Inflammatory Biomarkers in Aging

Insights from physical examination blood work data

Introduction

​A defining feature of aging is the gradual progression toward frailty as individuals move beyond their physical prime. Frailty compromises physical, mental, and cognitive functions in the elderly, making them more susceptible to a wide array of conditions, including infectious diseases, autoimmune disorders, metabolic imbalances, neurological decline, and cancer. This deterioration leads to a marked reduction in quality of life, particularly during its later stages.
 
The underlying physiological mechanisms of frailty remain an area of ongoing research, but systemic inflammation has emerged as a key contributing factor. This persistent, low-grade inflammation, often referred to as "inflammaging," is likely driven by a combination of factors, including cellular senescence, genetic predisposition, obesity, gut microbiome imbalances, immune system dysfunction, and chronic infections.
 
Clinicians monitor systemic inflammation by assessing specific biomarkers, tailored to the individual’s family history, initial symptoms, or diagnosed conditions. Table 1 provides a comprehensive overview of common inflammatory biomarkers. Physicians typically order these tests based on clear disease symptoms or to track the progression of conditions during treatment. However, healthy seniors with a family history of certain illnesses may proactively request specific biomarkers as part of routine blood work during physical exams. For those without a known family history of disease, testing for common inflammatory biomarkers can still be beneficial.
 
Given the recommendation for annual physical examinations for individuals aged 50 and older, incorporating a complete blood count (CBC) alongside key inflammatory biomarkers could facilitate the early detection and management of age-related conditions.

Table 1. Comprehensive but not necessarily exhaustive list of inflammatory biomarkers
 
Blood cell-derived

1. White Blood Cell Count (WBC)
2. Neutrophil-to-Lymphocyte Ratio (NLR)
3. Platelet-to-Lymphocyte Ratio (PLR)
4. Eosinophil Count
5. Basophil Count
6. Erythrocyte Sedimentation Rate (ESR)

 
Blood proteins
 
Cytokines

1. Interleukin-6 (IL-6)
2. Tumor Necrosis Factor-alpha (TNF-alpha)
3. Interleukin-1 beta (IL-1β)
4. Interleukin-8 (IL-8)
5. Monocyte Chemoattractant Protein-1 (MCP-1)

 
Adhesion proteins

1. Soluble Intercellular Adhesion Molecule-1 (sICAM-1)
2. Soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1)
3. Soluble E-Selectin (sE-Selectin)
4. Soluble P-Selectin (sP-Selectin)

 
Enzymes

1. Lactate Dehydrogenase (LDH)
2. Lipoprotein-associated Phospholipase A2 (Lp-PLA2)
3. Myeloperoxidase (MPO)

 
Others

1. C-Reactive Protein (CRP)
2. High-Sensitivity CRP (hs-CRP)
3. Fibrinogen
4. Ferritin
5. S100 Proteins (e.g., S100A8, S100A9)
6. Pentraxin 3 (PTX3)

 
Pteridine derivative

1. Neopterin

 

Benefits of tracking inflammatory markers in older adults and geriatric (65 and older)

​Early detection is part of preventive medicine, it helps manage and mitigate the development of diseases that are commonly associated with advancing age. Before discussing the benefits of tracking systemic inflammation with biomarkers with your primary care doctor, it is essential to weigh the pros and cons.
 
Pros:
 
1.Early detection of chronic inflammation: Systemic inflammation is associated with various age-related diseases, such as cardiovascular disease, diabetes, and cancer.
2.Risk stratification: Inflammatory biomarkers can help identify individuals at higher risk of developing age-related diseases.
3.Targeted interventions: Monitoring inflammation allows for tailored interventions, such as lifestyle modifications or pharmacological treatments, to reduce inflammation and disease risk.
4.Monitoring disease progression: Inflammatory biomarkers can track disease progression and treatment efficacy.
 
Cons:
 
1.Limited specificity: Inflammatory biomarkers are not specific to a single disease or condition, making interpretation challenging.
2.Variability: Inflammatory biomarker levels can fluctuate due to various factors, such as infections, stress, or medications.
3.Lack of standardization: Different assays and cut-off values can lead to inconsistent results.
4.Cost and resource utilization: Regular monitoring of inflammatory biomarkers may increase healthcare costs and resource utilization.
5.Uncertainty about treatment benefits: The effectiveness of anti-inflammatory interventions in preventing age-related diseases is still unclear.

