Top

Published in:

Open Access 01-07-2021 | Biomarkers | Invited Review

Transferring clinically established immune inflammation markers into exercise physiology: focus on neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and systemic immune-inflammation index

Authors: David Walzik, Niklas Joisten, Jonas Zacher, Philipp Zimmer

Published in: European Journal of Applied Physiology | Issue 7/2021

Abstract

Over the last decades the cellular immune inflammation markers neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII = NLR × platelets) have emerged in clinical context as markers of disease-related inflammation and are now widely appreciated due to their integrative character. Transferring these clinically established inflammation markers into exercise physiology seems highly beneficial, especially due to the low temporal, financial and infrastructural resources needed for assessment and calculation. Therefore, the aim of this review is to summarize evidence on the value of the integrative inflammation markers NLR, PLR and SII for depiction of exercise-induced inflammation and highlight potential applications in exercise settings. Despite sparse evidence, multiple investigations revealed responsiveness of the markers to acute and chronic exercise, thereby opening promising avenues in the field of exercise physiology. In performance settings, they might help to infer information for exercise programming by reflecting exercise strain and recovery status or periods of overtraining and increased infection risk. In health settings, application involves the depiction of anti-inflammatory effects of chronic exercise in patients exhibiting chronic inflammation. Further research should, therefore, focus on establishing reference values for these integrative markers in athletes at rest, assess the kinetics and reliability in response to different exercise modalities and implement the markers into clinical exercise trials to depict anti-inflammatory effects of chronic exercise in different patient collectives.

Arbiol-Roca A, Imperiali CE, Montserrat MM et al (2018) Reference intervals for a complete blood count on an automated haematology analyser Sysmex XN in healthy adults from the southern metropolitan area of Barcelona. EJIFCC 29:48–54PubMedPubMedCentral

Baird MF, Graham SM, Baker JS, Bickerstaff GF (2012) Creatine-kinase- and exercise-related muscle damage implications for muscle performance and recovery. J Nutr Metab. https://doi.org/10.1155/2012/960363CrossRefPubMedPubMedCentral

Behringer M, Montag J, Franz A et al (2014) Exhaustive exercise—a near death experience for skeletal muscle cells? Med Hypotheses 83:758–765. https://doi.org/10.1016/j.mehy.2014.10.005CrossRefPubMed

Bessa AL, Oliveira VN, Agostini GG et al (2016) EXERCISE intensity and recovery: biomarkers of injury, inflammation, and oxidative stress. J Strength Cond Res 30:311–319. https://doi.org/10.1519/JSC.0b013e31828f1ee9CrossRefPubMed

Bhat T, Teli S, Rijal J et al (2013) Neutrophil to lymphocyte ratio and cardiovascular diseases: a review. Expert Rev Cardiovasc Ther 11:55–59. https://doi.org/10.1586/erc.12.159CrossRefPubMed

Biino G, Santimone I, Minelli C et al (2013) Age- and sex-related variations in platelet count in italy: a proposal of reference ranges based on 40987 subjects’ data. PLoS ONE 8:1–7. https://doi.org/10.1371/journal.pone.0054289CrossRef

Brancaccio P, Maffulli N, Limongelli FM (2007) Creatine kinase monitoring in sport medicine. Br Med Bull 81–82:209–230. https://doi.org/10.1093/bmb/ldm014CrossRefPubMed

Cai J, Li H, Zhang C et al (2021) The neutrophil-to-lymphocyte ratio determines clinical efficacy of corticosteroid therapy in patients with COVID-19. Cell Metab 33:258-269.e3. https://doi.org/10.1016/j.cmet.2021.01.002CrossRefPubMedPubMedCentral

Campbell JP, Turner JE (2018) Debunking the myth of exercise-induced immune suppression: redefining the impact of exercise on immunological health across the lifespan. Front Immunol 9:1–21. https://doi.org/10.3389/fimmu.2018.00648CrossRef

Cerqueira É, Marinho DA, Neiva HP, Lourenço O (2020) Inflammatory effects of high and moderate intensity exercise—a systematic review. Front Physiol 10:1–14. https://doi.org/10.3389/fphys.2019.01550CrossRef

Chazaud B (2016) Inflammation during skeletal muscle regeneration and tissue remodeling: application to exercise-induced muscle damage management. Immunol Cell Biol 94:140–145. https://doi.org/10.1038/icb.2015.97CrossRefPubMed

