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Review

Defining the role of neutrophil-to-lymphocyte ratio in COPD: a systematic literature review

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Pages 3651-3662 | Published online: 05 Nov 2018

Abstract

COPD is characterized by a pulmonary and systemic inflammatory process. Several authors have reported the elevation of multiple inflammatory markers in patients with COPD; however, their use in routine clinical practice has limitations. The neutrophil-to-lymphocyte ratio (NLR) is a useful and cost-effective inflammatory marker derived from routine complete blood count. We performed a systematic literature review using the PRISMA statement. Twenty-two articles were included, recruiting 7,601 COPD patients and 784 healthy controls. Compared with controls, COPD patients had significantly higher NLR values. We found a significant correlation between the NLR and clinical/functional parameters (FEV1, mMRC, and BODE index) in COPD patients. Elevation of the NLR is associated with the diagnosis of acute exacerbation of COPD (pooled data propose a cut-off value of 3.34 with a median sensitivity, specificity, and area under the curve of 80%, 86%, and 0.86, respectively). Additionally, increased NLR is also associated with the diagnosis of a bacterial infection in exacerbated patients, with a cut-off value of 7.30, although with a low sensitivity and specificity. The NLR is an independent predictor of in-hospital and late mortality after exacerbation. In conclusion, the NLR could be a useful marker in COPD patients; however, further studies are needed to better identify the clinical value of the NLR.

Introduction

COPD is a major public health problem worldwide and is characterized by poorly reversible airflow limitation and/or alveolar abnormalities. It is usually associated by persistent respiratory symptoms, disease progression, and, in some patients, multiple acute exacerbations.Citation1 COPD accounted for 6% of all deaths globally in 2012 and is currently ranked as the fourth leading cause of death worldwide with a projection to increase in the coming decade.Citation2,Citation3 Chronic inflammation of the airways and the lung parenchyma is the classic paradigm for the pathogenesis of COPD and is associated with goblet cell proliferation, gland hyperplasia, fibrosis, collapse of small airways, and parenchymal destruction.Citation4 However, there is increasing evidence that COPD also results in systemic inflammation and extra-pulmonary manifestations.Citation5

Acute exacerbation of COPD (AECOPD) is related to more severe airway and systemic inflammation than in stable disease patients, and is associated with worse clinical symptoms, reduced lung function, increase hospitalization and intensive care unit admission rates, and more intensive treatments.Citation6,Citation7 The main causes of exacerbations in COPD are viral or bacterial infections, while 15%–20% are caused by other microorganisms or unspecified causes.Citation8

There are limited data regarding inflammatory biomarkers in stable and exacerbated patients in standard clinical practice. However, recent studies have shown that the neutrophil-to-lymphocyte ratio (NLR) is a reliable marker of systemic inflammation and a routinely performed test (complete blood counts), because of its rapidity and easy detection, availability, and cost-effectiveness.Citation9,Citation10 Based on the physiological response of circulating leukocytes to precipitating stress factors, with increased numbers of neutrophils and fewer lymphocytes, the ratio between these two subgroups has been evaluated in periods of inflammation in different diseases, such as lung cancer, colorectal cancer, end-stage renal disease, and acute coronary syndrome, among others.Citation11Citation14

The aim of the present systematic review was to investigate 1) the role of the NLR in the severity of COPD according to clinical and functional outcomes (airflow obstruction [FEV1], dyspnea [mMRC], and exercise capacity [BODE index]); 2) the relation between NLR and other inflammatory biomarkers; and 3) the ability of the NLR to detect or predict the diagnosis of exacerbation, bacterial infection, and mortality.

Materials and methods

Design

This systematic review was performed in accordance with the PRISMA statement.Citation15

Search strategy

The search was carried out using the databases PubMed/Medline, Google Scholar, Scielo, and Scopus, using a combination of the key words: “neutrophil-to-lymphocyte ratio”, “NLR”, “chronic obstructive pulmonary disease”, “COPD”, “lung disease”, “exacerbation”, “prognosis”, and “lung function”. The search included articles published up to January 2018 and was limited to English language studies. The automatic search was complemented by a manual search to identify relevant articles. The search results were exported to the reference manager EndNote (Thompson Reuters), with a total of 482 records identified after duplicates were removed.

Inclusion criteria and study eligibility

The articles were screened by abstracts and full text. Disagreements were resolved by a senior author. Articles that contained the following information were included: 1) diagnosis of COPD according to the GOLD or the American Thoracic Society or the European Respiratory Society, or clearly defined similar criteria; 2) analysis of the associations between NLR and clinical features or outcomes of COPD patients; and 3) NLR cut-off value. The exclusion criteria were 1) review articles, editorial comments, letters, conference abstracts; 2) preclinical studies; or 3) full text unavailable and non-English article.

