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) Free

Background: Acute chest syndrome (ACS) is the leading cause of morbidity and mortality in children with SCD, often developing during vaso-occlusive episodes (VOE) with minimal or no early clinical signs. Most children present with a normal lung exam, making prompt detection challenging. Secretory phospholipase A₂ (sPLA₂), a potent inflammatory mediator, has been shown to rise prior to ACS onset and may aid in predicting its development and severity in the acute setting.

Objective: Assess sPLA₂ as a marker for ACS risk and severity in patients with SCD hospitalized for VOE

Methods: Cross-sectional analysis of data from a multicenter, double-blind, placebo-controlled, phase-3 RCT (NCT04839354) evaluating intravenous arginine therapy in patients aged 3–21 years with SCD-VOE conducted at 10 pediatric emergency departments (ED) in the US, endorsed by the Pediatric Emergency Care Applied Research Network (PECARN). Plasma sPLA₂ levels at ED presentation, hospital day 2, and on the day of hospital discharge (DC) were analyzed via enzyme-linked immunosorbent assay (ELISA). sPLA₂ level ≥48 ng/mL is considered elevated based on an established SCD-specific cutoff. ACS severity was classified as mild (no oxygen/transfusion), moderate (required oxygen/transfusion), or severe (required BIPAP, intubation, or PICU admission). Vital signs and clinical labs were analyzed.

Results: Overall 271 patients were randomized, and 251 had sufficient blood samples for sPLA₂ assessment at presentation and were included in the analysis (mean age 14±4 years; 53% male, 73% HbSS/Sβ°, and 75% on hydroxyurea). Mean plasma sPLA₂ level at ED presentation was 116±131 ng/mL, with elevated levels ≥48 ng/mL in 60% of patients with VOE. ACS was diagnosed in 21% of patients enrolled (n=52), with 18 diagnosed in the ED and 34 were later diagnosed with ACS during admission. Although the majority of ACS patients (85%) had a normal respiratory exam at ED presentation, 71% had elevated sPLA₂ levels ≥48 ng/mL. Patients diagnosed with ACS at any point during enrollment (n=52) had significantly higher mean plasma sPLA₂levels (n=52) at ED presentation compared to patients with no ACS (n=199) (152±147 vs 107±126 ng/mL, p=0.01). Moreover, patients with ACS exhibited significantly higher mean peak plasma sPLA₂compared to subjects who never developed ACS (263±169 vs164±164 ng/mL respectively, p<0.001). The SCD-specific cutoff of sPLA₂≥48 ng/mL yielded a sensitivity=85%, specificity=33%, NPV=89% and PPV=25% in predicting ACS. When comparing serial plasma sPLA₂levels, mean sPLA₂ at ED presentation was highest among patients presenting with ACS (198±182 ng/mL, n=18) with a positive chest x-ray (CXR) in the ED, followed by those with a negative CXR in ED who developed ACS during hospitalization (128±120 ng/mL, n=34). Notably, both groups demonstrated significantly higher sPLA₂ levels at presentation compared to patients with No-ACS (106±125 ng/mL; p=0.02). This trend persisted throughout the hospital course, with mean sPLA₂ levels continuing to rise by Day 2 and remaining significantly elevated at DC in both ACS groups compared to No-ACS (p<0.001). In the ACS cohort, 19 (36%) cases were classified as mild, 24 (46%) as moderate, and 9 (17%) were severe. Plasma sPLA₂ levels at ED presentation increased with ACS severity, showing a stepwise rise from mild to moderate to severe cases. Subjects with severe ACS had a mean sPLA₂ level that is 1.5-fold higher than those with mild disease (192±200 vs 122±140 ng/mL respectively) though not significant with the small sample size. A total of 16 patients presented to the ED with fever and 60 patients developed fever during their hospital stay (total n=76). Peak plasma sPLA₂levels were significantly higher in febrile (n=76) versus afebrile (n=175) patients (254±19 vs 120±10 ng/mL, p<0.0001). ED plasma sPLA₂levels correlated positively with several vital signs and clinical laboratory parameters including 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). Moreover, sPLA₂correlated negatively with lymphocytes (r=-0.42, p<0.001) and hemoglobin/hematocrit (r=-0.26, p<0.001).

Conclusions: sPLA₂ remains promising as a biomarker for ACS risk. We show it is also associated with ACS severity in children with SCD, supporting its potential role in acute clinical decision-making. Combined with other predictors, it may enhance early diagnosis and guide management.