The utility of peripheral blood leucocyte ratios as biomarkers in infectious diseases: A systematic review and meta-analysis

Clark D Russell, Arun Parajuli, Hugo J Gale, Naomi S Bulteel, Philipp Schuetz, Cornelis P C de Jager, Anne J M Loonen, Georgios I Merekoulias, J Kenneth Baillie, Clark D Russell, Arun Parajuli, Hugo J Gale, Naomi S Bulteel, Philipp Schuetz, Cornelis P C de Jager, Anne J M Loonen, Georgios I Merekoulias, J Kenneth Baillie

Abstract

Objectives: To assess the utility of the neutrophil:lymphocyte (NLR), lymphocyte:monocyte (LMR) and platelet:lymphocyte ratios (PLR) as infection biomarkers.

Methods: PubMed/MEDLINE, Embase and Cochrane databases were searched to identify eligible articles. Studies of diagnosis, severity or outcome were included. PROSPERO systematic review registration CRD42017075032.

Results: Forty studies were included, reporting on bacterial and viral infections, malaria, and critical illness due to sepsis. Ten studies reported an association of higher NLR with bacteraemia, supported by meta-analysis of patient-level data (five studies, n = 3320; AUC 0.72, p<0.0001) identifying a cut-off of >12.65. Two studies reported an association with lower LMR and diagnosis of influenza virus infection in patients with respiratory tract infection. Meta-analysis of patient-level data (n = 85; AUC 0.66, p = 0.01) identified a cut-off of ≤2.06. The directionality of associations between NLR and outcomes in heterogeneous cohorts of critically ill adults with sepsis varied. Potential clinical utility was also demonstrated in pneumonia (NLR), pertussis (NLR), urinary tract infection (NLR), diabetic foot infections (NLR) and Crimean Congo Haemorrhagic Fever (PLR). Longitudinal measurement of LMR during respiratory virus infection reflected symptoms and NLR during sepsis and bacteraemia predicted mortality.

Conclusions: Peripheral blood leucocyte ratios are useful infection biomarkers, with the most evidence related to diagnosis of bacteraemia and influenza virus infection. In critical illness due to sepsis, a signal towards an association with NLR and outcomes exists, and NLR should be evaluated in future stratification models. Longitudinal measurement of ratios during infection could be informative. Overall, these biomarkers warrant further recognition and study in infectious diseases.

Keywords: Bacteremia; Blood platelets; Endotypes; Influenza; Lymphocytes; Monocytes; Neutrophils; Pneumonia; Sepsis; Stratified medicine.

Copyright © 2019. Published by Elsevier Ltd.

Figures

Fig. 1
Fig. 1
PRISMA flow diagram illustrating article selection process.
Fig. 2
Fig. 2
Infectious diseases and leucocyte ratios reported. a Infectious diseases and b leucocyte ratios reported in 40 included studies. Note that some studies reported more than one ratio and bacteraemia was reported separately in some studies so is included as an additional category when relevant, therefore each total exceeds 40. The ratios investigated in patients with infectious diseases shown in bold were considered to demonstrate potential clinical utility. CCHF: Crimean Congo haemorrhagic fever.
Fig. 3
Fig. 3
Meta-analysis results for NLR and bacteraemia. a NLR median and interquartile range derived from meta-analysis of patient-level data for 3320 patients. b Receiver operator characteristic analysis for NLR in predicting presence of bacteraemia in these patients.
Fig. 4
Fig. 4
Meta-analysis results for LMR and influenza virus infection. a LMR median and interquartile range derived from meta-analysis of patient-level data for 85 patients. b Receiver operator characteristic analysis for LMR in predicting presence of influenza virus infection in patients with symptomatic respiratory tract infection.

