Immunological Endotyping of Chronic Critical Illness after Severe Trauma or Sepsis

ABSTRACT
Severe traumatic injury and sepsis are acute pro-inflammatory insults that trigger a “genomic and cytokine storm”
by the host innate immune response that can result in multiple organ failure (MOF). Whereas many patients
previously succumbed to early refractory MOF, progressive advancements in resuscitation and organ support
have led to an increasing number of patients surviving to enter a state of chronic critical illness (CCI), defined as
a patient with an extended intensive care unit (ICU) stay and non-resolving organ dysfunction. Currently, as
many as 25% of trauma and 40% of septic patients in the ICU develop CCI. In addition to a prolonged hospital
course, these ICU “survivors” have recurrent infections, are unable to physically rehabilitate, and are frequently
discharged to high-resource care facilities with dismal long-term outcomes. Two clinical manifestations dominate
the course of the CCI phenotype: 1) recurrent nosocomial and post-discharge infections indicative of a state of
chronic immunosuppression, and 2) acute muscle wasting, weakness and physical debilitation indicative of
persistent inflammation. There is an expanding body of evidence that an underlying syndrome of persistent
inflammation, immunosuppression and catabolism (PICS) is a key mechanistic driver of CCI. We hypothesize
that PICS is its own unique immunological endotype independent of the index event, and is the shared
mechanistic pathway leading from either trauma or sepsis to the clinical phenotype of CCI. This maladaptive
host response is sustained by the ongoing release of endogenous alarmins (DAMPs) associated with end-organ
injury, as well as microbial products from primary/secondary infections (PAMPs). This failure to return to
immunologic homeostasis also drives the persistent organ dysfunction seen in CCI. Muscle, being both clinically
relevant and understudied, serves as a novel area of study from the standpoint of inflammation-mediated end-
organ injury both as a driver of acute muscle wasting, as well as a potential source of ongoing alarmin production
and release. The goals for our laboratory’s research program over the next five years include the following: 1)
characterize the heterogeneity of the host response after severe trauma and sepsis by identifying distinct
endotypes based on immune trajectory over time, and whether these endotypes are modified by sex, age and
ethnicity/race; 2) determine if the PICS endotype is the common mechanistic pathway after trauma or sepsis to
the clinical development of CCI; and 3) determine whether muscle inflammation is both a component of chronic
end-organ injury, as well as a mediator of systemic inflammation through the systemic release of endogenous
alarmins. The proposed work is novel, innovative and vital. There are currently no therapeutic interventions
other than supportive therapies for the increasingly common condition of CCI after trauma or sepsis. We believe
that only through a complete understanding of the immunological endotype of CCI can effective therapeutic
interventions be designed. Focusing on interactions between host immunity and muscle inflammation is a novel,
under-explored area of research for the long-term management of severe trauma and sepsis.

Grant Number: 5R35GM142481-05
NIH Institute/Center: NIH
Principal Investigator: Scott Brakenridge