FUNCTIONAL IMMUNOPHENOTYPING FOR PRECISION THERAPIES IN SEPSIS

Abstract

Sepsis remains a significant cause of morbidity and mortality worldwide. Although many more patients are surviving the acute event, a substantial number enters a state of persistent inflammation and immunosuppression, rendering them more vulnerable to infections. Modulating the host immune response has been a focus of sepsis research for the past 50 years, yet novel therapies have been few and far between. Although many septic patients have similar clinical phenotypes, pathways affected by the septic event differ not only between individuals but also within an individual over the course of illness. These differences ultimately impact overall immune function and response to treatment. Defining the immune state, or endotype, of an individual is critical to understanding which patients will respond to a particular therapy. In this review, we highlight current approaches to define the immune endotype and propose that these technologies may be used to "prescreen" individuals to determine which therapies are most likely to be beneficial.

Fig. 1.. The case for endotyping.

A, A novel therapy (drug A) is being tested in a cohort of septic patients. Each patient in the cohort belongs to one of three groups (endotypes), but they are indistinguishable based on clinical characteristics alone. Patients with endotype 1 will benefit from therapy A; patients with endotype 2 will experience harm from therapy A, and patients with endotype 3 will see no effect from therapy A. B, If patients are randomized to a therapeutic arm based on clinical characteristics alone, the overall benefit or harm will be obscured. C, If endotypes are defined prior to randomization, the relationship between endotype and effective therapy will be much clearer.

Fig. 2.. Giving the right drug to the right patient at the right time.

A, Sepsis is characterized by an early hyperinflammatory phase, with immune suppression beginning in the latter portion of the acute phase and (potentially) lasting for months afterwards (chronic phase). A patient’s endotype is dynamic over time and cannot be determined by clinical characteristics alone. Knowing a patient’s endotype at the time a treatment is administered is critical to choosing appropriate timing for a given therapy. B, Consider the example of an immunostimulant: if given during the hyperinflammatory phase (t₁), the effect will be amplification of the hyperinflammation with worsening early shock and organ dysfunction. However, if given after resolution of the acute inflammatory phase when the immunosuppression is most prominent (t₂), the result will be a quicker restoration of immune balance and potentially less long-term immune dysfunction.

Fig. 3.. A model for using endotyping to guide therapy.

Consider a scenario where there are two clinically identical patients with sepsis and three potential immunomodulatory therapies. When blood samples are drawn on hospital day 1 and stimulated with LPS, patient 1 has spontaneous TNF-α production and an augmented TNF-α response to LPS compared to a healthy control (e.g., a hyperinflammatory endotype). In contrast, patient 2 shows reduced TNF-α production after LPS stimulation (e.g., immune-suppressed endotype). However, later in his hospital course (day 5), patient 1 has transitioned to an immune-suppressed endotype, no longer producing TNF-α spontaneously and demonstrating a blunted response to LPS. Drug A potentiates the response to TNF-α, restoring a “healthy” response in immune-suppressed patient, but may exacerbate the inflammatory response in a hyperinflammed patient and is therefore less likely to benefit patient 1 on hospital day 1 but may benefit him on hospital day 5. Similarly, drug A may benefit patient 2 early in his hospital course, restoring a more appropriate immune response. In contrast, drug B blunts the response to TNF-α and is therefore likely to benefit patient 1 only on hospital day 1 and is unlikely to benefit patient 2. Drug C appears to stimulate the response to LPS in septic patients but not healthy controls; it will therefore likely benefit patient 1 only later in his course (hospital day 5) as well as patient 2 on hospital day 1. When patients are clinically similar, defining a patient’s endotype using rapid ex vivo assessment of immune function represents may help stratify therapeutic options.