Data extraction

A standardized extraction form was used to collect data. The data extracted were: 1) authors, year of publication, study design, and sample size; 2) participant characteristics (age, gender); 3) NLR cut-off value and accuracy characteristics; 4) total NLR value in patient subgroups (healthy controls, stable COPD, exacerbated COPD); 5) total NLR value in different severity subgroups according to GOLD; 6) correlation coefficient between NLR and FEV1; 7) correlation coefficient between NLR and clinical parameters of COPD (6-minute walking distance, body mass index, airflow obstruction, and mMRC dyspnea scale); and 8) correlation coefficient between NLR and other inflammatory markers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], and white blood cells).

Quality assessment

The quality of the included studies was analyzed using the Newcastle-Ottawa Quality Assessment Scale (NOS) for cohort, case-control, and cross-sectional studies. This scale is based on three characteristics: selection, comparability, and outcome or exposure (in case-control studies).Citation16 In this “star system”, a maximum of nine stars can be given for cohort and case-control studies, while cross-sectional studies can be given a maximum of ten stars. The thresholds for converting the NOS to Agency for Healthcare Research and Quality standards (good, fair, and poor) were: good quality – 3 or 4 stars in selection domain, 1 or 2 stars in comparability domain, and 2 or 3 stars in outcome/exposure domain; fair quality – 2 stars in selection domain, 1 or 2 stars in comparability domain, and 2 or 3 stars in outcome/exposure domain; and poor quality – 0 or 1 star in selection domain, or 0 stars in comparability domain, or 0 or 1 stars in outcome/exposure domain.Citation17

Statistical analysis

The continuous variables were expressed as mean ± SD. In articles in which the continuous variables were expressed as median and interquartile range, mean and SD were calculated according to Hozo et al.Citation18 Accuracy data and the correlation between the NLR and clinical parameters or other inflammatory markers were expressed as Pearson’s correlation coefficient or Spearman’s Rho. The differences in NLR between groups were estimated using one-way ANOVA with Bonferroni as post hoc test or an unpaired t-test. Statistical analysis was performed using SPSS v22 (IBM SPSS Inc., Armonk, NY, USA). Statistical significance was considered with a value of P<0.05.

Results

Selected studies

shows the flow diagram of the studies. A total of 803 references were found through the literature search (795 automatic searches and eight manual searches). Initially, 321 were duplicates, and the remaining 483 were screened by title and abstract; of these, 459 were excluded and 25 were selected for full-text screening, of which 22 were eligible for inclusion, recruiting a total of 8,385 patients (7,601 COPD patients and 784 healthy controls) with a mean age of 65.65±6.20 years, 5,812 (70%) males, and 2,573 (30%) females. summarizes the characteristics of the articles and the population included. Articles in which the same group of COPD patients was evaluated in both periods of the disease (stable and exacerbated) were considered as providing independent data for statistical analysis.Citation10,Citation19Citation21

Table 1 Characteristics of included articles and population

Figure 1 Flowchart of the systematic review.

Figure 1 Flowchart of the systematic review.

Quality assessment

The present systematic review included five cohort studies, six cross-sectional studies, and eleven case-control studies. Using the NOS form, 20 articles were identified as high quality (five cohort studies, five cross sectional studies, and ten case-control studies), and only two articles were identified as poor quality (one cross-sectional study and one case-control study) ().

Table 2 Study quality assessment using the Newcastle-Ottawa scale

Neutrophil-to-lymphocyte ratio and COPD exacerbation

The mean NLR values of healthy controls and stable and exacerbated COPD patients were extracted from 8,Citation10,Citation21,Citation23Citation28 18,Citation9,Citation10,Citation19Citation21,Citation23Citation25 and 17 articles,Citation9,Citation10,Citation19Citation26,Citation28,Citation32,Citation34Citation38 respectively. The pooled data showed that the mean NLR values of healthy controls, and stable and exacerbated COPD patients were 1.71±0.22, 2.97±1.10, and 7.76±3.79, respectively (). The NLR in COPD patients with exacerbation was significantly higher than that in stable patients and healthy controls (P<0.0005) (). There were no significant differences between stable COPD patients and healthy controls when one-way ANOVA with Bonferroni post hoc test was used, but differences were found using an unpaired t-test (P<0.0001).

Table 3 NLR value of healthy controls, and stable and exacerbated COPD patients

Figure 2 Neutrophil-to-lymphocyte ratio in healthy controls, and stable and exacerbated COPD patients.

Note: Box plots represent median, interquartile range, and range with outliers plotted separately.
Figure 2 Neutrophil-to-lymphocyte ratio in healthy controls, and stable and exacerbated COPD patients.

Two observational prospective studies have assessed the NLR as an independent predictor of COPD exacerbation during the first year follow-up, although only one found statistically significant differences (OR 2.083, 95% CI: 0.918–4.723, P=0.079Citation25 and OR 2.05, 95% CI: 1.03–4.06, P=0.041Citation33).