Common inflammatory biomarkers encountered during annual check-ups.
​

The following biomarkers are most prescribed during regular annual check-ups: C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR) and White Blood Cell Count (WBC). The popularity of these three biomarkers is due to the recommendations of medical societies and government agencies. They are well established, widely available, inexpensive, and easy to interpret.
 
C-Reactive Protein (CRP)
 
The weblink provides a more thorough discussion on C-Reactive Protein. For this discussion, suffice to know there are two types of C-Reactive Protein your doctor could prescribe: C-reactive protein (CRP) and high-sensitivity C-reactive protein (hs-CRP). They are both biomarkers of systemic inflammation, but differ in their sensitivity and clinical applications:
 
C-Reactive Protein (CRP):
 
1.Measures CRP levels above 1 mg/dL
2.Indicates acute inflammation or infection.
3.Used to diagnose and monitor conditions like bacterial infections, sepsis, and acute inflammatory diseases.
 
High-Sensitivity C-Reactive Protein (hs-CRP):
 
1.Measures CRP levels as low as 0.03 mg/dL
2.Detects chronic, low-grade inflammation.
3.Used to assess cardiovascular risk, monitor chronic inflammatory diseases, and predict disease progression.
 
Key differences:
 
1.Sensitivity: hs-CRP is more sensitive than CRP, allowing for detection of lower CR P levels.
2.Clinical application: CRP is for acute inflammation, while hs-CRP is for chronic inflammation and cardiovascular risk assessment.
3.Thresholds: CRP typically uses a threshold of 1 mg/dL, while hs-CRP uses thresholds of 0.1-0.3 mg/dL for cardiovascular risk stratification.
 
In summary, CRP is for acute inflammation, while hs-CRP is for chronic inflammation and cardiovascular risk assessment, allowing for earlier detection and intervention. The latter is more appropriate for tracking low grade systemic inflammation in older adults and geriatric.
 
Reference range [1,2]:
 
The normal reference ranges for C-reactive protein (CRP) and high-sensitivity CRP (hs-CRP) could vary depending on sources < 1mg/dL [1] or <0.5mg/dL [2]
 
For cardiac risk stratification:
Low: < 1.0 mg/dL
Average: 1.0-3.0 mg/dL
High: > 3.0 mg/dL
 
References
[1] Pagana KD, Pagana TJ, Pagana TN. Mosby’s Diagnostic and Laboratory Test Reference. 14th ed. St. Louis, MO: Elsevier; 2019. 295.
[2] ] Laboratory Reference Ranges in Healthy Adults. Updated: Apr 20, 2024
Author: Abimbola Farinde, PharmD, PhD. Medscape.
 
White Blood Cell Count (WBC)
 
Leukocytosis, or an elevated white blood cell (WBC) count, is a common physiological response to inflammation, infection, or tissue injury. While total WBC count can serve as a general indicator of inflammation, it has significant limitations. Factors such as stress, physical activity, or medications can also elevate WBC levels, reducing its specificity as an inflammation marker. Additionally, its sensitivity is limited, as a normal WBC count does not necessarily rule out chronic or low-grade inflammation. These limitations make WBC count a biomarker with low predictive value for inflammation. Moreover, WBC count alone cannot provide insight into the severity or specific nature of the inflammatory response.
 
WBC normal reference range*: 4000-10,000 per mcL
* Laboratory Reference Ranges in Healthy Adults. Updated: Apr 20, 2024
Author: Abimbola Farinde, PharmD, PhD. Medscape.
 
In modern medical practice, the assessment of inflammation rarely relies on WBC count alone. Instead, it is typically measured as part of a Complete Blood Count (CBC), which includes a differential white blood cell count. This differential provides more detailed information on lymphocytes, neutrophils, platelets, monocytes, eosinophils, and basophils. These additional data points enable clinicians to evaluate more sensitive inflammatory markers, such as the neutrophil-to-lymphocyte (N/L) ratio and the platelet-to-lymphocyte (P/L) ratio, as shown in Table 1. Other relevant biomarkers will be discussed in subsequent sections.

​ Neutrophil-to-Lymphocyte Ratio (NLR) [1]
 
The neutrophil-to-lymphocyte ratio (NLR), which reflects both innate and adaptive immune responses, is a more specific and sensitive marker of systemic inflammation. Clinicians frequently use NLR to monitor conditions such as sepsis, pneumonia (including COVID-19 pneumonia), cardiovascular disease, cancer, and major depressive disorder. Surgeons also employ NLR as a prognostic tool for assessing the risk of post-operative complications. For a detailed discussion of NLR, including guidelines for its use and references to relevant literature, please refer to the provided weblink.

