The neutrophil/lymphocyte ratio (NLR) has been gaining increasing attention across many fields of medicine within the past five years. Currently, there are 2,230 publications about this in PubMed, mostly within the past few years. This post will attempt to create a framework for understanding this ratio.
definition & physiology
The NLR is simply the number of neutrophils divided by the number of lymphocytes. Under physiologic stress, the number of neutrophils increases, while the number of lymphocytes decreases. The NLR combines both of these changes, making it more sensitive than either alone:
Endogenous cortisol and catecholamines may be major drivers of the NLR. Increased levels of cortisol are known to increase the neutrophil count while simultaneously decreasing the lymphocyte count.1 Likewise, endogenous catecholamines (e.g. epinephrine) may cause leukocytosis and lymphopenia.2 Cytokines and other hormones are also likely to be involved.
Thus, NLR is not solely an indication of infection or inflammation. Any cause of physiologic stress may increase the NLR (e.g. hypovolemic shock).
NLR increases rapidly following acute physiologic stress (<6 hours).3 This prompt response time may make NLR a better reflection of acute stress than labs which are more sluggish to respond (e.g. white blood cell count or bandemia).4
calculation & rough reference range
NLR may be calculated using either absolute cell counts or percentages, as shown here:
Interpretation of NLR depends on clinical context. However, to provide some idea of how to interpret this:
- A normal NLR is roughly 1-3.
- An NLR of 6-9 suggests mild stress (e.g. a patient with uncomplicated appendicitis).
- Critically ill patients will often have an NLR of ~9 or higher (occasionally reaching values close to 100).
This is only a very general interpretation of NLR. Clinical context should influence NLR interpretation considerably. For example, inflammatory disorders may tend to elevate NLR more than non-inflammatory disorders. Thus, a patient with sepsis and an NLR of 15 might not be tremendously ill, whereas a patient with a pulmonary embolism and an NLR of 15 is more worrisome.
NLR versus left-shift (i.e. bandemia)
NLR has some similarities to bandemia – both may be used to discern physiologic stress in the absence of a grossly abnormal white blood cell count.
The primary advantage of NLR over bandemia might be that it is more reproducibly measurable. At least three different definitions of band neutrophils exist in the literature.4 This leads to considerable variability between different hospitals regarding the normal range and sensitivity of bandemia.
pitfalls of NLR
The following pitfalls should be noted:5
- Exogenous steroid: May directly increase the NLR.
- Active hematologic disorder: Leukemia, cytotoxic chemotherapy, or granulocyte colony stimulating factor (G-CSF) may affect cell counts.
- HIV: Some studies have excluded patients with HIV. Overall the utility of NLR in this patient population remains unclear. Patients with advanced AIDS and chronic lymphopenia might be expected to have a higher baseline NLR.
The literature is chock full of studies using the NLR for everything from sepsis to cancer to restless leg syndrome.6 However, if NLR is an indicator of every disease, then it's actually an indicator of no disease. NLR obviously can't be a magical assay for every condition.
In order to use NLR wisely, we need to ask the right question at the right time. For example, let's consider two potential uses of NLR:
- (a) Distinguishing septic shock from cardiogenic shock among a population of shocked patients in an ICU.
- (b) Distinguishing toxic shock from adenovirus among a population of patients presenting with viral symptoms.
In the first scenario, all the patients are under a lot of physiologic stress (either from septic shock or cardiogenic shock). In the second scenario, patients with toxic shock will be under more physiologic stress than patients with influenza. So in scenario (a) NLR will fail, but in scenario (b) it may succeed.
The key to using NLR is finding a clinical scenario where the level of physiologic stress is revealing. Thus, the context and clinical question are crucially important. There are roughly three ways to use the NLR which make sense:
use #1: diagnosis based on detecting occult physiologic stress among patients with similar presentation
Two examples illustrate this:
- Among patients presenting to the emergency department with viral symptoms, most have minor viral ailments but a few will have meningitis or bacteremia (scenario (b) above).
- Among patients presenting to the emergency with right lower-quadrant pain, most will have gastroenteritis but a few will have appendicitis.
