Neutrophil kinetics and function after major trauma: A systematic review

Table 1 A summary of papers included in the review

Title of paper	Ref.	Year published	Number of patients recruited	Average ISS	Average age	Samples collected (time post injury)	Location of study	Major outcomes
Postinjury neutrophil priming and activation states: therapeutic challenges	Botha et al[12]	1994	10	N/A	N/A	3 h, 6 h, 12 h, 24 h, 48 h, 72 h, 96 h	United States	Functional states of NADP H, primed 6-24 h, unprimable > 48 h
Postinjury neutrophil priming and activation: an early vulnerable window	Botha et al[14]	1995	17	26.7	26.7	3 h, 6 h, 12 h, 24 h, 48 h, 72 h	United States	Priming occurs < 24 h after injury, but cells are resistant to priming 48 h after trauma
Early Neutrophil Sequestration after Injury: A Pathogenic Mechanism for Multiple Organ Failure	Botha et al[25]	1995	33	27.7	29.1	3 h, 6 h, 12 h, 24 h	United States	Neutrophil kinetics and CD11b expression suggest end organ sequestration predisposing to MODS
Base deficit after major trauma directly relates to neutrophil CD11b expression: a proposed mechanism of shock-induced organ injury	Botha et al[27]	1997	17	26.7	26	3 h, 6 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h	United States	Kinetics of neutrophilia, CD11b, CD18 and CD11a
Major injury induces increased production of IL10 in human granulocyte fractions	Koller et al[49]	1998	15	28	36	Daily between days 3-10	Germany	Neutrophils from trauma patients produce IL-10
The effects of trauma and sepsis on soluble L-selectin and cell surface expression on L-selectin and CD11b on leukocytes	Maekawa et al[32]	1998	20	20.1	45.6	ADM, every 30 min up to 4 h, every 3h up to 24 h, every 6 h up to 120 h	Japan	Neutrophil L selectin and CD11b both increase immediately and more slowly out to 24 h post trauma in ISS > 16 but not in ISS < 16
Polymorphonuclear Neutrophil Chemiluminescence in Whole blood from Blunt Trauma Patients with Multiple Injuries	Brown et al[56]	1999	12	36.4	49.5	< 24 h	United States	CR3a is a marker of neutrophil priming and is upregulated in trauma
Neutrophils are primed for cytotoxicity and resist apoptosis in injured patients at risk of for multiple organ failure	Biffl et al[13]	1999	12	22.6	N/A	Daily for 5 d	United States	Neutrophil apoptosis is delayed in trauma patients
Preferential Loss of CXCR-2 Receptor Expression and Function in Patients Who Have Undergone Trauma	Quaid et al[35]	1999	20	19	35	One sample within 24 h	United States	CXCR-2 expression and function are downregulated in severely injured patients
Superoxide production of neutrophils after severe injury: Impact of subsequent surgery and sepsis	Shih et al[57]	1999	18	26.2	41.6	1 d, 3 d, 7 d	Taiwan	Neutrophil superoxide production after trauma is initially increased but is then decreased in those who go on to develop multiorgan failure at day 7
Early role of neutrophil L-selectin in posttraumatic acute lung injury	Rainer et al[29]	2000	147	1	1	On admission to ED	Hong Kong	Total leukocyte and neutrophil counts, expression of L-selectin, and the ratio of neutrophil to plasma L-selectin increased with injury and were highest in those who developed acute lung injury (ALI). Soluble L-selectin decreased with injury severity and was lowest in those who developed ALI
Early Trauma polymorphonuclear neutrophil responses to chemokines are associated with development of sepsis, pneumonia and organ failure	Adams et al[34]	2001	15	34	36	12 h	United States	High CXCR2 activity correlated with ARDS. Low CXCR2 activity correlated with sepsis
Decreased leukotriene release from neutrophils after severe trauma: role of immature cells	Koller et al[40]	2001	15	35	35	1 sample, between 3-14 d	Germany	Neutrophils secrete less leukotrienes following trauma
Prospective study of neutrophil chemokine responses in trauma patients at risk for pneumonia	Tarlowe et al[36]	2005	32	27.4	35.1	ADM, 3 d, 7 d	United States	Prospectively assessed CXCR function and expression in neutrophils from trauma patients at high risk for pneumonia and their matched volunteer controls. CXCR2-specific calcium flux and chemotaxis were desensitized by injury, returning toward normal after 1 wk. CXCR1 responses were relatively maintained
Neutrophil priming for elastase release in adult blunt trauma patients	Bhatia et al[15]	2006	10	29.3	40.3	ADM, 24 h, 3 d, 5 d	United Kingdom	Neutrophils release more elastase after trauma
