Sepsis with multiorgan dysfunction syndrome (MODS) is a major contributor to morbidity and mortality in intensive care units (ICU) across the globe. Search has been ongoing to identify novel biomarkers of sepsis and potential molecular targets for specific therapies that may halt the progression to MODS. Extracellular histones have been identified as one such potential target in the last one-and-a half decade [1, 2].

Histones are essential intracellular proteins that play an important architectural role by providing a scaffold to the nuclear chromatin. These are also one of the sites for epigenetic modification, a key mechanism for gene regulation. However, the past few years of research has revealed the dark side of histones—once released out of the cells, the histones act as potent damage-associated molecular patterns (DAMPs) and potential mediators of inflammation and MODS [1].

Critically ill patients with varying conditions like sepsis, trauma, and pancreatitis have extensive cell damage that results in release of histones into the circulation [3]. These circulating histones form a component of the neutrophil extracellular network (NET) that has a role in containing further dissemination of pathogens. However, histones can lead to activation of toll-like receptors and other mediators, and initiate a cascade of inflammation leading to tissue injury. H3 and H4 histones have been particularly incriminated in this pathway [1].

There is a paucity of studies on the role of histones in critically ill children with sepsis. One of the first studies in this area conducted at a tertiary care hospital in India by Sidana et al. warrants attention [4]. This prospective observational study aimed to measure circulating histone H3 levels in children with severe sepsis, and evaluate its role in the severity of illness and organ dysfunction. Surprisingly, in contrast to the results of adult studies, the median H3 levels were found to be similar in children with sepsis admitted to pediatric ICU and healthy controls. Additionally, no significant difference was found in H3 levels between day 1 and day 3 of PICU admission with respect to severity of illness, organ dysfunction, or mortality.

Whether the nonelevation of histones in this study population is due to the influence of histone inhibitors like activated protein C (APC), C-reactive protein (CRP), or heparin; or is it a false-negative result driven by the absence of a continuous monitoring of histone levels, remains to be seen. Despite the nondiscriminatory results obtained, this is an important study on a relatively untouched domain, paving the way for future studies on the role of circulating histones in pediatric sepsis.

It has been shown that histones initiate and disseminate intravascular coagulation (DIC) by a novel mechanism. Histones substitute factor Va in an alternative prothrombinase that generates thrombin without phospholipids to propagate DIC [5]. Circulating histones also bind to platelets and cause platelet aggregation in animal models. Association between high histone levels and thrombocytopenia has been shown in critically ill adult patients [6]. The study by Sidana et al. also demonstrated higher H3 levels in patients with thrombocytopenia, though the difference was not statistically significant [4].

Though a small sample size and single-center nature of this study may preclude generalizability of their findings, Sidana et al. have raised important questions for future research. If histones show promise as potential outcome predictors in pediatric sepsis, antihistone therapy in the form of neutralizing antibodies, histone-binding proteins, and heparin may have potential in treating this life-threatening condition [1, 2].