Citation Information :
Sarkar PG, Pant P, Kumar J. Does Neutrophil-to-lymphocyte Ratio at Admission Predict Severity and Mortality in COVID-19 Patients? A Systematic Review and Meta-analysis. Indian J Crit Care Med 2022; 26 (3):361-375.
Background: Coronavirus disease-2019 (COVID-2019) pandemic continues to be a significant public health problem. Severe COVID-19 cases have a poor prognosis and extremely high mortality. Prognostic factor evidence can help healthcare providers understand the likely prognosis and identify subgroups likely to develop severe disease with increased mortality risk so that timely treatments can be initiated. This meta-analysis has been performed to evaluate the neutrophil-to-lymphocyte ratio (NLR) at admission as a prognostic factor to predict severe coronavirus disease and mortality.
Materials and methods: A literature search was conducted through April 30, 2021, to retrieve all published studies, including gray literature and preprints, investigating the association between NLR and severity or mortality in COVID-19 patients. Screening of studies and data extraction have been done by two authors independently. The methodological quality of the included studies was assessed by the Quality in Prognosis Studies (QUIPS) tool.
Results: Twenty-four studies involving 4,080 patients reported the prognostic value of NLR for severe COVID-19. The pooled sensitivity (SEN), specificity (SPE), and area under the curve were 0.75 (95% CI 0.69–0.80), 0.74 (95% CI 0.70–0.78), and 0.81 (95% CI 0.77–0.84). Fifteen studies involving 4,071 patients reported the prognostic value of NLR for mortality in COVID-19. The pooled sensitivity (SEN), specificity (SPE), and area under curve were 0.80 (95% CI 0.72–0.86), 0.78 (95% CI 0.69–0.85), and 0.86 (95% CI 0.83–0.89).
Conclusion: The prognostic value of NLR at admission for severity and mortality in patients with COVID-19 is good. Evaluating the NLR at admission can assist treating clinicians to identify early the cases likely to worsen. This would help to conduct early triage, identify potentially high-risk cases, and start optimal monitoring and management, thus reducing the overall mortality of COVID-19.
Trial registry: This meta-analysis was prospectively registered on PROSPERO database (Registration Number: CRD42021247801).
Shang W, Dong J, Ren Y, Tian M, Li W, Hu J, et al. The value of clinical parameters in predicting the severity of COVID-19. J Med Virol 2020;92(10):2188–2192. DOI: 10.1002/jmv.26031.
Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. Journal of the American Medical Association 2020;323(13):1239–1242. DOI: 10.1001/jama.2020.2648.
Mason RJ. Pathogenesis of COVID-19 from a cell biology perspective. Eur Respir J 2020;55(4):2000607. DOI: 10.1183/13993003.00607-2020.
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. Journal of the American Medical Association 2020;323(11):1061–1069. DOI: 10.1001/jama.2020.1585.
Maclay T, Rephann A. The impact of early identification and a critical care-based sepsis response team on sepsis outcomes. Crit Care Nurse 2017;37(6):88–91. DOI: 10.4037/ccn2017183.
Martin JB, Badeaux JE. Interpreting laboratory tests in infection: making sense of biomarkers in sepsis and systemic inflammatory response syndrome for intensive care unit patients. Crit Care Nurs Clin North Am 2017;29(1):119–130. DOI: 10.1016/j.cnc.2016.09.004.
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg 2010;8(5):336–341. DOI: 10.1016/j.ijsu.2010.02.007.
Hayden JA, van der Windt DA, Cartwright JL, Côté P, Bombardier C. Assessing bias in studies of prognostic factors. Ann Intern Med 2013;158(4):280. DOI: 10.7326/0003-4819-158-4-201302190-00009.
Assessing bias in studies of prognostic factors–PubMed. 2021. Available from: https://pubmed.ncbi.nlm.nih.gov/23420236/.
Yang A-P, Liu J, Tao W, Li H. The diagnostic and predictive role of NLR, d-NLR and PLR in COVID-19 patients. Int Immunopharmacol 2020;84:106504. DOI: 10.1016/j.intimp.2020.106504.