References

    1. Russell C.D., Baillie J.K. Treatable traits and therapeutic targets: goals for systems biology in infectious disease. Curr Opin Syst Biol. 2017;2:140–146.
    1. Schuetz P., Wirz Y., Sager R., et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis. Lancet Infect Dis. 2018;18(1):95–107.
    1. Schuetz P., Wirz Y., Sager R., et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2017;10
    1. de Jong E., van Oers J.A., Beishuizen A., et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16(7):819–827.
    1. Hotchkiss R.S., Tinsley K.W., Swanson P.E., et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol. 2001;166(11):6952–6963.
    1. Hotchkiss R.S., Swanson P.E., Freeman B.D., et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med. 1999;27(7):1230–1251.
    1. Drewry A.M., Samra N., Skrupky L.P., Fuller B.M., Compton S.M., Hotchkiss R.S. Persistent lymphopenia after diagnosis of sepsis predicts mortality. Shock. 2014;42(5):383–391.
    1. Felmet K.A., Hall M.W., Clark R.S., Jaffe R., Carcillo J.A. Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. J Immunol. 2005;174(6):3765–3772.
    1. Le Tulzo Y., Pangault C., Gacouin A., et al. Early circulating lymphocyte apoptosis in human septic shock is associated with poor outcome. Shock. 2002;18(6):487–494.
    1. Wyllie D.H., Bowler I.C., Peto T.E. Relation between lymphopenia and bacteraemia in UK adults with medical emergencies. J Clin Pathol. 2004;57(9):950–955.
    1. Brown K.A., Brain S.D., Pearson J.D., Edgeworth J.D., Lewis S.M., Treacher D.F. Neutrophils in development of multiple organ failure in sepsis. Lancet. 2006;368(9530):157–169.
    1. Moher D., Liberati A., Tetzlaff J., Altman D.G. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7)
    1. Hwang S.Y., Shin T.G., Jo I.J., et al. Neutrophil-to-lymphocyte ratio as a prognostic marker in critically-ill septic patients. Am J Emerg Med. 2017;35(2):234–239.
    1. Levy M.M., Fink M.P., Marshall J.C., et al. 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med. 2003;31(4):1250–1256.
    1. Liu X., Shen Y., Wang H., Ge Q., Fei A., Pan S. Prognostic significance of neutrophil-to-lymphocyte ratio in patients with sepsis: a prospective observational study. Mediat Inflamm. 2016;2016
    1. Riché F., Gayat E., Barthélémy R., Le Dorze M., Matéo J., Payen D. Reversal of neutrophil-to-lymphocyte count ratio in early versus late death from septic shock. Crit Care. 2015;19:439.
    1. Salciccioli J.D., Marshall D.C., Pimentel M.A., et al. The association between the neutrophil-to-lymphocyte ratio and mortality in critical illness: an observational cohort study. Crit Care. 2015;19:13.
    1. Yilmaz H., Cakmak M., Inan O., Darcin T., Akcay A. Can neutrophil-lymphocyte ratio be independent risk factor for predicting acute kidney injury in patients with severe sepsis. Ren Fail. 2015;37(2):225–229.
    1. Kutlucan L., Kutlucan A., Basaran B., et al. The predictive effect of initial complete blood count of intensive care unit patients on mortality, length of hospitalization, and nosocomial infections. Eur Rev Med Pharmacol Sci. 2016;20(8):1467–1473.
    1. Terradas R., Grau S., Blanch J., et al. Eosinophil count and neutrophil-lymphocyte count ratio as prognostic markers in patients with bacteremia: a retrospective cohort study. PLoS One. 2012;7(8):e42860.
    1. de Jager C.P., Wever P.C., Gemen E.F., et al. The neutrophil-lymphocyte count ratio in patients with community-acquired pneumonia. PLoS One. 2012;7(10):e46561.
    1. Zhang H.B., Chen J., Lan Q.F., Ma X.J., Zhang S.Y. Diagnostic values of red cell distribution width, platelet distribution width and neutrophil-lymphocyte count ratio for sepsis. Exp Ther Med. 2016;12(4):2215–2219.
    1. Laukemann S., Kasper N., Kulkarni P., et al. Can we reduce negative blood cultures with clinical scores and blood markers? Results from an observational cohort study. Medicine. 2015;94(49):e2264.
