The prognostic values of neutrophil to lymphocyte ratio in traumatically injured patients upon admission: A mini-Review

Abstract

Subsequent to trauma and systemic inflammatory response syndrome, the typical reaction is an enhancement of the total white blood cell count. Neutrophils are abundant circulating leukocytes in humans that play a crucial role in initial immune response against invading microbes through phagocytosis and exerting inflammatory mediators. However, lymphocytes are the main cellular compartments of the immune system that are negatively affected in the setting of trauma. The neutrophil to lymphocyte ratio (NLR), which can be easily measured in daily clinical practices, is an alternative marker of inflammation before any clinical findings can be observed. Therefore, in this mini-review study, we briefly discussed recent evidence on NLR variations at the time of hospitalization and its prognostic values in trauma patients. Most investigations declared high values of NLR potentially have a poor prognosis in traumatically ill patients on admission and contribute to coagulopathy, increased hospitalization and mortality. Moreover, given that various cut-off points have been considered for the NLR value, receiving a unique one and linking with subsequent outcomes of the disease should be in ongoing researches.

Introduction

Trauma is still the fifth leading cause of mortality globally. ¹ The most important part of trauma is the instant induction of a tremendous inflammatory response which accounts for further consequences, including secondary infection, prolonged hospital stay, multiple organ dysfunction, and mortality. ² Outcome prediction in acute trauma patients using simple, cost-effective, and readily accessible clinical data is an important research aim that has not been adequately achieved so far. Determining laboratory parameters participating in immune and inflammatory responses can aid clinicians in recognizing the degree of systemic inflammation and offer therapeutic strategies in traumatic patients to lessen worse consequences. ³

Neutrophils are abundant circulating leukocytes in humans comprising 60-70% of white blood cells (WBCs) accounting for initial immune response against invading microbes and damaged tissues by eliciting inflammatory mediators. ³ Activated neutrophils induce inflammation by producing and secreting cytokines, leukotrienes, chemokines, and prostaglandins. ⁴ On the other side, lymphocytes play a key role in controlling the onset of innate immune-mediated inflammation by releasing anti-inflammatory cytokines and prohibiting neutrophil infiltration. ⁵ Meanwhile, as neutrophils accumulate at the site of injury, lymphocytes are negatively influenced in the setting of the trauma.^6,7 The neutrophil to lymphocyte ratio (NLR) serves as an alternative marker of systemic response to physiological tensions. The prognostic value of NLR has been investigated in non-traumatic disorders where its variations can associate with worse outcomes of various inflammatory disorders^8–13 and has a higher sensitivity than leukocytosis. ¹⁴ Therefore, in this work, we provided an overview of recent evidence on NLR variations at the time of hospitalization and its prognostic values in injured patients.

Main text

The neutrophil to lymphocyte ratio (NLR) has been known as a simple and standard marker for the assessment of systemic inflammation and its outcomes in patients. ¹⁵ The component lab. data for NLR are readily accessible without putting any excessive burden on patient’s costs. Until now, several studies have evaluated the relationship between NLR and outcomes of various diseases, describing worse outcomes along with raising the NLR value.^16–20 Recent studies on critically ill patients who were admitted to the emergency department showed that the NLR value was independently related to the length of hospital stay and mortality, irrespective of the illnesses.^21–24 Moreover, NLR is a practical way to monitor critically ill trauma patients during hospitalization. For the first time, Dilektasli et al. reported the role of NLR in trauma patients. They demonstrated that on day 2 and 5 post-hospitalization, NLR levels were directly correlated with in-hospital fatality in surgical intensive care unit. Meanwhile, they declared that NLR values in the first 24 h are not a suitable predictive marker for outcomes of the complications. ²⁵ On the contrary, our team recently introduced a direct relationship between arrival NLR values and hospital decease in trauma patients. We also observed that higher injury severity score was accompanied by high values of admission NLR, suggesting the straight association between the severity of the injury and intensity of next inflammatory response activation. ²⁶ We proposed that high NLR values on patient arrival may be due to recruitment of neutrophils and macrophages, in the term of initial innate immune cells, to the site of injury and the need for neutrophil synthesis from the bone marrow (Figure 1(a)).^27,28 However, some researchers believed that lymphocytic anergy or loss occurred in trauma patients may be responsible for the elevation of NLR values.^29–31 In this case, Daithi S Heffernan showed that the mortality was highest in patients with lymphopenia that did not recover, highlighting the concept that recovery from lymphocyte loss is crucial for the survival of traumatically injured patients. ¹

Figure 1.

High NLR values of on-arrival traumatic patients. (a) Migration of innate (neutrophils and macrophages) and adaptive immune cells (Lymphocytes) to the site of injury. (b) The advantages and disadvantages of measuring NLR. Abbreviation: NLR; neutrophil-lymphocyte ratio.

