The Utility of the Neutrophil-to-Lymphocyte Ratio

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The complete blood count is one of the more commonly ordered test, along with the basic metabolic profile. The CBC gives you a ton of useful information when it comes to the etiology of anemia (not just from the hemoglobin/hematocrit, but also the mean corpuscular volume, red cell distribution width, etc), coagulation, and inflammation. The white blood cell count is commonly looked at as the marker of “infection” and either a low or high count was used as a criteria for SIRS per Sepsis-2 (1). While it lacks any specificity for infection, a leukocytosis in and of itself does not necessarily mean “inflammation.” Indeed, in many instances, especially early on during illness, the white count is actually fairly normal. It is not until you look at the differential where you can start to see some interesting things, namely that a large percentage (over 80%) of said white cells are neutrophils while lymphocytes make like 5% or less of the circulating white cells picked up by the blood count. In the past 2 decades, the use of the ratio of neutrophils to lymphocytes (either absolute neutrophil/absolute lymphocyte or % neutrophils/%lymphocytes) has been used as a marker of inflammation, comparable to CRP and even to procalcitonin when it comes to bacterial infection. This is useful, as the latter tests are either send outs or take a while to come back meaning the NLR is a good way to pick up forthcoming physiologic badness.

Early Data and Physiology

The majority of the literature on NLR came from the studies of Dr Zahorec, an anesthesiologist from Slovakia (2). One of the things he noticed post-operatively in patients has a significant increase in the serum procalcitonin as well as a profound decline in serum lymphocyte counts, which was also seen in severe sepsis, septic shock, and bacteremia. Indeed, this phenomena was also seen in several instances of critical illness such as ARDS, hemorrhagic shock, acute pancreatitis, trauma, and cardiogenic shock. 

The pathophysiology behind this phenomenon suggests that high levels of cortisol, prolactin, and catecholamines may be responsible for this redistribution (2, 3). A summary is listed in the table below, but it appears that the body, during initial stress, shifts to the use of the innate immune system as opposed to the adaptive immune system, resulting in demargination of neutrophils, as well as increased mobilization of immature neutrophils from the bone marrow long with apoptosis of the lymphocytes and their redistribution within the lymphatic system (3):

Indeed, during times of supraphysiologic stress a rise in neutrophils and a drop in lymphocytes is to be expected, with prolonged elevated NLR being a marker of a dysregulated immune system:

An interesting review article notes that catecholamine-induced immune changes leads to the increase of granulocytes and NK cells by allowing “pools” of white cells to be released from the spleen, bone marrow, lymphoid tissue, and leukocytes in circulation (4):

Interestingly, the authors do note that several older studies saw an increase in leukocytes with odd triggers: emotional stress prior to an operation, induced emotional distress (anger, joy, sadness, jealousy) following hypnosis, and physical exercise. This was also seen prior to an important exam. The rationale behind this makes sense; you opt for your body to use the innate immune system when an unknown organism comes into your body as opposed to the adaptive immune system, which takes time to kick in and requires prior exposure to said organism. As a result, in severe sepsis and shock, neutrophilia predominates.

The kinetics of neutrophilia are kind of interesting. As noted above, there are pools of neutrophils that are recruited to the site of infection that lead to a relative increase when compared to lymphocytes (5). During the first phase, which occurs during the first 12 to 24 hours after infection, the neutrophils from the spleen, lung, and stored mature neutrophils in the bone marrow are used up. Left shift, which is the phenomenon of immature neutrophils, has not occurred yet and it usually occurs anywhere from 4 hours up to 12 hours after bacterial infection. In the second phase, the left shift increases from 15% to its highest ratio followed by a drop to around 15% in the third phase, where recovery from bacterial infection has started.  Finally, in the fourth phase the left shift goes away. 

Of course, not all infections may lead to this phenomenon, with infections such as endocarditis and some abscesses not having a left shift due to the bone marrow being able to keep up with production of mature neutrophils without significant depletion, or neutrophils not being able to make it to the site of infection in the first place. As such, the NLR may be a more useful parameter. 

