Neutrophil-to-lymphocyte ratio is an emerging prognostic predictor of patient outcomes in various pathologies, among which primarily are cases of bacterial infection and inflammatory processes [40]. Its significance in TBI is not well understood due to uncertainty in the precise biological process that lymphocytes mediate in the brain following such injuries [20,40]. In cases of general tissue injury, neutrophils are among the first cellular responders, mediating destruction of pathological specimens and initiating an initial inflammatory response [41]. Within a week, the cellular majority shifts towards macrophages that have a role in cellular repair and fibrosis. The cytokines and biological alterations at the site of injury have been hypothesized to activate T-lymphocytes and further induce healing processes [42]. Given the different functions of neutrophils and lymphocytes, the prognostic function of the different compositions of both cellular types cannot be understated [40]. A lower NLR would be suggestive of greater lymphocyte counts that are associated with cellular repair. A higher NLR would suggest the contrary, a perpetual state of acute inflammation associated with high neutrophil counts [40]. The latter has been found to be correlated with poorer outcomes and is commonly found in higher-severity TBI cases [40].

Neutrophils are generally thought to be the first responders to sites of tissue injury and mediate an innate immune response by way of phagocytosis and degranulation. Both processes actively recruit other leukocytes to action through cytokine and chemokine signaling [43]. At this point, cells such as macrophages/monocytes work to destroy pathogens, phagocytose, and clear debris [44]. The immune system then progresses towards an adaptive response with the activation of B and T (CD 4, CD8) lymphocytes with the help of antigen-presenting cells [45]. This simplified immune response timeline normally ends with the clearance of these cells along with dampened recruitment through inflammation suppression. The overall process of acute inflammation suppression and tissue healing after infection, infiltration, etc. is a rather complicated interplay between a variety of mediators, in which many leukocytes including macrophages and lymphocytes signal both pro-inflammatory and anti-inflammatory cytokines [46]. Two well-studied opposing profiles include the M1/M2 macrophage and Th1/Th2 helper T cell balance. The former cell types are responsible for inducing inflammation and cytotoxicity, while the latter cell types generally promote tissue healing and reduced inflammation [47,48]. Additionally, regulatory T cells/suppressor T cells also contribute to the downregulation of immune responses. Their role is particularly integral to autoimmune disorders [49]. Given that multiple cell types are involved in both propagating and terminating acute immune responses, we cannot simply use NLR as a substitute measure for quantifying acute inflammation. However, that does not mean NLR does not provide any insight into the progression of an acute immune response.

A large neutrophil count might indicate inflammation levels are elevated from baseline based on two concepts: 1. an acute immune response is likely in its initial stages and 2. neutrophils are generally unidirectional in promoting an inflammatory response [50]. Although it is not known how well NLR is directly correlated with inflammation, the results did show a significant difference in NLRs between patients who experienced favorable outcomes (GOS of 4–5) post-TBI and those who experienced unfavorable outcomes (GOS of 1–3). With regards to evaluations of unfavorable versus favorable outcomes for TBI patients, the Glasgow Outcome Scale (GOS) has not only been one of the oldest standard measures by which clinicians have assessed acute closed head injuries, but also one of the most popular ones as well [51]. The GOS is an ordinal scale for evaluating TBI patients measured at discharge [37]. The measure delineates patient outcomes into categories of Death (1), Persistent Vegetative State (2), Severe Disability (3), Moderate Disability (4) and Good Recovery (5) [37]. These values can subsequently be dichotomized into unfavorable outcomes (categories 1–3) and favorable outcomes (4–5) [37]. Its prognostic application, marked inter-rater reliability, and validity have been explored and refined over the last 40 years, and its ease of use and utility have allowed it to serve for numerous clinical guidelines for TBI cases over alternative scales, such as both the disability rating scale (DRS) and the Barthel Activities of Daily Living index (ADL) [52]. Additionally, studies have found it to outrank DRS measures in correlations to self-reported measures of depression, mental well-being and neurobehavioral and functioning outcomes in patients suffering from TBIs [53].

Correlation between NLR and GCS has been found with both reliably assessing outcomes for patients with mild TBI [46]. However, previous studies have shown that NLR has a similar if not more objective predictive value given that its measurements do not rely on subjective measurements of patient well-being, decreasing the possibility of human error [54,55]. NLR measurements are also independent of the patient’s ventilation status, state of consciousness, and other factors that might affect how accurately a measurement can be taken with GCS or GOS. Should NLR be found to have the same prognostic power as GCS or GOS in TBI patients, this would provide health professionals with another objective lab test option predictive of outcomes specific to TBI severity. As such, NLR could have immense clinical utility in the early medical management and subsequent treatment course of patients with TBI. In a clinical setting and if more widely studied, it could be argued that the benefits of correlation between NLR and outcome measures outweigh the lack of a known mechanism. There are, however, well-studied blood-based biomarkers specific to neuroinflammation [56]. Unfortunately, these measures are not readily available from routine tests including complete blood count (CBC) with differential [57]. Further studies are needed to shed more understanding on how NLR relates to TBI outcomes. In a shorter time frame, it might be possible to implement NLR in conjunction with other measures suggestive of inflammation, infection, injuries such as fever, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), or plasma viscosity (PV) in order to circumvent the time and costs of longer and more costly tests/imaging.