Table 2. Examples of NLR used in various pathological states (adapted from data provided in reference [1])

 

Sepsis	Urothelial Cancer
>/=5 Local Infection <10 >/=10 Systemic Infection <13 >/=13 Sepsis <15 >/= 15 Septic shock	</=5 Progression free survival >/=5 Metastatic disease
Covid 19	Cardiovascular Diseases
>/=4.5 Disease severity >6.1 Disease severity requiring corticosteroid. =15 (+/-9) Need for Invasive Mechanical Ventilator	>4.5 coronary heart disease >3.6 Atherosclerotic carotid plaques

 

Forget P. et al. [3] recently reported that the average NLR in healthy individuals is 1.65, with a lower limit of 0.78 and an upper limit of 3.53, based on 95% confidence intervals. When compared to standard hematological ranges [4], the calculated lower and upper limits for NLR are 1.67 and 2.0, respectively.
 
References
[1] Buonacera A, Stancanelli B, Colaci M and Malatino L. Neutrophil to Lymphocyte Ratio: An Emerging Marker of the Relationships between the Immune System and Diseases. Int. J. Mol. Sci. 2022; 23(7), 3636; https://doi.org/10.3390/ijms23073636
[2] Mazza MG, Lucchi S, Tringali AGM, Rosetti A, Botti ER, Clerici M. Neutrophil/lymphocyte ratio and platelet/lymphocyte ratio in mood disorders: A meta-analysis. Progress in Neuropsychopharmacology & Biological Psychiatry 2018; 84, 229-236. https://doi.org/10.1016/j.pnpbp.2018.03.012
[3] Forget P, Khalifa C, Defour J-P, Latinne D, Van Pel M-C & De Koch M. What is the normal value of the neutrophil-to-lymphocyte ratio? BMC Research Notes 2017; 10, 12. https://doi.org/10.1186/s13104-016-2335-5
[4] Laboratory Reference Ranges in Healthy Adults. Updated: Apr 20, 2024
Author: Abimbola Farinde, PharmD, PhD. Medscape.
 
Platelet-to-Lymphocyte Ratio (PLR) [1]
 
In addition to their primary role in hemostasis (blood clot formation), platelets are actively involved in both innate and adaptive immunity. First, blood clotting forms a physical barrier against invading pathogens, indirectly supporting immune defense. Platelets also participate in a process known as immune thrombosis, where they collaborate with neutrophils and monocytes to control the spread of infection through targeted clot formation. At sites of injury or infection, platelets interact with leukocytes, contributing to inflammation by secreting cytokines, chemokines, and other inflammatory mediators.
 
In adaptive immunity, platelets express receptors for IgG on their surface. By binding to IgG-opsonized target cells, they release reactive oxygen species, host defense peptides, and proteases, facilitating direct pathogen destruction. Given their diverse immunological roles, the platelet-to-lymphocyte ratio (PLR) serves as a valuable marker for assessing inflammation.
 
Elevated PLR has been linked to a range of diseases, particularly in cardiovascular health (e.g., all phases of coronary artery disease [2,3], atherosclerosis, arrhythmias, valvular disease, myocardial infarction, heart failure, peripheral arterial disease, and acute ischemic stroke), rheumatic conditions (e.g., rheumatoid arthritis, systemic lupus erythematosus [4]), neurological disorders (e.g., bipolar disorder [5-7], attention deficit hyperactivity disorder (ADHD) [6], traumatic brain injury [8]), metabolic diseases (e.g., insulin resistance and type 2 diabetes), infectious diseases (e.g., predicting the severity of COVID-19), and various cancers (e.g., ovarian, cervical, prostate, and advanced-stage cancers).
 
Conversely, a low PLR indicates the absence of a proinflammatory or prothrombotic state. It may also be indicative of thrombocytopenia.
 
Based on clinical experience, the standard PLR for a healthy individual is typically less than 150 [1]. According to standard hematological ranges [9], the calculated lower and upper limits are 73 and 150, respectively.
 
