Trends in blood transfusion, hydroxyurea use, and iron overload among children with sickle cell disease enrolled in Medicaid, 2004-2019.

BACKGROUND: There have been significant changes in clinical guidelines for sickle cell disease (SCD) over the past two decades, including updated indications for hydroxyurea, transfusions, and iron overload management. In practice however, there are few studies that examine SCD care utilization over time. METHODS: We conducted a serial cross-sectional cohort study of pediatric SCD patients from 2004 to 2019 using Georgia Medicaid claims data. For each year, we reported receipt of any transfusion, chronic transfusion, or three or more filled hydroxyurea prescriptions. For children receiving chronic transfusion (six or more annual transfusions), we evaluated iron overload diagnosis, monitoring, and chelation use. Among children with sickle cell anemia (SCA), we examined rates of transfusions and hydroxyurea use. The Cochran-Armitage test was used to assess trend. RESULTS: There were 5316 unique children 2-18 years old with SCD enrolled in Georgia Medicaid from 2004 to 2019. Children receiving any transfusion increased from 2004 to 2010, then stabilized. In SCA patients, chronic transfusions initially increased from 2004 to 2010, then stabilized from 2010 to 2019. For chronically transfused children, monitoring of iron burden and filled chelator prescriptions both increased significantly. Hydroxyurea use in SCA patients increased from 12% to 37%, with increases noted within each age group, most notably from 21% to 60% in the 13-18-year-old cohort. CONCLUSION: We demonstrated changes in SCD care utilization over time, including increased hydroxyurea use, changes in transfusion rates, and increased attention to iron overload management. While trends in clinical management do follow updates in treatment guidelines, there is still delayed and suboptimal uptake of guideline recommendations in pediatric SCD patients.

Are children with sickle cell disease at particular risk from the harmful effects of air pollution? Evidence from a large, urban/peri-urban cohort.

INTRODUCTION: Pathophysiologic pathways of sickle cell disease (SCD) and air pollution involve inflammation, oxidative stress, and endothelial damage. It is therefore plausible that children with SCD are especially prone to air pollution's harmful effects. METHODS: Patient data were collected from a single-center, urban/peri-urban cohort of children with confirmed SCD. Daily ambient concentrations of particulate matter (PM2.5 ) were collected via satellite-derived remote-sensing technology, and carbon monoxide (CO), nitrogen dioxide (NO2 ), and ozone from local monitoring stations. We used multivariable regression to quantify associations of pollutant levels and daily counts of emergency department (ED) visits, accounting for weather and time trends. For comparison, we quantified the associations of pollutant levels with daily all-patient (non-SCD) ED visits to our center. RESULTS: From 2010 to 2018, there were 17,731 ED visits by 1740 children with SCD (64.8% HbSS/HbSß0 ). Vaso-occlusive events (57.8%), respiratory illness (17.1%), and fever (16.1%) were the most common visit diagnoses. Higher 3-day (lags 0-2) rolling mean PM2.5 and CO levels were associated with daily ED visits among those with SCD (PM2.5 incident rate ratio [IRR] 1.051 [95% confidence interval: 1.010-1.094] per 9.4 µg/m3 increase; CO 1.088 [1.045-1.132] per 0.5 ppm). NO2 showed positive associations in secondary analyses; ozone levels were not associated with ED visits. The comparison, all-patient ED visit analyses showed lower IRR for all pollutants. CONCLUSIONS: Our results suggest short-term air pollution levels as triggers for SCD events and that children with SCD may be more vulnerable to air pollution than those without SCD. Targeted pollution-avoidance strategies could have significant clinical benefits in this population.

Impact of arginine therapy on mitochondrial function in children with sickle cell disease during vaso-occlusive pain.

Altered mitochondrial function occurs in sickle cell disease (SCD), due in part to low nitric oxide (NO) bioavailability. Arginine, the substrate for NO production, becomes acutely deficient in SCD patients with vaso-occlusive pain episodes (VOE). To determine if arginine improves mitochondrial function, 12 children with SCD-VOE (13.6 ± 3 years; 67% male; 75% hemoglobin-SS) were randomized to 1 of 3 arginine doses: (1) 100 mg/kg IV 3 times/day (TID); (2) loading dose (200 mg/kg) then 100 mg/kg TID; or (3) loading dose (200 mg/kg) followed by continuous infusion (300 mg/kg per day) until discharge. Platelet-rich plasma mitochondrial activity, protein expression, and protein-carbonyls were measured from emergency department (ED) presentation vs discharge. All VOE subjects at ED presentation had significantly decreased complex-V activity compared to a steady-state cohort. Notably, complex-V activity was increased at discharge in subjects from all 3 arginine-dosing schemes; greatest increase occurred with a loading dose (P < .001). Although complex-IV and citrate synthase activities were similar in VOE platelets vs steady state, enzyme activities were significantly increased in VOE subjects after arginine-loading dose treatment. Arginine also decreased protein-carbonyl levels across all treatment doses (P < .01), suggesting a decrease in oxidative stress. Arginine therapy increases mitochondrial activity and reduces oxidative stress in children with SCD/VOE. This trial was registered at www.clinicaltrials.gov as #NCT02536170.

