Secretory phospholipase A2 (sPLA2) during vaso-occlusive pain episodes (VOE) and acute chest syndrome (ACS) in sickle cell disease (SCD): results from a prospective multi-center randomized controlled trial (RCT)
Noor Alzraikat, Rawan Korman, Fahd Ahmad, Gladstone Airewele, Bolanle Akinsola, Nitya Bakshi, David C Brousseau, Kathleen Brown, Andrew D Campbell, T Charles Casper, Todd P Chang, Corrie E Chumpitazi, Daniel Cohen, Keli D Coleman, Andrea T Cruz, Carlton Dampier, Christopher Denton, Angela Ellison, Melanie E Fields, Hailey Jensen, Elizabeth S Klings, Dunia Hatabah, Sara Leibovich, Derek Meyer, Seth Otto, Chris A Rees, Allison Remiker, Nidhi V Singh, Alexis A Thompson, Elliott Vichinsky, Anthony Villella, Bridget Wynn, Claudia R MorrisAbstract
Background
Acute chest syndrome (ACS) is a leading cause of morbidity and mortality in children with sickle cell disease (SCD), often developing during vaso-occlusive episodes (VOE) with minimal early signs. Most children present with a normal lung exam, making early detection challenging. sPLA2, a potent inflammatory mediator, rises before ACS onset and may help predict its development and severity. We aimed to assess sPLA2 as a marker for ACS risk and severity in SCD-VOE
Methods
Cross-sectional analysis of a multicenter, double-blind, phase-3 randomized controlled trial evaluating IV arginine therapy in patients aged 3–21 years with SCD-VOE at 10 US EDs, with 9 in the Pediatric Emergency Care Applied Research Network. sPLA2 levels at ED presentation, day 2, and discharge (DC) were analyzed by enzyme-linked immunosorbent assay. Levels ≥48 ng/mL were considered elevated. ACS severity was classified as mild (no oxygen/transfusion), moderate (oxygen/transfusion), or severe (BIPAP, intubation, PICU admission).
Results
Of 271 enrolled, 251 had sufficient samples for sPLA2 analysis. Demographics are shown in Table 1. Mean sPLA2 at ED presentation was 116±131 ng/mL; 60% had elevated levels. ACS occurred in 21%, with 18 diagnosed in the ED and 34 during hospitalization. Despite normal lung exam in 85%, 71% had elevated sPLA2. Patients diagnosed with ACS at any point had significantly higher sPLA2 at presentation compared to patients without ACS (152±146 vs 106±125 ng/mL, p = 0.01), and higher peak levels (263±169 vs164±164 ng/mL, p < 0.001). The sPLA2≥48 ng/mL cutoff yielded a sensitivity=85%, specificity=33%, NPV=89% and PPV=25% in predicting ACS. Mean sPLA2 at presentation was highest in those with ACS and positive chest x-ray (CXR) (198±182 ng/mL), followed by those with negative initial CXR who later developed ACS (128±120 ng/mL); both significantly higher than no ACS (106±125 ng/mL; p = 0.02). Levels rose further by Day 2 and remained elevated at DC (p < 0.001). Among ACS cases, 36% were mild, 46% moderate, and 17% severe with stepwise rise by severity. (severe 192±200 vs mild 122±140 ng/mL). Peak sPLA2 was higher in febrile vs afebrile patients (254±19 vs 120±10 ng/mL, p < 0.0001). ED sPLA2 correlated positively with heart rate (r = 0.42, p < 0.001), respiratory rate (r = 0.14, p = 0.02), white blood cells (r = 0.48, p < 0.001) and neutrophils (r = 0.40, p < 0.001), and negatively with lymphocytes (r=-0.42, p < 0.001) and hemoglobin/hematocrit (r=-0.26, p < 0.001).
Conclusions
sPLA2 is a promising biomarker for ACS risk and correlates with severity in children with SCD, with potential to enhance early diagnosis and guide management.