European Journal of Applied Physiology (2021) 121:1803–1814 https://doi.org/10.1007/s00421-021-04668-7 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 David Walzik1  · Niklas Joisten1  · Jonas Zacher2  · Philipp Zimmer1 Received: 18 December 2020 / Accepted: 16 March 2021 / Published online: 31 March 2021 © The Author(s) 2021 Abstract Over the last decades the cellular immune inflammation markers neutrophil-to-lymphocyte ratio (NLR), platelet-to-lym- phocyte 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 investiga- tions 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. Keywords Physical activity · Exercise · Training · Recovery · Inflammation · Biomarker Abbreviations Introduction CK C reatine kinase CRP C -reactive protein Acute inflammation is a physiological response of the human IL-6 Interleukin-6 body to local tissue damage, aiming at restoring tissue integ- NLR N eutrophil-to-lymphocyte ratio rity and tissue homeostasis in both physiological context PLR Platelet-to-lymphocyte ratio such as exercise (Chazaud 2016) and pathological context SII Systemic immune-inflammation index such as disease (Eming et al. 2017). Although this response is essential for long-term health, it is often accompanied by negatively perceived side effects such as swelling, pain, heat, redness and impaired function, which are mainly mediated by vasodilation and increased perfusion. Beside this vascu- Communicated by Michael Lindinger. lar response, a cellular response is initiated by the immune Philipp Zimmer system to identify and eliminate the inflammatory triggers * Philipp.zimmer@tu-dortmund.de and remove damaged tissue (Medzhitov 2008). Since tissue damage can occur in response to different stimuli, the conno- 1 Institute for Sport and Sport Science, TU Dortmund tation of acute inflammation is context dependent. In clinical University, Dortmund, Germany context a bacterial infection might cause acute inflammation 2 Institute for Cardiovascular Research and Sport Medicine, and even provoke severe complications, while this is rarely German Sport University Cologne, Cologne, Germany Vol.:(012 3456789) 1804 European Journal of Applied Physiology (2021) 121:1803–1814 the case in response to mechanical tissue damage, as induced are of great benefit in exercise settings since they allow an in skeletal muscle by strenuous exercise. Here, acute inflam- objective and physiology-based insight into the individual mation represents a transient state, which can be seen as the inflammatory state. Beside basic research approaches inves- first step of the subsequent recovery process (Peake et al. tigating the physiology behind acute and chronic exercise- 2017). In both cases inflammation aims at restoring tissue induced alterations of immune homeostasis in different pop- function and usually resolves as soon as homeostasis is re- ulations, further application includes performance and health established (Eming et al. 2017). However, if inflammatory settings. In performance settings, inflammation markers are processes do not result in restoration of homeostasis, acute frequently used to measure exercise strain and recovery pro- inflammation remains unresolved, ultimately resulting in cesses, as indicated by altered values in response to acute chronic inflammation, a hallmark and central risk factor of exercise. Return to baseline of these markers is interpreted various medical conditions (Nathan and Ding 2010). In this as restoration of homeostasis, suggesting completion of the context, attention has been drawn to the potential benefit of recovery process. Reflecting individual recovery kinetics, chronic exercise interventions. While acute exercise induces inflammation markers are, therefore, assessed to improve an inflammatory response, chronic exercise has shown to exercise programming by adjusting exercise characteris- exert anti-inflammatory effects via several mechanisms, tics (e.g., frequency, intensity, type, time) to the individual thereby bearing strong potential in the prevention and treat- recovery state. However, prior correlation of the respective ment of diseases linked to chronic inflammation (Gleeson inflammation markers with performance measures is cru- et al. 2011). cial to ensure validity. Apart of post-exercise deviations, Due to the fact that acute inflammation occurs in both altered baseline concentrations of several biomarkers have clinical and exercise-based settings, it is no surprise to see additionally been suspected to depict periods of overtraining a rising number of clinical inflammation