Aberrant regulation of polymorphonuclear phagocyte responsiveness in multi-trauma patients	Hietbrink et al[30]	2006	13	21	40	ADM, 3 d, 5 d, 7 d	Netherlands	Priming markers low in first week. Decreased responsiveness to fMLP with increased ISS
Neutrophil-derived circulating free DNA: a potential prognostic marker for posttraumatic development of inflammatory second hit and sepsis	Margraf et al[58]	2008	37	31.6	45	ADM, daily for 10 d	Germany	Kinetics of NET formation, 3 patterns of kinetics
Early expression changes of complement regulatory proteins and C5a receptor (CD88) on leukocytes after multiple injury in humans	Amara et al[39]	2010	12	48	38	4 h, 12 h, 24 h, 120 h, 240 h after trauma	Germany	Complement regulators and CD88 on neutrophils are significantly altered following trauma. CD55 is elevated, shows decreased expression
Nature of Myeloid Cells Expressing Arginase 1 in Peripheral Blood After Trauma	Bryk et al[45]	2010	10	18.63	43.7	< 24 h, 3-7 d, 14-21 d	United States	MDSCs derived from major trauma patients show increased arginase activity, allowing modulation of T cell responses
Divergent adaptive and innate immunological responses are observed in humans following blunt trauma	Kasten et al[11]	2010	22	22.8	36.3	1 sample, between 24-96 h	United States	CD11b kinetics, lipid rafts, phosphorylated Akt increased in trauma
A genomic storm in critically injured humans	Xiao et al[19]	2011	167	31.3	34	< 12 h, 1 d, 4 d, 7 d, 14 d, 21 d, 28 d	United States	Genomics of response to trauma, anti- and pro-inflammatory mechanisms activated simultaneously
A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1	Pillay et al[33]	2011	N/A	N/A	N/A	N/A	Netherlands	ROS-induced immunosuppressive CD16bright/CD62L dim neutrophil population first isolated
Kinetics of the innate immune response after trauma: implications for the development of late onset sepsis	Hietbrink et al[8]	2012	36	24.2	45	3-12 h, daily for 10 d	Netherlands	Kinetics of neutrophilia, CRP, IL-6, CD11b, FcγRII, CXCR1, respiratory burst, CD88
Molecular mechanisms underlying delayed apoptosis in neutrophils from multiple trauma patients with and without sepsis	Paunel-Görgülü et al[59]	2012	24	46.7	41.7	Routinely until 10 d	Germany	Neutrophil apoptosis is reduced after trauma and patients undergoing a post-trauma course complicated by sepsis exhibit different expression of pro- and anti-apoptotic regulators
Increased MerTK expression in circulating innate immune cells of patients with septic shock	Guignant et al[60]	2013	51	38	35	24-48 h	France	TAM receptors are differentially upregulated in sepsis and trauma
IL33-mediated ILC2 activation and neutrophil IL5 production in the lung response after severe trauma: A reverse translation study from a human cohort to a mouse trauma model	Xu et al[48]	2017	472	20.2	N/A	ADM, < 24 h, daily for 7 d	United States	IL33 kinetics, neutrophils produce IL-5
Prehospital immune responses and development of multiple organ dysfunction syndrome following traumatic injury: a prospective cohort study	Hazeldine et al[23]	2017	89	24	41	< 1 h after trauma, 4-12 h, 24-48 h	United States	Early kinetics of neutrophil phenotype, including neutrophilia, cytokines, NETs, CD11b, and CD16/CD62L subsets
Early decreased neutrophil responsiveness is related to late onset sepsis in multitrauma patients: An international cohort study	Groeneveld et al[31]	2017	109	1	1	On arrival	Netherlands, South Africa	Reduced fMLP responsiveness in a cohort study at early time points and in association with septic shock
Heparin-binding protein as a biomarker of post-injury sepsis in trauma patients	Halldorsdottir et al[28]	2018	97	33	47	1 d, 3 d, 5 d	Sweden	HBP is a marker of neutrophil activation and correlates with ISS
A rise in neutrophil size precedes organ dysfunction after trauma	Hesselink et al[26]	2018	81	1	1	ADM, 6 h, 12 h, 24 h, 48 h	Netherlands	In patients who developed organ failure a significant increase in neutrophil count, size and complexity, and a decrease in lobularity were seen after trauma
Neutrophil-derived long noncoding RNA IL-7R predicts development of multiple organ dysfunction syndrome in patients with trauma	Jin et al[55]	2020	60	23.5	51.5	ADM	China	Neutrophil derived lnc-IL7R negatively correlates with MODS and mortality
New automated analysis to monitor neutrophil function point-of-care in the intensive care unit after trauma	Hesselink et al[5]	2020	15	33	1	<12 h, 3 d, 6 d, 10 d, 15 d	Netherlands	Patterns of phagosomal acidification correlate with infection, neutrophil CD16/CD62L subsets
