superior outcome in both patients with ACS and non-ACS sickle cell crisis. Further studies are warranted to elucidate if asthma is associated with a milder form of sickle cell crisis which may correlate with the physiologic basis of these associations. Disclosures No relevant conflicts of interest to declare.

A Clinical Pathway Reduces Admissions for Vaso-Occlusive Pain in Sickle Cell Disease

Vaso-occlusive pain, a primary feature of sickle cell disease (SCD), leads to high acute care utilization, including frequent hospital admission. Though limited by a paucity of high quality evidence, guideline recommendations for the inpatient management of vaso-occlusive pain include rapid and continual pain assessment, early and individualized pain control, and intravenous fluid resuscitation (Yawn et. al. JAMA). However, research suggests that inpatient vaso-occlusive pain management varies significantly within institutions (Co et. al. Jt Comm J Qual Saf). Clinical pathways, which are a mechanism for increasing evidence-based management within an institution to standardize and improve quality of care, have been shown to reduce variation in vaso-occlusive pain management (Morrisey et. al. Pediatr Blood Cancer). We developed and implemented a clinical pathway for the management of vaso-occlusive pain using evidence-based interventions and expert consensus guidelines and hypothesized that it would improve clinical outcomes. The pathway was implemented as an electronic orderset and providers were educated on its use, which was voluntary. A retrospective chart review was then performed of adult patients admitted to Tulane Hospital for vaso-occlusive pain during one year prior to and following pathway implementation (344 total admissions, 112 total patients). Outcome measures were hospital length of stay (LOS), rate of 30-day readmission, median number of hospitalizations over one year prior to and after pathway implementation, and incidence of acute chest syndrome. Use of patient-controlled analgesia (PCA) and intravenous (IV) promethazine were used as surrogate measures of pathway utilization. Data were summarized in terms of medians (IRQ) for continuous outcomes (analyzed with the Wilcoxon Rank Sum Test) and percentages for categorical variables (analyzed with the Pearson's Chi-Squared Test). Following pathway implementation, we observed a statistically significant decrease in median number of admissions per patient (2 vs. 1, p=0.0027), an increase in PCA use (3.6% vs. 87.3%, p&lt;0.0001), and a decrease in IV promethazine use (78% vs. 36%, p&lt;0.0001). We observed trends toward decreased 30-day readmission (26% vs 20%, p=0.6105) and increased acute chest syndrome incidence (12% vs 18%, p=0.157), but these trends were not statistically significant. No effect was found on hospital LOS. Increased PCA use and decreased IV promethazine use suggest high pathway utilization among providers. We suspect the decrease in median admissions occurred due to improved discharge planning, primarily arranging close followup, given that lack of an outpatient provider is a known risk factor for hospital admission for vaso-occlusive pain (Brodsky Am J Med). Despite the reduction in median admissions, the observed decrease in readmission rates was not statistically significant, possibly due to insufficient study power. A nonsignificant change in readmission rates may also suggest that additional interventions need to be developed and evaluated to address socioeconomic barriers to outpatient healthcare access, such as financial insecurity and missed appointments, which have also been identified as modifiable risk factors for readmission (Cronin et. al. Hematology). The lack of an effect on hospital LOS may be due to the confounding variable of pain episode severity, which is difficult to control for given the absence of a biomarker for vaso-occlusive disease severity. Thus, we suggest 30-day readmission and total hospital days be used as primary outcome measures in future studies. By increasing evidence-based and expert consensus management of vaso-occlusive pain, clinical pathways may decrease hospital admissions for SCD patients. More research is needed to evaluate interventions to mitigate socioeconomic risk factors for readmission, which may then be incorporated into future clinical pathways to reduce readmission rates. Disclosures Debord: Stryker Orthopaedics: Consultancy, Other: ceives salary as well as is a stock holder with Stryker.

Evaluation of a Non-Parenteral Opioid Analgesia Protocol for Acute Sickle Cell Pain Episodes in Children.

