Current updates in precision and personalized medicine in sepsis and trauma

Abstract

Precision and personalized medicine remain an elusive but illustrious goal in the realm of critical care, particularly in the areas of trauma and sepsis. These aims specifically refer to data gathering, interpretation, and treatment application on an individualized basis in the clinical care of patients. Until now, personalized medicine has mainly remained focused on genetics and epigenetic phenomena and has propelled clinical care forward, especially in the field of oncology. Advances in technology and methodology continue to proliferate in early-phase research, and some of these advancements are well poised to break into the clinical sphere of critical care. Here, we describe 2 topics at the forefront of investigation with potent and imminent potential for clinical application.

Extracellular Vesicles

Extracellular vesicles (EVs), and exosomes in particular, are a novel area of research with significant potential for applications in personalized medicine. Cells are known to secrete precious biomolecular cargo within these endosome- or plasma membrane-derived blebs. The cargo includes lipids, protein, as well as messenger RNA and micro RNAs (miRNAs), which are known to modify the expression of destination protein at the transcript level. Exosomes have been identified as biomarkers and potential targets for intervention in various clinical conditions, including critical illness, trauma (including burns), and sepsis.^1-3

More specifically, exosomes mediate some of the complex multisystem pathophysiology that account for the acute inflammatory state in trauma and critically ill patients. Injured tissues release damage-associated molecular patterns via exosomes to initiate the inflammatory cascade utilizing multiple mechanisms within the innate immune system, including transcription modification by way of nuclear factor kappa B, macrophage polarization, and the release of proinflammatory mediators interleukin (IL) 1B, IL-6, and tumor necrosis factor alpha (TNF-α), among many others.^1,2,4 The implication of activating these systems is an altered cytokine milieu, which may predispose some individuals to septic complications related to trauma and critical illness.

Although sepsis is known to be a well-characterized barrage of inflammatory cytokines in response to an infectious process, it remains difficult to manage in its most flagrant forms. These nanoparticles may prove helpful. Mainstay management requires infectious source control. The body’s innate immune response creates a proinflammatory state, which, in excess, causes hypotension and the complications of shock, including organ failure. Effective regulators of this system may be modified by EV cargo, including miRNA. In one study, miRNA was delivered to macrophages via B cell exosomes and demonstrated decreased levels of lipopolysaccharide (LPS)-induced TNF-α with lower cytotoxicity compared to standard non-liposomal transfection agents. In this same study, exosomes were shown to be an effective method of delivery of a specific anti-inflammatory miRNA in a mouse model.⁵ Separately, it has been shown that curcumin delivery via exosomes mitigates LPS-induced septic shock response in an animal model, providing evidence for the efficacy and safety of such methods.^5,6 Furthermore, specific anti-inflammatory miRNAs are promulgated as a result of exosome treatment in both macrophages and mouse models.⁷ Macrophage polarization is affected by miRNA, specifically miR-155, which is derived from M1 macrophages during proinflammatory states.⁸ Its expression is Induced by TNF-α and interferon beta. These findings may prove useful in mitigating or modulating the massive inflammatory response to infectious sources in the setting of sepsis.

Another effect of EVs is coagulopathy, which can be induced by trauma or sepsis alone. In sepsis, higher concentrations of EVs coincide with proinflammatory and procoagulant states and contribute to deranged fibrinolysis.⁹ In septic states, EV cargo includes membrane-exposed tissue factor phosphatidylserine, a potent initiator of disseminated intravascular coagulation.^9,10 EVs derived from red blood cells in stored blood activate endothelial cells as well as thrombin generation, even in the absence of tissue factor.¹⁰ In vivo, this has been replicated in healthy mice receiving exosomes from trauma and hemorrhagic shock mice, which then develop pulmonary endotheliopathy and coagulopathy as demonstrated by intravascular fibrin deposition.¹¹ These effects persist across organ systems, as demonstrated by brain-derived EVs from septic rats inducing systemic coagulation.¹²

There is much excitement about these extracellular carriers, not just as membrane-bound messengers but also as biomarkers with utility in stratifying injury and illness severity with clinical predictive power. In fact, the number and concentration of EVs have been shown to correlate with injury severity in burn patients.¹ The EVs in this study demonstrated higher levels of C-reactive protein, which was associated with a dysregulated postinjury inflammatory state and a longer length of hospital stay in burn patients. In regard to trauma, exosomes mediate the hematopoietic response to critical illness. Plasma-derived exosomes suppress hematopoietic progenitor cell growth in trauma patients compared to clinical controls.¹³ These trauma-induced exosomes may prove predictive in triaging critically ill trauma patients.