Davison G, Diment BC (2010) Bovine colostrum supplementation attenuates the decrease of salivary lysozyme and enhances the recovery of neutrophil function after prolonged exercise. Br J Nutr 103:1425–1432. https://doi.org/10.1017/S0007114509993503CrossRefPubMed

Dziedzic A, Bijak M (2019) Interactions between platelets and leukocytes in pathogenesis of multiple sclerosis. Adv Clin Exp Med 28:277–285. https://doi.org/10.17219/acem/83588CrossRefPubMed

El-Sayed MS, Sale C, Jones PGW, Chester M (2000) Blood hemostasis in exercise and training. Med Sci Sports Exer 32:918–925. https://doi.org/10.1097/00005768-200005000-00007CrossRef

Eming SA, Wynn TA, Martin P (2017) Inflammation and metabolism in tissue repair and regeneration. Science (80-) 356:1026–1030. https://doi.org/10.1126/science.aam7928CrossRef

Fest J, Ruiter R, Ikram MA et al (2018) Reference values for white blood-cell-based inflammatory markers in the Rotterdam study: a population-based prospective cohort study. Sci Rep 8:1–7. https://doi.org/10.1038/s41598-018-28646-wCrossRef

Fischer CP (2006) Interleukin-6 in acute exercise and training: what is the biological relevance? Exerc Immunol Rev 12:6–33PubMed

Gleeson M (2002) Biochemical and immunological markers of overtraining. J Sport Sci Med 1:31–41

Gleeson M, Bishop NC, Stensel DJ et al (2011) The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat Rev Immunol 11:607–610. https://doi.org/10.1038/nri3041CrossRefPubMed

Gonçalves CAM, Dantas PMS, dos Santos IK et al (2020) Effect of acute and chronic aerobic exercise on immunological markers: a systematic review. Front Physiol 10:1–11. https://doi.org/10.3389/fphys.2019.01602CrossRef

Gonda K, Shibata M, Sato Y et al (2017) Elevated neutrophil-to-lymphocyte ratio is associated with nutritional impairment, immune suppression, resistance to S-1 plus cisplatin, and poor prognosis in patients with stage? IV gastric cancer. Mol Clin Oncol. https://doi.org/10.3892/mco.2017.1438CrossRefPubMedPubMedCentral

Guthrie GJK, Charles KA, Roxburgh CSD et al (2013) The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer. Crit Rev Oncol Hematol 88:218–230. https://doi.org/10.1016/j.critrevonc.2013.03.010CrossRefPubMed

Hemond CC, Glanz BI, Bakshi R et al (2019) The neutrophil-to-lymphocyte and monocyte-to-lymphocyte ratios are independently associated with neurological disability and brain atrophy in multiple sclerosis. BMC Neurol 19:1–10. https://doi.org/10.1186/s12883-019-1245-2CrossRef

Howard R, Kanetsky PA, Egan KM (2019) Exploring the prognostic value of the neutrophil-to-lymphocyte ratio in cancer. Sci Rep 9:1–10. https://doi.org/10.1038/s41598-019-56218-zCrossRef

Hu B, Yang XR, Xu Y et al (2014) Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepatocellular carcinoma. Clin Cancer Res 20:6212–6222. https://doi.org/10.1158/1078-0432.CCR-14-0442CrossRefPubMed

Huang Y, Deng W, Zheng S et al (2018) Relationship between monocytes to lymphocytes ratio and axial spondyloarthritis. Int Immunopharmacol 57:43–46. https://doi.org/10.1016/j.intimp.2018.02.008CrossRefPubMed

Islas-Vazquez L, Aguilar-Cazares D, Galicia-Velasco M et al (2020) IL-6, NLR, and SII markers and their relation with alterations in CD8+ T-lymphocyte subpopulations in patients treated for lung adenocarcinoma. Biology (Basel). https://doi.org/10.3390/biology9110376CrossRef

Joisten N, Walzik D, Schenk A et al (2019) Aqua cycling for immunological recovery after intensive, eccentric exercise. Eur J Appl Physiol 119:1369–1375. https://doi.org/10.1007/s00421-019-04127-4CrossRefPubMed