The burden of respiratory syncytial virus infections among children with sickle cell disease.

BACKGROUND: Although respiratory syncytial virus (RSV) is the leading cause of pediatric lower respiratory tract infections, the burden of RSV in children with sickle cell disease (SCD) is unknown. METHODS: We conducted a retrospective, nested, case-control study of children with SCD <18 years who had respiratory viral panels (RVPs) performed at Children's Healthcare of Atlanta from 2012 to 2019. We abstracted the medical records to describe the demographics, clinical features, and outcomes of children who tested positive for RSV (cases) versus children who tested negative (controls). We calculated the annual incidence of RSV and related hospitalization rates with 95% confidence intervals (CIs) and used multivariate logistic regression to evaluate associations. RESULTS: We identified 3676 RVP tests performed on 2636 patients over seven respiratory seasons resulting in 219/3676 (6.0%) RSV-positive tests among 160/2636 (6.1%) patients. The average annual incidence of laboratory-confirmed RSV infection among children with SCD was 34.3 (95% CI 18.7-49.8) and 3.8 (95% CI 0.5-7.0) cases per 1000 person-years for those <5 years and 5-18 years, respectively. The RSV-related hospitalization rate for children <5 years was 20.7 (95% CI 8.5-32.8) per 1000 person-years. RSV-positive cases were significantly younger than RSV-negative patients (3.8 years vs 7.6 years, P < .001). Of RSV-positive cases, 22 (13.8%) developed acute chest syndrome and nine (5.6%) required intensive care, which was not significantly different from RSV-negative children with SCD. CONCLUSION: RSV infections are common in children with SCD with higher burden in younger patients. RSV is associated with considerable morbidity, including higher rates of hospitalization compared to the general population.

Microbiology and radiographic features of osteomyelitis in children and adolescents with sickle cell disease.

BACKGROUND: Children with sickle cell disease (SCD) are at increased risk for bacterial infections including osteomyelitis (OM). Fever and bone pain, key presenting symptoms of OM, are common in SCD, thus complicating diagnosis. We reviewed presentation, imaging features, and microbiologic etiologies of children with SCD treated for OM. METHODS: The comprehensive SCD clinical database of children and adolescents with SCD followed at a single, large tertiary pediatric center were searched to identify all diagnostic coding for potential cases of osteomyelitis in children ages 6 months to 21 years from 2010 to 2019. Medical charts were reviewed to determine OM diagnostic probability based on radiographic and microbiologic findings and the duration of prescribed antibiotic treatment for OM. RESULTS: Review of 3553 patients (18 039 person-years) identified 20 episodes of probable OM in 19 children. Magnetic resonance imaging (MRI) findings to support OM were definitive in 4/19 (21%), probable in 10/19 (53%), suspected in 5/19 (26%), based on blinded radiologist review. Blood and/or operative cultures from bone and tissue debridement isolated Salmonella species in seven (35%) cases and methicillin-susceptible Staphylococcus aureus (MSSA) in two (10%). Six patients received antibiotic treatment prior to obtainment of cultures. Of culture-positive cases, MRI findings for OM were definitive or probable in six of nine (67%), suspected in three of nine (33%). CONCLUSIONS: Distinction between OM and sickle-related bone infarct or vasoocclusion is difficult based on imaging findings alone. Early attainment of blood and operative cultures increases the likelihood of identifying and adequately treating OM.

Influenza vaccine effectiveness and disease burden in children and adolescents with sickle cell disease: 2012-2017.