The key here is that within a narrow clinical context, specific diagnoses are often associated with higher levels of physiologic stress (e.g. appendicitis causes more physiologic stress than gastroenteritis). In contrast, the NLR won't necessarily be able to sort out diagnoses associated with similar levels of physiologic stress (e.g. meningitis versus toxic shock).
use #2: prognostication for patients with a known diagnosis
Among a group of patients with a known diagnosis, NLR may reveal which patients are the sickest. Similar to use #1 above, the key here is that we are starting with a fairly homogeneous group of patients. NLR then allows us to determine which patients are under the most physiologic stress (implying worse prognosis).
use #3: individual trajectory over time
Trending out NLR over time within an individual patient may provide some information about the amount of physiologic stress they are under. An NLR which decreases may be a favorable sign, whereas if the NLR increases this might suggest treatment failure. Predicted NLR trajectories will vary depending on the diagnosis and anticipated clinical course.
diagnosis of appendicitis
A recent meta-analysis of NLR for the diagnosis of appendicitis pooled 17 studies to reach the following conclusions:7
- NLR >4.7 is 89% sensitive and 90% specific for the diagnosis of appendicitis.
- NLR >8.8 is 77% sensitive and 100% specific for a diagnosis of complicated appendicitis.
The role of NLR in appendicitis diagnosis still remains debatable. However, it seems clear that NLR is a considerable improvement upon the white blood cell count (and should arguably replace the white blood count in any diagnostic consideration).
diagnosis of bacteremia
Several studies have evaluated the ability of NLR to detect bacteremia, mostly in heterogeneous populations of patients presenting to an emergency department. Its performance is poor. Meta-analysis shows that with a cutoff of ~10, NLR has a sensitivity of 72% and specificity of 60%.8
Nonetheless, NLR easily out-performs the white blood cell count (which has terrible performance here).9,10
Performance of the NLR for bacteremia among undifferentiated patients is limited due to the heterogeneous nature of this population (figure below). Many patients have severe physiologic stress (with elevated NLR) without bacteremia. Alternatively, some patients with bacteremia tolerate this surprisingly well and aren't very ill. In short, it's unrealistic to expect NLR to perform well in this context. This isn't a failure of the test itself, but rather it represents a failure to apply the test appropriately.
diagnosis of septic shock
Ljungstrom et al evaluated the performance of several markers among a population of 1,572 patients admitted to the emergency department with a clinical suspicion of sepsis.11 As shown below, no single test was fabulous. Overall, NLR had similar performance compared to lactate or procalcitonin:
The performance of various test cutoffs are shown here:
At a cutoff of 3 (the upper limit of normal), NLR has a higher sensitivity for sepsis than any other test (95%). Thus, a normal NLR (<3) argues against sepsis. Alternatively, if the NLR is well over 10, this would support a sepsis diagnosis. Intermediate values fall within a grey zone.
The limitations of NLR here are similar to those encountered with bacteremia above: within a heterogeneous patient population, it's challenging to interpret the NLR. Nonetheless, extreme values of NLR may be informative.
prognostication of pulmonary embolism
Several studies have evaluated the use of NLR to predict mortality in pulmonary embolism. Meta-analysis suggests that NLR may be more strongly predictive of mortality than troponin.12,13
One limitation of the above meta-analysis is that different studies used varying cutoff values for NLR (most studies used cutoffs between 5.5-5.9 but one study used a cutoff of 9.2). Data from the two most contradictory studies are shown below:14,15
Despite disagreement between the studies, the following interpretation of NLR in the context of PE may be reasonable:
The challenge in PE is always integrating the myriad of prognostic indicators (e.g. if the CT shows right ventricular strain, then an echocardiogram showing the same thing may seem scary but it adds no new information). Thus, it's unclear how much an NLR would add to the prognosis of a patient who already had numerous prognostic tests performed (e.g. troponin, brain natriuretic peptide, echocardiogram, lactate). One potential role of NLR could be an early red flag that the patient is high-risk, because the NLR will generally be obtained with the initial laboratory panel (thus being immediately available on all patients).
prognostication of acute pancreatitis
NLR is fairly good at predicting severe pancreatitis (area under the ROC curve of ~0.75) and mortality (area under the ROC curve of ~0.8).16–20 NLR out-performs C-reactive protein, a test which is occasionally recommended for prognostication in pancreatitis.20,21 The table below shows a rough guide to interpretation of NLR in the context of acute pancreatitis.
