Global mortality from pediatric sepsis has been reported to be as high as 25% (Weiss et al. Am J Respir Crit Care Med. 2015;191:1147-1157). While it can occur early (less than three days) secondary to shock, it is more common for it to occur later from multiple organ failure (MOF), neurologic injury, single-organ respiratory failure, and/or nonseptic comorbidity (Weiss et al. Pediatr Crit Care Med. 2017;18:823-830). Because most of the later deaths occur secondary to MOF, research in adults and children has focused on the role inflammation pathobiology plays in the development of organ failure. Specifically, three inflammation phenotypes related to organ failure in sepsis have been found to occur both alone and in overlapping fashion: 1) immunoparalysis-associated MOF (IPMOF), 2) thrombocytopenia-associated MOF (TAMOF), and 3) sequential liver failure-associated MOF (SMOF).
Adult trials have studied therapies targeting the exact immunopathology related to these syndromes, and a pediatric study was conducted on the use of therapeutic plasma exchange in children with TAMOF (Fortenberry et al. Crit Care Med. 2019;47:e173-e181). Carcillo (Pediatr Crit Care Med. 2019. Epub ahead of print) conducted a prospective multicenter cohort study comparing mortality in children with severe sepsis and MOF who present with one of four phenotypes: IPMOF, TAMOF, SMOF, or MOF without any immunologic phenotypes. They also investigated the association between these phenotypes and macrophage activation syndrome, a potential common pathway of uncontrolled inflammation (Carcillo et al. Pediatr Crit Care Med. 2017;18:S32-S45).
Carcillo et al enrolled 401 children between the ages of 44 weeks gestational age and 18 years who presented with severe sepsis and who had indwelling catheters for drawing blood. Screening occurred twice per week to enroll only children who survived their initial presentation (greater than three days). The patients were then determined to have one of the four phenotypes based on specific clinical criteria and confirmatory biomarkers that were measured twice a week up to 28 days.
They found that, among the 401 patients with pediatric severe sepsis, 112 had single organ failure, 188 had MOF without any immunologic phenotype, and 101 had MOF with one of the immunologic phenotypes: 85 (21%) had IPMOF, 37 (9%) had TAMOF, and 7 (1.7%) had SMOF. They also found that those with the immunologic phenotypes (IPMOF, TAMOF, and SMOF) had higher mortality (20%, 43%, and 43% respectively), longer pediatric intensive care unit length of stay (17.9 days, 23 days, and 41 days respectively), and higher incidences of macrophage activation syndrome (17.6%, 37.8%, and 100%, respectively), than those without immunologic phenotypes. Other parameters, such as the need for extracorporeal membrane oxygenation or ventilation, were no different.
The implementation of initiatives to recognize and treat septic shock early with antibiotics and fluids has been found to significantly decrease mortality. However, recent studies have identified specific inflammation phenotypes that develop later and can lead to higher mortality. The development of treatment for each phenotype, targeting the specific defects in inflammation, will no doubt be the next step in managing these critically ill patients. Carcillo et al have provided the essential background data needed to develop these therapies via clinical trials.
Author of this installment of Concise Critical Appraisal:
Daniel E. Sloniewsky, MD, is an associate professor in the Division of Pediatric Critical Care Medicine in the Department of Pediatrics at Stony Brook Long Island Children’s Hospital. Dr. Sloniewsky is an editor of Concise Critical Appraisal.