BACKGROUND: Data are limited on the burden of influenza and seasonal influenza vaccine effectiveness (VE) in children with sickle cell disease (SCD). METHODS: We used a prospectively collected clinical registry of SCD patients 6 months to 21 years of age to determine the influenza cases per 100 patient-years, vaccination rates, and a test-negative case-control study design to estimate influenza VE against medically attended laboratory-confirmed influenza infection. Influenza-positive cases were randomly matched to test-negative controls on age and influenza season in 1:1 ratio. We used adjusted logistic regression models to compare odds ratio (OR) of vaccination in cases to controls. We calculated VE as [100% × (1 - adjusted OR)] and computed 95% confidence intervals (CIs) around the estimate. RESULTS: There were 1037 children with SCD who were tested for influenza, 307 children (29.6%) had at least one influenza infection (338 infections, incidence rate 3.7 per 100 person-years; 95% CI, 3.4-4.1) and 56.2% of those tested received annual influenza vaccine. Overall VE pooled over five seasons was 22.3% (95% CI, -7.3% to 43.7%). Adjusted VE estimates ranged from 39.7% (95% CI, -70.1% to 78.6%) in 2015/2016 to -5.9% (95% CI, -88.4% to 40.4%) in the 2016/17 seasons. Influenza VE varied by age and was highest in children 1-5 years of age (66.6%; 95% CI, 30.3-84.0). Adjusted VE against acute chest syndrome during influenza infection was 39.4% (95% CI, -113.0 to 82.8%). CONCLUSIONS: Influenza VE in patients with SCD varies by season and age. Multicenter prospective studies are needed to better establish and monitor influenza VE among children with SCD.

Health literacy and knowledge of chronic transfusion therapy in adolescents with sickle cell disease and caregivers.

BACKGROUND: Patients with sickle cell disease (SCD) may require chronic transfusion therapy (CTT) for prevention of stroke or other complications. Limited health literacy (HL) is common and is associated with poor health-related knowledge and outcomes in chronic disease. We sought to assess HL and transfusion knowledge in patients with SCD on CTT and their caregivers. METHODS: A cross-sectional study of patients was conducted in outpatient hematology clinics. Forty-five pairs of adolescent patients and caregivers and 20 caregivers of pre-adolescent patients completed the Newest Vital Sign HL assessment and answered questions assessing SCD and transfusion knowledge. Community-level median income and unemployment rates were estimated from Census data. We computed the correlation of HL with knowledge and compared each to Census variables, payor status, educational attainment, and stroke. RESULTS: HL was inadequate in 22 (34%) caregivers and 31 (69%) adolescents. Adequate caregiver HL was associated with higher educational attainment but not community-level socioeconomics or payor status. Mean knowledge score was lower in adolescents than in caregivers and correlated with age in adolescents (r = 0.42, P = .004). HL correlated with knowledge (r = 0.46, P < .0001). There were no significant correlations of HL or knowledge between adolescents and their caregivers. Neither HL nor knowledge was associated with prior stroke. The greatest knowledge was demonstrated for iron overload and SCD genotype, whereas knowledge gaps existed in alloimmunization, indication for CTT, and SCD curative therapy. CONCLUSIONS: Enhanced educational resources in transfusion therapy, alloimmunization, and curative therapy are needed for patients with SCD and caregivers of all HL levels.

Incidence of invasive Haemophilus influenzae infections in children with sickle cell disease.

BACKGROUND: Children with sickle cell disease (SCD) are at increased risk for invasive infection with encapsulated bacteria. Antibiotic prophylaxis and immunizations against Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) have decreased the overall incidence of invasive infections and have shifted distribution of serotypes causing disease toward those not covered by immunizations. We sought to determine the current incidence of invasive H. influenzae infections in children with SCD and to describe the clinical features and management of these infections. METHODS: Microbiology reports of a large pediatric tertiary care center were reviewed to identify all isolates of H. influenzae detected in sterile body fluid cultures from January 1, 2010 to December 31, 2017. Results were compared with the center's comprehensive clinical database of all children with SCD to identify all cases of children ages 0 to18 years with SCD with invasive H. influenzae disease for the same time period. RESULTS: We captured 2444 patients with SCD, with 14,336 person-years. There were eight episodes of H. influenzae bacteremia in seven children with SCD (five type f, two non-typable, one type a). Most episodes (7 of 8) were in children < 5 years. The incidence rate of invasive H. influenzae in SCD was 0.58/1000 person-years for ages 0 to 18 years and 1.60/1000 person-years for children age < 5 years. There were no deaths from H. influenzae infection. CONCLUSIONS: In the era of universal antibiotic prophylaxis and immunization against Hib, invasive H. influenzae disease due to nonvaccine serotypes remains a risk for children with SCD, particularly those under five years of age.

Losartan therapy decreases albuminuria with stable glomerular filtration and permselectivity in sickle cell anemia.

