In recent years, the role of the neutrophil to lymphocyte ratio (NLR) has gained significant attention in a variety of malignant diseases including colorectal cancer, hepatocellular cancer, advanced pancreatic cancer, ovarian cancer and oesophageal cancer, as an independent predictor of morbidity and mortality[1-5]. A systematic review including 40,559 patients showed that a high pre-operative NLR was associated with overall survival and disease-free survival in solid tumours[6]. Likewise, a clinical study including 404 patients with gastric cancer undergoing curative gastrectomy showed that a high pre-operative NLR (NLR > 3) independently predicted the development of postoperative infectious complications and NLR > 3 was independently associated with overall- and cancer-specific survival[7]. A cohort study including 418 patients reported that NLR was the most efficient biomarker to predict recurrence-free survival, cancer-specific survival and overall survival in patients undergoing radical cystectomy for bladder cancer compared to platelet-lymphocyte ratio and absolute platelet counts[8]. Moreover, NLR has been studied in a range of clinical non-surgical settings and has e.g. been shown to be a better indicator than total white blood cell count in the staging of acute pancreatitis[9]. Whether preoperative NLR predicts morbidity and mortality after benign surgery is unclear. The purpose of this systematic review was to investigate whether a pre-operative NLR is a predictor of postoperative morbidity and mortality after benign surgery.

Methods

  A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines (PRISMA)[10]. A version of the review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42016050756).

  The population was limited to patients ≥18 years who underwent benign surgery. Studies including patients who underwent transplantation or patients with cancer were excluded. Only studies with a pre-operative NLR were included. Outcomes were postoperative morbidity and mortality. We excluded non-English publications and unpublished studies including proceeding abstracts. Date of publication was not restricted. A literature search was conducted in November 2017 in PubMed, Scopus, Embase and the Cochrane Library. In PubMed the following search terms were used: Humans, adults, surgical specialties, surgery, operation, surgical procedures - operative, resection, incision, neutrophils, lymphocytes, neutrophil, lymphocyte, neutrophil/lymphocyte, neutrophil-to-lymphocyte ratio, NLR, survival, mortality, mortalities, death, morbidity, mortalities, morbidities. The PubMed MesH terms were modified to corresponding terms in the other databases. Reference lists from included articles were manually searched for additional publications of relevance. Two reviewers independently screened all articles on title and abstract and resolved disagreement through discussion.

  Two reviewers extracted data on; author, study design, number of participants, characteristics of the population, type of surgery and priority, lengths of follow-up, pre-operative NLR and clinical outcomes. Disagreements were resolved through discussion.

Methodological quality assessment

  A Cochrane Risk Of Bias Assessment Tool: for Non-Randomized Studies of Interventions (ACROBAT-NRSI) was used to assess the methodological quality of the individual studies[11]. The quality assessment evaluated the potential risk of introducing bias or limit applicability of the studies. ACROBAT-NRSI assesses the studies across seven specified domains of bias distributed in two types of pre-intervention bias, one kind of intervention bias and four types of post-intervention bias. All studies were rated on the risk of pre-intervention bias, intervention bias and post-intervention bias. The rating was divided into ‘low’, ‘moderate’, ‘serious’, ‘high’ or ‘non relevant’. For each study, the overall risk of bias was determined by the highest rated risk of bias in any of the domains.

Results

  A total of 4,663 articles were identified in the PubMed database, Scopus, EMBASE and Cochrane clinical trials. After manual removal of 534 duplicates, 4,129 articles were left for screening on title and abstract. 4,012 articles were excluded after screening on title and abstract. After full-text review, 94 articles were excluded and 23 articles were included in the systematic review. Furthermore, a manual search of reference lists led to inclusion of 2 additional articles, figure 1.

Figure 1: Flowchart of included articles and the screening process. The violation of any inclusion criterion resulted in the exclusion of the article.

Study characteristics

  25 clinical studies with a total of 10,015 patients were included[12-36]. The studies consisted of 10 prospective cohort studies[12-14,18,19,22,25-28] retrospective cohort studies[15-17,20,21,23,29-36] and two case-control study[24,31]. Lengths of follow-up ranged from one day to108 months after surgery.

The mean age ranged from 37.6 ± 13.1 years[36] to 82 ± 8years[28], table1.

