Sputum IL-6 Level Is a Potential Predictor and Severity Marker of Acute Chest Syndrome in Sickle Cell Disease

Introduction Acute chest syndrome (ACS), one of the most severe and frequent complications of sickle cell disease (SCD) occurs in approximately 20% of vaso-occlusive crisis (VOC) episodes. While it is a major cause of mortality and morbidity, and is responsible for increased hospitalization lengths and costs, reliable predictive markers of ACS occurrence are still lacking. We recently reported dramatically high IL-6 levels in the sputum from children with SCD during ACS, and steady-state levels were also found to be positively correlated with the number of past ACS episodes.

Methods We conducted a prospective observational study between December 2020 and March 2022 in a French pediatric university-hospital SCD reference center and collected induced sputum during the first 48 hours of hospitalization for VOC, allowing us to compare sputum IL-6 levels between 11 children who developed secondary ACS and 18 children who did not. IL-6 levels were also measured in sputum samples collected during the first 72 hours of ACS in 26 patients between March 2018 and March 2022 in order to compare these levels according to several ACS severity markers.

Results Mean sputum IL-6 level measured in the first 48 hours of VOC was increased in patients who developed secondary ACS (1881.6 ± 3499.2 pg/mL) compared to patients who did not (5.4 ± 14.9 pg/mL, p=0.037). Moreover, among patients with VOC preceding ACS, mean sputum IL-6 level was higher (5131.3 ± 4322.2 pg/mL) in patients with chest pain and/or isolated respiratory symptoms (abnormal respiratory rate and/or desaturation without auscultatory or radiographic abnormality at this stage) compared to patients without (24.6 ± 57.9 pg/mL, p=0.003). Sputum IL-6 level measured in the first 72 hours of ACS was higher in patients with than without maximal oxygen need ≥ 2 L/min (8007.7 ± 9919.2 vs 5157.1 ± 11806.8 pg/mL, p=0.018), bilateral and/or extensive opacities on chest X-ray (8578.1 ± 11578.3 vs 880.3 ± 705.3 pg/mL, p=0.002), erythrocytapheresis requirement (12427.4 ± 11873.0 vs 4301.5 ± 9301.2 pg/mL, p=0.002), and mechanical (invasive and non-invasive) ventilation ≥ 5 days (9124.3 ± 12115.4 vs 1575.9 ± 1317.7 pg/mL, p=0.030).

Conclusions These findings suggest that sputum IL-6 level measured during VOC might be used as a predictive marker of ACS occurrence, especially in patients with chest pain and/or respiratory symptoms without an established diagnosis of ACS. Sputum IL-6 level could also be used at the onset of ACS as a marker of severity to help guide therapeutic strategies. Further studies are needed to develop predictive scores integrating this novel marker in the management of ACS.

de Montalembert:Addmedica: Membership on an entity's Board of Directors or advisory committees; Vertex: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Chhun:Lundbeck: Consultancy; Promise: Consultancy. Hermine:AB science: Current equity holder in private company; AB science, Inatherys, BMS, Novartis: Research Funding; AB science, BMS, Kyte Gilead: Honoraria.