Sickle cell nephropathy begins with hyperfiltration and microalbuminuria and may progress to renal failure. The aim of this study was to determine the effects of losartan on glomerular function and albumin excretion in sickle cell anemia (SCA). Individuals with SCA on hydroxyurea with persistent albuminuria were enrolled in a 1-year study of losartan. Glomerular filtration rate (GFR) measured by iohexol clearance, albumin excretion rate (AER), and fractional clearance of dextran were assessed at baseline, short-term (1-2month), and long-term (≥12month) intervals. Twelve subjects (6 microalbuminuria, 6 macroalbuminuria) completed short-term studies; 8 completed long-term studies. Baseline GFR was 112ml/min/1.73m2 (71-147ml/min/1.73m2). AER decreased significantly at the short-term (median decrease -134 mcg/min, p=0.0063). GFR was not significantly-different at short-term or long-term intervals. Dextran clearance improved for diameters smaller than albumin (<36Å) but not larger sizes. Losartan therapy for ≥1year in sickle nephropathy results in lower albumin excretion with stable GFR. Filtration of neutral molecules ≥36Å was not changed by losartan, suggesting that the effect of losartan is a mechanism other than alteration of glomerular filtration size-selectivity.

Hydroxyurea effectiveness in children and adolescents with sickle cell anemia: A large retrospective, population-based cohort.

The clinical efficacy of hydroxyurea in patients with sickle cell anemia (SCA) has been well established. However, data about its clinical effectiveness in practice is limited. We evaluated the clinical effectiveness of hydroxyurea in a large pediatric population using a retrospective cohort, pre-post treatment study design to control for disease severity selection bias. The cohort included children with SCA (SS, Sß0 thalassemia) who received care at Children's Healthcare of Atlanta (CHOA) and who initiated hydroxyurea in 2009-2011. Children on chronic transfusions, or children with inadequate follow up data and/or children who had taken hydroxyurea in the 3 years prior were excluded. For each patient healthcare utilization, laboratory values, and clinical outcomes for the 2-year period prior to hydroxyurea initiation were compared to those 2 years after initiation. Of 211 children with SCA who initiated hydroxyurea in 2009-2011, 134 met eligibility criteria. After initiation of hydroxyurea, rates of hospitalizations, pain encounters, and emergency department visits were reduced by 47% (<0.0001), 36% (P = 0.0001) and 43% (P < 0.0001), respectively. Average hemoglobin levels increased by 0.7 g/dl (P < 0.0001). Hydroxyurea effectiveness was similar across gender, insurance types and age, although there was a slightly greater reduction in hospitalizations in younger children. Am. J. Hematol. 92:77-81, 2017. © 2016 Wiley Periodicals, Inc.

Changes in urine albumin to creatinine ratio with the initiation of hydroxyurea therapy among children and adolescents with sickle cell disease.

BACKGROUND: Renal damage is a progressive complication of sickle cell disease (SCD) that begins in childhood and may progress to renal failure and early mortality in 12% of adults with hemoglobin SS (HbSS) SCD. Early sickle nephropathy is characterized by hyperfiltration and microalbuminuria; therefore, urine albumin to creatinine ratio (ACR) is an effective screening tool for its detection. PROCEDURE: This study investigated the effect of hydroxyurea (HU) therapy on urine ACR levels among children with SCD. A retrospective review was conducted to identify all patients with HbSS or HbSß0 thalassemia of age 7-18 years who began HU therapy in 2011-2013; a control group of patients not on HU were matched by age and baseline hemoglobin. All urine ACR measurements ≤24 months prior to and ≥24 months after HU initiation were recorded. RESULTS: There were 63 eligible patients on HU and 13 (25%) with albuminuria prior to HU initiation. Among those with baseline albuminuria, the median ACR was 96 mg/g prior to HU, 39 mg/g at 1 year (P = 0.02), and 25 mg/g at 2 years (P = 0.03). Albuminuria normalized in 37.5% (6/16) after 1 year and 61% (8/13) after 2 years of HU therapy. Among those without albuminuria prior to HU, 13% (6/47) developed albuminuria during HU therapy. Sixteen percent (13/80) of control patients had albuminuria in the beginning of study period, which normalized in 15% (two of 13) of patients at 1-year follow up. CONCLUSION: Introduction of HU is associated with significant decreases in urine ACR in children with SCD and albuminuria.

Impact of red blood cell alloimmunization on sickle cell disease mortality: a case series.