The accuracy of NLR data for detecting COPD exacerbation was described in seven articles ().Citation9,Citation10,Citation23,Citation24,Citation26,Citation34,Citation35 The median cut-off value for a high NLR was 3.34 (range 1.5–3.35) with a sensitivity, specificity, and under the curve (AUC) being in the range 69%–93%, 59%–90%, and 0.58–0.89, respectively. Three articles described the accuracy of NLR data for distinguishing between bacterial and non-bacterial exacerbation in patients admitted to the emergency room with a diagnosis of acute exacerbation of COPD.Citation28,Citation32,Citation36 The median cut-off value for detecting bacterial infection in exacerbated patients was 7.30 (range 4.52–11.5) with a sensitivity, specificity, and AUC in the range 61%–91%, 46%–73.1%, and 0.58–0.79, respectively ().

Table 4 Accuracy data of NLR for detecting COPD global and bacterial infection exacerbation

Correlation between NLR and clinical outcomes in COPD patients

Six authors evaluated the correlation between NLR and FEV1.Citation24Citation26,Citation30,Citation33,Citation34 In four articles, the data were analyzed using Pearson’s correlation coefficientCitation24Citation26,Citation33 and in two using Spear-man’s rank correlation (Spearman’s Rho) (). Five articles showed a significant negative correlation between the two parameters. Pooled data showed a median Pearson’s correlation of −0.22 (range −0.17 to −0.28) and a median Spearman’s correlation of −0.43 (range −0.38 to −0.49).

Table 5 Correlation data between NLR and FEV1

Three articles evaluated the relationship between the NLR values and GOLD stages,Citation22,Citation23,Citation31 and a pooled analysis showed no significant differences in NLR values between GOLD stages (GOLD 1/2: 2.40±0.36 and GOLD 3/4: 2.22±0.36; P=0.63). However, one study showed positive linear relationship between NLR and COPD severity in the stable group, whereas the results in patients exacerbated in stages 1 and 4 were similar ().Citation23

Table 6 NLR during stable and exacerbation periods according to GOLD stage

The correlation between NLR and other clinical parameters was evaluated by two authors.Citation25,Citation30 However, the heterogeneity in the statistical analysis precludes pooling the results. Furutate et alCitation30 showed a significant positive correlation between NLR and mMRC or BODE index (Rho=0.403; P<0.001 and Rho=0.46; P<0.001, respectively). Likewise, Lee et alCitation25 showed a significant positive correlation between these parameters (r=0.39; P=0.01 and r=0.45; P=0.003, respectively).

NLR and other inflammatory biomarkers in COPD patients

Data on the correlation between NLR and other inflammatory parameters were extracted from ten articles ().Citation9,Citation10,Citation22Citation24,Citation26,Citation28,Citation30,Citation34,Citation38 CRP was the most frequently evaluated parameter.Citation9,Citation10,Citation22Citation24,Citation26,Citation28,Citation30,Citation38 The pooled data show that the median correlation between NLR and CRP values was Rho=0.43 (range 0.20–0.48) in stable COPD patients. In exacerbated COPD patients, four articles analyzed the data using Pearson’s correlation coefficientCitation9,Citation10,Citation26,Citation38 and two using Spearman’s rank correlation (Spearman’s Rho),Citation22,Citation23 showing a median of 0.46 (range 0.28–0.60) and 0.59 (range 0.53–0.66), respectively. In all articles, the correlation was statistically significant. Analyzing the comparative individual studies, a similar trend was observed in both CRP and NLR markers during the stable and exacerbation phases of COPD (CRP 7.39±8.15 mg/dL stable vs 26.49±24.32 mg/dL exacerbated; P<0.001). The median cut-off value of CRP for detecting AECOPD was 2.56 mg/dL (range 1.17–3.35) with a sensitivity, specificity, and AUC in the range 68%–91%, 52%–62%, and 0.75–0.82, respectively.

Table 7 Correlation between NLR and other inflammatory parameters in COPD patients

The second most studied parameter was ESR. The pooled data show that the median correlation between NLR and ESR values was r=0.42 (range 0.27–0.71)Citation10,Citation26 and Rho=0.49 (range 0.29–0.55)Citation34 in exacerbated patients, and only one article showed a significant correlation between parameters in total COPD patients (Rho=0.26; P<0.001).Citation24 Likewise, three articles showed a significant positive correlation between NLR and leukocytes.Citation10,Citation26,Citation34 The pooled data show a median Pearson’s correlation of r=0.49 (range 0.30–0.69). Only one article reported Spearman’s Rho (Rho=0.33; P<0.05),Citation34 and the correlation between NLR and leukocytes was evaluated only in exacerbated COPD patients.

Analyzing individual studies for which data were available,Citation9,Citation10,Citation19,Citation20,Citation22Citation24,Citation26,Citation28,Citation32 although all markers showed significant differences in mean values between the stable and exacerbation phases, the difference was quantitatively greater in the NLR (3.57±1.54 stable vs 6.72±4.77 exacerbated) than in the absolute values of neutrophils (5.76±1.08×103/µL stable vs 7.36±1.55×103/µL exacerbated) or lymphocytes (1.54±0.59×103/µL stable vs 1.19±0.54×103/µL exacerbated) assessed separately, with differences between their absolute values being 3.15, 1.6, and −0.35, respectively.