  The studies were divided into three categories according to the type of surgery: cardiac surgery (N = 11)[12-17,28,30-32,37], vascular surgery (N = 6)[1-23,33] and non-cardiac non-vascular surgery (N = 8)[24-27,29,34-36] including four studies in orthopaedic surgery[24,25,29,35], two studies in abdominal surgery[26,36], one study in urology[34] and one study in miscellaneous types of non-cardiac non-vascular surgery[27].

Table 1: Clinical studies assessing Neutrophile to Lymphocyte Ratio prior to benign surgery.

*clavien-dindo ≥ 3

Continuous data were expressed as mean +/- standard deviation unless indicated otherwise

95% CI: 95% confidence interval; q1: 1st quartile; q3: 3th quartile

AF: Atrial Fibrillation; AKI: Acute Kidney Injury; ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase; AUC: Area Under the Curve (i.e., ROC curve); CABG: Coronary Artery Bypass Grafting; CAD: Coronary Artery Disease; CAE: Combined Adverse Events (myocardial infarction, cardiac reoperation, prolonged mechanical ventilation ( > 48h), prolonged hospital stay, rehospitalization or mortality); CCS: Canadian Cardiovascular Society; CEA: Carotid Endarterectomy; DBP: Diastolic Blood Pressure; HB: Hemoglobin; HTN: Hypertensive; HR: Hazard Ratio; LOS: Length of hospital stay; LVEF: Left Ventricular Ejection Fraction; MCV: Mean Corpuscular Volume; MI: Myocardial infarction; MICS: Minimally Invasive Cardiac Surgery; MPV: Mean Platelet Volume; NLR: Neutrophil-Lymphocyte Ratio; OR: Odds Ratio; PCI: Percutaneous Coronary Intervention; PLR: Platelet:Lymphocyte Ratio; PPS: Post –Pericadiotomy Syndrome; PTH: Parathyroid Hormone; rAAA: ruptured Abdominal Aortic Aneurysm; RDW: Red Cell Distribution Width; ROC: Receiver Operating Characteristic; RV: Right Ventricular; SBP: Systolic Blood Pressure; SVGF: Saphenous Vein Graft Patency

Cardiac surgery

  Six studies included patients undergoing coronary artery bypass grafting (CABG)(n = 4,771)[12-15,31,32] and one study included patients undergoing CABG, isolated single cardiac valve surgery and combined surgery (n = 1500)[29]. An eighth study included patients undergoing different types of open cardiac or thoracic aortic surgery with cardio-pulmonary bypass (n = 590)[19]. A ninth study included patients with advanced heart failure who received left ventricular assist devices (n = 273)[17]. Two studies included patients who underwent surgery for acute type I aorta dissection (n = 288)[21,30] table 1.

  In one study patients who underwent CABG with a high preoperative NLR (NLR > 3.00 (2.30-3.85)) had a significantly higher risk of developing atrial fibrillation compared with patients with a low NLR[14]. Another study found no association between high NLR and atrial fibrillation[38], table 2.

  NLR was independently associated with the risk of saphenous vein graft failure[15], adjusted OR = 1,39 (1,19-1,61), and was an independent predictor for combined adverse events[29], OR = 0.21 (0.2-0.3), table 2. NLR was independently associated with sternum revision[38], adjusted OR = 2.95 (1.32-6.63), but no association was found between NLR and post-pericardiotomy syndrome[31] or neurologic events[38] in patients who underwent CABG, table 2.

  NLR was also independently associated with right ventricular failure[17] in patients with advanced heart failure implanted with left ventricular assist devices OR = 1.12, CI = 1.04-1.20, p = 0.003), table 2.

  Likewise, patients with an NLR ≥ 2 had a significantly higher risk of developing acute kidney injury[16], table 2.

  NLR was independently associated with multi-organ dysfunction, major bleeding and hospital-related infection[30], in patients with aorta dissection, table 2.

  Six studies evaluated the association between preoperative NLR and postoperative mortality[12,13,30,37,39,40]. All but one study[39] reported a high pre-operative NLR to be associated with overall postoperative mortality[12,13,32,36,40], table 2.

