Neutrophil-to-lymphocyte ratio as an independent predictor for unfavorable functional outcome in aneurysmal subarachnoid hemorrhage

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OBJECTIVE

Stroke-associated immunosuppression and inflammation are increasingly recognized as factors triggering infections and thus potentially influencing outcome after stroke. Several studies have demonstrated that elevated neutrophil-to-lymphocyte ratio (NLR) is a significant predictor of adverse outcomes for patients with ischemic stroke or intracerebral hemorrhage. Thus far, in patients with subarachnoid hemorrhage the association between NLR and outcome is insufficiently established. The authors sought to investigate the association between NLR on admission and functional outcome in aneurysmal subarachnoid hemorrhage (aSAH).

METHODS

This observational study included all consecutive aSAH patients admitted to a German tertiary center over a 5-year period (2008–2012). Data regarding patient demographics and clinical, laboratory, and in-hospital measures, as well as neuroradiological data, were retrieved from institutional databases. Functional outcome was assessed at 3 and 12 months using the modified Rankin Scale (mRS) score and categorized into favorable (mRS score 0–2) and unfavorable (mRS score 3–6). Patients’ radiological and laboratory characteristics were compared between aSAH patients with favorable and those with unfavorable outcome at 3 months. In addition, multivariate analysis was conducted to investigate parameters independently associated with favorable outcome. Receiver operating characteristic (ROC) curve analysis was undertaken to identify the best cutoff for NLR to discriminate between favorable and unfavorable outcome in these patients. To account for imbalances in baseline characteristics, propensity score matching was carried out to assess the influence of NLR on outcome measures.

RESULTS

Overall, 319 patients with aSAH were included. Patients with unfavorable outcome at 3 months were older, had worse clinical status on admission (Glasgow Coma Scale score and Hunt and Hess grade), greater amount of subarachnoidal and intraventricular hemorrhage (modified Fisher Scale grade and Graeb score), and higher rates of infectious complications (pneumonia and sepsis). A significantly higher NLR on admission was observed in patients with unfavorable outcome according to mRS score (median [IQR] NLR 5.8 [3.0–10.0] for mRS score 0–2 vs NLR 8.3 [4.5–12.6] for mRS score 3–6; p < 0.001). After adjustments, NLR on admission remained a significant predictor for unfavorable outcome in SAH patients (OR [95% CI] 1.014 [1.001–1.027]; p = 0.028). In ROC analysis, an NLR of 7.05 was identified as the best cutoff value to discriminate between favorable and unfavorable outcome (area under the curve = 0.614, p < 0.001, Youden’s index = 0.211; mRS score 3–6: 94/153 [61.4%] for NLR ≥ 7.05 vs 67/166 [40.4%] for NLR < 7.05; p < 0.001). Subanalysis of patients with NLR levels ≥ 7.05 vs < 7.05, performed using 2 propensity score–matched cohorts (n = 133 patients in each group), revealed an increased proportion of patients with unfavorable functional outcome at 3 months in patients with NLR ≥ 7.05 (mRS score 3–6 at 3 months: NLR ≥ 7.05 82/133 [61.7%] vs NLR < 7.05 62/133 [46.6%]; p = 0.014), yet without differences in mortality at 3 months (NLR ≥ 7.05 37/133 [27.8%] vs NLR < 7.05 27/133 [20.3%]; p = 0.131).

CONCLUSIONS

Among aSAH patients, NLR represents an independent parameter associated with unfavorable functional outcome. Whether the impact of NLR on functional outcome is related to preexisting comorbidities or represents independent causal relationships in the context of stroke-associated immunosuppression should be investigated in future studies.

ABBREVIATIONS aSAH = aneurysmal subarachnoid hemorrhage; AUC = area under the curve; DSA = digital subtraction angiography; GCS = Glasgow Coma Scale; ICH = intracerebral hemorrhage; IVH = intraventricular hemorrhage; mFisher = modified Fisher Scale; mRS = modified Rankin Scale; NLR = neutrophil-to-lymphocyte ratio; PS = propensity score; ROC = receiver operating characteristic; WFNS = World Federation of Neurosurgical Societies.
Article Information

Contributor Notes

Correspondence Stefan T. Gerner: University Hospital Erlangen, Germany. stefan.gerner@uk-erlangen.de.INCLUDE WHEN CITING Published online February 1, 2019; DOI: 10.3171/2018.9.JNS181975.Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
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References
  • 1

    Azab BCamacho-Rivera MTaioli E: Average values and racial differences of neutrophil lymphocyte ratio among a nationally representative sample of United States subjects. PLoS One 9:e1123612014

    • Search Google Scholar
    • Export Citation
  • 2

    Balkwill FMantovani A: Inflammation and cancer: back to Virchow? Lancet 357:5395452001