Two studiesCitation19,Citation20 analyzed the relationship between eosinophilia and the NLR in acute and stable phase patients. In both studies, the NLR was higher in patients with a lower percentage of eosinophils (<2%) both in stable COPD (overall mean value, 6.99±1.25 vs 3.99±0.71, P=0.001) and in AECOPD (11.33±2.11 vs 4.25±0.65, P=0.001).

Prognostic significance of NLR in COPD patients

Five articles found that the NLR represents an independent predictor of mortality in COPD patients ().Citation19Citation21,Citation27,Citation37 Saltürk et alCitation19 and Rahimirad et alCitation37 conducted a multivariate analysis and found that high NLR values represent an independent predictor of in-hospital mortality during exacerbation, showing 2–3.5-fold more probability (OR 1.96, 95% CI: 1.13–3.39; P=0.016 and OR 3.586, 95% CI: 1.69–7.60; P=0.001, respectively) with a median NLR cut-off value of 10 (range 4–16). On the other hand, Duman et al,Citation20 Xiong et al,Citation27 and Kumar et alCitation21 found that the NLR is an independent predictor of early (first 90 days) and late (within 6 and 24 months) mortality during the follow-up after exacerbation. According to Duman et al,Citation20 there was an almost twofold (OR 1.79, 95% CI: 1.37–2.34; P=0.001) higher probability of mortality within 6 months after exacerbation with an NLR cut-off value of 7, while Xiong et alCitation27 showed that there was an almost fourfold (OR 3.95, 95% CI: 2.54–6.38; P<0.001) higher probability of mortality within 24 months after exacerbation with an NLR cut-off value of 3.3.

Table 8 Predictive value of NLR in COPD patients’ mortality based on multivariate analysis

Discussion

COPD is characterized by an increase in pulmonary and systemic inflammatory responsesCitation39 that are maintained after smoking cessation and could progressively increase over time.Citation40 Different studies have shown that lung inflammation induced by COPD is mediated by innate and adaptive immune system deprivation.Citation41,Citation42

Changes in the innate immune system in COPD patients are related to injury of the alveolar epithelium, a decrease in phagocytosis mediated by macrophages, a reduction in dendritic cells in airways, and an increase in neutrophil migration into the airways that is not accompanied by correct bacterial clearance. This neutrophil migration stimulates cytokine production and subsequent destruction of lung tissue,Citation40,Citation43Citation45 which leads to changes in the microbiome of patients with COPD that seem to be related to the perpetuation of the inflammatory response in the airway despite the cessation of smoking.Citation46

Changes in the adaptive immune system are due to an increase in CD8+ T lymphocytes within the airway,Citation42 which has been related to the production of larger amounts of cytotoxic perforins, granzyme B, and macrophage elastase (MMP-12), leading to tissue damage.Citation47 On the other hand, some studies have found that CD4+ T lymphocytes participate in the amplification of the adaptive immune response.Citation48 In addition, they seem to play a role in the development of autoimmunity;Citation49 however, the clinical role of these data remains to be elucidated.

Several studies have suggested that patients with COPD present elevated serum inflammatory markers. It has been estimated that ~70% of patients with COPD have at least one elevated serum inflammatory parameter.Citation49 Some data have shown that the persistent elevation of inflammatory markers is related to the progression of the disease,Citation50 clinical and functional parameters,Citation51 and the development of comorbidities.Citation40 The most studied serum inflammatory markers are CRP, IL-6, and TNF-α.Citation50 However, their use in routine clinical practice has limitations, while NLR is a rapid, easy, and cost-effective method derived from routine complete blood count tests. The NLR has been reported to be a useful indicator of clinical outcome and severity in malignant and inflammatory diseases.Citation51Citation54

In the present study, the NLR showed a positive and significant correlation with other traditional inflammatory markers such as CRP, leukocytes, and ESR. Analyzing the comparative individual studies, a similar trend was observed in both CRP and NLR markers during the stable and exacerbation phases of COPD. Therefore, the data seem to indicate that both are equally effective in the detection of AECOPD. However, NLR is easy to calculate from a routine complete blood count and is cheaper than serum CRP-level measurement. On the other hand, the difference is quantitatively greater in the NLR compared to absolute values of neutrophils and lymphocytes, which is expected, since the NLR includes both biomarkers. This analysis shows the potential usefulness of NLR as an inflammatory marker in patients with COPD and indicates the possibility of using the NLR as a useful marker in routine clinical practice, although more validation studies are required in this regard.