Joisten N, Proschinger S, Rademacher A et al (2020) High-intensity interval training reduces neutrophil-to-lymphocyte ratio in persons with multiple sclerosis during inpatient rehabilitation. Mult Scler J. https://doi.org/10.1177/1352458520951382CrossRef

Kakanis MW, Peake J, Brenu EW et al (2010) The open window of susceptibility to infection after acute exercise in healthy young male elite athletes. Exerc Immunol Rev 16:119–137. https://doi.org/10.1016/j.jsams.2010.10.642CrossRefPubMed

Kasapis C, Thompson PD (2005) The effects of physical activity on serum C-reactive protein and inflammatory markers: a systematic review. J Am Coll Cardiol 45:1563–1569. https://doi.org/10.1016/j.jacc.2004.12.077CrossRefPubMed

Kerksick CM, Kreider RB, Willoughby DS (2010) Intramuscular adaptations to eccentric exercise and antioxidant supplementation. Amino Acids 39:219–232. https://doi.org/10.1007/s00726-009-0432-7CrossRefPubMed

Korkmaz A, Yıldız A, Türker Duyuler P et al (2018) Combination of change in hematological parameters with exercise stress test to predict coronary artery disease. J Clin Lab Anal 32:1–5. https://doi.org/10.1002/jcla.22205CrossRef

Lee EC, Fragala MS, Kavouras SA et al (2017) Biomarkers in sports and exercise: tracking health, performance, and recovery in athletes. J Strength Cond Res 31:2920–2937. https://doi.org/10.1519/JSC.0000000000002122CrossRefPubMedPubMedCentral

Liao YH, Sung YC, Chou CC, Chen CY (2016) Eight-week training cessation suppresses physiological stress but rapidly impairs health metabolic profiles and aerobic capacity in elite taekwondo athletes. PLoS ONE 11:e0160167. https://doi.org/10.1371/journal.pone.0160167CrossRefPubMedPubMedCentral

Luan YY, Yao YM (2018) The clinical significance and potential role of C-reactive protein in chronic inflammatory and neurodegenerative diseases. Front Immunol 9:1–8. https://doi.org/10.3389/fimmu.2018.01302CrossRef

Luo H, He L, Zhang G et al (2019) Normal reference intervals of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and systemic immune inflammation index in healthy adults: a large multi-center study from western China. Clin Lab 65:255–265. https://doi.org/10.7754/Clin.Lab.2018.180715CrossRef

Mackinnon LT, Hooper SL, Jones S et al (1997) Hormonal, immunological, and hematological responses to intensified training in elite swimmers. Med Sci Sports Exerc 29:1637–1645. https://doi.org/10.1097/00005768-199712000-00014CrossRefPubMed

Makras P, Koukoulis GN, Bourikas G et al (2005) Effect of 4 weeks of basic military training on peripheral blood leucocytes and urinary excretion of catecholamines and cortisol. J Sports Sci 23:825–834. https://doi.org/10.1080/02640410400021815CrossRefPubMed

McMurray RG, Hackney AC (2005) Interactions of metabolic hormones, adipose tissue and exercise. Sport Med 35:393–412. https://doi.org/10.2165/00007256-200535050-00003CrossRef

Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454:428–435. https://doi.org/10.1038/nature07201CrossRefPubMed

Meng X, Chang Q, Liu Y et al (2018) Determinant roles of gender and age on SII, PLR, NLR, LMR and MLR and their reference intervals defining in Henan, China: a posteriori and big-data-based. J Clin Lab Anal 32:1–8. https://doi.org/10.1002/jcla.22228CrossRef

Murase Y, Shimizu K, Tanimura Y et al (2016) Salivary extracellular heat shock protein 70 (eHSP70) levels increase after 59 min of intense exercise and correlate with resting salivary secretory immunoglobulin A (SIgA) levels at rest. Cell Stress Chaperones 21:261–269. https://doi.org/10.1007/s12192-015-0656-2CrossRefPubMed

Nathan C, Ding A (2010) Nonresolving inflammation. Cell 140:871–882. https://doi.org/10.1016/j.cell.2010.02.029CrossRefPubMed

Nieman DC, Simondie S, Henson DA et al (1995) Lymphocyte proliferative response to 2.5 hours of running. Int J Sports Med 16:404–409. https://doi.org/10.1055/s-2007-973028CrossRefPubMed