  • 3

    Bhat TTeli SRijal JBhat HRaza MKhoueiry G: Neutrophil to lymphocyte ratio and cardiovascular diseases: a review. Expert Rev Cardiovasc Ther 11:55592013

    • Search Google Scholar
    • Export Citation
  • 4

    Castelino DJMcNair PKay TW: Lymphocytopenia in a hospital population—what does it signify? Aust N Z J Med 27:1701741997

  • 5

    Chen-Roetling JRegan RF: Targeting the Nrf2-heme oxygenase-1 axis after intracerebral hemorrhage. Curr Pharm Des 23:222622372017

  • 6

    D’Agostino RB Jr: Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 17:226522811998

    • Search Google Scholar
    • Export Citation
  • 7

    Darsaut TEJack ASKerr RSRaymond J: International Subarachnoid Aneurysm Trial—ISAT part II: study protocol for a randomized controlled trial. Trials 14:1562013

    • Search Google Scholar
    • Export Citation
  • 8

    Elkins JVeltkamp RMontaner JJohnston SCSinghal ABBecker K: Safety and efficacy of natalizumab in patients with acute ischaemic stroke (ACTION): a randomised, placebo-controlled, double-blind phase 2 trial. Lancet Neurol 16:2172262017

    • Search Google Scholar
    • Export Citation
  • 9

    Fang YNTong MSSung PHChen YLChen CHTsai NW: Higher neutrophil counts and neutrophil-to-lymphocyte ratio predict prognostic outcomes in patients after non-atrial fibrillation-caused ischemic stroke. Biomed J 40:1541622017

    • Search Google Scholar
    • Export Citation
  • 10

    Frontera JAFernandez ASchmidt JMClaassen JWartenberg KEBadjatia N: Defining vasospasm after subarachnoid hemorrhage: what is the most clinically relevant definition? Stroke 40:196319682009

    • Search Google Scholar
    • Export Citation
  • 11

    Germanson TPLanzino GKongable GLTorner JCKassell NF: Risk classification after aneurysmal subarachnoid hemorrhage. Surg Neurol 49:1551631998

    • Search Google Scholar
    • Export Citation
  • 12

    Gibson PHCuthbertson BHCroal BLRae DEl-Shafei HGibson G: Usefulness of neutrophil/lymphocyte ratio as predictor of new-onset atrial fibrillation after coronary artery bypass grafting. Am J Cardiol 105:1861912010

    • Search Google Scholar
    • Export Citation
  • 13

    Giede-Jeppe ABobinger TGerner STSembill JASprügel MIBeuscher VD: Neutrophil-to-lymphocyte ratio is an independent predictor for in-hospital mortality in spontaneous intracerebral hemorrhage. Cerebrovasc Dis 44:26342017

    • Search Google Scholar
    • Export Citation
  • 14

    Gökhan SOzhasenekler AMansur Durgun HAkil EUstündag MOrak M: Neutrophil lymphocyte ratios in stroke subtypes and transient ischemic attack. Eur Rev Med Pharmacol Sci 17:6536572013

    • Search Google Scholar
    • Export Citation
  • 15

    Graeb DARobertson WDLapointe JSNugent RAHarrison PB: Computed tomographic diagnosis of intraventricular hemorrhage. Etiology and prognosis. Radiology 143:91961982

    • Search Google Scholar
    • Export Citation
  • 16

    Hanley JAMcNeil BJ: The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 143:29361982

    • Search Google Scholar
    • Export Citation
  • 17

    Höllig ARemmel DStoffel-Wagner BSchubert GACoburn MClusmann H: Association of early inflammatory parameters after subarachnoid hemorrhage with functional outcome: A prospective cohort study. Clin Neurol Neurosurg 138:1771832015

    • Search Google Scholar
    • Export Citation
  • 18

    Hug ADalpke AWieczorek NGiese TLorenz AAuffarth G: Infarct volume is a major determiner of post-stroke immune cell function and susceptibility to infection. Stroke 40:322632322009

    • Search Google Scholar
    • Export Citation
  • 19

    Jaja BNRSaposnik GLingsma HFMacdonald EThorpe KEMamdani M: Development and validation of outcome prediction models for aneurysmal subarachnoid haemorrhage: the SAHIT multinational cohort study. BMJ 360:j57452018

    • Search Google Scholar
    • Export Citation
  • 20

    Lattanzi SCagnetti CProvinciali LSilvestrini M: Neutrophil-to-lymphocyte ratio predicts the outcome of acute intracerebral hemorrhage. Stroke 47:165416572016

    • Search Google Scholar
    • Export Citation
  • 21

    Li JChen QLuo XHong JPan KLin X: Neutrophil-to-lymphocyte ratio positively correlates to age in healthy population. J Clin Lab Anal 29:4374432015