Ok F, Erdogan O, Durmus E, Carkci S, Canik A. Predictive values of blood urea nitrogen/creatinine ratio and other routine blood parameters on disease severity and survival of COVID-19 patients. J Med Virol 2021;93(2):786–793. DOI: 10.1002/jmv.26300.
Liu J, Liu Y, Xiang P, Pu L, Xiong H, Li C, et al. Neutrophil-to-lymphocyte ratio predicts critical illness patients with 2019 coronavirus disease in the early stage. J Transl Med 2020;18(1):206. DOI: 10.1186/s12967-020-02374-0.
Fu J, Kong J, Wang W, Wu M, Yao L, Wang Z, et al. The clinical implication of dynamic neutrophil to lymphocyte ratio and D-dimer in COVID-19: a retrospective study in Suzhou China. Thromb Res 2020;192:3–8. DOI: 10.1016/j.thromres.2020.05.006.
Zeng Z-Y, Feng S-D, Chen G-P, Wu J-N. Predictive value of the neutrophil to lymphocyte ratio for disease deterioration and serious adverse outcomes in patients with COVID-19: a prospective cohort study. BMC Infect Dis 2021;21(1):80. DOI: 10.1186/s12879-021-05796-3.
Ramos-Peñafiel CO, Santos-González B, Flores-López EN, Galván-Flores F, Hernández-Vázquez L, Santoyo-Sánchez A, et al. Usefulness of the neutrophil-to-lymphocyte, monocyte-to-lymphocyte and lymphocyte-to-platelet ratios for the prognosis of COVID-19-associated complications. Gac Med Mex 2020;156(5): 405–411. DOI: 10.24875/GMM.M20000428.
Wang X, Li X, Shang Y, Wang J, Zhang X, Su D, et al. Ratios of neutrophil-to-lymphocyte and platelet-to-lymphocyte predict all-cause mortality in inpatients with coronavirus disease 2019 (COVID-19): a retrospective cohort study in a single medical centre. Epidemiol Infect 2020;148:e211. DOI: 10.1017/S0950268820002071.
Sun S, Cai X, Wang H, He G, Lin Y, Lu B, et al. Abnormalities of peripheral blood system in patients with COVID-19 in Wenzhou, China. Clin Chim Acta Int J Clin Chem 2020;507:174–180. DOI: 10.1016/j.cca.2020.04.024.
Bastug A, Bodur H, Erdogan S, Gokcinar D, Kazancioglu S, Kosovali BD, et al. Clinical and laboratory features of COVID-19: predictors of severe prognosis. Int Immunopharmacol 2020;88:106950. DOI: 10.1016/j.intimp.2020.106950.
Cheng B, Hu J, Zuo X, Chen J, Li X, Chen Y, et al. Predictors of progression from moderate to severe coronavirus disease 2019: a retrospective cohort. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis 2020;26(10):1400–1405. DOI: 10.1016/j.cmi.2020.06.033.
Brozek JL, Canelo-Aybar C, Akl EA, Bowen JM, Bucher J, Chiu WA, et al. GRADE Guidelines 30: the GRADE approach to assessing the certainty of modeled evidence—An overview in the context of health decision-making. J Clin Epidemiol 2021;129:138–150. DOI: 10.1016/j.jclinepi.2020.09.018.
Benschop RJ, Rodriguez-Feuerhahn M, Schedlowski M. Catecholamine-induced leukocytosis: early observations, current research, and future directions. Brain Behav Immun 1996;10(2):77–91. DOI: 10.1006/brbi.1996.0009.
Can E, Hamilcikan Ş, Can C. The value of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio for detecting early-onset neonatal sepsis. J Pediatr Hematol Oncol 2018;40(4):e229–e232. DOI: 10.1097/MPH.0000000000001059.
Dirican A, Kucukzeybek BB, Alacacioglu A, Kucukzeybek Y, Erten C, Varol U, et al. Do the derived neutrophil to lymphocyte ratio and the neutrophil to lymphocyte ratio predict prognosis in breast cancer? Int J Clin Oncol 2015;20(1):70–81. DOI: 10.1007/s10147-014-0672-8.