The pooling of data in this systematic review demonstrated that the NLR value was significantly elevated in stable COPD patients compared with healthy subjects, which suggests that systemic inflammation is persistent in this population. This observation is consistent with other published data that showed elevation of inflammatory markers such as IL-6 and CRP in patients with stable COPD compared with healthy controls.Citation55Citation57

It was also shown that exacerbated COPD patients had significantly higher NLR values compared with stable COPD patients. In addition, it was observed that the NLR decreased in patients with exacerbated COPD after recovery of the exacerbation.Citation10,Citation19,Citation21 These findings are consistent with other studies in which the same behavior of other inflammatory markers was observed, along with a greater inflammatory response during exacerbation of COPD.Citation58,Citation59 Taken together, these data suggest that the NLR is a marker that could be used to evaluate the inflammatory status of patients with COPD and predict the remission of the inflammatory process during exacerbations. In the present systematic review, only one out of two single studies found that elevation of the NLR is an independent predictor of acute exacerbation in patients with COPD, with a twofold increase in the likelihood of exacerbation in patients with a high NLR in the stable phase. A previous prospective study demonstrated that the single best predictor of future exacerbations, across all GOLD stages, was a treated exacerbation in the year before study entry (OR 4.30, 95% CI: 3.58–5.17; P<0.001).Citation60 Other studies have also shown a predictive value of other inflammatory markers for acute exacerbation in COPD patients.Citation58,Citation61 Hence, the discordant findings of the NLR in the present review do not support the value of this marker as a predictor of future exacerbations. However, the NLR seems to be a good marker for detecting an acute exacerbation in COPD patients. The pooled data indicate that a cut-off value of 3.34 would allow the diagnosis of acute exacerbation with a median AUC of 0.86, sensitivity of 80%, and specificity of 86%. Similarly, the pooled data suggest a median cut-off value of 7.30 for detecting infectious exacerbation of COPD patients with a median AUC of 0.75, but with a wide range of cut-off values and rather low sensitivity (76.8%) and specificity (52%). The possibility that the NLR could predict bacterial exacerbation appears more interesting, in view of its clinical implications. Although the results shown here do not support this hypothesis, future studies are required to validate this information.

In our review, the NLR was higher in patients with a lower percentage of eosinophils (<2%) both in stable COPD and in AECOPD, and it should be noted that these patients presented greater therapeutic failure after corticosteroid treatment for the exacerbation. These findings agree with other studies that show a negative correlation between the eosinophil count and bacterial isolates in the sputum of patients with stable COPD.Citation62 The percentage of blood eosinophils is also inversely correlated to the presence of bacterial infection in AECOPD.Citation62 Hence, the combination of both markers (NLR and eosinophilia) could identify a therapeutic phenotype (the one that requires antibiotic and/or the one that requires systemic corticosteroids). Therefore, NRL could be used to monitor the exacerbation and to support therapeutic decision making.

On the other hand, no statistically significant differences were found in the NLR when patients were stratified using the GOLD airflow obstruction classification. However, one study showed a positive linear relationship between NLR and COPD severity in the stable group.Citation23 The data regarding the association of inflammatory markers with GOLD classification are contradictory. In this regard, De Moraes et alCitation55 found no direct association between IL-6 and IL-8 and the severity of COPD in ex-smokers. Nevertheless, Mathanraj et alCitation63 and Torres-Ramos et alCitation56 reported a significant increase in TNF-α and CRP, respectively, according to GOLD stage. The findings in the different studies show the heterogeneity of the cohorts studied and the potential impact of comorbidities associated with COPD on systemic inflammatory markers. In addition, a high percentage of patients in GOLD stage II (about 22% according to the ECLIPSE study)Citation60 also have frequent exacerbations, which are related to an increased and persistent inflammatory status in the stable stage.

The relationship between inflammatory markers and clinical/functional parameters in COPD patients was described in some articles. A positive correlation between IL-6 and a rapid decline in FEV1 has been demonstrated previously.Citation51,Citation59 Other authors reported a significant correlation between IL-6, CRP, and BODE index.Citation64,Citation65 These data suggest that the inflammatory status of COPD patients is associated with disease progression, and worsening dyspnea and exercise tolerance.Citation55 In the present review, some authors found a moderate correlation between NLR and FEV1, mMRC, and BODE index. These findings suggest that NLR could be used as a clinical performance marker in COPD patients.Citation25,Citation30

The prognostic value of different inflammatory markers in COPD patients has previously been reported by other authors. In a cross-sectional prospective study, Shafiek et alCitation66 found that high levels of IL-6 predict in-hospital mortality. Similarly, a recent meta-analysis found that a high baseline level of CRP is significantly associated with higher late mortality in COPD patients.Citation67 Other inflammatory markers such as IL-1β and fibronectin have also been described to be associated with mortality of COPD.Citation68 In the present study, we found that the NLR is an independent predictor of in-hospital mortality, with 2–3.5-fold higher probability of mortality with a median NLR cut-off value of 10. In addition, the NLR seems to be an independent predictor of late mortality, with a high NLR value being associated with two- to four fold higher probability of death after exacerbation. All-cause mortality analysis is the method most usually performed in the studies, and the influence of other systemic diseases (such as lung cancer) on the NLR may introduce a certain bias. However, in favor of the NLR as an AECOPD biomarker, Rahimirad et alCitation37 showed a statistically significant relationship between the ratio and the in-hospital mortality due to respiratory causes.

