Abstract
Dysregulated host immune responses to infection often occur, leading to sepsis, multiple organ failure, and death. Some patients rapidly recover from sepsis, but many develop chronic critical illness (CCI), a debilitating condition that impacts functional outcomes and long-term survival. The “Persistent Inflammation, Immunosuppression, and Catabolism Syndrome” (PICS) has been postulated as the underlying pathophysiology of CCI. We propose that PICS is initiated by an early genomic and cytokine storm in response to microbial invasion during the early phase of sepsis. However, once source control, antimicrobial coverage, and supportive therapies have been initiated, we propose that the persistent inflammation in patients developing CCI is a result of ongoing endogenous alarmin release from damaged organs and loss of muscle mass. This ongoing alarmin and danger-associated molecular pattern signaling causes chronic inflammation and a shift in bone marrow stem cell production toward myeloid cells, contributing to chronic anemia and lymphopenia. We propose that therapeutic interventions must target the chronic organ injury and lean tissue wasting that contribute to the release of endogenous alarmins and the expansion and deposition of myeloid progenitors that are responsible for the propagation and persistence of CCI.
Highlights
Normal protective host responses to infection often become excessive, resulting in the systemic inflammatory response syndrome (SIRS) that can cause a clinical trajectory of refractory shock, fulminant multiple organ failure (MOF), and early in-hospital death
myeloid-derived suppressor cell (MDSC) are a heterogeneous population of immature myeloid cells that accumulate during pathologic conditions such as cancer or sepsis [23]
We propose, based on new information, that the underlying pathobiology which drives PICS and critical illness” (CCI) is a maladaptive self-perpetuating cycle of persistent inflammation involving reduced host protective immunity, continued organ injury and its sequelae, loss of muscle mass and function, changes in bone marrow (BM) function predominated by “emergency myelopoiesis,” and failure of metabolic adaptation (Figure 2) [22, 24, 27, 32, 33]
Summary
Normal protective host responses to infection often become excessive, resulting in the systemic inflammatory response syndrome (SIRS) that can cause a clinical trajectory of refractory shock, fulminant multiple organ failure (MOF), and early in-hospital death Until recently, this was a common clinical scenario (occurring in >35% of those with sepsis), and a tremendous effort has been directed at understanding and treating this response. Sepsis survivors who developed CCI were significantly older and had more hospital-acquired (rather than communityacquired) infections [27] These subjects exhibited persistent inflammation, as demonstrated by elevated plasma cytokine concentrations, and increased immunosuppressive proteins (sPD-L1 or IL-10) (Figure 4) [27].
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