markers such as or increased susceptibility to infection (Gleeson 2002; Lee C-reactive protein (CRP) or interleukin-6 (IL-6) find their et al. 2017). In health settings, inflammation markers are way into exercise physiology. These inflammation markers assessed to reflect anti-inflammatory properties of chronic are usually assessed as objective correlates of inflammatory exercise in different pathologies. More precisely, baseline processes to give an insight into the individual inflammatory inflammation markers have been shown to decrease as a con- state, thereby allowing predictions as to when and how the sequence of regular exercise training, especially in medical next exercise session can be carried out (Pedlar et al. 2019). conditions linked to chronic inflammation, e.g. cardiovas- Building upon this, the aim of the present review is to assess cular and neoplastic diseases (Gleeson et al. 2011; Ortega the potential value of the novel but clinically established 2016). In view of these benefits, blood-derived inflammation cellular immune inflammation markers neutrophil-to-lym- markers are increasingly assessed in both performance and phocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and health-related exercise settings. However, due to numerous systemic immune-inflammation index (SII = NLR × plate- markers with potential application (Lee et al. 2017; Reichel lets) in the field of exercise physiology. After focusing on et al. 2020), only some of the frequently assessed are pre- strengths and limitations of some of the most frequently sented in the following paragraphs. used inflammation markers in exercise settings, we seek to A hallmark of exercise is the mechanical strain on highlight the benefits and potential applications of the cal- muscle tissue. Therefore, muscle-derived damage mark- culated markers NLR, PLR and SII in performance- and ers have received considerable research attention as indi- health-related exercise settings. By providing a detailed cators of exercise stress and recovery process in the past description on how to interpret these markers we want to decades. With creatine kinase (CK) one of these markers emphasize their practical relevance and encourage future was first applied in exercise context as early as 1965 (Vej- exercise research to implement them in both clinical inter- jajiva and Teasdale 1965). While originally used as a bio- vention trials and elite sport settings. marker in clinical conditions linked to muscle tissue damage (e.g., myocardial infarction, myopathies), CK is nowadays frequently assessed in exercise context as well. As a key Inflammation markers—from clinical enzyme in ATP regeneration, it is suspected to leak into context to exercise physiology peripheral blood via the lymphatic system after microtrauma in skeletal muscle, mostly induced by high mechanical strain When considering blood-derived inflammation markers, it on muscle tissue (e.g., eccentric exercise). An interesting is important to keep in mind that they mostly originate from alternative hypothesis suspects volitional expulsion of CK clinical settings. Inflammatory processes, patient character- in metabolically stressed cells to avoid cell death (Behringer istics and (patho) physiology can differ considerably com- et al. 2014). Although correlation of CK concentrations with pared to exercise settings, thereby potentially changing the performance parameters was demonstrated in several inves- way of interpretation. Nonetheless, inflammation markers tigations (Baird et al. 2012), its usefulness as a biomarker in 1 3 European Journal of Applied Physiology (2021) 121:1803–1814 1805 exercise settings is discussed controversially due to several exercise, thereby questioning their benefit in exercise set- limitations. Firstly, there is a great interindividual variability tings (Reichel et al. 2020). Additionally, the high methodo- in dependence on subject characteristics (e.g., sex, ethnicity, logical resources needed for determination render a frequent age, muscle mass), making determination of individual refer- assessment impractical. ence values a crucial step for frequent assessment. Secondly, Finally, exercise-induced inflammation is also reflected values differ depending on the applied exercise stimulus, by the cellular compartment of the immune system. Since with the highest values occurring after exercise modalities immunological alterations are part of any inflammatory related to a high amount of muscle damage (e.g., prolonged reaction, immune cells are an interesting target in exercise and