Immunopathology of Chronic Critical Illness in Sepsis Survivors: Role of Abnormal Myelopoiesis

Sepsis remains the single most common cause of mortality and morbidity in hospitalized patients requiring intensive care. Although earlier detection and improved treatment bundles have reduced in-hospital mortality, long-term recovery remains dismal. Sepsis survivors who experience chronic critical illness often demonstrate persistent inflammation, immune suppression, lean tissue wasting, and physical and functional cognitive declines, which often last in excess of 1 year. Older patients and those with preexisting comorbidities may never fully recover and have increased mortality compared with individuals who restore their immunologic homeostasis. Many of these responses are shared with individuals with advanced cancer, active autoimmune diseases, chronic obstructive pulmonary disease, and chronic renal disease. Here, we propose that this resulting immunologic endotype is secondary to a persistent maladaptive reprioritization of myelopoiesis and pathologic activation of myeloid cells. Driven in part by the continuing release of endogenous alarmins from chronic organ injury and muscle wasting, as well as by secondary opportunistic infections, ongoing myelopoiesis at the expense of lymphopoiesis and erythropoiesis leads to anemia, recurring infections, and lean tissue wasting. Early recognition and intervention are required to interrupt this pathologic activation of myeloid populations.