    1. Lowsby R., Gomes C., Jarman I., et al. Neutrophil to lymphocyte count ratio as an early indicator of blood stream infection in the emergency department. Emerg Med J. 2015;32(7):531–534.
    1. Loonen A.J., de Jager C.P., Tosserams J., et al. Biomarkers and molecular analysis to improve bloodstream infection diagnostics in an emergency care unit. PLoS One. 2014;9(1):e87315.
    1. de Jager C.P., van Wijk P.T., Mathoera R.B., de Jongh-Leuvenink J., van der Poll T., Wever P.C. Lymphocytopenia and neutrophil-lymphocyte count ratio predict bacteremia better than conventional infection markers in an emergency care unit. Crit Care. 2010;14(5):R192.
    1. Ljungstrom L., Pernestig A.K., Jacobsson G., Andersson R., Usener B., Tilevik D. Diagnostic accuracy of procalcitonin, neutrophil-lymphocyte count ratio, C-reactive protein, and lactate in patients with suspected bacterial sepsis. PLoS One. 2017;12(7)
    1. Eren S.H., Zengin S., Büyüktuna S.A., Gözel M.G. Clinical severity in forecasting platelet to lymphocyte ratio in Crimean-Congo hemorrhagic fever patients. J Med Microbiol. 2016;65(10):1100–1104.
    1. Cevik M.A., Erbay A., Bodur H., et al. Clinical and laboratory features of Crimean-Congo hemorrhagic fever: predictors of fatality. Int J Infect Dis: Off Publ Int Soc Infect Dis. 2008;12(4):374–379.
    1. Wasano K., Kawasaki T., Yamamoto S., et al. Pretreatment hematologic findings as novel predictive markers for facial palsy prognosis. Otolaryngol Head Neck Surg. 2016;155(4):581–587.
    1. Peitersen E. Bell's palsy: the spontaneous course of 2,500 peripheral facial nerve palsies of different etiologies. Acta Otolaryngol Suppl. 2002;549:4–30.
    1. Hato N., Fujiwara T., Gyo K., Yanagihara N. Yanagihara facial nerve grading system as a prognostic tool in Bell's palsy. Otol Neurotol: Off Publ Am Otol Soc Am Neurotol Soc Eur Acad Otol Neurotol. 2014;35(9):1669–1672.
    1. Bucak A., Ulu S., Oruc S., et al. Neutrophil-to-lymphocyte ratio as a novel-potential marker for predicting prognosis of Bell palsy. Laryngoscope. 2014;124(7):1678–1681.
    1. McClain M.T., Park L.P., Nicholson B., et al. Longitudinal analysis of leukocyte differentials in peripheral blood of patients with acute respiratory viral infections. J Clin Virol. 2013;58(4):689–695.
    1. Cunha B.A., Connolly J.J., Irshad N. The clinical usefulness of lymphocyte:monocyte ratios in differentiating influenza from viral non-influenza-like illnesses in hospitalized adults during the 2015 influenza A (H3N2) epidemic: the uniqueness of HPIV-3 mimicking influenza A. Eur J Clin Microbiol Infect Dis. 2016;35(1):155–158.
    1. Merekoulias G., Alexopoulos E.C., Belezos T., Panagiotopoulou E., Jelastopulu D.M. Lymphocyte to monocyte ratio as a screening tool for influenza. PLoS Curr. 2010;2:RRN1154.
    1. Siniorakis E.E., Tsarouhas K., Tsitsimpikou C., et al. Neutrophil to lymphocyte (N/L) and platelet to lymphocyte (P/L) ratios in differentiating acute heart failure from respiratory infection. Curr Vasc Pharmacol. 2017;15(5):477–481.
    1. Yoon N.B., Son C., Um S.J. Role of the neutrophil-lymphocyte count ratio in the differential diagnosis between pulmonary tuberculosis and bacterial community-acquired pneumonia. Ann Lab Med. 2013;33(2):105–110.
    1. Iliaz S., Iliaz R., Ortakoylu G., Bahadir A., Bagci B.A., Caglar E. Value of neutrophil/lymphocyte ratio in the differential diagnosis of sarcoidosis and tuberculosis. Ann Thorac Med. 2014;9(4):232–235.
    1. Ganeshalingham A., McSharry B., Anderson B., Grant C., Beca J. Identifying children at risk of malignant bordetella pertussis infection. Pediatr Crit Care Med. 2017;18(1):e42–e47.
    1. Lee J.W., Park J.S., Park K.B., Yoo G.H., Kim S.S., Lee S.M. Prediction of renal cortical defect and scar using neutrophil-to-lymphocyte ratio in children with febrile urinary tract infection. Nuklearmedizin. 2017;56(3):109–114.