eccentric exercise), thereby limiting applicability in context. Although acute exercise generally induces a strong other exercise settings (Brancaccio et al. 2007). Thirdly, leukocytosis, kinetics of leukocyte subsets can differ con- there also seem to be differences in CK-response depending siderably. For instance, neutrophil and lymphocyte counts on training status, leading to distinction of high-responders increase during exercise (neutrophilia, lymphocytosis), but and low-responders (Vincent and Vincent 1997). A recent show different post-exercise kinetics. The response of neu- investigation on the reliability of different recovery biomark- trophils is marked by a persistent neutrophilia, while lym- ers revealed a moderate reliability of CK in response to acute phocyte counts decrease within 10–15 min after exercise aerobic exercise. Interestingly, when accounting for training cessation (lymphocytopenia) (Shek et al. 1995; Pedersen status, reliability was poor in the trained subgroup, thereby et al. 1998). Mechanistically, neutrophilia and lymphocy- further complicating the use of CK as muscle damage bio- tosis are explained by mobilization of marginal immune marker, especially in athletes, where it is most frequently cell pools in the liver, spleen, lung and on vessel walls via assessed (Reichel et al. 2020). However, it is important to the action of catecholamines and increased shear stress separate exercise-induced muscle damage from inflamma- mediated by higher perfusion (Simpson et al. 2015). The tion as such. While CK—though characterized by several persistent neutrophilia is additionally promoted by a cor- limitations—is a biomarker of muscle damage, its role in tisol-induced release of neutrophils from the bone marrow classic inflammatory processes is rather inferior. (Yamada et al. 2000). Beside affecting the absolute number When looking for markers that depict exercise-induced of neutrophils and lymphocytes, catecholamines and gluco- inflammation, immunological parameters represent an eas- corticoids also impact immune cell function (Simpson et al. ily accessible physiological resource. Due to the strong 2015) and act differently in healthy individuals compared involvement of the immune system in inflammatory pro- to diseased (McMurray and Hackney 2005; Ortega 2016). cesses, several components of both the humoral and cel- While the mechanisms behind neutrophilia and lymphocy- lular compartment have been considered as inflammation tosis are fairly well understood, post-exercise lymphocyto- markers in exercise settings (Gonçalves et al. 2020). As part penia is interpreted differentially. One hypothesis suspects of the humoral compartment acute phase reactants such as an impaired immune function due to apoptosis of lympho- CRP are frequently assessed. Similar to CK, its use in exer- cytes after acute strenuous bouts of exercise (Kakanis et al. cise settings originates from a clinical background, where 2010), while another hypothesis assumes emigration of lym- CRP is used as a general marker of inflammation in a broad phocytes from the circulation to peripheral tissue, thereby range of diseases (Luan and Yao 2018). While CRP levels increasing immune competence and surveillance (Campbell generally increase in response to acute exercise, baseline and Turner 2018). Whether acute exercise causes an increase levels seem to decrease in response to chronic training, or decrease in infection risk of healthy individuals remains thereby reflecting the (anti-)inflammatory effects of acute inconclusive until today and is still a topic of hot debate and chronic exercise (Kasapis and Thompson 2005). Aside (Simpson et al. 2020). However, independent of the immu- of CRP, another frequently applied inflammation marker nological consequences, leukocyte count seems to represent is the inflammatory cytokine IL-6, which is substantially a useful physiological correlate of inflammatory processes, involved in the innate and adaptive immune response, e.g. as reinforced by numerous investigations in exercise settings via the production of acute phase proteins and the prolifera- (Peake et al. 2005; Cerqueira et al. 2020). tion of T- and B-cells (Van Snick 1990). Serving as a general marker of inflammation in clinical context it was transferred to exercise settings after discovering that peripheral IL-6 Introducing the cellular immune concentrations increase in response to acute exercise. In fact, inflammation markers NLR, PLR and SII skeletal muscle contractions themselves are responsible for the majority of exercise-induced