Table 2:

aOR: Adjusted odds ratio

COPD: Chronic obstructive pulmonary disease

uOR: unadjusted odds ratio

WCC: White cell count

Vascular surgery

  Two studies included patients undergoing surgery for aortic aneurysms (n = 782)[18,20]. A high preoperative NLR was shown to be a predictor of postoperative short- and long-term mortality[18,20] and postoperative morbidity[20], table 3. Morbidity was defined according to the Clavien-Dindo classification ≥ 3[20].

  In patients who underwent elective carotid endarterectomy[19] or embolectomy for acute limb ischemia[23], a high pre-operative NLR (NLR ≥ 5[19] and NLR ≥ 5.2[23]) predicted postoperative cognitive dysfunction[19] and poor limb survival[23], table 3.

  NLR was an independent predictor of myocardial infarction, stroke and death, in patients with critical limb ischemia, who underwent major amputation[33], table 3.

  In patients who underwent lower limb revascularization, no association was shown between preoperative NLR and postoperative graft patency in the multivariate analysis[22].

Table 3:

aOR: Adjusted odds ratio

PLR: Platelet Lymphocyte Count

RDW: Red Cell Distribution Witdt

uOR: Unadjusted Odds Ratio

Non-cardiac non-vascular surgery

  A study including 1,087 patients examined whether preoperative NLR predicted the risk of infection in patients undergoing total knee arthroplasty[24]. Non-infected patients had a significantly lower NLR than infected patients after surgery[24], table 4. A second study included 294 patients aged 60 years and over undergoing hip-fracture surgery[28]. NLR predicted both postoperative myocardial injury (NLR > 5.1)[28] and in-hospital mortality (NLR > 8.5)[28], table 4. A third study included 56 patients who underwent limb amputation as a result of diabetic foot ulcer[35] and a fourth study included 104 patients with hip fractures undergoing surgery[25]. NLR did not predict mortality after surgery[25,35].

  A fifth study on 108 patients examined the risk of postoperative complications in patients with Crohn’s disease who underwent abdominal surgery[36]. NLR predicted postoperative complications, a OR = 2.78 (1.04-7.43)[36], table 4. Another study on 82 patients examined the risk of postoperative complications within 30 days of major abdominal surgery[26]. There was no significant difference in preoperative NLR for patients with or without medical- or surgical complications[26], table 4.

  A study examined NLR as a predictor of early penile prosthesis implant infection[34]. A preoperative NLR ≥ 6.2 was associated with postoperative infectious events[34], table 4.

  Finally, a study included 60 patients who underwent elective surgery due to intestinal disease, expansive process of the central nervous system or degenerated hip disease[27]. Preoperative NLR did not predict the risk of postoperative sepsis within day 5 of surgery[27].

Table 4:

Risk of bias within the studies

The methodological assessment is summarized in table 5.

  In 23 out of 25 studies, risk of bias was scored to moderate. Two studies were scored to serious risk of bias, since there was no adjustment for confounding[18,24]. The populations examined were generally representative with patients of all ages in both genders. The quality of definitions according to diagnosis was specific in general. Objectives and cut-offs were in the majority of studies decided in advance and definitions of postoperative outcomes were clear. The studies differed in clinical diagnostic methods but followed clinical standards.

Table 5: Risk of bias within studies.

Discussion

  A total of 25 clinical observational studies with 10,015 surgical patients were included. All but two studies in cardiac- and vascular surgery showed a significant association between preoperative NLR and postoperative mortality while 11out of 13 studies reported that high NLR predicted postoperative cardiovascular morbidity. In orthopaedic surgery, NLR predicted troponin elevation after hip surgery and postoperative infections after knee surgery, while no association was shown between preoperative NLR and postoperative complications in patients amputated due to diabetic foot ulcers. NLR predicted postoperative complications after prosthesis implantation[34] and bowel resection[36].

NLR did not predict the risk of postoperative complications after abdominal and miscellaneous non-cardiac surgery.