Okyay GU, Inal S, Öneç K et al (2013) Neutrophil to lymphocyte ratio in evaluation of inflammation in patients with chronic kidney disease. Ren Fail 35:29–36. https://doi.org/10.3109/0886022X.2012.734429CrossRefPubMed

Ortega E (2016) The “bioregulatory effect of exercise” on the innate/inflammatory responses. J Physiol Biochem 72:361–369. https://doi.org/10.1007/s13105-016-0478-4CrossRefPubMed

Pagola I, Morales JS, Alejo LB et al (2020) Concurrent exercise interventions in breast cancer survivors with cancer-related fatigue. Int J Sports Med 41:790–797. https://doi.org/10.1055/a-1147-1513CrossRefPubMed

Peake JM, Nosaka K, Suzuki K (2005) Characterization of inflammatory responses to eccentric exercise in humans. Exerc Immunol Rev 11:64–85PubMed

Peake JM, Neubauer O, Gatta PAD, Nosaka K (2017) Muscle damage and inflammation during recovery from exercise. J Appl Physiol 122:559–570. https://doi.org/10.1152/japplphysiol.00971.2016CrossRefPubMed

Pedersen BK, Rohde T, Ostrowski K (1998) Recovery of the immune system after exercise. Acta Physiol Scand 162:325–332. https://doi.org/10.1046/j.1365-201X.1998.0325e.xCrossRefPubMed

Pedlar CR, Newell J, Lewis NA (2019) Blood biomarker profiling and monitoring for high-performance physiology and nutrition: current perspectives, limitations and recommendations. Sport Med 49:185–198. https://doi.org/10.1007/s40279-019-01158-xCrossRef

Posthuma JJ, van der Meijden PEJ, ten Cate H, Spronk HMH (2015) Short- and Long-term exercise induced alterations in haemostasis: a review of the literature. Blood Rev 29:171–178. https://doi.org/10.1016/j.blre.2014.10.005CrossRefPubMed

Quartuccio L, Sonaglia A, McGonagle D et al (2020) Profiling COVID-19 pneumonia progressing into the cytokine storm syndrome: results from a single Italian Centre study on tocilizumab versus standard of care. J Clin Virol 129:104444. https://doi.org/10.1016/j.jcv.2020.104444CrossRefPubMedPubMedCentral

Reichel T, Boßlau TK, Palmowski J et al (2020) Reliability and suitability of physiological exercise response and recovery markers. Sci Rep 10:1–11. https://doi.org/10.1038/s41598-020-69280-9CrossRef

Schlagheck ML, Walzik D, Joisten N et al (2020) Cellular immune response to acute exercise: comparison of endurance and resistance exercise. Eur J Haematol 105:75–84. https://doi.org/10.1111/ejh.13412CrossRefPubMed

Shek PN, Sabiston BH, Buguet A, Radomski MW (1995) Strenuous exercise and immunological changes: a multiple-time-point analysis of leukocyte subsets, CD4/CD8 ratio, immunoglobulin production and NK cell response. Int J Sports Med 16:466–474. https://doi.org/10.1055/s-2007-973039CrossRefPubMed

Simpson RJ, Kunz H, Agha N, Graff R (2015) Exercise and the regulation of immune functions. Prog Mol Biol Transl Sci 135:355–380. https://doi.org/10.1016/bs.pmbts.2015.08.001CrossRefPubMed

Simpson RJ, Campbell JP, Gleeson M et al (2020) Can exercise affect immune function to increase susceptibility to infection? Exerc Immunol Rev 26:8–22PubMed

Stojkovic Lalosevic M, Pavlovic Markovic A, Stankovic S et al (2019) Combined diagnostic efficacy of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and mean platelet volume (MPV) as biomarkers of systemic inflammation in the diagnosis of colorectal cancer. Dis Markers 2019:6036979. https://doi.org/10.1155/2019/6036979CrossRefPubMedPubMedCentral

Svendsen IS, Killer SC, Carter JM et al (2016) Impact of intensified training and carbohydrate supplementation on immunity and markers of overreaching in highly trained cyclists. Eur J Appl Physiol 116:867–877. https://doi.org/10.1007/s00421-016-3340-zCrossRefPubMedPubMedCentral

Turkmen K, Erdur FM, Ozcicek F et al (2013) Platelet-to-lymphocyte ratio better predicts inflammation than neutrophil-to-lymphocyte ratio in end-stage renal disease patients. Hemodial Int 17:391–396. https://doi.org/10.1111/hdi.12040CrossRefPubMed