increases in IL-6, making Although total leukocyte count is a useful measure to depict it an attractive biomarker to depict exercise-induced inflam- general inflammation, it fails to consider the distinct kinet- mation (Fischer 2006). However, for both CRP and IL-6 only ics of different leukocyte subsets. Tackling this problem, moderate reliability was found in response to acute aerobic the integrative cellular immune inflammation markers NLR, 1 3 1806 European Journal of Applied Physiology (2021) 121:1803–1814 PLR and SII have emerged in clinical context during the leukocyte subsets, but takes platelet counts into considera- past decades. Considering multiple immune cell popula- tion. Beside the well-known role of platelets in primary tions, they provide a multifactorial insight into inflamma- haemostasis, they also exhibit various pro-inflammatory tory processes. Although no conclusions can be drawn on properties, underlining their value as inflammation marker the kinetics of lymphocyte subsets such as T- and B-cells, (Zarbock et al. 2007). Similar to NLR, current research has these markers are increasingly implemented as inflammatory mainly focused on diseased populations, establishing both and prognostic markers in various clinical conditions such as NLR and PLR as inflammation markers in diseases such as neoplastic (Howard et al. 2019; Yang et al. 2020), neurologi- cancer (Stojkovic Lalosevic et al. 2019). In some medical cal (Hemond et al. 2019) or cardiovascular diseases (Bhat conditions (e.g., renal disease) PLR was even found to be et al. 2013). Moderate to high correlations between these a better marker of disease-related inflammation than NLR markers and well-established inflammation markers such as (Turkmen et al. 2013), thereby raising interesting questions white blood cell count (Gonda et al. 2017), CRP (Huang as to which marker proves more beneficial. Surprisingly, et al. 2018; Quartuccio et al. 2020), IL-6 (Islas-Vazquez PLR has thus far found very little consideration in the con- et al. 2020; Zhu et al. 2020) and erythrocyte sedimentation text of exercise (see section “Current state of knowledge— rate (Huang et al. 2018) additionally underline the suitabil- NLR, PLR and SII in exercise physiology”), most likely ity for depiction of inflammatory processes. Surprisingly, due to the combination of two apparently distinct blood application of these markers in exercise settings is sparse so cell populations. Similar to exercise-induced neutrophilia, far. Since the integrative value of the markers is exploited in platelet counts rise acutely in response to exercise (throm- clinical context to adapt therapeutic measures to the patient’s bocytosis) due to a fresh release from the bone marrow, inflammatory status (Cai et al. 2021), conclusions in exercise spleen and pulmonary intravascular pools (El-Sayed et al. settings could be drawn in a similar manner, e.g. to custom 2000). Therefore, PLR can be seen as an alternative to NLR, exercise programs to the individual recovery needs. Con- replacing neutrophils with platelets in the calculation of the sidering these potential benefits, we seek to introduce the cellular immune inflammation markers (see Fig. 1). Consid- clinically established cellular immune inflammation mark- ering exercise-induced thrombocytosis, PLR seems equally ers NLR, PLR and SII in the field of exercise physiology, valuable to depict inflammation in response to acute exer- thereby highlighting their potential value in depiction of cise. Similar to NLR highest PLR values arise when platelet exercise-induced inflammation. counts are high and lymphocyte counts are low. As a calculated ratio of leukocyte subsets the NLR was Only recently, Hu et al. (2014) introduced the SII as a first proposed as an inflammatory marker after observing third cellular immune inflammation marker that integrates that cancer patients exhibit sustained neutrophilia accom- the kinetics of NLR and PLR into one single parameter. panied by lymphocytopenia (Zahorec 2001). Since then, While NLR and PLR are calculated as ratios of two dif- numerous studies have investigated the value of NRL as ferent blood cell populations, respectively, the SII consid- an inflammatory and prognostic marker in cancer settings ers three populations by multiplying the NLR with platelet (Guthrie et al. 2013) and other diseases (Bhat et al. 2013; counts (see Fig. 1). In clinical context, the SII has since then Okyay et al. 2013). Interestingly, the NLR has also been gained remarkable popularity as inflammation-based prog- studied