References
[1] Biomarkers of Inflammation: Platelet/Lymphocyte Ratio (PLR). ODX Research
[2] Yüksel M, Yildiz A, Oylumlu M, Akyüz A, Aydin M, Kaya H, Acet H, Polat N, Bilik MZ, Alan S. The association between platelet/lymphocyte ratio and coronary artery disease severity. The anatolian journal of cardiology. 2015;15, 640.
[3] Akboga MK, Canpolat U, Yayla C, Ozcan F, Ozeke O, Topaloglu S, Aras D. Association of platelet to lymphocyte ratio with inflammation and severity of coronary atherosclerosis in patients with stable coronary artery disease. Angiology. 2016; 67, 89-95.
[4] El Said NY, El Adle S, Fathi HM. Clinical significance of platelet-lymphocyte ratio in systemic lupus erythematosus patients: Relation to disease activity and damage. The Egyptian Rheumatologist 2022; 44, 224-229. https://doi.org/10.1016/j.ejr.2021.12.005
[5] Kalelioglu T, Akkus M, Karamustafalioglu N, Genc A, Genc ES, Cansiz A, Emul M. Neutrophil-lymphocyte and platelet-lymphocyte ratios as inflammation markers for bipolar disorder. Psychiatry Res. 2015; 228, 925-927. http://dx.doi.org/10.1016/j.psychres.2015.05.110
[6] Mazza MG, Lucchi S, Tringali AGM, Rosetti A, Botti ER, Clerici M. Neutrophil/lymphocyte ratio and platelet/lymphocyte ratio in mood disorders: A meta-analysis. Progress in Neuropsychopharmacology & Biological Psychiatry 2018; 84, 229-236. https://doi.org/10.1016/j.pnpbp.2018.03.012
[5] Fusar-Poli L, Natale L, Amerio A, Cimpoesu P, Filioli PG, Aguglia E, Amore M, Serafini G and Aguglia A. Neutrophil-to-Lymphocyte, Platelet-to-Lymphocyte and Monocyte-to-Lymphocyte Ratio in Bipolar Disorder. Brain Sci. 2021; 11, 58. https://doi.org/10.3390/brainsci11010058
[7] Avcil S. Evaluation of the neutrophil/lymphocyte ratio, platelet/ lymphocyte ratio, and mean platelet volume as inflammatory markers in children with attention-deficit hyperactivity disorder. Psychiatry and Clinical Neurosciences 2018; 72: 522–530. doi:10.1111/pcn.12659
[8] Li W & Deng W. Platelet‑to‑lymphocyte ratio predicts short‑term mortality in patients with moderate to severe traumatic brain injury. Nature Scientific Reports 2022; 12:13976. https://doi.org/10.1038/s41598-022-18242-4
[9] Medscape: Laboratory Reference Ranges in Healthy Adults. Updated: Apr 20, 2024
Author: Abimbola Farinde, PharmD, PhD.
 
Absolute Monocyte Count, Monocyte-to-Lymphocyte Ratio (MLR) and Lymphocyte-to-Monocyte Ratio (LMR)
 
Circulating monocytes play a crucial role in both the innate and adaptive immune systems. Upon migrating into tissues, monocytes differentiate into macrophages and dendritic cells, key mediators of chronic inflammation, tissue repair, and immune regulation. In addition to their differentiation, monocytes can perform phagocytosis, present antigens by incorporating antigen fragments into MHC molecules for T-cell activation, and produce cytokines such as TNF-alpha, IL-1beta, IL-6, and IL-12. These functions enable monocytes to be actively involved in the immune response. They are also critical during the resolution phase of inflammation, helping to clear cellular debris and promote tissue healing.
 
Given their pivotal role in inflammation, the Absolute Monocyte Count (AMC), the Monocyte-to-Lymphocyte Ratio (MLR), and its inverse, the Lymphocyte-to-Monocyte Ratio (LMR), have proven to be valuable diagnostic and prognostic biomarkers for various diseases.
 
Excess monocytes in peripheral blood (monocytosis) could be attributed to many disease states. For example, chronic inflammation, sepsis, necrosis, diabetes, atherosclerosis, stress response, Cushing’s Syndrome, immune diseases, viral fever, sarcoidosis and chronic myelomonocytic leukemia. On the other hand, very low monocyte count (monocytopenia) is often associated with immune suppressive therapy with glucocorticoid.
 
Reference monocytes count in healthy individuals ranges from 200-800 per microliter. [1]
 
Over the last decade the Monocyte-to-Lymphocyte ratio (MLR) and the Lymphocyte-to-Monocyte Ratio (LMR) were found to be diagnostic or prognostic for many disease states including cancer (e.g. solid tumors [2], prostate cancer [3], hepatocellular carcinoma [4], non-small cell lung cancer [5], all cancer mortality [6]), Type 2 diabetes [7], Parkinson’s disease [8], chronic kidney disease [9], coronary artery disease [10] and many others.
 
