Neutrophil kinetics and function after major trauma: A systematic review

Abstract

Background: Immune dysfunction following major traumatic injury is complex and strongly associated with significant morbidity and mortality through the development of multiple organ dysfunction syndrome (MODS), persistent inflammation, immunosuppression, and catabolism syndrome and sepsis. Neutrophils are thought to be a pivotal mediator in the development of immune dysfunction.

Aim: To provide a review with a systematic approach of the recent literature describing neutrophil kinetics and functional changes after major trauma in humans and discuss hypotheses as to the mechanisms of the observed neutrophil dysfunction in this setting.

Methods: Medline, Embase and PubMed were searched on January 15, 2021. Papers were screened by two reviewers and those included had their reference list hand searched for additional papers of interest. Inclusion criteria were adults > 18 years old, with an injury severity score > 12 requiring admission to an intensive care unit. Papers that analysed major trauma patients as a subgroup were included.

Results: Of 107 papers screened, 48 were included in the review. Data were heterogeneous and most studies had a moderate to significant risk of bias owing to their observational nature and small sample sizes. Key findings included a persistently elevated neutrophil count, stereotyped alterations in cell-surface markers of activation, and the elaboration of heterogeneous and immunosuppressive populations of cells in the circulation. Some of these changes correlate with clinical outcomes such as MODS and secondary infection. Neutrophil phenotype remains a promising avenue for the development of predictive markers for immune dysfunction.

Conclusion: Understanding of neutrophil phenotypes after traumatic injury is expanding. A greater emphasis on incorporating functional and clinically significant markers, greater uniformity in study design and assessment of extravasated neutrophils may facilitate risk stratification in patients affected by major trauma.

Keywords: Immunophenotypes; Inflammation; Intensive care units; Multiple trauma; Neutrophils; Systemic inflammatory response syndrome.

Figure 1

PRISMA diagram summarising included studies. Further characteristics of each study are available in Table 1.

Figure 2

Schematical representation of neutrophil changes over time following major trauma, differentiated by complicated or uncomplicated clinical course. Complicated course indicates subsequent sepsis or multiple organ dysfunction, where evidence exists in the literature. A: Neutrophil number post injury relative to pre-injury/control levels; B: Neutrophil responsiveness (CD11b or FC Gamma receptor II upregulation in response to fMLP) following injury relative to control; C: Immunosuppressive CD16^bright/CD62L^dim neutrophils as percentage of total neutrophils relative to control. No data exist for the presence of these cells more than 4 d after trauma or in complicated/uncomplicated courses.

Figure 3

Neutrophil extravasation and resultant immune dysfunction. Tissue damage caused by injury leads to danger associated molecular pattern, catecholamine and corticosteroid release, which result in neutrophil egress from the bone marrow, as well as increased production through emergency granulopoiesis. This leads to a circulating neutrophilia and altered phenotypes of circulating neutrophils as discussed in text. It is hypothesised that hyperinflammatory cells expressing high levels of adhesion markers transmigrate into the demarginated pool in the lungs, spleen, liver and other end organs, where they may cause further inflammation through NETosis, degranulation and phagocytosis, leading to organ dysfunction. The loss of these highly inflammatory cells from the circulation leads to remaining neutrophils being dysfunctional, predisposing the individual to immune failure and secondary infection. Figure produced using Biorender.