As for potential for clinical applications, exosome delivery has been shown to be safe and effective in various models of illness and disease due to their low immunogenicity.¹⁴ Extensive review of various methods of delivery demonstrates high efficiency with transfection with the caveat of the possible adverse side effects of transfection agents.¹⁴

Microbiome

The intestinal microbiome maintains a critical role in overall homeostasis and is also at the forefront of potential for clinical interventions in sepsis and critical care. Although this is recognized, the complex interplay of commensal organisms with the host intestinal milieu and its multiorgan systems evades much scientific illumination. The most obvious role in trauma, critical care, and sepsis is susceptibility to loss of mucosal integrity, which facilitates dysbiosis (which is often a decrease in diversity) and leads to increased gut permeability.

Homeostasis depends on the symbiosis of intestinal microbiota and its human host. Sepsis and its complications are associated with dysbiosis. These associations have been well described. DNA sequencing is used to characterize the diversity, richness, and relative ratios of intestinal flora. A balance of commensal organisms facilitates the maintenance of the gut barrier. This is best evidenced by the pathologic overgrowth of certain species in inflammatory states in human patients, including the increased quantity of staphylococcus and pseudomonas with smaller quantities of the obligate anaerobes that normally inhabit the intestinal wall, especially Bifidobacterium and Lactobacillus.¹⁵ Commensal organisms maintain the intestinal barrier, preventing pathogens from violating the brush border of intestinal epithelium in the setting of flourishing beneficial intestinal flora. Sepsis is associated with dysregulated tight junction proteins, including occludins, claudins, and junctional adhesion molecules.

Some of the most enticing data on clinical applications comes from studies involving fecal microbiota transplant (FMT) in both sepsis and trauma. As the field has garnered interest in traumatic neurology injury, it has been shown that a mouse model of spinal cord injury regains the function and integrity of the gut barrier after FMT. Animal studies demonstrate a role for FMT in sepsis, possibly due to the restoration of appropriate proportions of commensal organisms, which may help restore the integrity of the intestinal wall. This may prove useful as both a marker and management in trauma and sepsis for restoring intestinal homeostasis.¹⁶ Currently, FMT has only been used clinically in the management of Clostridium difficile refractory to antibiotic treatment and inflammatory bowel disease. To date, there are no published clinical trials of FMT in sepsis; however, a few published clinical cases report some beneficial results with apparent safety. In one study, a young woman with septic shock and copious liquid stools received a donor fecal transplant via post-pyloric gastrointestinal tract with improvement in signs of septic shock and a profound decrease in stool output by 7 days. The microbiome characteristics of her stool output were marked by a decrease in opportunistic proteobacteria phyla.¹⁷ Similarly, 2 older male patients critically ill in septic shock with watery diarrhea were given FMT and showed a decrease in stool output as well as opportunistic proteobacteria. This correlated with decreased levels of serum IL-6, C-reactive protein, and erythrocyte sedimentation rate.¹⁸ In a 3-patient case series, critically ill patients with profuse watery diarrhea and septic shock were given FMT, and 1 of 3 showed full resolution of watery stool and sepsis. This patient’s stool sample demonstrated a shift in phyla, demonstrating the removal of Haeomphilus parainfluenzae and concomitant increase in commensal Bacteroidetes, corroborating the notion that effective FMT necessitates an appropriate redistribution of opportunistic versus commensal phyla.¹⁹

In conclusion, research in the domains of the intestinal microbiome and exosomes is ripe for clinical application of personalized and precision medicine in the care of trauma patients and sepsis. Exosomes display an aptitude for predictive power, patient stratification, and even intervention delivery. The effects of these disease processes on the microbiome and measures to mitigate them provide avenues for intervention that could be applied clinically using FMT to restore the microbial milieu and intestinal integrity. Given these advances in research, their clinical applications will prove promising in trauma and sepsis.