Meanwhile, a paucity of literature has revealed the effect of lymphocytosis in the early phase of trauma on increased mortality, which means low NLR values are correlated with poor prognosis. ³² Lymphocytosis possibly occurs following some stressful and urgent medical conditions, including non-surgical trauma, cardiac emergencies, abdominal pain and obstetric emergencies, instead of the neutrophilic response.^33,34 Another study conducted by Menyar et al. showed that on-admission NLR was higher in the patients who survived abdominal trauma in comparison with deceased patients. The optimal cut-off of NLR for predicting mortality was 18.5; however, due to the low specificity and sensitivity of the measured NLR, this marker was not valuable for timely management of injured patients. ³⁵

Nevertheless, most researchers have found that increased levels of the NLR value in the first hours of hospitalization among trauma illnesses have a poor prognosis.^36–39 In the study conducted by Li Li et al. on 1000 patients with severe intracerebral hemorrhage, the risk of in-hospital decease rose more than two folds by each increase in NLR, and NLR>7.68 upon admission had a higher risk of death. ⁴⁰ Consistently, Chen et al. found out that high levels of NLR at admission significantly associated with the risk for coagulopathy in traumatic brain injuries (TBI). Considerably, TBI patients with coagulopathy have more severe brain injuries and vigorous inflammatory reactions than those without coagulopathy signs. ⁴¹ Therefore, Alexiou et al. introduced the value of NLR as a predictive biomarker for coagulopathy in TBI patients with a cut-off value of 4.2. ⁴² Lattanzi et al. also demonstrated that higher levels of NLR in patients with spontaneous intracerebral hemorrhage within 24 h from onset were independently accompanied with more 30 days mortality and morbidity. ⁴³ In parallel, Defort et al. determined higher levels of NLR in intracerebral hemorrhage patients with Glasgow Coma Scale (GCS)≤8 5 after injury, while the evaluated NLR cut-off value was 0.118. ⁴⁴ However, our team achieved a cut-off value >5.27 for NLR upon the arrival of trauma patients. ²⁶ These controversial values for NLR cut-off potentially stem from an unrecognized certain normal value of NLR. For instance, Forget et al. evaluated the normal NLR values in healthy adults between 0.78 and 3.53. ⁴⁵ While another study claimed that among 700 hospital employees without active disease, 90–95% had an NLR between three and 5. ⁴⁶ Although it is unclear whether this value varies with age, overall, a normal NLR value under five seems appropriate, and our cut-off value >5.27 might be favorable. Therefore, NLR has the potential of being an early prognostic marker to guide clinicians in determining the level of care and interventions essential for these patients. Meanwhile, the remaining question is the accuracy and reliability of the NLR which needs comprehensive investigations on multiple traumas in a large population. Some literature demonstrated that the poor prognostic value of NLR in TBI is independent of the severity of the trauma so that NLR has been correlated with poor prognosis even in mild TBI.^47,48 This might reduce the efficiency of NLR as a favorable prognostic indicator for identification of TBI severity (Figure 1(a) and (b)). Moreover, inconsistent findings observed among literature may derive from the differences in inclusion criteria, different time intervals from injury to hospitalization, and the type of trauma. Considerably, both extremely high and low neutrophil counts, to a certain degree, show that the value of NLR may lead to poor outcomes. ⁴⁹ Hence, myriad cut-off points have been demonstrated for NLR in trauma patients, highlighting ongoing studies is a prerequisite for finding a unique cut-off, particularly, providing a comprehensive meta-analysis of NLR cut-off points for each anatomical organ may aid in this setting.

The NLR is a simple test that has been investigated in various inflammatory diseases, particularly in trauma cases. Several peer-reviewed and meta-analysis studies have focused on the prognostic values of NLR variation in critical trauma patients during different timeframe from admission. Although we couldn’t cover all relevant literature investigating the prognostic aspects of NLR in trauma or supportive other inflammatory diseases with NLR variations in this overview study, we aimed to highlight the recent evidence related to on-admission NLR variations and suggest its promising role in aiding clinicians’ decision-making process alongside other clinical and laboratory parameters.

Conclusion

Anticipating unfavorable outcomes or mortality in trauma conditions can provide a significant benefit in decision-making for injury management. The evaluation of NLR at the time of admission is an easy and cost-effective prognostic biomarker that reflects the systemic inflammatory response to physiological pressures. High values of NLR are mostly related to the severity of the injury and the intensity of the inflammatory reaction, which can predict the risk of hospital decease in trauma victims as well as coagulopathy occurrence in TBI patients. However, reaching an optimal cut-off point has been a matter of debate so far. Combining NLR with other inexpensive biomarkers, alongside clinical findings, might further increase accuracy in the prediction of traumatic outcomes.