Loonen AJM, de Jager CPC, Tosserams J, Kusters R, Hilbink M, Wever PC, et al. Biomarkers and molecular analysis to improve bloodstream infection diagnostics in an emergency care unit. PLoS One 2014;9(1):e87315. DOI: 10.1371/journal.pone.0087315.
Yodying H, Matsuda A, Miyashita M, Matsumoto S, Sakurazawa N, Yamada M, et al. Prognostic significance of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in oncologic outcomes of esophageal cancer: a systematic review and meta-analysis. Ann Surg Oncol 2016;23(2):646–654. DOI: 10.1245/s10434-015-4869-5.
Acet H, Ertaş F, Akıl MA, Özyurtlu F, Polat N, Bilik MZ, et al. Relationship between hematologic indices and global registry of acute coronary events risk score in patients with ST-segment elevation myocardial infarction. Clin Appl Thromb 2016;22(1):60–68. DOI: 10.1177/1076029614533145.
Zahorec R. Ratio of neutrophil to lymphocyte counts--rapid and simple parameter of systemic inflammation and stress in critically ill. Bratisl Lek Listy 2001;102(1):5–14. PMID: 11723675.
Singhal T. A review of coronavirus disease-2019 (COVID-19). Indian J Pediatr 2020;87(4):281–286. DOI: 10.1007/s12098-020-03263-6.
Mangalmurti N, Hunter CA. Cytokine storms: understanding COVID-19. Immunity 2020;53(1):19–25. DOI: 10.1016/j.immuni.2020.06.017.
Zhang X, Tan Y, Ling Y, Lu G, Liu F, Yi Z, et al. Viral and host factors related to the clinical outcome of COVID-19. Nature 2020;583(7816):437–440. DOI: 10.1038/s41586-020-2355-0.
van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential therapeutic targets. Nat Rev Immunol 2017;17(7):407–420. DOI: 10.1038/nri.2017.36.
Simadibrata DM, Calvin J, Wijaya AD, Ibrahim NAA. Neutrophil-to-lymphocyte ratio on admission to predict the severity and mortality of COVID-19 patients: a meta-analysis. Am J Emerg Med 2021;42:60–69. DOI: 10.1016/j.ajem.2021.01.006.
Lagunas-Rangel FA. Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): a meta-analysis. J Med Virol 2020;92(10):1733–1734. DOI: 10.1002/jmv.25819.
Ghahramani S, Tabrizi R, Lankarani KB, Kashani SMA, Rezaei S, Zeidi N, et al. Laboratory features of severe vs non-severe COVID-19 patients in Asian populations: a systematic review and meta-analysis. Eur J Med Res 2020;25(1):30. DOI: 10.1186/s40001-020-00432-3.
Li X, Liu C, Mao Z, Xiao M, Wang L, Qi S, et al. Predictive values of neutrophil-to-lymphocyte ratio on disease severity and mortality in COVID-19 patients: a systematic review and meta-analysis. Crit Care Lond Engl 2020;24(1):647. DOI: 10.1186/s13054-020-03374-8.
Asghar A, Saqib U, Aijaz S, Bukhari KHS, Hayat A. Utility of neutrophil-to-lymphocyte ratio, platelets-to-lymphocyte ratio and call score for prognosis assessment in covid-19 patients. PAFMJ 2020 9;70(2): S590-S596.
Liu YP, Li GM, He J, Liu Y, Li M, Zhang R, et al. Combined use of the neutrophil-to-lymphocyte ratio and CRP to predict 7-day disease severity in 84 hospitalized patients with COVID-19 pneumonia: a retrospective cohort study. Ann Transl Med 2020;8(10):635.
Basbus L, Lapidus MI, Martingano I, Puga MC, Pollán J. [Neutrophil to lymphocyte ratio as a prognostic marker in COVID-19]. Medicina (Mex). 2020;80 Suppl 3:31–6.