Regarding the potential effect of the patient’s treatment on the NLR, most studies in this review excluded patients with a history of antibiotic treatment and the use of systemic steroids in at least the two preceding months. Hence, treatment with steroids was started at the time of AECOPD diagnosis; it was thus able to influence the subsequent neutrophil and lymphocyte counts, but not the baseline measurement. Dividing patients into two groups according to systemic glucocorticoid use at baseline, Sørensen et alCitation29 concluded that treatment with systemic glucocorticoids has a significant impact on the ability of inflammatory biomarkers to predict all-cause mortality, with higher mortality in the group not undergoing this treatment. The use of inhaled corticosteroids to treat COPD patients is not recorded in the studies, and so the potential effect of this therapy on the NLR is unknown.

Limitations

There are several limitations in this systematic review. First, most studies included were retrospective, with the possibility of selection bias. Second, most studies included had a small number of patients. Furthermore, the heterogeneity in the methodology and the primary outcomes between studies limited the gathering of some clinical parameters evaluated. No meta-analysis was possible due to the heterogeneity and the impossibility of extracting the necessary data.

Conclusion

In conclusion, this is the most comprehensive systematic review to date to show that the NLR is higher in stable COPD patients than healthy controls, and that the NLR is also higher in exacerbated compared with stable COPD patients. The NLR is a good marker for detecting acute exacerbation in COPD patients. This systematic review proposes a cut-off value of 3.34, which achieves an acceptable degree of accuracy. There was no evidence of a relationship between NLR and GOLD airflow obstruction classification. However, we found that there was a significant correlation between the NLR and clinical/functional parameters (FEV1, mMRC, and BODE index) in COPD patients, which suggests that a high NLR could be associated with a worsening of dyspnea, clinical performance, and degree of bronchial obstruction. Besides, we found that the NLR may provide an added value to predict the risk of in-hospital and late mortality in COPD patients. Further prospective studies to address confounders with larger sample sizes and including different disease stages are needed to better identify the clinical value of the NLR.

Author contributions

All authors contributed toward data acquisition, analysis and interpretation of results, drafting and critically revising the paper, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Acknowledgments

The publication of this systematic review was supported by a grant from the Instituto de Salud Carlos III (Grant FIS-PI16/00193, co-funded by European Regional Development Fund [ERDF], a way to build Europe) to Salud Santos. The authors received no compensation related to the development of the manuscript.

Disclosure

The authors report no conflicts of interest in this work.

