Monitoring Inflammation: The Neutrophil-to-Lymphocyte Ratio

This blog post is a companion piece to a YouTube video, which you can access here.

In this blog post, you will be introduced to the most easily obtainable biomarker that is a proxy for chronic inflammation – the neutrophil-to-lymphocyte ratio.


Unlike specific markers of inflammation like C-reactive protein, fibrinogen, or malondialdehyde, your neutrophils and lymphocytes are regularly calculated as part of a standard metabolic panel. By dividing your absolute neutrophil count by your absolute lymphocyte count, you can quickly produce the highly predictive ratio that is a valuable indicator of systemic inflammation.


Below, we will take a brief tour through the various illnesses in which elevated NLRs are predictive, beginning with death in general.


The NLR


First suggested as a marker of systemic inflammation and stress in 2001, the neutrophil/lymphocyte ratio (NLR) is a predictive and easily obtainable marker of human health[i]. An average NLR is 1.65, with a healthy range from 0.78-3.53[ii].


Mortality


This year, it was shown that an elevated NLR is associated with increased all-cause mortality in the general US population – it is a predictor of death. It is associated with increased mortality from heart disease, cerebrovascular disease, lower respiratory disease, influenza, and kidney disease[iii].


The Brain


1. Adolescents:

a. An elevated NLR is found in children with ADHD[iv].

b. Adolescents with major depressive disorder (MDD) have higher NLRs[v].

c. Elevated NLRs are found among those with autism spectrum disorder (ASD)[vi].

2. Mental illness:

a. Among people with MDD, those with elevated NLRs are more likely to have exhibited suicidal behavior[vii].

b. Patients with bipolar disorder (BPD) exhibit elevated NLRs[viii], though it may be more pronounced in males[ix]. BPD patients exhibit higher NLRs than patients with MDD[x].

c. Patients with schizophrenia also exhibit elevated NLRs[xi] and elevated NLRs are associated with severity of symptoms[xii]. Antipsychotic treatment reduces the NLR among schizophrenics[xiii].

3. Addiction:

a. Methamphetamine abusers have lower NLRs than the average population, implying that methamphetamine use has some effect on the immune system[xiv].

4. Neurodegenerative disease:

a. In multiple sclerosis, NLR elevation is associated with severity of neurological disability[xv] and with disease activity[xvi].

i. Interestingly, in MS, HIT cardio lowers the NLR via a hormetic effect on inflammation modulation[xvii].

b. The NLR is elevated among those with Parkinson’s Disease[xviii].

c. Unlike in idiopathic Parkinson’s Disease, in Alzheimer’s Disease, average NLRs are similar to healthy controls[xix].

d. In the elderly, elevated NLRs are associated generally with cognitive impairment[xx].


Autoimmune Disease


1. Gastrointestinal:

a. In Crohn’s Disease, NLR associates with erythrocyte sedimentation rate (ESR), with CRP, with malondialdehyde, and with total white blood cell count (WBC). In ulcerative colitis, similar associations were found, in addition to fecal lactoferrin and fecal calprotectin (unless patients took an anti-TNF drug).


2. Thyroid:

a. An elevated NLR is associated with Hashimoto’s thyroiditis[xxi].

b. Elevated NLRs are associated with relapse in patients with Grave’s Disease being treated with antithyroid drugs[xxii].


3. Arthritis:

a. NLR is elevated in rheumatoid arthritics, though it does not associate closely with disease activity[xxiii].

b. NLR is a predictor of the severity of knee osteoarthritis[xxiv].


4. IgA nephropathy:

a. Elevated NLRs are associated with poorer outcomes in this autoimmune kidney disease[xxv].


5. Psoriasis:

a. People with psoriasis have increased risk of cardiovascular disease. NLR is a proxy for subclinical atherosclerosis among patients with psoriasis[xxvi].


Cardiovascular Disease


1. Heart failure:

a. NLR is inversely associated with left ventricular ejection fraction among patients with heart failure. A cut off of 3.0 predicted heart failure with 86% sensitivity and 78% specificity. NLR could also predict death with a 75% sensitivity and 62% specificity during a 13 month follow up if a cut off of 5.1 was used. PLR is a comparatively inferior biomarker for heart failure[xxvii].


2. Stroke:

a. A meta-analysis found that in both ischemic and hemorrhagic stroke, elevated baseline NLR is associated with worse outcomes. It is also associated with a higher recurrence of ischemic stroke[xxviii].

b. A meta-analysis found that it also predicts hemorrhagic transformation from ischemic cerebral infarction[xxix].