We evaluated a protocol comprising intranasal diamorphine (IND) combined with oral short and modified-release morphine for children at the emergency department (ED) with acute painful episodes of sickle cell disease (SCD). In a retrospective audit of 83 episodes in 38 children, the mean time between arrival in the treatment area and the administration of IND was 10 min (range <5 min to 1.39 h). IND was administered in <5 min in 43 (51.6%), and in <20 min in 75 (90.4%) episodes. Persisting pain, requiring background analgesia with modified-release oral morphine, was required in 25 (30.1%) episodes. Inadequate control of pain requiring a switch to intravenous morphine PCA was required in eight episodes in four patients. Acute chest syndrome (ACS) developed in four of 83 episodes (4.8%, 95% CI 0.2–9.4%) and in four of 38 children (10.5%, 95% CI 0.7–20.5%). In conclusion, this protocol enabled the rapid administration of strong opioid analgesia in an ED setting, and may reduce the short and long-term adverse effects associated with parenteral opioids in children. There was no evidence of an increased incidence of ACS associated with use of oral morphine.

PS1520 INCENTIVE SPIROMETRY TO PREVENT ACUTE CHEST SYNDROME IN ADULTS WITH SICKLE CELL DISEASE; A MULTICENTER RANDOMIZED CLINICAL TRIAL

Background: Amongst patients with sickle cell disease (SCD) the leading cause of death is the acute chest syndrome (ACS). This pneumonia-like complication frequently occurs during or shortly after a vaso-occlusive crisis (VOC). In pediatric patients hospitalized for VOC, incentive spirometry has demonstrated to prevent the development of ACS. Aims: This study was designed to determine if a comparable effect of incentive spirometry can be demonstrated in adult patients with SCD. Furthermore, we aimed to validate the ability of the Bartolucci score to identify patients at risk of ACS and assessed the value of procalcitonin as a potential biomarker for ACS. In addition, clinical characteristics and laboratory results were determined to identify potential risk factors. Methods: In this multicenter prospective randomized trial, we included consecutive adult patients (≥18 yr) admitted for VOC presenting with chest or back pain above the diaphragm. Patients were randomly assigned to spirometry or control group. Patients presenting with ACS were excluded. A chest radiograph was performed 5 days after admission, or sooner when clinically indicated, in order to diagnose pulmonary abnormalities. ACS was defined as a new infiltrate/atelectasis combined with pulmonary symptoms. At presentation, procalcitonin plasma levels were assessed and the Bartolucci risk score was calculated to determine to the risk of developing ACS for each patient. In addition, clinical and laboratory parameters were compared between patients with and without ACS during admission. Results: In total 66 episodes of hospitalization for VOC in 48 patients were included. Median age was 26 years and 46 of the hospitalizations concerned patients with a severe genotype (HbSS/HbSβ0 thalassemia) versus 20 hospitalization with a mild genotype (HbSC/HbSβ+thalassemia). The overall incidence of ACS in this study cohort was 19.7%. In the spirometry group, ACS was diagnosed in 5/34 (14.7%) hospitalizations compared to 8/32 (25%) hospitalizations in the control group (OR 0.5 [0.15–1.8]; P = .293). Twelve of the 13 ACS episodes occurred in patients with a severe genotype. The Bartolucci risk score could be calculated for 50 hospitalizations. The scores area under the curve (AUC) was 0.747 (P = .013), with a negative predictive value (NPV) of 94% and a positive predictive value (PPV) of 31%. No difference in procalcitonin plasma levels were found between patients with and patients without ACS (0.52 ± 1.56 μg/ml versus 0.56 ± 1.44 μg/ml, respectively). At baseline, hemoglobin levels were significantly lower while LDH plasma levels, leukocyte and platelet counts were significantly higher in ACS hospitalizations as compared to non-ACS hospitalizations. Patients who developed ACS showed significantly more documented fever during admission (61.5% vs 17.0%) and a longer length of hospital stay (median 10.0 days vs 4.5 days). Summary/Conclusion: Incentive spirometry did not significantly reduce the development of ACS in this prospective study in adult patients with SCD admitted with VOC and pain above the diaphragm. Procalcitonin plasma levels and the Bartolucci score could not accurately identify patients that at risk to develop ACS, but a low score appeared to be a reliable tool to identify patients with a low risk of ACS.