References

  • VogelmeierCFCrinerGJMartinezFJGlobal strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD executive summaryAm J Respir Crit Care Med2017195555758228128970
  • LozanoRNaghaviMForemanKGlobal and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010Lancet201238098592095212823245604
  • MathersCDLoncarDProjections of global mortality and burden of disease from 2002 to 2030PLoS Med2006311e44217132052
  • MacneeWPathogenesis of chronic obstructive pulmonary diseaseProc Am Thorac Soc20052425826616267346
  • WalterREWilkJBLarsonMGSystemic inflammation and COPD: the Framingham Heart StudyChest20081331192517908709
  • ZhouXLiQZhouXExacerbation of Chronic Obstructive Pulmonary DiseaseCell Biochem Biophys201573234935527352322
  • GroenewegenKHPostmaDSHopWCIncreased systemic inflammation is a risk factor for COPD exacerbationsChest2008133235035718198263
  • SethiSMurphyTFInfection in the pathogenesis and course of chronic obstructive pulmonary diseaseN Engl J Med2008359222355236519038881
  • KurtipekEBekciTTKesliRSamiSSTerziYThe role of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in exacerbation of chronic obstructive pulmonary diseaseJ Pak Med Assoc201565121283128726627508
  • TaylanMDemirMKayaHAlterations of the neutrophil-lymphocyte ratio during the period of stable and acute exacerbation of chronic obstructive pulmonary disease patientsClin Respir J Epub201586
  • CedrésSTorrejonDMartínezANeutrophil to lymphocyte ratio (NLR) as an indicator of poor prognosis in stage IV non-small cell lung cancerClin Transl Oncol2012141186486922855161
  • WalshSRCookEJGoulderFJustinTAKeelingNJNeutrophil-lymphocyte ratio as a prognostic factor in colorectal cancerJ Surg Oncol200591318118416118772
  • NúñezJNúñezEBodíVUsefulness of the neutrophil to lymphocyte ratio in predicting long-term mortality in ST segment elevation myocardial infarctionAm J Cardiol2008101674775218328833
  • TurkmenKErdurFMOzcicekFPlatelet-to-lymphocyte ratio better predicts inflammation than neutrophil-to-lymphocyte ratio in end-stage renal disease patientsHemodial Int201317339139623522328
  • MoherDLiberatiATetzlaffJAltmanDGPRISMA GroupPreferred reporting items for systematic reviews and meta-analyses: the PRISMA statementAnn Intern Med2009151426426919622511
  • WellsGASheaBO’ConnellDThe Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses Available from: www.ohrica/programs/clinical_epidemiology/oxford.aspAccessedJanuary 10, 2018
  • ViswanathanMPatnodeCDBerkmanNDRecommendations for assessing the risk of bias in systematic reviews of health-care interventionsJ Clin Epidemiol201897263429248724
  • HozoSPDjulbegovicBHozoIEstimating the mean and variance from the median, range, and the size of a sampleBMC Med Res Methodol2005511315840177
  • SaltürkCKarakurtZAdiguzelNDoes eosinophilic COPD exacerbation have a better patient outcome than non-eosinophilic in the intensive care unit?Int J Chron Obstruct Pulmon Dis2015101837184626392758
  • DumanDAksoyEAgcaMCThe utility of inflammatory markers to predict readmissions and mortality in COPD cases with or without eosinophiliaInt J Chron Obstruct Pulmon Dis2015102469247826648709
  • KumarPLawSSriramKBEvaluation of platelet lymphocyte ratio and 90-day mortality in patients with acute exacerbation of chronic obstructive pulmonary diseaseJ Thorac Dis2017961509151628740663
  • GünayESarınç UlaşlıSAkarONeutrophil-to-lymphocyte ratio in chronic obstructive pulmonary disease: a retrospective studyInflammation201437237438024078279
  • BilirBAltıntaşNAydınMThe Predictive Role of Neutrophil to Lymphocyte ratio in Chronic Obstructive Pulmonary DiseaseEur J Gen Med2016132105110
  • InEKuluöztürkMÖnerÖDeveciFThe Importance of Neutrophil-to-Lymphocyte Ratio in Chronic Obstructive Pulmonary DiseaseTurk Thorac J2016172414629404122
  • LeeSJLeeHRLeeTWUsefulness of neutrophil to lymphocyte ratio in patients with chronic obstructive pulmonary disease: a prospective observational studyKorean J Intern Med201631589189827017385
  • YousefAMAlkhiaryWRole of neutrophil to lymphocyte ratio in prediction of acute exacerbation of chronic obstructive pulmonary diseaseEgypt J Chest Dis Tuberc20176614348
  • XiongWXuMZhaoYWuXPudasainiBLiuJMCan we predict the prognosis of COPD with a routine blood test?Int J Chron Obstruct Pulmon Dis20171261562528243079
  • FarahRIbrahimRNassarMNajibDZivonyYEshelEThe neutrophil/lymphocyte ratio is a better addition to C-reactive protein than CD64 index as a marker for infection in COPDPanminerva Med201759320320928185443
  • SørensenAKHolmgaardDBMygindLHJohansenJPedersenCNeutrophil-to-lymphocyte ratio, calprotectin and YKL-40 in patients with chronic obstructive pulmonary disease: correlations and 5-year mortality – a cohort studyJ Inflamm201512120
  • FurutateRIshiiTMotegiTThe neutrophil to lymphocyte ratio is related to disease severity and exacerbation in patients with chronic obstructive pulmonary diseaseIntern Med201655322322926831014
  • DuyarSSPlatelet to Lymphocyte Ratio as a Novel Prognostic Marker in Male Patients with Chronic Obstructive Pulmonary DiseaseInt J Respir Pulm Med201631043
  • van de GeijnGMDenkerSMeuleman-van WaningVEvaluation of new laboratory tests to discriminate bacterial from nonbacterial chronic obstructive pulmonary disease exacerbationsInt J Lab Hematol201638661662827459873
  • LeeHUmSJKimYSAssociation of the neutrophil-to-lymphocyte ratio with lung function and exacerbations in patients with chronic obstructive pulmonary diseasePLoS One2016116e015651127258044
  • Mohamed-HusseinAAlySSAsmaaMZahranAMNeutrophil CD64 and neutrophil/lymphocyte ratio as predictors of hospital outcome in acute exacerbation COPDIJASRM20172717