Point-of-Care analysis of neutrophil phenotypes: A first step toward immune-based precision medicine in the Trauma ICU	Spijkerman et al[24]	2020	32	N/A	N/A	ADM to trauma bay	Netherlands	CD16/CD62L neutrophil subtype correlates with infection
Olfactomedin 4 Positive Neutrophils are Upregulated Following Hemorrhagic Shock	Kassam et al[61]	2020	56	N/A	41.5	ADM, 3 d, 7 d	United States	Increased OLFM4+ neutrophil fraction after blunt trauma associated with increased ICU length of stay, ventilator days
Current Concepts of the inflammatory response after major trauma – an update	Giannoudis[18]	2003	Review Paper	2	2	2	United Kingdom	Malignant SIRS can develop into MODS or ARDS, however main effect of trauma on neutrophils is suppressive
Trauma: The role of the innate immune system	Hietbrink et al[4]	2006	Review Paper	2	2	2	Netherlands	Neutrophils are the main effector cells leading to MODS, an overactive SIRS can lead to CARS/MARS
The systemic inflammatory response induced by trauma is reflected by multiple phenotypes of blood neutrophils	Pillay et al[3]	2007	Review Paper	2	2	2	Netherlands	Description of cell surface markers and their role in normal neutrophil function and in trauma
Postinjury immune monitoring: can multiple organ failure be predicted?	Visser et al[46]	2008	Review Paper	2	2	2	Netherlands	Excessive neutrophilia in the hours post trauma increase risk of MODS and mortality. Severity of the initial SIRS causes the depth of immunosuppression
Trauma equals danger – damage control by the immune system	Stoecklein et al[62]	2012	Review Paper	2	2	2	United States	Trauma induces immunosuppression, characterised clinically as CARS or MARS (mixed antagonist response syndrome)
The impact of trauma on neutrophil function	Hazeldine et al[16]	2014	Review Paper	2	2	2	United Kingdom	Sequestration of neutrophils in organs may lead to ARDS, whilst leaving the circulation open to infection
The systemic immune response to trauma: an overview of pathophysiology and treatment	Lord et al[17]	2014	Review Paper	2	2	2	United Kingdom	Heightened SIRS suppresses immune responses resulting in inflammation and cellular immunoparalysis, contradictory accumulation in organs causes organ dysfunction
Assessing the Immune Status of critically ill trauma patients by flow cytometry	Kuethe et al[63]	2014	Review Paper	2	2	2	United States	CD66b and CD11b are selective markers for neutrophils when expressed together. Neutrophils differentially regulate cell surface markers based on activation
The role of neutrophils in immune dysfunction during severe inflammation	Leliefeld et al[42]	2016	Review Paper	2	2	2	Netherlands	NETosis occurs in response to IL-8, TNFα and LPS, under the control of NADPH oxidase. Massive neutrophil release from the bone marrow may result in exhaustion
Neutrophils in critical illness	McDonald[64]	2018	Review Paper	2	2	2	Canada	TREM-1 may assist in differentiating sterile from septic SIRS, as TREM-1 only upregulates in sepsis
Innate Immunity in the Persistent Inflammation, Immunosuppression and Catabolism Syndrome and its implications for therapy	Horiguchi et al[6]	2018	Review paper	2	2	2	United States	Major DAMPs in trauma include HMGB1, mtDNA, ATP and cfDNA. Result in neutrophils releasing IL-6, TNFα, IFNγ, and ROS. Neutrophils exist in resting, primed and active states
Danger signals in the ICU	Schenck et al[10]	2018	Review Paper	2	2	2	United States	mtDNA is a main DAMP in trauma due to similarities to bacterial DNA. Early neutrophil chemotaxis is DAMP dependent
Neutrophil heterogeneity and its role in infectious complications after severe trauma	Hesselink et al[9]	2019	Review Paper	2	2	2	Netherlands	Activated neutrophils leave the blood, leaving dysfunctional neutrophils behind. Analysis of low density neutrophils, CD16/CD62L subtypes
Does neutrophil phenotype predict the survival of trauma patients?	Mortaz et al[1]	2019	Review Paper	2	2	2	Iran	CD11b is considered a marker of poor prognosis, increased CXCR2 relates to risk of ARDS. Understanding phenotype could allow use as a predictive tool

¹Trauma cohorts divided into subgroups, full group statistics not available.

²Review article.

N/A: Not available; ADM: Admission; HMGB1: High mobility group box 1; mtDNA: Mitochondrial nucleic acids; cfDNA: Cell free DNA.