The influence of physiologic stress on lymphocyte count was seen in a study where healthy volunteers received a dose of 4ng/kg of lipopolysaccharide aka endotoxin (6). Lymphocytes decreased by a maximum of 83% with the nadir being observed at 280 min:

This was also seen in a study of 90 ICU oncology patients who had either major surgery, SIRS, or sepsis (7). Serial CBC revealed all had a significant drop in their lymphocyte percentage after initial physiological stressor. 

In one patient, the NLR increased within 6 hours of cardiac arrest, suggesting it may be a useful marker early on and the first sign of physiologic stress. 

Utility for Infectious Disease Diagnostics

The idea behind using NLR here is to gauge whether or not someone may have an infection. As highlighted above, while CRP and procalcitonin may be more specific markers of inflammation, they’re not usual labs that are tracked during a hospitalization (with some exceptions) nor are they ordered upon initial presentation to an ED. As such, using the NLR may provide some predictive ability for infection. 

In a ED cohort of 746 patients, 92 patients with bacteremia were compared with 92 patients without bacteremia (8). While WBC and neutrophils were not different between groups, CRP, lymphocytes, and NLR were significantly different between groups, with NLR being much higher in the bacteremic group:

Moreover, it seemed to perform better than other CBC parameters and performed as well as CRP when it came to predicting bacteremia in the ED:

The difference was also seen in an ED study of 2000 patients (9). While WBC count was not different between bacteremic and non-bacteremic patients, the NLR was significantly higher in the bacteremic group:

While NLR is useful, it may not be as accurate as CRP or other inflammatory markers. For instance, a Swedish study evaluated several biomarkers, including NLR, for the diagnosis of sepsis (10). In this cohort of 1572 patients presenting to the ED, the NLR performed better than lactic acid and procalcitonin, but not as good as CRP when using either Sepsis-2 or Sepsis-3 criteria:

Notably, both procalcitonin and lactic acid were much more sensitive but all had fairly good NPV. A large series of 1767 patients evaluated the utility of PCT, lactate, total WBC count, and NLR for predicting bacteremia in inpatients (11). While there was no difference in those patients who had an organism isolated in terms of WBC or lactate, NLR was significantly elevated in the bacteremic patients:

Notably, the sensitivity was lower than that for procalcitonin. A meta-analysis of 8 studies (12), totaling 7095 patients, found that the sensitivity of NLR to predict bacteremia was 0.723 (95% CI 0.66 to 0.77). Specificity was 0.596 (95% CI 0.556 to 0.634). Given how common CBCs are, the NLR is a useful tool to predict bacterial infections. 

Prognostication

Given that an elevated NLR, particularly one that is elevated for a while, denotes dysregulated inflammation, it stands to reason it could be used to predict mortality in septic patients. And of course, you would be right. An observational cohort study of 333 ICU patients (13) found that NLR values were higher in bacteremic patients than those without bacteremia (22 vs 14, p = 0.00). Further, NLR had a decent power for predicting unfavorable outcomes when compared to neutrophils alone (AUC 0.695 for NLR vs 0.633 for neutrophils) but lower than the APACHE II score (0.828). This was also seen in the multivariate logistic regression analysis:

Along with age and the APACHE II score, NLR had some degree of power in predicting mortality which is good considering we always get CBCs daily. 

NLR has also been used to gauge mortality. A single-center retrospective study of 1395 patients presenting to the ED found that 28-day mortality was highest in the lowest and highest NLR groups (14):

Indeed, Cox regression analysis found that both low (adjusted HR 2.25, 95% CI 1.63-3.11) and high (adjusted HR 2.65, 95% CI 1.64-4.29) NLR were significantly associated with higher 28-day mortality. A retrospective study of 770 ICU patients had several interesting findings as it relates to NLR (15). First, those with higher NLR had partial resistance and full-blown resistance to antibiotics when compared to the antibiotic group. Second, higher rate of nonresponsiveness to typical ICU therapies (antibiotics, mechanical ventilation) were found in those who had higher NLR at day 1. 