  • Acartürk TunçayEKarakurtZAksoyEEosinophilic and non-eosinophilic COPD patients with chronic respiratory failure: neutrophil-to-lymphocyte ratio as an exacerbation markerInt J Chron Obstruct Pulmon Dis2017123361337029200843
  • TanrıverdiHÖrnekTErboyFComparison of diagnostic values of procalcitonin, C-reactive protein and blood neutrophil/lymphocyte ratio levels in predicting bacterial infection in hospitalized patients with acute exacerbations of COPDWien Klin Wochenschr201512719–2075676325586444
  • RahimiradSGhaffaryMRRahimiradMHRashidiFAssociation between admission neutrophil to lymphocyte ratio and outcomes in patients with acute exacerbation of chronic obstructive pulmonary diseaseTuberk Toraks2017651253128621246
  • YaoCLiuXTangZPrognostic role of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio for hospital mortality in patients with AECOPDInt J Chron Obstruct Pulmon Dis2017122285229028814856
  • AngelisNPorpodisKZarogoulidisPAirway inflammation in chronic obstructive pulmonary diseaseJ Thorac Dis20146Suppl 1S167S17224672691
  • KingPTInflammation in chronic obstructive pulmonary disease and its role in cardiovascular disease and lung cancerClin Transl Med2015416826220864
  • ShaykhievRCrystalRGInnate immunity and chronic obstructive pulmonary disease: a mini-reviewGerontology201359648148924008598
  • NurwidyaFDamayantiTYunusFThe Role of Innate and Adaptive Immune Cells in the Immunopathogenesis of Chronic Obstructive Pulmonary DiseaseTuberc Respir Dis2016791513
  • VlahosRBozinovskiSRole of alveolar macrophages in chronic obstructive pulmonary diseaseFront Immunol2014543525309536
  • GiviMERedegeldFAFolkertsGMortazEDendritic cells in pathogenesis of COPDCurr Pharm Des201218162329233522390696
  • HoenderdosKCondliffeAThe neutrophil in chronic obstructive pulmonary diseaseAm J Respir Cell Mol Biol201348553153923328639
  • SzeMADimitriuPAHayashiSThe lung tissue microbiome in chronic obstructive pulmonary diseaseAm J Respir Crit Care Med2012185101073108022427533
  • MaenoTHoughtonAMQuinteroPAGrumelliSOwenCAShapiroSDCD8+ T Cells are required for inflammation and destruction in cigarette smoke-induced emphysema in miceJ Immunol2007178128090809617548647
  • JuJAn Increased Proportion of Apoptosis in CD4+ T Lymphocytes Isolated from the Peripheral Blood in Patients with Stable Chronic Obstructive Pulmonary DiseaseTuberc Respir Dis2018812132137
  • OhJYSinDDLung inflammation in COPD: why does it matter?F1000 Med Rep201242323236338
  • SuBLiuTFanHInflammatory Markers and the Risk of Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-AnalysisPLoS One2016114e015058627104349
  • DonaldsonGCSeemungalTAPatelISAirway and systemic inflammation and decline in lung function in patients with COPDChest200512841995200416236847
  • CataudellaEGiraffaCMDi MarcaSNeutrophil-To-Lymphocyte Ratio: An Emerging Marker Predicting Prognosis in Elderly Adults with Community-Acquired PneumoniaJ Am Geriatr Soc20176581796180128407209
  • IsaacVWuCYHuangCTBauneBTTsengCLMclachlanCSElevated neutrophil to lymphocyte ratio predicts mortality in medical inpatients with multiple chronic conditionsMedicine20169523e383227281085
  • YuYQianLCuiJValue of neutrophil-to-lymphocyte ratio for predicting lung cancer prognosis: a meta-analysis of 7,219 patientsMol Clin Oncol20177349850628811903
  • de MoraesMRda CostaACCorrêaKSJunqueira-KipnisAPRabahiMFInterleukin-6 and interleukin-8 blood levels’ poor association with the severity and clinical profile of ex-smokers with COPDInt J Chron Obstruct Pulmon Dis2014973574325114519
  • Torres-RamosYDGarcía-GuillenMLOlivares-CorichiIMHicksJJCorrelation of Plasma Protein Carbonyls and C-Reactive Protein with GOLD Stage Progression in COPD PatientsOpen Respir Med J200931616619461898
  • AgustíAEdwardsLDRennardSIPersistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotypePLoS One201275e3748322624038
  • GallegoMPomaresXCapillaSC-reactive protein in outpatients with acute exacerbation of COPD: its relationship with microbial etiology and severityInt J Chron Obstruct Pulmon Dis2016112633264027799762
  • Emami ArdestaniMZaerinORole of Serum Interleukin 6, Albumin and C-Reactive Protein in COPD PatientsTanaffos201514213414026528368
  • HurstJRVestboJAnzuetoAEvaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary diseaseN Engl J Med2010363121128113820843247
  • KoutsokeraAKostikasKNicodLPFittingJWPulmonary biomarkers in COPD exacerbations: a systematic reviewRespir Res201314111124143945
  • KolsumUDonaldsonGCSinghRBlood and sputum eosinophils in COPD; relationship with bacterial loadRespir Res20171818828482840
  • MathanrajSVysakKYuvarajanSCorrelation of serum TNF alpha level with severity of chronic obstructive pulmonary diseaseInt J Res Med Sci20175833093316
  • MeshramPLShindeSNRamrajeNNHegdeRRStudy of inflammatory markers and BODE index in chronic obstructive pulmonary diseaseLung India2018351374029319032
  • Garcia-RioFMiravitllesMSorianoJBSystemic inflammation in chronic obstructive pulmonary disease: a population-based studyRespir Res20101116320500811
  • ShafiekHOutcome Predictors of Severe Acute Exacerbation of Chronic Obstructive Pulmonary Disease: Role of Inflammatory BiomarkersInt J Respir Pulm Med201632047
  • LeuzziGGaleoneCTavernaFSuatoniPMorelliDPastorinoUC-reactive protein level predicts mortality in COPD: a systematic review and meta-analysisEur Respir Rev20172614316007028143876
  • KellyEOwenCAPinto-PlataVCelliBRThe role of systemic inflammatory biomarkers to predict mortality in chronic obstructive pulmonary diseaseExpert Rev Respir Med201371576423362815