Chronic Critical Illness and the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome

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.

Phenotypic heterogeneity by site of infection in surgical sepsis: a prospective longitudinal study

“…They represent a major challenge based on their high frequency and poor outcomes. They also best represent the clinical phenotype of what we call PICS-CCI [24,25]. The challenge will be to identify early those abdominal sepsis patients (roughly one third) who have a likelihood to progress into CCI and thus potentially benefit from novel multimodality interventions directed at the underlying pathobiology of PICS.…”

“…The clinical component of this translational research program was a 5-year prospective longitudinal cohort study which collected the data included in this manuscript. Other reports from this team science effort indicate that PICS-CCI in surgical ICU sepsis and trauma patients is a valid concept [25][26][27].…”

Influencia de la infección SARS-CoV-2 sobre enfermedades neurodegenerativas y neuropsiquiátricas: ¿una pandemia demorada?

“…En este sentido se sabe que las respuestas inmunes desreguladas tras infecciones pueden persistir en lo que se ha denominado Sindrome de inflamación-inmunosupresion y catabolismo persistente (SIICP). Se ha propuesto que esta situación inmunológica específica es iniciada por una tormenta de citoquinas durante fases agudas de cuadros infecciosos de forma similar a como ocurre en la Enfermedad Covid19 y es el resultado de la liberación continua de unas moléculas a las que se ha llamado "alarminas endógenas" o "patrones moleculares asociados al peligro" (DAMPs) por parte de los órganos dañados que provoca una situación de inflamación crónica sistémica y un cambio en la producción de células madre de médula ósea hacia células mieloides, lo que contribuye a la anemia crónica y la linfopenia [16].…”

General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections

“…fibrinogen, and plasminogen activator inhibitor-1. During the acute-phase reaction, myelopoiesis is favored at the expense of both lymphopoiesis and hematopoiesis, explaining in part the persistent lymphopenia and anemia of critical illness (18). Substance P is an example of an effector of the sensory afferent nervous system, while hypothalamic corticotropin releasing hormone (CRH), vasopressin, cortisol, the catecholamines (norepinephrine and epinephrine), and peripheral neuronal CRH represent effectors of the stress system [reviewed in (19)].…”

“…Independently of age and comorbidities, patients with elevated circulating biomarkers of inflammation and hemostasis at hospital discharge have persistent elevation over time with increased risk for cardiovascular events, re-hospitalizations, and 1-year mortality (41,45,46). "Persistent Inflammation, Immunosuppression, and Catabolism Syndrome" (PICS) has been postulated as the underlying pathophysiology of chronic critical illness (CCI) (18,47). About 50% of sepsis patients have a debilitating condition characterized by a self-perpetuating cycle of persistent low-grade systemic inflammation mimicking chronic stress (elevated cortisol) (44,48,49), glucocorticoid resistance, altered hemostasis (50,51), mitochondrial dysfunction (52,53), and accelerated inflamm-aging (9,54), with increased risk for chronic inflammatory systemic diseases (7,55).…”