Moreover, NLR was higher in patients with septic shock and those who died in the ICU compared to those without septic shock and survivors. Similarly, in a cohort of 2147 ICU patients, NLR was higher in the non-surviving group (16):

NLR was also correlated with higher mortality in multivariate analysis, however it was outperformed by other parameters such as the CRP/albumin ratio and RDW:

In a cohort of 1154 patients admitted to the ICU (17), NLR was associated with higher 1-year mortality (16.26 in the non-survivor group vs 10.18 in the survivor group, p <0.001). In pyogenic liver abscesses, the use of NLR was associated with higher likelihood of death, with AUC for NLR being 0.941 for a cut-off value of 19.7 (18). In a large study of over 32,000 patients (19), increasing NLR in the general population was associated with higher overall mortality (HR 1.14, 95% CI 1.10-1.17 per quartile), as well as being associated with higher mortality due to specific causes including heart disease (HR 1.17, 95% CI 1.06-1.29), chronic lower respiratory disease (HR 1.24, 95% CI 1.04-1.47), influenza/pneumonia (1.26, 95% CI 1.03-1.54), and kidney disease (1.62, 95% CI 1.21-2.17). 

A single-center ICU study of 130 septic shock patients found that neutrophil values were similar between survivors and non-survivors, however lymphocytes were significantly higher in the non-survivor group, yielding a lower NLR (20):

Moreover, early death patients tended to have lower NLR values when compared to survivors (12.5 for survivors vs 5 for early death, within 4 days) as well as those who died after 5 days (7). 

Final Thoughts


Given how common the CBC is, I am surprised not a lot of people know about the NLR. One caveat is that this is not specific for infections but rather any physiologic stress. This has been used in acute pulmonary embolism, acute pancreatitis, and cardiogenic shock. So think of this as an early marker for physiologic stress rather that pure infection. It is useful since you always get a CBC and patients who show up early will have some derangements in their NLR. 

References:

