Biomarkers of Immunity: Neutrophil:Lymphocyte Ratio (NLR)

Optimal Takeaways

The neutrophil:lymphocyte ratio (NLR) reflects essential components of the cell-mediated inflammatory response, i.e., from neutrophils and lymphocytes. It is considered a marker of systemic inflammation even if the total white blood cell count is in the normal range. The NLR will increase with physiological stress such as multiple trauma, major surgery, shock, or sepsis and may predict disease severity and poorer prognosis and outcomes.

An elevated NLR can be associated with cardiovascular disease, congestive heart failure, metabolic syndrome, diabetes, thyroid dysfunction, renal or hepatic dysfunction, acute pancreatitis, hypertension, Alzheimer’s disease, inflammatory disorders, bacterial infection, and malignancy. A decreased NLR may suggest a viral infection rather than a bacterial infection which is instead characterized by an elevated NLR.

Standard Range: 1.00 – 3.00 Ratio

The ODX Range: 1.00 – 1.70 Ratio          

Low NLR may be associated with a viral versus a bacterial infection or adrenal insufficiency (Farkas 2020).

High NLR is a marker of systemic inflammation and is associated with cardiovascular disease, myocardial infarction, endothelial dysfunction, hyperlipidemia, metabolic syndrome, obesity, diabetes mellitus, hypertension, and undesirable lifestyle habits (Balta 2016). Elevated NLR is also associated with all-cause mortality, heart failure (Kim 2018), increased adverse cardiac events and mortality in stable CAD patients (Uysal 2016), atherosclerosis, elevated coronary artery calcium, arterial stiffness, neoplastic disease (Gürel 2019), bacterial infection, septicemia (Naess 2017), severe sepsis, septic shock (Zahorec 2001), more severe and fatal COVID-19 (Koc 2022), systemic inflammation, toxic shock syndrome, hypovolemic shock, exogenous steroids, and elevations in cortisol and catecholamines (Farkas 2020).

Elevated NLR is associated with decreased omega-3 index below 6.6%, rheumatoid arthritis, altered innate-adaptive immune system balance (McBurney 2022), severe acute pancreatitis, and organ failure with NLR above 10 (Wang Y 2017).

Overview

Neutrophils and lymphocytes participate in cell-mediated inflammatory responses. The neutrophil:lymphocyte ratio (NLR) is a biomarker of inflammation that helps evaluate the risk of cardiovascular disease and adverse events, the severity of infection or inflammatory disease, and all-cause mortality (Gürel 2015, Kim 2018). Generally, a higher neutrophil:lymphocyte ratio (NLR) correlates with poor prognosis and higher mortality rates, even when white blood cell count is normal (Lee 2018, Gürağaç 2016). An elevated NLR is associated with an increased probability of bacterial infection and a lower likelihood of viral infection (Naess 2017).

The neutrophil:lymphocyte ratio may be higher in older individuals and men. A study of 413 healthy individuals 21-66 years of age participating in a healthcare prevention program observed a mean NLR of 1.65 with a range of 0.78-3.53 in this adult, non-geriatric population. A similar NLR range was observed for 29 healthy controls (Forget 2017).

Data review from The Rotterdam Study, a prospective population-based cohort study of 8,711 adults 45 years or older, found that the mean NLR was 1.76, with values increasing in general with age. At the same time, men tended to have a higher NLR than women overall. A significantly higher mean NLR of 2.24 was seen in individuals with an elevated CRP above 10 mg/L (Fest 2018). Higher NLRs in the study were also observed in subjects with a lower socioeconomic status, smokers, diabetics, and those with cancer or cardiovascular disease history. Ultimately, NLR was significantly and independently associated with all-cause and CVD mortality. When assessed by quintiles, those in the lowest two quintiles, defined as an NLR below 1.3, or 1.3-1.59, had the best survival rate, while those in the highest quintile above 2.41 had the worst (Fest 2019).