Van Snick J (1990) Interleukin-6: an overview. Annu Rev Immunol 8:253–278. https://doi.org/10.1146/annurev.iy.08.040190.001345CrossRefPubMed

Vejjajiva A, Teasdale GM (1965) Serum creatine kinase and exercise. Br Med J 2:646. https://doi.org/10.1136/bmj.2.5462.646-cCrossRefPubMedCentral

Vincent HK, Vincent KR (1997) The effect of training status on the serum creatine kinase response, soreness and muscle function following resistance exercise. Int J Sports Med 18:431–437. https://doi.org/10.1055/s-2007-972660CrossRefPubMed

Wahl P, Mathes S, Bloch W, Zimmer P (2020) Acute impact of recovery on the restoration of cellular immunological homeostasis. Int J Sports Med 41:12–20. https://doi.org/10.1055/a-1015-0453CrossRefPubMed

Wang R, Chen PJ, Chen WH (2011) Diet and exercise improve neutrophil to lymphocyte ratio in overweight adolescents. Int J Sports Med 32:982–986. https://doi.org/10.1055/s-0031-1283185CrossRefPubMed

Wei CY, Chen CY, Liao YH et al (2017) Deep ocean mineral supplementation enhances the cerebral hemodynamic response during exercise and decreases inflammation postexercise in men at two age levels. Front Physiol 8:1016. https://doi.org/10.3389/fphys.2017.01016CrossRefPubMedPubMedCentral

Yamada M, Suzuki K, Kudo S et al (2000) Effect of exhaustive exercise on human neutrophils in athletes. Luminescence 15:15–20. https://doi.org/10.1002/(SICI)1522-7243(200001/02)15:1%3c15::AID-BIO570%3e3.0.CO;2-OCrossRefPubMed

Yang R, Chang Q, Meng X et al (2018) Prognostic value of systemic immune-inflammation index in cancer: a meta-analysis. J Cancer 9:3295–3302. https://doi.org/10.7150/jca.25691CrossRefPubMedPubMedCentral

Yang YL, Wu CH, Hsu PF et al (2020) Systemic immune-inflammation index (SII) predicted clinical outcome in patients with coronary artery disease. Eur J Clin Invest 50:e13230. https://doi.org/10.1111/eci.13230CrossRefPubMed

Zahorec R (2001) Ratio of neutrophil to lymphocyte counts—rapid and simple parameter of systemic inflammation and stress in critically ill. Bratisl Lek Listy 102:5–14PubMed

Zarbock A, Polanowska-Grabowska RK, Ley K (2007) Platelet-neutrophil-interactions: linking hemostasis and inflammation. Blood Rev 21:99–111. https://doi.org/10.1016/j.blre.2006.06.001CrossRefPubMed

Zhu Z, Cai T, Fan L et al (2020) Clinical value of immune-inflammatory parameters to assess the severity of coronavirus disease 2019. Int J Infect Dis 95:332–339. https://doi.org/10.1016/j.ijid.2020.04.041CrossRefPubMedPubMedCentral

Title: Transferring clinically established immune inflammation markers into exercise physiology: focus on neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and systemic immune-inflammation index
Authors: David Walzik
Niklas Joisten
Jonas Zacher
Philipp Zimmer
Publication date: 01-07-2021
Publisher: Springer Berlin Heidelberg
Keyword: Biomarkers
Published in: European Journal of Applied Physiology / Issue 7/2021
Print ISSN: 1439-6319
Electronic ISSN: 1439-6327
DOI: https://doi.org/10.1007/s00421-021-04668-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Transferring clinically established immune inflammation markers into exercise physiology: focus on neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and systemic immune-inflammation index

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 7/2021

Individual cardiovascular responsiveness to work-matched exercise within the moderate- and severe-intensity domains

Sprint interval training (SIT) reduces serum epidermal growth factor (EGF), but not other inflammatory cytokines in trained older men

Association between O2 kinetics and O2max in groups differing in fitness status

A clinical evaluation of VO2 kinetics in kidney transplant recipients

Wearing compression tights post-exercise enhances recovery hemodynamics and subsequent cycling performance

Post-exercise cardiac autonomic and cardiovascular responses to heart rate-matched and work rate-matched hypoxic exercise