BACKGROUND: Although red blood cell (RBC) transfusion represents an integral component of sickle cell disease (SCD) care, transfusion support for some patients can result in alloimmunization to RBC antigens. Alloimmunized patients with SCD appear to experience worse survival compared to nonalloimmunized patients. While this difference in mortality may in part be due to underlying immunologic differences related to disease severity, it may also reflect direct clinical consequences of RBC alloimmunization. Alloimmunized patients have an increased risk of serious hemolytic transfusion reactions (HTRs) and may not receive adequate RBC transfusion support due to lack of compatible RBC units. CASE REPORT: This study reports on five RBC alloimmunized patients with SCD who died, to illustrate the concept that RBC alloimmunization itself contributes to premature death. RESULTS: The clinical course for each of the reported patients provides insight into the direct and indirect consequences of RBC alloimmunization, where patients experienced delayed HTRs or did not receive needed RBC transfusions. CONCLUSION: Future work examining the clinical impact of RBC alloimmunization should not only consider HTRs but should also address the potential consequences associated with difficulties in obtaining compatible blood.

Improved Splenic Function After Hematopoietic Stem Cell Transplant for Sickle Cell Disease.

BACKGROUND: Splenic dysfunction is a significant complication of sickle cell disease (SCD). Hematopoietic stem cell transplant (HSCT) is a proven cure for SCD; however, its long-term effect on splenic function is not well characterized. PROCEDURE: We conducted a retrospective cohort study of pediatric patients who had HSCT for SCD at two transplant centers. (99m) Tc liver-spleen (LS) scans were blindly reviewed and classified as demonstrating absent, decreased, or normal splenic uptake. RESULTS: Considering all engrafted nonsplenectomized Hb SS and Sß(0) -thalassemia patients with LS scans available, at a median of 2.0 years post-HSCT (range 1.0-9.3 years) eight of 53 (15%) had normal, 40 of 53 (75%) decreased, and five of 53 (9%) absent splenic uptake. More patients had splenic uptake after HSCT: pre-HSCT 14/38 (37%) versus post-HSCT 34/38 (89%), P < 0.0001. Older age at HSCT was associated with worse splenic function post-HSCT (median age at HSCT for absent uptake 16.6 years vs. present uptake 8.0 years, P = 0.030). Extensive chronic GVHD was also more common in patients with absent splenic uptake compared to patients with present uptake (absent 40% vs. present 6%, P = 0.064). CONCLUSIONS: HSCT significantly improves splenic function for most pediatric patients with SCD, but older patient age at time of HSCT and extensive chronic GVHD appear to be risk factors for poor post-HSCT splenic function.

Therapeutic phlebotomy is safe in children with sickle cell anaemia and can be effective treatment for transfusional iron overload.

Serial phlebotomy was performed on sixty children with sickle cell anaemia, stroke and transfusional iron overload randomized to hydroxycarbamide in the Stroke With Transfusions Changing to Hydroxyurea trial. There were 927 phlebotomy procedures with only 33 adverse events, all of which were grade 2. Among 23 children completing 30 months of study treatment, the net iron balance was favourable (-8·7 mg Fe/kg) with significant decrease in ferritin, although liver iron concentration remained unchanged. Therapeutic phlebotomy was safe and well-tolerated, with net iron removal in most children who completed 30 months of protocol-directed treatment.

Biomarkers of splenic function in infants with sickle cell anemia: baseline data from the BABY HUG Trial.

We evaluated spleen function in 193 children with sickle cell anemia 8 to 18 months of age by (99m)Tc sulfur-colloid liver-spleen scan and correlated results with clinical and laboratory parameters, including 2 splenic biomarkers: pitted cell counts (PIT) and quantitative Howell-Jolly bodies (HJB) enumerated by flow cytometry. Loss of splenic function began before 12 months of age in 86% of infants in association with lower total or fetal hemoglobin and higher white blood cell or reticulocyte counts, reinforcing the need for early diagnosis and diligent preventive care. PIT and HJB correlated well with each other and liver-spleen scan results. Previously described biomarker threshold values did define patients with abnormal splenic function, but our data suggest that normal spleen function is better predicted by PIT of ≤1.2% or HJB ≤55/10(6) red blood cells and absent function by PIT ≥4.5% or HJB ≥665/10(6). HJB is methodologically advantageous compared with PIT, but both are valid biomarkers of splenic function. This trial was registered at www.clinicaltrials.gov as #NCT00006400.

Sex and frequency of pain episodes are associated with acute pain trajectories in adolescents with sickle cell disease.