Risk-stratification in pancreatitis shouldn't focus extensively on NLR (other factors such as organ function are far more important). However, if there is a desire for a prognostic laboratory test as a tie-breaker to help guide disposition, NLR may provide some information.
prognostication of septic shock
This is a bit tricky. Before we get into NLR, take a moment to consider the relationship between cortisol and mortality in septic shock. As shown above, this relationship is a bit of a J-shaped curve:22
- Low levels of cortisol may correlate with somewhat increased mortality – this may reflect either exhaustion of the adrenal glands or underlying adrenal insufficiency. Lack of any cortisol response is pathological, leaving the patient vulnerable to stress.
- Intermediate levels of cortisol seem to correlate with the best survival.
- Highest levels of cortisol correlate with the worst survival – these patients are under extremely intense physiologic stress.
Data regarding NLR mirrors this J-shaped curve:23
This emphasizes the importance of using the NLR in an evidence-based fashion. A priori, one might expect that a low NLR would carry a favorable prognosis. However, within the context of septic shock a normal NLR is maladaptive – and this actually carries an unfavorable prognosis. It's interesting to speculate that septic patients with an NLR <2 have a sluggish endogenous response to stress, and therefore might benefit from exogenous steroid and catecholamine support. Another driver of poor outcomes in the low NLR group is likely cancer-related neutropenia.
This implies that overall, prognostication should combine both the NLR and the patient's degree of hemodynamic instability. As suggested below, a low NLR may be reassuring only in a hemodynamically stable patient:
trajectory of bacteremia
Terradas 2012 evaluated NLR trends among patients with bacteremia (figure below).24 Among survivors, NLR decreased over a few days. Alternatively, non-survivors had persistently elevated NLR values. This suggests that persistent elevation of NLR over several days is a poor prognostic sign, raising a question of treatment failure:
trajectory of intracranial hemorrhage
Wang 2018 reported NLR trends among patients with spontaneous intracranial hemorrhage (figure below).25 Nonsurvivors experienced an increase in NLR over 24-48 hours, whereas survivors had a stable NLR. At baseline, all patients had fairly low NLR, suggesting that intracranial hemorrhage doesn't necessarily trigger a strong systemic stress response.
overall: use of NLR to gauge trajectory
This section again emphasizes the importance of interpreting the NLR within the proper context. For a patient with bacteremia, then NLR will initially be high, but should decrease with therapy. Alternatively, in the context of intracranial hemorrhage, the NLR starts out low and usually remains low in survivors. No universal statement can be made regarding NLR across disease states; kinetics will vary depending on the natural history of any specific disease.
NLR is far from a perfect test. However, what it lacks in accuracy it makes up for in speed and cost. Nearly all patients will receive a differential cell count on admission, so the NLR is free and promptly available shortly after admission (the data is sitting right there in the chart). Most patients will also receive serial blood counts during admission, allowing the NLR to be followed over time.
It makes sense to use the NLR in place of the white blood cell count. In every study directly comparing NLR with white blood count, the NLR has proven to be far more accurate. Our use of white blood cell count as a clinical marker is based upon inertia – we're used to it and it's immediately available. Automatic ordering of a white blood cell count makes it nearly impossible to de-adopt the use of this test. Given the availability of NLR, using NLR to replace white blood cell count seems like a natural evolution.
The goal of this post isn't to encourage everyone to start making major clinical decisions based on NLR immediately. Rather, it is intended as a stimulus to begin paying attention to the NLR. Start looking at your patients' NLRs and considering how this fits into their diagnoses and prognoses. Over time this will calibrate your clinical judgement regarding how NLR may fit into your patient population and clinical contexts.
- Neutrophil-to-lymphocyte ratio (NLR) is easily calculated from the differential cell count. As such, it's immediately available (for free) upon admission in all of your patients.
- NLR is a reflection of physiologic stress, perhaps tied most directly to cortisol and catecholamine levels.
- NLR can be a useful tool to sort out patients who are sicker, compared to those who are less sick (it's not specific to infection).
- NLR has proven more useful than white blood cell count (WBC) when the two are directly compared. Ultimately, NLR may be a logical replacement for the WBC. In some situations, NLR is competitive with more expensive biomarkers (e.g. procalcitonin, lactate).
- Within specific clinical contexts (e.g. pancreatitis, pulmonary embolism), NLR may have surprisingly good prognostic value.
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