Inflammatory Response and Anti-Inflammatory Treatment in Persistent Inflammation-Immunosuppression-Catabolism Syndrome (PICS)

Abstract

Many patients now survive their initial critical events but subsequently develop chronic critical illness (CCI). CCI is characterized by prolonged hospital stays, poor outcomes, and significant long-term mortality. The incidence of chronic critical illness (CCI) is estimated to be 34.4 cases per 100,000 population. The incidence varies significantly with age, peaking at 82.1 cases per 100,000 in individuals aged 75-79. The one-year mortality rate among CCI patients approaches 50%. A subset of these patients enters a state of persistent inflammation, immune suppression, and ongoing catabolism, a condition termed persistent inflammation, immunosuppression, and catabolism syndrome (PICS) in 2012. In recent years, some progress has been made in treating PICS. For instance, recent advancements such as the persistent expansion of MDSCs (myeloid-derived suppressor cells) and the mechanisms underlying intestinal barrier dysfunction have provided new directions for therapeutic strategies, as discussed below. Persistent inflammation, a key feature of PICS, has received comparatively little research attention. In this review, we examine the potential pathophysiological changes and molecular mechanisms underlying persistent inflammation and its role in PICS. We also discuss current therapies about inflammation and offer recommendations for managing patients with PICS.

Keywords: anti-inflammatory therapy; chronic critical illness; immunosuppression; inflammation; persistent inflammatory-immunosuppressive-catabolic syndrome.

Figure 1

Athophysiological mechanisms of persistent inflammation in PICS. This figure illustrates the pathophysiological mechanisms underlying Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) following severe trauma. Key risk factors for PICS include severe trauma, advanced age (≥65 years), and severe acute pancreatitis (SAP). In patients with PICS, ongoing catabolic processes result in malnutrition, muscle wasting, and immune suppression. Concurrently, muscle breakdown products and exogenous pathogens stimulate the release of damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), perpetuating a chronic inflammatory state. SAP or trauma can also drive the migration of granulocytes from the bone marrow to sites of injury or infection, promoting the expansion of myeloid cells. This immune suppression contributes to recurrent infections and inflammatory responses, leading to further depletion of energy and nutrient stores. (Created with BioRender.com).

Figure 2

Summary diagram of potential anti-inflammatory treatments for Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS). This diagram illustrates a multifaceted approach to anti-inflammatory therapy for PICS, incorporating immunomodulation, nutritional support (amino acids, Omega-3), gastrointestinal regulation (probiotics), antioxidants, and MDSC inhibitors (microRNA, sildenafil, IL-1R/IL-6R antagonists). It also features cell death pathway inhibitors (RIPK1, RIPK3, MLKL) aimed at reducing inflammation. Additionally, the therapy includes immunomodulatory cytokines (GM-CSF, IFN-γ, IL-7, IL-15), cell therapy and gene editing related to the regulatory T Cells, and early exercise therapy as preventative measures. Collectively, these strategies represent comprehensive interventions at the nutritional, immune, and molecular levels to enhance anti-inflammatory effects.