  NLR reflects a systemic inflammatory state[24]. This association between the inflammatory response and the clinical outcome after surgery is complex. In studies investigating NLR in relation to cancer surgery, it has been reported that neutrophils secrete factors favourable for growth of malignant solid tumours e.g. tumour growth promoting factors[6,41,42]. However, the pathophysiological link between preoperative NLR and clinical outcomes after benign surgery is unclear. Neutrophils release inflammatory mediators, proteolytic enzymes, arachidonic acid derivatives, and superoxide radicals that may promote rupture of coronary plaques and cause further tissue injury[13]. NLR could reflect an imbalance in the acute immunological response. The antibacterial response of natural killer cells and activated T-cells may be supressed by an increased number of neutrophils[47]. The high NLR may then reflect an increased neutrophil-dependent inflammatory response and a decreased lymphocyte-mediated antibacterial immune response[47]. This may weaken the lymphocyte-mediated antibacterial immune response contributing to an increased bacterial invasion and growth[47]. Moreover, a low lymphocyte count indicates a state of immunosuppression and physiological stress that have adverse effects on the overall clinical outcome after surgery[20].

  A clinical study with 211 patients[43] showed that relative lymphopenia is significantly associated with survival of patients with known or suspected stable coronary artery disease. A low relative lymphocyte count may reflect the cortisol-induced stress response[43]. Therefore, the relative lymphocyte count could be a marker of the systemic stress induced by the adrenal axis[43]. Furthermore, a study including 309 patients diagnosed with acute heart failure[49] showed, that a low absolute lymphocyte count was associated with greater in-hospital mortality[49] and that a low absolute lymphocyte count was an independent predictor of all-cause mortality[49].

  The prognostic value of NLR has been compared with other inflammatory biomarkers. In prosthetic joint surgery, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were used to predict prosthetic joint infections. A study including 1087 patients[49] concluded that NLR together with C-reactive protein (CRP)and ESR would increase the accuracy of the diagnosis and prediction of prosthetic joint infection after total knee arthroplasty[49].

  WBC count is included in scoring systems of systemic inflammatory response syndrome[50]. Like WBC, NLR has been shown to predict the risk of sepsis in critically ill patients[50]. A study including 3,227 patients with acute myocardial infarction reported that WBC count was an independent predictor of death or myocardial infarction within 7 years[51]. The best predictive values in the study were a high neutrophil count or a low lymphocyte count resulting in a high NLR[51].

  Moreover, the NLR was shown to be a better predictor of bacteraemia than the currently used inflammatory markers (CRP, WBC and ESR), which had a poor prognostic value compared with the NLR[51]. These results were confirmed in a clinical study including 395 patients[52] diagnosed with community acquired pneumonia. NLR had a higher prognostic accuracy compared with neutrophil count, WBC count, lymphocyte count and CRP[52].

  Additionally, a study[53] including 92 patients with suspected community-acquired bacteraemia showed NLR to be a superior predictor of bacteraemia compared to CRP, WBC and ESR[53]. Hence, NLR is an easy available and inexpensive method whose predictive value has great potential.

Strengths and limitations

  The systematic review was performed according to the PRISMA guidelines. The systematic literature search was performed in four major medical databases. Registration on PROSPERO secured transparency of the study. We excluded studies on patients undergoing transplantation due to the potential confounding of immunosuppressive medicine. The studies reported a variety of predictive NLR cut-off values. In heart surgery, the predictive NLR cut-off value was around 3, while the cut-off value in vascular surgery was around 4.5. In a majority of studies, NLR > 5 was considered to be predictive of clinical outcomes after cancer- surgery[54,55]. The predictive NLR cut-off value seems to depend on the population and type of surgery. With regard to non-cardiac non-vascular surgery, further studies are needed to come closer to a NLR cut-off. Even though a larger number of studies were included in the systematic review a meta analysis was not performed due to heterogeneous clinical outcomes and a heterogeneous reporting of short- and long-term postoperative mortality. The studies in non-cardiac non-vascular surgery were minor studies. The non-significant findings could be due to a lack of power. Therefore, to corroborate or invalidate NLR as a prognostic biomarker in patients undergoing non-cardiac non-vascular surgery further studies with larger populations are needed.

Conclusion

  NLR predicted short-term mortality after cardiac- and vascular surgery. In 11 out of 13 studies, a high NLR predicted postoperative cardiovascular morbidity. In orthopaedic surgery, a high NLR predicted postoperative myocardial injury and mortality after hip surgery and postoperative infections after knee surgery. In general surgery, NLR predicted postoperative complications in patients with Crohn’s disease undergoing bowel resection and postoperative infectious complications. NLR has potential as a prognostic biomarker in patients undergoing benign surgery, however, the prognostic impact of NLR should be further explored in patients undergoing non-cardiac non-vascular surgery.

Conflict of interest: none

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