Risk factors, biomarkers, and mechanisms for persistent inflammation, immunosuppression, and catabolism syndrome (PICS): a systematic review and meta-analysis

Abstract

Introduction: Persistent inflammation, immunosuppression, and catabolism syndrome (PICS) has been proposed as an endotype of chronic critical illness (CCI). The aim of this systematic review is to synthesise the available evidence of risk factors, biomarkers, and biological mechanisms underlying PICS.

Methods: MEDLINE, CENTRAL, and EMBASE were searched on June 2, 2023. Our population of interest was adult intensive care unit survivors. The exposure group was patients with PICS and the comparator group was patients with no PICS, CCI, or rapid recovery. Mean differences were pooled for each biomarker using a random effects DerSimonian-Laird method. Risk of bias assessment was done using the Newcastle-Ottawa Scale.

Results: Six papers were included. Five were single-centre retrospective cohort studies, and one was a prospective cohort study, with sample sizes ranging from 22 to 391 patients. Two studies showed an increased incidence of PICS with age, and two studies showed an association between PICS and Charlson Comorbidity Index scores. PICS was associated with requiring mechanical ventilation in four studies. Meta-analysis showed a 34.4 mg L^-1 higher C-reactive protein (95% confidence interval [CI] 12.7-56.2 mg L^-1; P<0.01), a 4.4 g L^-1 lower albumin (95% CI 0.5-8.3 g L^-1; P<0.01), and a 0.36×10⁹ L^-1 lower lymphocyte count (95% CI 0.25-0.47×10⁹ L^-1; P=0.01) in the PICS compared with the non-PICS group. There are a large variety of other potential biomarkers but limited validation studies. The overall quality of evidence is limited, and these results should be interpreted accordingly.

Conclusions: While older patients and those with co-morbidities could be at greater risk for PICS, acquired risk factors, such as injury severity, are potentially more predictive of PICS than intrinsic patient characteristics. There are many potential biomarkers for PICS, but limited validation studies have been conducted. Persistent myeloid-derived suppressor cell expansion, the continual release of danger-associated molecular patterns and pathogen-associated molecular patterns propagating inflammation, and bioenergetic failure are all mechanisms underlying PICS that could offer potential for novel biomarkers and therapeutic interventions.

Clinical trial registration: International Prospective Register of Systematic Reviews (PROSPERO; CRD42023427749).

Keywords: PICS; catabolism; chronic critical illness; immunosuppression; intensive care; persistent inflammation; post-intensive care syndrome.

Fig 1

Summary diagram of the risk factors and pathophysiological mechanisms for PICS. An acute critical illness can lead to rapid recovery, early death, or CCI/PICS. Intrinsic risk factors before day 0 and acquired risk factors between days 0 and 14 for the development of CCI/PICS are shown. The three possible causal relationships between CCI and PICS are also shown. 1) PICS could be a consequence of ongoing organ dysfunction in CCI. 2) PICS could be a pathophysiological mechanism of CCI. 3) PICS could be an endotype of CCI. Finally, the diagram shows the pathogenic systemic milieux that have been linked to PICS and contribute to the self-perpetuating cycle of inflammation, immunosuppression, and catabolism, that can lead to indolent death. APACHE II, acute physiologic and chronic health evaluation; ARDS, acute respiratory distress syndrome; CCI, chronic critical illness; DAMP, danger-associated molecular pattern; DIC, disseminated intravascular coagulation; ECMO, extracorporeal membrane oxygenation; MDSC, myeloid-derived suppressor cell; MV, mechanical ventilation; PAMP, pathogen-associated molecular pattern; PICS, persistent inflammation, immunosuppression, and catabolism syndrome; RRT, renal replacement therapy; SOFA, Sequential Organ Failure Assessment. Created with BioRender.com.

Fig 2

PRISMA flow diagram of the included and excluded articles from this systematic review. PICS, persistent inflammation, immunosuppression, and catabolism syndrome; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Fig 3

Forest plots of studies reporting biomarker outcomes demonstrated as a weighted mean difference using frequentist meta-analysis. Alb, albumin; CI, confidence interval; CRP, C-reactive protein; df, degrees of freedom; PICS, persistent inflammation, immunosuppression, and catabolism syndrome; sd, standard deviation; TLC, total lymphocyte count.

Fig 4

Summary diagram of potential biomarkers for PICS. This illustration highlights a range of biomarkers, organised by pathophysiological mechanism, and their potential utility in the early diagnosis, prognostication, and monitoring of PICS. 3 MEH, urinary 3-methylhistidine; Alb, albumin; ALC, absolute lymphocyte count; Ang2, angiopoietin-2; CRP, C-reactive protein; DIC, disseminated intravascular coagulation; GLP-1, glucagon-like peptide-1; IGFBP-3, insulin-like growth factor binding protein 3; IL-6, interleukin 6; IL-8, interleukin 8; IL-10, interleukin 10; IP-10, interferon gamma-induced protein; IPA, indole-3-propionate; NLR, neutrophil:lymphocyte ratio; Phe, phenylalanine; PICS, persistent inflammation, immunosuppression, and catabolism syndrome; SDF, stromal cell-derived factor; sPD-L1, soluble programmed death ligand-1; Trp, tryptophan; Tyr, tyrosine; UCR, urea: creatinine ratio; VEGF, vascular endothelial growth factor. Created with BioRender.com.