in the context of exercise as early as 1995 (Nieman nostic marker, mainly in cancer settings (Yang et al. 2018). et al. 1995). Since sustained neutrophilia and lymphocyto- However, to our knowledge there has been no investigations penia are also characteristic for the early recovery stages on the potential value of SII in the context of exercise out- after exercise, transfer of the NLR as an acute inflammation side of work from our group (see section “Current state of marker seems reasonable. However, only few studies have knowledge—NLR, PLR and SII in exercise physiology”). assessed this potential value in the context of exercise since By multiplying NLR values with platelet counts, the effect then (see section “Current state of knowledge—NLR, PLR of exercise-induced neutrophilia and lymphocytopenia (as and SII in exercise physiology”). By integrating the kinet- indicated by NLR) is amplified by the effect of thrombocy- ics of the two largest leukocyte subsets into one condensed tosis. Considering various exercise-responsive blood com- parameter, NLR seems to have high potential as an inflam- ponents, SII might constitute a versatile and robust marker in mation marker in exercise settings with increased values the assessment of exercise-induced inflammation and could indicating ongoing inflammatory processes. Considering the represent an alternative or addition to frequently assessed kinetics of NLR, the highest values arise when neutrophils inflammation markers. Similar to NLR, highest SII values counts are high and lymphocytes counts are low (see Fig. 1). occur when neutrophil and platelet counts are high and lym- A second cellular immune inflammation marker is the phocyte counts are low (see Fig. 1). PLR. In contrast to NLR, this marker is not only based on 1 3 European Journal of Applied Physiology (2021) 121:1803–1814 1807 Fig. 1 Calculation of the cellular immune inflammation markers acute exercise are represented by different height, with higher place- neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio ment indicating higher concentrations. Dashed lines indicate division (PLR) and systemic immune-inflammation index (SII). Altered con- of blood cell populations; solid lines indicate multiplication. Numeric centrations of the underlying blood cell populations in response to reference values were extracted from Arbiol-Roca et al. (2018) To enable frequent utilization of the integrative mark- Current state of knowledge—NLR, PLR ers in clinical context, several authors have determined and SII in exercise physiology age- and gender-stratified reference values for NLR, PLR and SII in healthy individuals at rest (see Table 1) (Fest To date, evidence regarding the potential value of NLR, PLR et al. 2018; Meng et al. 2018; Luo et al. 2019). However, and SII as cellular immune inflammation markers for the since reference values were reported by different descrip- depiction of exercise-induced inflammation is limited. How- tive statistics (e.g., mean, median, chosen percentiles), ever, due to the low temporal, financial and infrastructural results are hard to compare and seem to vary slightly resources needed for assessment and calculation, application across the investigations. While the impact of gender was in exercise settings seems highly feasible and easy to imple- fairly consistent with higher PLR and SII in women and ment. Including these markers in both performance- and higher NLR in men, the impact of age was reported dif- health-related exercise settings might enable an integrative ferently by the authors. Interestingly, Fest et al. (2018) depiction of exercise-induced inflammation, as reflected by revealed that baseline values of NLR and SII increase with cellular alterations within the bloodstream. In competitive age, which might be attributed to the higher prevalence sport these markers might facilitate depiction of exercise of inflammation-linked pathologies in elderly. In contrast, strain and recovery processes or help identify periods of PLR decreases with age, which is in accordance with the increased infection risk or overtraining, thereby improving lower platelet counts found in old individuals (Biino et al. exercise programming. In health settings, they might indi- 2013). A further stratification factor that was unfortunately cate anti-inflammatory effects of chronic exercise, especially not considered is body mass index. Since body composi- in patients exhibiting chronic inflammation. tion can impact baseline values of inflammatory markers Given these potential applications, the