Pathophysiology of Compensatory Anti-Inflammatory Response Syndrome (CARS)
CARS represents a systemic immunosuppressive state characterized by global deactivation of immune function that develops as a counter-regulatory mechanism to excessive inflammation, fundamentally involving reprogramming of circulating leukocytes rather than complete immunosuppression. 1
Core Pathophysiologic Mechanism
The fundamental process involves a compartmentalized immune response where circulating leukocytes undergo functional reprogramming to silence acute proinflammatory genes while maintaining anti-infectious capabilities. 1 This is not a global immune defect but rather an adapted response aimed at restoring homeostasis after severe inflammatory insults. 2
Temporal Relationship with SIRS
- CARS develops concomitantly with or following the systemic inflammatory response syndrome (SIRS), representing the body's attempt to counterbalance overzealous inflammation from infectious (sepsis) or non-infectious triggers. 1, 3
- The timing and relative magnitude of CARS development profoundly impacts patient outcomes, with excessive or prolonged CARS leading to increased susceptibility to nosocomial infections. 2
Cellular and Molecular Mechanisms
Cytokine Production Cascade
Following initial proinflammatory cytokine release (TNF-α, IL-1, IL-6, IL-8), antiinflammatory cytokines are induced simultaneously, and when these become systemically dominant, CARS manifests clinically. 4
The specific sequence involves:
- Initial activation of inflammation-charged cells (macrophages, neutrophils, endothelial cells, fibroblasts) at injury sites produces proinflammatory cytokines that amplify through autocrine and paracrine mechanisms. 4
- Compensatory production of antiinflammatory cytokines (IL-4, IL-10) follows, and excessive production leads to systemic immunosuppression. 4, 3
Role of CCL2 and Neutrophils
CCL2 (CC chemokine ligand 2) produced by peripheral blood neutrophils from SIRS patients serves as a critical trigger for CARS manifestation by converting normal T cells into CARS effector cells capable of producing IL-4 and IL-10. 5
Key mechanistic details:
- Neutrophils from SIRS patients, but not normal neutrophils, produce CCL2 into culture fluids, which then drives T helper cell type 2 differentiation. 5
- CARS effector cells do not develop in neutrophil-depleted SIRS models or when anti-CCL2 antibodies are administered, confirming CCL2's essential role. 5
Functional Consequences
Leukocyte Reprogramming
Circulating leukocytes exhibit altered but not globally defective function, with suppression of certain acute inflammatory responses while maintaining some anti-infectious capabilities. 1 This represents functional reprogramming rather than complete immunologic failure.
Tissue-Level Effects
Within tissues, leukocytes remain primed or activated rather than immunosuppressed, demonstrating the compartmentalized nature of CARS. 1 This spatial heterogeneity explains why patients can simultaneously exhibit systemic immunosuppression yet maintain localized inflammatory responses.
Clinical Manifestations
When compensatory antiinflammatory reactions become sufficiently severe, CARS manifests clinically as anergy with markedly increased susceptibility to opportunistic infections. 4 This immunosuppressive state explains the enhanced vulnerability of intensive care patients to nosocomial infections observed in clinical practice. 1
Balance Between SIRS and CARS
The immune system is controlled by the balance between proinflammatory and antiinflammatory cytokine production, with patient outcomes determined by whether this balance tips toward excessive inflammation (SIRS) or excessive immunosuppression (CARS). 4, 2
Critical Pitfalls
Animal "two-hit" models demonstrating enhanced infection susceptibility after initial insult are highly dependent on experimental procedures and may not fully replicate human CARS pathophysiology. 1 Clinicians should recognize that CARS represents an adaptive rather than purely pathologic response, though excessive or prolonged CARS becomes maladaptive. 2
No standardized concrete diagnostic criteria for CARS exist, making it primarily a pathogenetic concept rather than a discrete clinical diagnosis. 4 Recognition requires integration of clinical context (recent severe inflammation or infection), evidence of immunosuppression (anergy, opportunistic infections), and when available, analysis of cytokine profiles and leukocyte surface molecules. 4