An increased ratio of neutrophils to lymphocytes is associated with elevated inflammatory markers and cytokines, including tumor necrosis factor-alpha, IL-6, IL7, IL-8, IL-12, and IL-17 (Venkatraghavan 2015). Increased NLR is observed with the cytokine storm associated with more severe COVID-19, even though COVID is caused by viral infection. The higher mean NLR in COVID-19 patients with cytokine storm and increased risk of mortality was 11, ­versus an NLR of 2.5 in COVID-19 patients without cytokine storm (Koc 2022). Researchers suggest that an increased NLR may be partially due to a combination of cortisol and catecholamines, bioactive compounds that increase neutrophils and decrease lymphocytes. The increase in NLR that follows acute physiological stress occurs rapidly and may be an early indicator of the disease severity than total WBCs and the “left shift” increase in immature immune cells. However, the NLR must be interpreted in the context of a comprehensive clinical evaluation (Farkas 2020).

An increased NLR may reflect an increased risk of abnormal blood pressure and glucose regulation. A cross-sectional study of 1070 healthy subjects 16-75 years of age found that the incidence of hypertension and diabetes increased above the lowest tertile for an NLR of 0.17-1.51 and was highest for those with an NLR above 2.57 (Imtiaz 2012).

Elevated NLR is associated with cardiometabolic disorders as well as a severe infection. Increased NLR is also observed in congestive heart failure, atherosclerotic changes, cardiovascular disease, diabetes mellitus, hypertension, severe acute pancreatitis, sepsis, and septic shock (Imtiaz 2012, Wang Y 2017, Venkatraghavan 2015, Wang H 2017, Afari 2016, Zahorec 2001). Elevated NLR can be considered a marker of systemic inflammation in these and other cardiometabolic disorders, including metabolic syndrome, obesity, hyperlipidemia, endothelial dysfunction, and undesirable lifestyle habits. An NLR of 4.5 or above independently predicted an infarct-related occluded artery in those with acute myocardial infarction (Balta 2016).

Elevations in white blood cells are associated with atherosclerosis, a primarily inflammatory disorder at the heart of cardiovascular disease. In one prospective observational study of 3,277 high-risk coronary angiography patients, an NLR above 4.71 was an independent predictor of myocardial infarction and death, compared to low risk with an NLR below 1.96. Researchers note that the assessment of white blood cell counts and NLR should be an inherent part of cardiovascular risk assessment (Horne 2005). A later study of 194 coronary angiography patients found an increased risk of severe atherosclerosis with an NLR above 2.54. Researchers recommend evaluating NLR before angiography to identify those at the highest risk Uysal 2016).

An NLR above 3 was an independent marker for endothelial dysfunction in a cross-sectional study of 1,816 asymptomatic individuals with no history of cardiovascular disease. An elevated NLR was also significantly associated with an abnormal albumin/creatinine ratio, a marker of endothelial dysfunction (Martinez 2016).

Accumulating research suggests an association between an elevated NLR and worse outcomes for several cancers, including breast, ovarian, gastroesophageal, pancreas, colon, colorectal, hepatocellular, biliary tract, kidney, and urothelium (Gürağaç 2016, McNamara 2014), in some cases when NLR rose above 1.8 (Faria 2016). An elevated NLR also appears to reflect more aggressive disease associated with advanced tumor stage and metastases and reduced overall survival (Guthrie 2013, Sahin 2017, Bowen 2017). An NLR above 2.27 was also significantly associated with increased mortality in individuals not diagnosed with cancer (Davis 2016).

Individuals with bipolar disorder and major depressive disorder were found to have elevated NLR values as well, likely a reflection of the inflammatory nature of these mood disorders (Mazza 2018, Giynas 2017). The inverse relationship between NLR and omega-3 Index (O3I) is also likely a reflection of inflammatory potential. In a population of 28,871 healthy individuals, an omega-3 index above 6.6% was associated with a mean NLR of 1.96, while a decrease in O3I below 6.6% was associated with an increasing NLR above 2.12 (McBurney 2022).

Some associations have been observed between elevated NLR, cognitive decline, and Alzheimer’s disease, although further research is recommended to thoroughly investigate the association (Kuyumcu 2012, Rembach 2014, Halazum 2014).

References

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