few studies that substantially, consideration as stratification factor is war- have investigated NLR, PLR and SII in the context of exer- ranted in future investigations. cise showed promising results. In response to acute exercise 9 of 11 studies revealed an increase of NLR (see Table 2), suggesting good suitability for depiction of exercise-induced inflammation. Additionally, Joisten et al. (2020) demon- strated an intensity-dependent increase of NLR in response to acute exercise with significantly higher NLR values 1 3 1808 European Journal of Applied Physiology (2021) 121:1803–1814 1 3 Table 1 Reference values for NLR, PLR and SII in healthy individuals at rest Study Data reported as NLR [AU] PLR [AU] SII [× 109/L] Fest et al. (2018) Mean (2.5th, 97.5th percentile)  Male 1.88 (0.88, 4.14) 112 (57, 230) 453 (185, 1168)  Female 1.68 (0.8, 3.8) 126 (65, 246) 463 (194, 1169)  Aged 45–54 1.63 (0.8, 3.44) 118 (62, 211) 456 (189, 1063)  Aged 55–64 1.61 (0.79, 3.53) 116 (60, 226) 436 (186, 1109)  Aged 65–74 1.82 (0.86, 3.92) 119 (60, 239) 455 (186, 1131)  Aged 75–84 2.02 (0.96, 4.53) 127 (61, 268) 500 (196, 1373)  Aged ≥ 85 2.13 (0.89, 5.86) 131 (63, 282) 522 (205, 1798) Meng et al. (2018) Median (25th, 75th percentile)  Male 1.72 (1.39, 2.17) 102 (85, 124) 358 (275, 466)  Female 1.71 (1.35, 2.18) 115 (95, 140) 374 (282, 497)  Aged 18–65 1.71 (1.36, 2.17) 106 (88, 128) 366 (278, 480)  Aged > 65 1.85 (1.46, 2.36) 139 (116, 169} 366 (275, 488) Luo et al. (2019) Median (2.5th, 97.5th percentile)  Male 1.75 (0.89, 3.95) 94 (46, 181) 329 (142, 764)  Female 1.78 (0.87, 4.06) 105 (51, 206) 341 (141, 850)  Aged 18–64 1.76 (0.88, 4.02) 100 (49, 198) 337 (145, 810)  Aged 65–79 1.81 (0.89, 3.91) 90 (42, 187) 312 (124, 784) NLR Neutrophil-to-lymphocyte ratio, PLR Platelet-to-lymphocyte ratio, SII Systemic immune-inflammation index, AU Arbitrary unit European Journal of Applied Physiology (2021) 121:1803–1814 1809 occurring after acute high intensity interval training com- platelets into peripheral circulation (Posthuma et al. 2015). pared to moderate continuous training in persons suffering Considering the effect of chronic exercise on the PLR, no from multiple sclerosis. Comparing the different studies per- alterations were found after 3 weeks of endurance exercise formed on NLR, acute exercise-induced increases can reach in a population suffering from multiple sclerosis (Joisten up to six-fold above baseline with absolute values over 10 et al. 2020). These results seem surprising since persons (Nieman et al. 1995). In contrast, chronic exercise interven- with multiple sclerosis generally exhibit increased platelet tions seem to show conflicting results at first sight. How- counts associated with chronic inflammation (Dziedzic and ever, when accounting for the applied exercise intervention, Bijak 2019) and chronic exercise has shown to lower inflam- results appear more conclusive. While intensified training matory mediators (Gleeson et al. 2011). As a consequence periods with the aim of overstressing athletes resulted in an of this, the baseline PLR would be expected to decrease. increased baseline NLR (Mackinnon et al. 1997; Svendsen However, non-responsiveness of platelets to chronic exer- et al. 2016), physiological training interventions induced a cise might be suspected as a potential reason for unaltered decrease in both healthy (Makras et al. 2005) and diseased values. Regarding the inconsistent results of the few studies populations (Wang et al. 2011; Joisten et al. 2020). The conducted so far and the lack of chronic exercise interven- applicability of NLR as a marker of inflammatory status is tions in healthy individuals, there is an urgent need for fur- further reinforced by the significant correlation of decreased ther research approaches focusing on the potential value of baseline NLR and IL-6 concentrations obtained by Wang PLR as an exercise-induced inflammation marker in different et  al. (2011) in response to a 4-week exercise and diet populations and exercise modalities. intervention in overweight adolescents. Conversely, when For SII even less evidence is available in the context of exercise activity was decreased, anti-inflammatory effects exercise. However, three of the four studies conducted so far of chronic exercise quickly diminished. In a study investi- showed an increased SII after acute exercise, thereby indi- gating the impact of 8 weeks of detraining on inflammatory cating a potentially promising role as inflammation marker status, an increase in NLR by 48.2% was observed (Liao in exercise