    • Search Google Scholar
    • Export Citation
  • 22

    Libby P: What have we learned about the biology of atherosclerosis? The role of inflammation. Am J Cardiol 88 (7B):3J6J2001

  • 23

    Liesz ARüger HPurrucker JZorn MDalpke AMöhlenbruch M: Stress mediators and immune dysfunction in patients with acute cerebrovascular diseases. PLoS One 8:e748392013

    • Search Google Scholar
    • Export Citation
  • 24

    Mendelow ADGregson BAFernandes HMMurray GDTeasdale GMHope DT: Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial. Lancet 365:3873972005

    • Search Google Scholar
    • Export Citation
  • 25

    Muckart DJBhagwanjee S: American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference definitions of the systemic inflammatory response syndrome and allied disorders in relation to critically injured patients. Crit Care Med 25:178917951997

    • Search Google Scholar
    • Export Citation
  • 26

    Quinn TJSingh SLees KRBath PMMyint PK: Validating and comparing stroke prognosis scales. Neurology 89:99710022017

  • 27

    Rankin J: Cerebral vascular accidents in patients over the age of 60. I. General considerations. Scott Med J 2:1271361957

  • 28

    Rueda-Clausen CFLópez-Jaramillo PLuengas Cdel Pilar Oubiña MCachofeiro VLahera V: Inflammation but not endothelial dysfunction is associated with the severity of coronary artery disease in dyslipidemic subjects. Mediators Inflamm 2009:4691692009

    • Search Google Scholar
    • Export Citation
  • 29

    Sarrafzadeh ASchlenk FMeisel ADreier JVajkoczy PMeisel C: Immunodepression after aneurysmal subarachnoid hemorrhage. Stroke 42:53582011

    • Search Google Scholar
    • Export Citation
  • 30

    Singhal GJaehne EJCorrigan FToben CBaune BT: Inflammasomes in neuroinflammation and changes in brain function: a focused review. Front Neurosci 8:3152014

    • Search Google Scholar
    • Export Citation
  • 31

    Tao CWang JHu XMa JLi HYou C: Clinical value of neutrophil to lymphocyte and platelet to lymphocyte ratio after aneurysmal subarachnoid hemorrhage. Neurocrit Care 26:3934012017

    • Search Google Scholar
    • Export Citation
  • 32

    Tao XXie LDuan CDai SRen JYan Y: Up-regulation of interferon regulatory factor 3 involves in neuronal apoptosis after intracerebral hemorrhage in adult rats. Neurochem Res 41:293729472016

    • Search Google Scholar
    • Export Citation
  • 33

    Tejerina EEsteban AFernández-Segoviano PFrutos-Vivar FAramburu JBallesteros D: Accuracy of clinical definitions of ventilator-associated pneumonia: comparison with autopsy findings. J Crit Care 25:62682010

    • Search Google Scholar
    • Export Citation
  • 34

    van Swieten JCKoudstaal PJVisser MCSchouten HJvan Gijn J: Interobserver agreement for the assessment of handicap in stroke patients. Stroke 19:6046071988

    • Search Google Scholar
    • Export Citation
  • 35

    Vergouwen MDVermeulen Mvan Gijn JRinkel GJWijdicks EFMuizelaar JP: Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke 41:239123952010

    • Search Google Scholar
    • Export Citation
  • 36

    Wang FHu SDing YJu XWang LLu Q: Neutrophil-to-lymphocyte ratio and 30-day mortality in patients with acute intracerebral hemorrhage. J Stroke Cerebrovasc Dis 25:1821872016

    • Search Google Scholar
    • Export Citation
  • 37

    Wang XArima HAl-Shahi Salman RWoodward MHeeley EStapf C: Rapid blood pressure lowering according to recovery at different time intervals after acute intracerebral hemorrhage: pooled analysis of the INTERACT studies. Cerebrovasc Dis 39:2422482015

    • Search Google Scholar
    • Export Citation
  • 38

    Westendorp WFVermeij JDZock EHooijenga IJKruyt NDBosboom HJ: The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial. Lancet 385:151915262015

    • Search Google Scholar
    • Export Citation
  • 39

    Wilson MLGaido L: Laboratory diagnosis of urinary tract infections in adult patients. Clin Infect Dis 38:115011582004

  • 40

    Xanthos DNSandkühler J: Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci 15:43532014

    • Search Google Scholar
    • Export Citation
  • 41

    Yang BWang SYu SChen YLi LZhang H: C1q/tumor necrosis factor-related protein 3 inhibits oxidative stress during intracerebral hemorrhage via PKA signaling. Brain Res 1657:1761842017

    • Search Google Scholar
    • Export Citation
  • 42

    Zahorec R: Ratio of neutrophil to lymphocyte counts—rapid and simple parameter of systemic inflammation and stress in critically ill. Bratisl Lek Listy 102:5142001

    • Search Google Scholar
    • Export Citation
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