For more than half a century clinicians and researchers have debated if patients benefit from or are harmed by adjunctive corticosteroid administration for septic shock (1–3). It is likely that a truly definitive answer to this question remains elusive because of the heterogeneity of the sepsis population (4,5). Accordingly, the article by Klowak et al (6) published in this issue of Pediatric Critical Care Medicine is of interest, as it reports results of a retrospective descriptive investigation examining the association of corticosteroid administration with 28-day mortality for a cohort of children with septic shock exhibiting differential baseline mortality risk assessed by PEdiatRic SEpsis biomarkEr Risk modEl (PERSEVERE)-II, a biomarker-based stratification tool for (pediatric) sepsis. This article (6) and the corresponding secondary analysis of a multicenter observational study is notable in three regards: 1) It provides an excellent example of an iterative, rigorous clinical research program; 2) It escalates concern regarding knee-jerk prescription of corticosteroids for pediatric sepsis; and 3) It encourages development of real-time protein and messenger RNA (mRNA) quantification tools to facilitate clinical decision making around corticosteroid prescription for septic shock.

It is refreshing but not unexpected to read another legacy chapter emanating from the Hector Wong Laboratory and the Genomics of Pediatric Septic Shock Investigators. Previous research infrastructure from these investigators supporting the current investigation is substantial, with some highlights noted below. On reviewing this timeline of sepsis biomarker studies targeting enrichment, prediction and prognostication (7), post-graduate trainees and junior faculty might reflect on the consistent research focus as well as the patience and determination required for a successful research enterprise, beginning with the realization that what seems like one well-defined project may unfold as a life-time discovery quest. A successful research program may encounter explosive, paradigm-shifting revelations, but typically it progresses iteratively, deliberately, one step building on another.

2009: Differential gene expression among children with septic shock: Common patterns of up-regulated gene expression correspond to inflammation and innate immunity, while repressed expression is common among genes related to adaptive immunity (8).

2009: Among 6,934 differentially regulated genes, pediatric septic shock subclasses are discovered through genome-wide expression profiling. Phenotypic analyses reveal that children in subclass (endotype) A are younger, with higher illness severity and risk of mortality compared with children in Subclasses (endotypes) B and C (9).

2010: Development of clinically feasible and robust stratification strategy for children with septic shock. Expression mosaics representing 100 class-defining genes are generated using the Gene Expression Dynamics Inspector (10). Visual analogs of pediatric sepsis gene expression subclasses become obvious, even to the casual observer.

2012: Twelve gene expression probes reflect readily measured serum proteins with biological plausibility for possible association septic shock outcomes (11). PERSEVERE reliably identifies children at risk of death and greater illness severity from pediatric septic shock. PERSEVERE-I biomarkers include C-C motif chemokine ligand 3, interleukin-8, heat shock protein 70 kDa 1B, granzyme B, and matrix metallopeptidase 8.

2014: Updated PERSEVERE-I estimates mortality probability reliably in a heterogeneous test cohort of children with septic shock and provides information beyond a physiology-based scoring system (12).

2014: Pediatric septic shock is generally characterized by early repression of genes corresponding to the adaptive immune system. Corticosteroid administration to children with septic shock is associated with additional repression of adaptive immunity-related genes, compared with patients who do not receive corticosteroids (13).

2015: After adjusting for illness severity (Pediatric Risk of Mortality score), chronic comorbid conditions, and age, adjunctive corticosteroid administration is independently associated with an increased risk of mortality among subjects in gene expression subclass (endotype) A (odds ratio [OR], 4.1; 95% CI, 1.4–12.0; p = 0.011), but not for the subjects in subclass (endotype) B (14).

2016: PERSEVERE-II: Addition of platelet count to PERSEVERE-I improves utility as a sepsis prognostic enrichment tool (15).

2017: Improved risk stratification in pediatric septic shock employing combined protein and mRNA biomarkers, PERSEVERE-XP (reflecting the integration of PERSEVERE with gene expression data), significantly improves on PERSEVERE and implicates tumor suppressor protein p53 in the pathophysiology of septic shock (16). Subsequent simplification of the septic shock endotyping utilizing four genes (17).

2019: Prospective clinical testing and experimental validation of the PERSEVERE risk stratification model (18).

2020: PERSEVERE demonstrates modest performance for estimating hospital mortality in an external cohort of children with community-acquired septic shock (19). Additionally, PERSEVERE biomarkers, measured early during the acute phase of septic shock, exhibit utility for estimating risk of persistent, serious health-related quality of life deterioration at 3 months following hospital admission among children surviving sepsis, albeit with a different decision tree than the original PERSEVERE mortality prediction model.

2021: External corroboration that adjunctive corticosteroid therapy may be harmful among adult patients with septic shock and endotype A (20).

Multiple previous observational studies have reported no benefit or potential harm associated with prescription of corticosteroids for pediatric septic shock; reviewed (2). In a previous analysis of 496 children with septic shock, Klowak et al (6) did not identify an association between corticosteroid administration and mortality when stratifying by PERSEVERE-I (21). As outlined above, however, the PERSEVERE-II biomarker, with inclusion of platelet count, has improved prognostic accuracy compared with PERSEVERE-I. Using this improved sepsis prognostication tool, the investigators now report that children with a low baseline mortality risk by PERSEVERE-II did not exhibit increased mortality associated with corticosteroid exposure (OR, 0.20; 95% CI, 0.02–1.73; p = 0.15). Alternatively, children with a high baseline mortality risk by PERSEVERE-II who were administered corticosteroids exhibited a higher odds of death (OR, 4.10; 95% CI, 1.70–9.86; p = 0.002), complicated course (OR, 7.02; 95% CI, 3.16–15.59; p < 0.001), more organ dysfunctions (OR, 1.46; 95% CI, 1.26–1.66; p < 0.001), and fewer ICU-free days (p < 0.0001). In a similar fashion, as outlined above, children and adults with endotype A, particularly those who persist with endotype A, and are treated with corticosteroids, exhibited a marked increased risk for complicated intensive care course and mortality (14,22). Both PERSEVERE-II and pediatric sepsis endotypes are undergoing prospective validation in a contemporary pediatric septic shock cohort as one aim of the Stress Hydrocortisone In Pediatric Septic Shock (NCT03401398) investigation. The notion that a trial of corticosteroid for septic shock “can’t hurt” is naive. Regrettably, what clinicians do not know can hurt (the patient).

Biological science has positioned care providers at the brink of precision/personalized medicine. Hematology-oncology can cite numerous (impressive, humbling) applications of this technology (23), but the story of PERSEVERE and endotypes in (pediatric) septic shock is one small but compelling example for critical care practitioners. Applied science with oversight from engineering needs to translate laboratory investigations and retrospective database interrogations like that of Klowak et al (6) into tools for real-time clinical decision support in the ICU. Rapid turnaround protein (24) and mRNA (25) quantification methodologies are already realities. Beyond basic scientists unraveling the genetics and molecular biology of critical illness and its treatment, such tools must represent research priorities in order for the field of critical care to embrace the future.

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