Li H, Zhao M, Xu Y. [Biochemical analysis between common type and critical type of COVID-19 and clinical value of neutrophil/lymphocyte ratio]. Nan Fang Yi Ke Da Xue Xue Bao 2020 30;40(7):965–971.
Zha Q. Study on early laboratory warning of severe COVID-19. Lab Med 35(6):557–560.
Fei M, Tong F, Tao X, Wang J. [Value of neutrophil-to-lymphocyte ratio in the classification diagnosis of coronavirus disease 2019]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2020 May;32(5):554–8.
Xia X, Wen M, Zhan S, He J, Chen W. [An increased neutrophil/lymphocyte ratio is an early warning signal of severe COVID-19]. Nan Fang Yi Ke Da Xue Xue Bao 2020 30;40(3):333–336.
Noor A, Akhtar F, Tashfeen S, Anwar N, Saleem B, Khan SA, et al. Neutrophil-to-Lymphocyte Ratio, derived Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio and Lymphocyte-to-Monocyte Ratio as risk factors in critically ill COVID-19 patients, a single centered study. J Ayub Med Coll Abbottabad 2020;32 (Suppl 1)(4):S595–S601.
Tatum D, Taghavi S, Houghton A, Stover J, Toraih E, Duchesne J. Neutrophil-to-Lymphocyte Ratio and Outcomes in Louisiana COVID-19 Patients. Shock Augusta Ga 2020;54(5):652–658.
Seyit M, Avci E, Nar R, Senol H, Yilmaz A, Ozen M, et al. Neutrophil to lymphocyte ratio, lymphocyte to monocyte ratio and platelet to lymphocyte ratio to predict the severity of COVID-19. Am J Emerg Med 2021;40:110–114.
Lin S, Mao W, Zou Q, Lu S, Zheng S. Associations between hematological parameters and disease severity in patients with SARS-CoV-2 infection. J Clin Lab Anal 2021;35(1):e23604.
Mousavi-Nasab SD, Mardani R, Nasr Azadani H, Zali F, Ahmadi Vasmehjani A, Sabeti S, et al. Neutrophil to lymphocyte ratio and C-reactive protein level as prognostic markers in mild versus severe COVID-19 patients. Gastroenterol Hepatol Bed Bench 2020;13(4): 361–366.
Chen F-F, Zhong M, Liu Y, Zhang Y, Zhang K, Su D-Z, et al. The characteristics and outcomes of 681 severe cases with COVID-19 in China. J Crit Care 2020;60:32–37.
Yan X, Li F, Wang X, Yan J, Zhu F, Tang S, et al. Neutrophil to lymphocyte ratio as prognostic and prognostic factor in patients with coronavirus disease 2019: A retrospective cross-sectional study. J Med Virol 2020;92(11):2573–2581.
Song H SH. Prognostic value of multiple inflammatory indexes on the prognosis of patients with corona virus disease 2019. Card Cerebr Pneumal Vasc Dis 2020;28(6):13–16.
Xu J-B, Xu C, Zhang R-B, Wu M, Pan C-K, Li X-J, et al. Associations of procalcitonin, C-reaction protein and neutrophil-to-lymphocyte ratio with mortality in hospitalized COVID-19 patients in China. Sci Rep 2020 14;10(1):15058.
Ye W, Chen G, Li X, Lan X, Ji C, Hou M, et al. Dynamic changes of D-dimer and neutrophil-lymphocyte count ratio as prognostic biomarkers in COVID-19. Respir Res 2020 3;21(1):169.
Zeng F, Li L, Zeng J, Deng Y, Huang H, Chen B, et al. Can we predict the severity of coronavirus disease 2019 with a routine blood test? Pol Arch Intern Med 2020 29;130(5):400–406.
Eslamijouybari M, Heydari K, Maleki I, Moosazadeh M, Hedayatizadeh-Omran A, Vahedi L, et al. Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios in COVID-19 Patients and Control Group and Relationship with Disease Prognosis. Casp J Intern Med 2020;11 (Suppl 1):531–535.