Initial bleeding in the brain and prolonged vessel leakage is critical TBI outcome measures because they compromise blood-brain barrier (BBB) integrity. The BBB refers to the collective endothelial cell layer lining the capillaries of the central nervous system (CNS) [58]. Since the site of exchange between the brain and perfusing arteries occurs at the level of the capillaries, the structure and function of the endothelial cells largely determine which molecules and ions are free to enter and exit the CNS. The tight junctions that connect these cells ensure an extremely low rate of transfer between the brain and peripheral vascular system with the exception of highly specific transporters [54]. Interestingly, leukocyte adhesion molecules are expressed at very low levels by these endothelial cells, suggesting that the prevention of immune cell entry into the CNS is a strong indicator of the proper functioning and maintenance of the BBB [55]. On the other hand, injuries to blood vessels and associated cell linings result in an elevation of leukocyte extravasation through endothelial cells and into brain tissue [59]. BBB breakdown also allows for the passage of many damaging infiltrates in addition to peripheral immune cells including reactive oxygen species (ROS), increased microglia and astrocytes, and water [60]. Rapid accumulation of fluid around the brain can lead to sustained cerebral edema if not naturally restored by normal BBB filtration or rescued through surgical intervention [61]. Leukocyte-cytokine signaling and subsequent inflammation contribute to impairment of the cellular repair vital to restoring BBB integrity [59]. Without this normal filtration process, uncontrolled cerebral edema and intracranial pressure (ICP) in conjunction with elevated secondary inflammation allow intracranial hemorrhaging and hematomas to continue and expand respectively [62]. In addition to the opportunistic infiltration afforded by trauma to the central nervous system (CNS), neutrophils also contribute to neural damage by way of neutrophil extracellular traps (NETs), which are structures released by neutrophils aimed to trap then neutralize or eliminate pathogens [63]. As a byproduct, NETs generate an overabundance of harmful cytotoxic proteins, further interfering with cellular repair [64]. NET dysregulation has been implicated in pathologies ranging from autoimmune disorders such as psoriasis to cancers, trauma, and neurodegenerative diseases.

Furthermore, studies applied variant criteria in patient inclusion—while the majority excluded cases involving immunosuppressive conditions, major heart/systemic illnesses, prior brain trauma, and strokes, a few did not. Comorbidities such as hypertension and diabetes were not controlled for in studies and therefore, this should be acknowledged when interpreting the results of both the individual studies and the current analysis. Pre-existing immunosuppressive conditions present a particular challenge to correlating NLRs with secondary TBI outcomes relating to inflammatory-based damage and repair interference. Chronic inflammation in an aging population, known as inflammaging, has been linked to a variety of chronic conditions including neurodegenerative diseases [77]. If a patient’s neutrophils are already elevated at baseline, then NLR loses its temporal resolution. It becomes more difficult to determine if a patient is presenting with an earlier or later acute immune response as a direct response to TBI because of background inflammation and the accompanying physiological standards for that one patient. The progression from innate to adaptive immune response, including lymphocytes, within the context of chronic inflammation, is as well understood as a short-term acute response. Transitions such as M1/M2 macrophage and Th1/Th2 do not necessarily proceed in the same manner, and immune cell roles are less well understood in these cases [78]. Although in these cases NLR is less useful as an inflammatory marker, it might still provide temporal insight when used as a comparative marker to other NLRs obtained with the same hospital course. Assuming there are no interactions between chronic and acute inflammation, the difference between two NLRs short-term would theoretically cancel out background levels of inflammation, neutrophil and lymphocyte levels, etc. Admittedly, this is an oversimplified solution to this issue of pre-existing comorbidities. Practically speaking, it would make more sense to corroborate NLR with other measures to compensate where NLR fails to succeed. These limitations addressed within the paper have also been reflected within measures of the GOS. Measurements via GOS evaluations have been noted to lack comprehensive consideration of both patient heterogeneity and underlying comorbidities [79,80]. As such, efforts have been made to expand the dichotomy of unfavorable to favorable outcomes from a fixed scale to a sliding scale that accounts for previous patient histories, but the implementation of such analyses into evaluations of patient outcomes is ongoing, and may be the subject of future evaluations of TBI outcomes [80,81]. Additionally, regarding symptomatic presentation, the majority of included studies did not report some or all of the symptoms that were recorded in our review, or reported this data in a format that could not be accurately translated to a binary yes-or-no format (e.g., reporting LOC as a duration of <30 min., 30 min. to 24 h., and >24 h. without specifying the number of patients in the <30 min. category that did not experience LOC altogether).