    1. Han S.Y., Lee I.R., Park S.J., Kim J.H., Shin J.I. Usefulness of neutrophil-lymphocyte ratio in young children with febrile urinary tract infection. Korean J Pediatr. 2016;59(3):139–144.
    1. Sen V., Bozkurt I.H., Aydogdu O., et al. Significance of preoperative neutrophil-lymphocyte count ratio on predicting postoperative sepsis after percutaneous nephrolithotomy. Kaohsiung J Med Sci. 2016;32(10):507–513.
    1. Dogruel F., Gonen Z.B., Gunay-Canpolat D., Zararsiz G., Alkan A. The neutrophil-to-lymphocyte ratio as a marker of recovery status in patients with severe dental infection. Med Oral Patol Oral Cir Bucal. 2017;22(4):e440–e445.
    1. Yapıcı O., Berk H., Öztoprak N., Seyman D., Tahmaz A., Merdin A. Can ratio of neutrophil-to-lymphocyte count and erythrocyte sedimentation rate in diabetic foot infecti on predict osteomyelitis and/or amputation. Hematol Rep. 2017;9(1):6981.
    1. Baglam T., Binnetoglu A., Yumusakhuylu A.C., Gerin F., Demir B., Sari M. Predictive value of the neutrophil-to-lymphocyte ratio in patients with deep neck space infection secondary to acute bacterial tonsillitis. Int J Pediatr Otorhinolaryngol. 2015;79(9):1421–1424.
    1. Kahramanca S., Kaya O., Özgehan G., et al. Are neutrophil-lymphocyte ratio and platelet-lymphocyte ratio as effective as Fournier's gangrene severity index for predicting the number of debridements in Fournier's gangrene? Ulus Travma Acil Cerrahi Derg. 2014;20(2):107–112.
    1. Lin T.Y., Ou C.H., Tzai T.S., et al. Validation and simplification of Fournier's gangrene severity index. Int J Urol: Off J Jpn Urol Assoc. 2014;21(7):696–701.
    1. Li J.S., Sexton D.J., Mick N., et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2000;30(4):633–638.
    1. Turak O., Özcan F., Işleyen A., et al. Usefulness of neutrophil-to-lymphocyte ratio to predict in-hospital outcomes in infective endocarditis. Can J Cardiol. 2013;29(12):1672–1678.
    1. Cherfane C.E., Gessel L., Cirillo D., Zimmerman M.B., Polyak S. Monocytosis and a low lymphocyte to monocyte ratio are effective biomarkers of ulcerative colitis disease activity. Inflamm Bowel Dis. 2015;21(8):1769–1775.
    1. Farah R., Hamza H., Khamisy-Farah R. A link between platelet to lymphocyte ratio and helicobacter pylori infection. J Clin Lab Anal. 2018;32(1):e22222.
    1. Farah R., Khamisy-Farah R. Association of neutrophil to lymphocyte ratio with presence and severity of gastritis due to helicobacter pylori infection. J Clin Lab Anal. 2014;28(3):219–223.
    1. Jafarzadeh A., Akbarpoor V., Nabizadeh M., Nemati M., Rezayati M.T. Total leukocyte counts and neutrophil-lymphocyte count ratios among helicobacter pylori-infected patients with peptic ulcers: independent of bacterial CagA status. Southeast Asian J Trop Med Public Health. 2013;44(1):82–88.
    1. Kotepui M., PhunPhuech B., Phiwklam N., Uthaisar K. Differentiating between dengue fever and malaria using hematological parameters in endemic areas of Thailand. Infect Dis Poverty. 2017;6(1):27.
    1. Kotepui M., Phunphuech B., Phiwklam N., Chupeerach C., Duangmano S. Effect of malarial infection on haematological parameters in population near Thailand-Myanmar border. Malar J. 2014;13:218.
    1. Organisation W.H. Severe malaria. Trop Med Int Health. 2014;19(Suppl 1):7–131.
    1. van Wolfswinkel M.E., Vliegenthart-Jongbloed K., de Mendonça Melo M., et al. Predictive value of lymphocytopenia and the neutrophil-lymphocyte count ratio for severe imported malaria. Malar J. 2013;12:101.
    1. Berens-Riha N., Kroidl I., Schunk M., Alberer M, Beissner M, Pritsch M, et al. Evidence for significant influence of host immunity on changes in differential blood count during malaria. Malar J. 2014;13:155.

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