  1. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992 Jun;20(6):864-74. PMID: 1597042.
  2. Zahorec R. Neutrophil-to-lymphocyte ratio, past, present and future perspectives. Bratisl Lek Listy. 2021;122(7):474-488. doi: 10.4149/BLL_2021_078. PMID: 34161115.
  3. Karakonstantis S, Kalemaki D, Tzagkarakis E, Lydakis C. Pitfalls in studies of eosinopenia and neutrophil-to-lymphocyte count ratio. Infect Dis (Lond). 2018 Mar;50(3):163-174. doi: 10.1080/23744235.2017.1388537. Epub 2017 Oct 26. PMID: 29070003.
  4. Benschop RJ, Rodriguez-Feuerhahn M, Schedlowski M. Catecholamine-induced leukocytosis: early observations, current research, and future directions. Brain Behav Immun. 1996 Jun;10(2):77-91. doi: 10.1006/brbi.1996.0009. PMID: 8811932.
  5. Honda T, Uehara T, Matsumoto G, Arai S, Sugano M. Neutrophil left shift and white blood cell count as markers of bacterial infection. Clin Chim Acta. 2016 Jun 1;457:46-53. doi: 10.1016/j.cca.2016.03.017. Epub 2016 Mar 28. PMID: 27034055.
  6. Jilma B, Blann A, Pernerstorfer T, Stohlawetz P, Eichler HG, Vondrovec B, Amiral J, Richter V, Wagner OF. Regulation of adhesion molecules during human endotoxemia. No acute effects of aspirin. Am J Respir Crit Care Med. 1999 Mar;159(3):857-63. doi: 10.1164/ajrccm.159.3.9805087. PMID: 10051263.
  7. 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. English, Slovak. PMID: 11723675.
  8. de Jager CP, van Wijk PT, Mathoera RB, de Jongh-Leuvenink J, van der Poll T, Wever PC. Lymphocytopenia and neutrophil-lymphocyte count ratio predict bacteremia better than conventional infection markers in an emergency care unit. Crit Care. 2010;14(5):R192. doi: 10.1186/cc9309. Epub 2010 Oct 29. PMID: 21034463; PMCID: PMC3219299.
  9. Lowsby R, Gomes C, Jarman I, Lisboa P, Nee PA, Vardhan M, Eckersley T, Saleh R, Mills H. Neutrophil to lymphocyte count ratio as an early indicator of blood stream infection in the emergency department. Emerg Med J. 2015 Jul;32(7):531-4. doi: 10.1136/emermed-2014-204071. Epub 2014 Sep 2. PMID: 25183249.
  10. Ljungström L, Pernestig AK, 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 Jul 20;12(7):e0181704. doi: 10.1371/journal.pone.0181704. PMID: 28727802; PMCID: PMC5519182.
  11. Marik PE, Stephenson E. The ability of Procalcitonin, lactate, white blood cell count and neutrophil-lymphocyte count ratio to predict blood stream infection. Analysis of a large database. J Crit Care. 2020 Dec;60:135-139. doi: 10.1016/j.jcrc.2020.07.026. Epub 2020 Aug 8. PMID: 32799183.
  12. Jiang J, Liu R, Yu X, Yang R, Xu H, Mao Z, Wang Y. The neutrophil-lymphocyte count ratio as a diagnostic marker for bacteraemia: A systematic review and meta-analysis. Am J Emerg Med. 2019 Aug;37(8):1482-1489. doi: 10.1016/j.ajem.2018.10.057. Epub 2018 Oct 30. PMID: 30413366.
  13. 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. Mediators Inflamm. 2016;2016:8191254. doi: 10.1155/2016/8191254. Epub 2016 Mar 24. PMID: 27110067; PMCID: PMC4823514.
  14. Hwang SY, Shin TG, Jo IJ, Jeon K, Suh GY, Lee TR, Yoon H, Cha WC, Sim MS. Neutrophil-to-lymphocyte ratio as a prognostic marker in critically-ill septic patients. Am J Emerg Med. 2017 Feb;35(2):234-239. doi: 10.1016/j.ajem.2016.10.055. Epub 2016 Oct 27. PMID: 27806894.
  15. Sarı R, Karakurt Z, Ay M, Çelik ME, Yalaz Tekan Ü, Çiyiltepe F, Kargın F, Saltürk C, Yazıcıoğlu Moçin Ö, Güngör G, Adıgüzel N. Neutrophil to lymphocyte ratio as a predictor of treatment response and mortality in septic shock patients in the intensive care unit. Turk J Med Sci. 2019 Oct 24;49(5):1336-1349. doi: 10.3906/sag-1901-105. PMID: 31648506; PMCID: PMC7018205.
  16. Deniz M, Ozgun P, Ozdemir E. Relationships between RDW, NLR, CAR, and APACHE II scores in the context of predicting the prognosis and mortality in ICU patients. Eur Rev Med Pharmacol Sci. 2022 Jun;26(12):4258-4267. doi: 10.26355/eurrev_202206_29063. PMID: 35776025.
  17. Ham SY, Yoon HJ, Nam SB, Yun BH, Eum D, Shin CS. Prognostic value of neutrophil/lymphocyte ratio and mean platelet volume/platelet ratio for 1-year mortality in critically ill patients. Sci Rep. 2020 Dec 9;10(1):21513. doi: 10.1038/s41598-020-78476-y. PMID: 33299038; PMCID: PMC7726551.
  18. Park KS, Lee SH, Yun SJ, Ryu S, Kim K. Neutrophil-to-lymphocyte ratio as a feasible prognostic marker for pyogenic liver abscess in the emergency department. Eur J Trauma Emerg Surg. 2019 Apr;45(2):343-351. doi: 10.1007/s00068-018-0925-8. Epub 2018 Feb 26. PMID: 29480320.
  19. Song M, Graubard BI, Rabkin CS, Engels EA. Neutrophil-to-lymphocyte ratio and mortality in the United States general population. Sci Rep. 2021 Jan 11;11(1):464. doi: 10.1038/s41598-020-79431-7. PMID: 33431958; PMCID: PMC7801737.
  20. 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 Dec 16;19:439. doi: 10.1186/s13054-015-1144-x. PMID: 26671018; PMCID: PMC4699332.

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