Introduction/Objective: Acute pain episodes are a major cause of health care utilization (HCU) in sickle cell disease (SCD), and adolescence is associated with increased pain frequency. We sought to determine whether there were differences in acute pain trajectories by sex and frequency of pain episodes among adolescents with SCD who presented to the emergency department (ED). Methods: Retrospective review of electronic health records from a large, multicampus, pediatric SCD program. Results: Of the 113 adolescents included, the mean age was 16.6 (SD 0.9), 41.6% (n = 47) were female, 77.9% (n = 88) had HbSS or a similarly severe genotype, and 43.4% (n = 49) had ≥3 episodes of HCU for pain, which we defined as having history of high HCU for pain. Those with a history of high HCU for pain had higher mean pain intensity scores at presentation, were more likely to receive either intravenous or intranasal opioids, and were more likely to be hospitalized. In a model considering the 3-way interaction between sex, history of high HCU for pain, and follow-up time from the initial pain intensity score, adjusted for opioid per kilogram body weight, and prescription of hydroxyurea, adolescent female patients with high HCU for pain had the slowest decline in pain intensity during treatment for acute pain in the ED. Conclusion: Sex and history of high HCU for pain are associated with acute pain trajectories in adolescents with SCD presenting to the ED. These novel findings should be confirmed in future prospective studies.

Pneumococcal infections in children with sickle cell disease before and after pneumococcal conjugate vaccines.

Children with sickle cell disease (SCD) are at increased risk of invasive pneumococcal disease (IPD). Over 25 years, the Georgia Emerging Infections Program/Centers for Disease Control and Prevention Active Bacterial Core Surveillance network identified 104 IPD episodes among 3707 children with hemoglobin SS (HbSS) or HbSC aged <10 years, representing 6% of IPD in Black or African American children residing in Metropolitan Atlanta (reference population). Children with IPD and HbSS/SC were older than those with IPD in the reference population (P < .001). From 1994-1999 to 2010-2018, IPD declined by 87% in children with HbSS aged 0 to 4 years, and by 80% in those aged 5 to 9 years. However, IPD incidence rate ratios when comparing children with SCD with the reference population increased from 20.2 to 29.2 over these periods. Among children with HbSS and IPD, death declined from 14% to 3% after 2002, and meningitis declined from 16% to 8%. Penicillin resistance was more prevalent in children with SCD before 7-valent pneumococcal conjugate vaccine (PCV7) licensure. After 2010, all IPD serotypes were not included in the 13-valent PCV (PCV13). Within 3 years of vaccination, the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) against non-PCV13 serotypes included in PPSV23 plus 15A/15C was 92% (95% confidence interval, 40.8- 99.0, P = .014; indirect-cohort effect adjusted for age and hydroxyurea). PPSV23 would cover 62% of non-PCV13 serotype IPD in children with SCD, whereas PCV15, PCV20, and PCV21/V116 (in development) could cover 16%, 51%, and 92%, respectively. Although less frequent, IPD remains a life-threatening risk in children with SCD. Effective vaccines with broader coverage could benefit these children.

Refining the value of secretory phospholipase A2 as a predictor of acute chest syndrome in sickle cell disease: results of a feasibility study (PROACTIVE).

Acute chest syndrome (ACS) is defined as fever, respiratory symptoms and a new pulmonary infiltrate in an individual with sickle cell disease (SCD). Nearly half of ACS episodes occur in SCD patients already hospitalized, potentially permitting pre-emptive therapy in high-risk patients. Simple transfusion of red blood cells may abort ACS if given to patients hospitalized for pain who develop fever and elevated levels of secretory phospholipase A2 (sPLA2). In a feasibility study (PROACTIVE; ClinicalTrials.gov NCT00951808), patients hospitalized for pain who developed fever and elevated sPLA2 were eligible for randomization to transfusion or observation; all others were enrolled in an observational arm. Of 237 enrolled, only 10 were randomized; one of the four to receive transfusion had delayed treatment. Of 233 subjects receiving standard care, 22 developed ACS. A threshold level of sPLA2 ≥ 48 ng/ml gave optimal sensitivity (73%), specificity (71%) and accuracy (71%), but a positive predictive value of only 24%. The predictive value of sPLA2 was improved in adults and patients with chest or back pain, lower haemoglobin concentration and higher white blood cell counts, and in those receiving less than two-thirds maintenance fluids. The hurdles identified in PROACTIVE should facilitate design of a larger, definitive, phase 3 randomized controlled trial.