settings (see Table 2). Similar to NLR and PLR, et al. 2016). Additionally, the results of studies investigating high intensity modalities elicited the most pronounced intensified training periods indicate a potential application response with values around three- to four-fold above base- of NLR as marker of chronic exercise overload (Mackinnon line and absolute values over 1000 (Wahl et al. 2020). Due et al. 1997; Svendsen et al. 2016). Indeed increased NLR to the integration of exercise-induced neutrophilia, lympho- has previously been discussed as a potential immune inflam- cytopenia and thrombocytosis, there seems to be a strong mation marker for impending overtraining (Gleeson 2002). physiological basis for the application of SII as inflammation Compared to NLR, far less evidence is available on the marker in response to acute exercise. Additionally, the SII PLR in the context of exercise. Of the five studies investigat- seems to depict anti-inflammatory effects of chronic exercise ing the impact of acute exercise on the PLR, three showed in a similar manner as the NLR, as indicated by a decrease increased values post-exercise, indicating an inflamma- in baseline values after 3 weeks of high intensity interval tory response (see Table 2). Considering exercise-induced training in persons suffering from multiple sclerosis (Jois- thrombocytosis instead of neutrophilia, PLR might, there- ten et al. 2020). However, since all investigations on the fore, serve as a useful alternative or addition to NLR, as potential value of SII as inflammation marker in the context indicated by increases in both markers in response to acute of acute or chronic exercise are from our group, replication exercise in healthy (Wahl et al. 2020) and diseased popula- and extension of our results in future research endeavours tions (Korkmaz et al. 2018). Interestingly, PLR values were is urgently needed. A summary of current studies assessing altered more profoundly by high intensity exercise modali- NLR, PLR and SII in the context of both acute and chronic ties with values around twice higher than at rest and absolute exercise interventions is provided in Table 2. values over 200 (Wahl et al. 2020). A possible explanation for this might be the exercise-dependent mobilization of 1 3 1 810 European Journal of Applied Physiology (2021) 121:1803–1814 1 3 Table 2 Overview of studies assessing NLR, PLR or SII as inflammation markers in exercise settings Study N Study population Intervention NLR PLR SII Acute exercise  Bessa et al. (2016) 19 Healthy young male cyclists 6x “all out reps” at 85% 1RM for squat and bench ↑ NA NA press followed by 1 h cycling at 85% V O2peak  Davison and Diment (2010) 20 Healthy young males 2 h cycling at 64% VO2max ↑ NA NA  Joisten et al. (2019) 20 Healthy young males 300 countermovement jumps ↑ – ↑  Joisten et al. (2020)b 35 Old males and females with MS HIIT: 5 × 1.5 min cycling at 95–100% HRmax - ↑ – 33 MCT: 24 min cycling at 65% HRmax – – –  Kerksick et al. (2010) 30 Healthy young males 100 eccentric knee extensions ↑ NA NA  Korkmaz et al. (2018) 113 Old males and females with symp- Treadmill exercise according to Bruce protocol ↑ ↑ NA toms of CAD  Murase et al. (2016) 16 Healthy young males 59 min cycling at 75% VO2max ↑ NA NA  Nieman et al. (1995)a 22 Healthy middle-aged male runners 2.5 h running at 75% VO2max ↑ NA NA  Schlagheck et al. (2020) 24 Healthy young males MCT: 45 min cycling at 60% PPO – – ↑ 24 RE: 5 exercise machines, each 4 × 8–10 reps at – – – 70% 1RM  Wahl et al. (2020) 12 Healthy young male triathletes/ HIIT: 4 × 4 min at 90–95% PPO ↑ ↑ ↑ cyclists HIIT: 4 × 30 s “all out” ↑ ↑ ↑  Wei et al. (2017) 12 Healthy young males Cycling to volitional exhaustion at 75% VO2max – NA NA 9 Healthy middle-aged males Cycling to volitional exhaustion at 75% VO2max ↑ NA NA Chronic exercise  Joisten et al. (2020)b 35 Old males and females with MS 3 weeks, 3x/week HIIT: 5 × 1.5 min cycling at 95–100% ↓ – ↓ H Rmax 33 3 weeks 3x/week MCT: 24 min cycling at 65% HRmax – – –  Mackinnon et al. (1997) 24 Healthy female and male elite swim- 4 weeks 6x/week twice a day progressive intensified ↑ NA NA mers swim training  Makras et al. (2005) 48 Healthy young males 4 weeks 5x/week moderate intermittent mixed EE and RE ↓ NA NA  Pagola et al. (2020) 13 Old females with breast cancer 16 weeks 2x/week for 75 min intensive mixed EE and RE – NA NA 10 16 weeks 2x/week unsupervised moderate mixed EE and – NA NA RE  Svendsen et al. (2016) 13 Healthy young male cyclists 8 days of intensified cycling training (increased volume ↑ NA NA and intensity)  Wang et al. (2011) 43 Obese male adolescents 4 weeks 6x/week twice a day 2 h mixed EE ↓ NA NA European Journal of Applied Physiology (2021) 121:1803–1814 1811 Limitations and future perspectives Considering blood-derived inflammation markers, caution is warranted what conclusions can be drawn from them, since this can differ depending on their physiological ori- gin. Therefore, it is important to stress that NLR, PLR and SII are inflammation markers based on cellular alterations within the bloodstream. In contrast to muscle-derived dam- age markers such as CK, they allow no assessment of the occurrence of tissue damage or the associated repair pro- cesses. Instead, they should be seen as markers of general inflammation in both performance and health-related exer- cise settings. However, to enable regular assessment, resting values for athletes and kinetics of different exercise modali- ties have to be established. While already described by sev- eral authors in the general population (Fest et al. 2018; Meng et al. 2018; Luo et al. 2019), reference values for athletes and kinetics of different exercise modalities are lacking thus far. Further investigations should, therefore, focus on assessing NLR, PLR and SII in athletes and stratify values by age, gender, training status and exercise modality to determine a baseline range. In this context special consideration should be given to exercise-specific influencing variables such as haematocrit, dietary habits, hydration and hormonal status, since these parameters might influence baseline levels and exercise kinetics. After establishing baseline values, alterations of these val- ues could be utilized for exercise programming. Regarding the reliability of these markers, a recent study by Reichel et al. (2020) assessed intraclass correlation coefficients between two identical strenuous endurance exercise protocols for several biomarkers, identifying some promising candidates for fre- quent assessment. Surprisingly, immune cell counts were not altered by the exercise protocol and only moderate reliability was found for NLR, PLR and SII. Since strenuous exercise is known to induce strong immunological alterations, the obtained results seem inconclusive and limit the power of the reliability found for NLR, PLR and SII since their calcula- tion depends directly on immunological alterations. Further research investigating the reliability of the cellular immune inflammation markers in response to different exercise modali- ties is, therefore, strongly warranted. Although other methodo- logical approaches such as flow cytometry offer a more pre- cise insight into cellular alterations of the immune system in response to exercise, calculation of NLR, PLR and SII is much more feasible and facilitates frequent assessment in practical exercise settings such as competitive sport or rehabilitation programs. Implementing these markers into routine assess- ments might enable athletes and coaches to infer information on individual recovery needs and help clinical practitioners monitor the anti-inflammatory effects of long-term exercise in patients with chronic inflammation. Since calculation of 1 3 Table 2 (continued) Significant changes of NLR, PLR and SII are reported as differences from baseline to post-exercise (time effects) to show suitability for depiction of exercise-induced inflammation 1RM One-repetition maximum, CAD Coronary artery disease, EE Endurance exercise, HIIT High intensity interval training, HRmax Maximum heart rate, MCT Moderate continuous training, MS Multiple sclerosis, NA Not assessed, NLR Neutrophil-to-lymphocyte ratio, PLR Platelet-to-lymphocyte ratio, PPO Peak power output, RE Resistance exercise, Reps Repetitions, SII Systemic immune-inflammation index, VO2max Maximal oxygen consumption, VO2peak Peak oxygen consumption ↑ Significant increase ↓ Significant decrease – No significant changes a Results were assessed as differences from a passive control group b Results were obtained in the same study 1 812 European Journal of Applied Physiology (2021) 121:1803–1814 these markers can be performed with a simple blood count, References we strongly encourage future research approaches in exercise physiology to incorporate the presented cellular inflammation Arbiol-Roca A, Imperiali CE, Montserrat MM et al (2018) Reference markers. intervals for a complete blood count on an automated haematology analyser Sysmex XN in healthy adults from the southern metro- politan area of Barcelona. 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