Biomarkers in Pediatric ARDS: Future Directions

Orwoll, Benjamin E.; Sapru, Anil

Some of the most intensely studied protein biomarkers of critical illness belong to the large family of inflammatory cytokines dubbed interleukins (ILs). Many of the members of this family have been studied in other forms of critical illnesses, some of which are recognized ARDS risk factors, such as sepsis, trauma, or postoperative states. IL-1 and its antagonist IL-1 receptor antagonist (IL-1ra) have been found in BAL fluid and correlate with ARDS severity and outcome in adults (74) . In children, IL-1 has not been correlated with ARDS, though it significantly elevated among a cohort of children with severe acute respiratory syndrome (SARS) (16) . IL-6 is another important inflammatory cytokine, and elevated plasma and BAL fluid levels have been associated with ARDS in adults (74) (75) (76) (77) as well as plasma in children and neonates with RDS (14, 18, 19) . In studies of children with burn-related inhalation injury and severe influenza, IL-6 levels were associated with increased mortality (14, 17) , in agreement with adult data (78) . IL-1 and IL-6 levels in BAL fluid were also both found to be elevated in premature babies with RDS and were correlated with the development of chronic lung disease (CLD) (56, 58, 59) . As a biomarker of response to therapy, IL-6 was recently found to decrease in response to glucocorticoid (GC) therapy in a randomized trial of GC therapy in children (20) . The relationship of the inflammatory cytokine response to ventilation strategies was also demonstrated in the landmark ARDSNet trial of low-tidal-volume ventilation, where IL-6 and IL-8 levels were observed to decrease in the low-tidalvolume group compared with the controls (79, 80) . IL-8, another inflammatory cytokine, is elevated in the plasma and BAL fluid of adults with ARDS and is associated with organ failure and mortality in adults (75, 77, 81) . In children with ARDS and RDS, the plasma and BAL fluid IL-8 levels are elevated (21, 58) , but the relationship with outcomes remains less clear. However, in a cohort that included critically ill children with influenza and 27% ARDS prevalence, non-survivors had dramatically higher plasma IL-8 concentrations than survivors, suggesting a possible role as a prognostic factor in pARDS more generally (14) . IL-10 is a major anti-inflammatory cytokine, and elevations in plasma and BAL fluid have been associated with the development of ARDS as well as with ARDS mortality in adults (80, 82, 83) . It appears that an early rise in IL-10 at the onset of ARDS is followed by normalization of levels over the first 21 days of illness (74) , and this pattern was also seen in children with ARDS, both with and without steroid therapy (16, 20) . IL-10 is elevated in newborns with RDS (22), independent of gestational age, and has also been associated with increased development of ARDS and increased mortality among pediatric burn patients with inhalation injury (17) . Several other cytokines of the IL family, including IL-4, IL-7, and IL-13 (each in pediatric burn patients) (17), IL-12 (RDS) (22) , and IL-17 (pARDS) (20) , have been associated with the outcomes from lung injury in individual studies. Comparing nonsurvivors to survivors from the previously mentioned cohort of severe influenza patients, the investigators also found significant elevations in granulocyte-macrophage colony-stimulating factor, interferon-inducible protein 10, monocyte chemotactic protein 1, and macrophage inflammatory protein 1α (14) , thoug