3. Calcific aortic valve disease (CAVD):

a. NLR is elevated among CAVD patients compared to controls. Among CAVD patients, tricuspid aortic valve (TAV) patients had higher NLR and lower CRPs than bicuspid aortic valve (BAV) patients[xxx].


4. Atherosclerosis:

a. Among the morbidly obese, NLR is associated with CRP, visceral adiposity, leptin and adiponectin, and the development of atherosclerosis[xxxi].

b. Among the elderly, NLR predicts carotid artery plaques better than CRP or fibrinogen[xxxii].

c. NLR (and PLR) are associated with symptomatic internal carotid artery stenosis[xxxiii].


5. Atrial fibrillation:

a. Patients with non-valvular atrial fibrillation had higher NLRs, with a cut off of 2.1 being predictive[xxxiv].


Cancer


1. A systematic review of studies using the NLR with cancer patients found that[xxxv]:

a. NLR was more prognostic for upper gastrointestinal cancers, for advanced or inoperable tumors, while it was less prognostic for operable cancers like colorectal cancer.

b. NLR associated well with CRP and hypoalbuminemia.

c. Threshold ratios of elevated NLR ranged from over 2.5 to over 5.


2. Liver cancer:

a. NLR predicts the likelihood of HCC recurrence consequent to liver transplantation[xxxvi].

i. Using a cut off of 4, patients with low NLRs had a 5-year survival rate of 89% while patients with high NLRs had a survival rate of 30%.

ii. While tumor expression of IL-17 was similar between groups, serum and peritumoral IL-17 was significantly higher in the high NLR group.

iii. While lymphocyte count was not associated with survival outcomes, the neutrophil count was.

iv. Because IL-18 (which promotes angiogenesis) was not associated with the NLR, but both IL-17 and CRP were, the authors concluded that the NLR predicts HCC recurrence via acting as a proxy for an inflammatory microenvironment, not angiogenesis.


3. Thyroid cancer:

a. Elevated NLR following treatment is associated with poor outcomes in differentiated thyroid cancers[xxxvii] and in the rarer, and much deadlier, undifferentiated thyroid cancers (i.e. anaplastic thyroid cancer)[xxxviii].


Metabolic Diseases


1. Type 1 diabetes (T1D):

a. There is relationship between NLR and aortic stiffness among T1D patients[xxxix].


2. Type 2 diabetes (T2D):

a. The NLR is found to be elevated in prediabetic and diabetic patients, while the platelet-to-lymphocyte (PLR) is decreased in prediabetic and early diabetic patients but elevated in late-stage diabetes[xl].

b. The combination of physical activity and a low NLR produce a synergistic effect on the quality of life of T2D patients[xli].

c. The NLR is a predictor of atrial fibrillation among diabetics[xlii].


3. NAFLD:

a. Elevated NLRs predict both steatohepatitis and fibrosis in patients with NAFLD[xliii], though it loses its prognostic value for higher levels of steatosis[xliv].


Kidney Health


1. Diabetic nephropathy:

a. NLR is associated with worsening renal function among diabetics[xlv].

2. Chronic kidney disease (CKD):

a. Elevated NLRs associate with the incidence of cardiovascular events among people with CKD[xlvi].

3. End stage renal disease (ESRD):

a. Among patients on hemodialysis, NLR (and PLR) associated with hs-CRP and inflammation[xlvii].

Organ Transplantation

1. Heart transplantation:

a. NLR predicts mortality from heart transplantation, with a cut off of 2.41 having an 86% sensitivity and a 67% specificity[xlviii].

2. Liver transplantation:

a. NLR predicts mortality from liver transplantation, with patients carrying NLRs north of 5 dying over 10x more frequently than those with NLRs less than 2[xlix].


Viruses and Bacteria


1. SARS-CoV-2:

a. NLR is an independent risk factor for mortality among COVID-19 patients. There is an 8% increase in mortality per unit increase in NLR[l].

2. Hepatitis:

a. While the NLR is associated with hepatitis C, the PLR is a superior predictor[li].

3. Bacterial infection:

a. An NLR cut off of 6.2 well-predicts bacterial infection[lii].

b. The NLR is associated with severity of gastritis due to H. pylori infection[liii].


Other Ailments


1. NLR has been suggested as a prognostic biomarker for severe tinnitus[liv].

2. Elevated NLRs are associated with mortality among critically ill patients[lv].

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