A normal MLR in healthy individuals typically ranges from 0.1 to 0.3, although reference values may vary slightly depending on the laboratory and population studied. According to standard hematological ranges [11], the calculated lower and upper limits are 0.17 and 0.20, respectively.
 
MLR values that tend to be associated various level of inflammation can be broken down as follows:
 
- Normal MLR: 0.1-0.3
- Mild inflammation MLR: 0.3-0.5
- Moderate inflammation MLR: 0.5-0.8
- Severe inflammation MLR: >0.8
 
While keeping in mind that MLR can fluctuate due to various factors, such as: age, sex, time of day, physical activity, infections and medications.
 
For studies considering LMR, the above ranges are inverted as LMR = 1/MLR:
Normal LMR range: 10-3.33
Normal LMR calculated from hematological standards: 5.88-5.00
Mild inflammation MLR: 3.33-2.00
Moderate inflammation MLR: 2.00-1.25
Severe inflammation MLR: <1.25
 
References
[1] Medscape: Laboratory Reference Ranges in Healthy Adults. Updated: Apr 20, 2024
Author: Abimbola Farinde, PharmD, PhD.
[2] Nishijima T, Muss HB, Shachar SS, Tamura K and Takamatsu Y. Prognostic value of lymphocyte-to-monocyte ratio in patients with solid tumors: A systematic review and meta-analysis.  
[3] Wang L, Li X, Liu M, Zhou X and Shao J. Association between monocyte-to-lymphocyte ratio and prostate cancer in the U.S. population: a population-based study. Front. Cell Dev. Biol. 2024; 12,1372731.  https://doi.org/10.3389/fcell.2024.1372731
[4] Minici R, Venturini M, Guzzardi G, Fontana F, Coppola A, Piacentino F, Torre F, Spinetta M, Maglio P, Guerriero P et al. A Multicenter International Retrospective Investigation Assessing the Prognostic Role of Inflammation-Based Scores (Neutrophil-to-Lymphocyte, Lymphocyte-to-Monocyte, and Platelet-to-Lymphocyte Ratios) in Patients with Intermediate-Stage Hepatocellular Carcinoma (HCC) Undergoing Chemoembolizations of the Liver. Cancers 2024; 16, 1618. https://doi.org/10.3390/cancers16091618
[5] Tanaka H, Ono T, Kajima M, Manabe Y, Fujimoto K, Yuasa Y, Shiinoki  and Matsuo M. Reports of Practical Oncology and Radiotherapy 2024; 29, 228–235. DOI: 10.5603/rpor.100168
[6] Yang L, Sun X, Chen S, Shao H. Lymphocyte-to-Monocyte Ratio: A Simple and Effective Inflammation Marker in Predicting Mortality of Non-Institutionalized Americans with Cancers. Academic Journal of Medicine & Health Sciences 2024; 5, 71-9.
[7] Dayama N, Yadav SK, Saxena P, Sharma A, Kashnia R and Sharda K. A Study of Relationships between the HbA1c Level and Inflammatory Markers, Neutrophil-to-Lymphocyte Ratio, and Monocyte-to-Lymphocyte Ratio in Controlled and Uncontrolled Type 2 Diabetes Mellitus. J Assoc Physicians India 2024; 72, 24–26.
[8] Li F, Weng G, Zhou H, Zhang W, Deng B, Luo Y, Tao X, Deng M, Guo H, Zhu S and Wang Q. The neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and neutrophil-to-high-density-lipoprotein ratio are correlated with the severity of Parkinson’s disease. Front. Neurol. 2024 ; 15,1322228. doi: 10.3389/fneur.2024.1322228
[9] Liu W, Weng S, Cao C, Yi Y, Wu Y, & Peng D (). Association between monocyte-lymphocyte ratio and all-cause and cardiovascular mortality in patients with chronic kidney diseases: A data analysis from national health and nutrition examination survey (NHANES) 2003-2010. Renal Failure 2024; 46(1). https://doi.org/10.1080/0886022X.2024.2352126
[10] Vakhshoori M, Nemati S, Sabouhi S, et al. Prognostic impact of monocyte-to-lymphocyte ratio in coronary heart disease: a systematic review and meta-analysis. Journal of International Medical Research. 2023; 51(10). doi:10.1177/03000605231204469
[11] Medscape: Laboratory Reference Ranges in Healthy Adults. Updated: Apr 20, 2024
Author: Abimbola Farinde, PharmD, PhD.
 
The Systemic Inflammatory Index (SII) and the Systemic Inflammation Response Index (SIRI)
 
Since clinicians typically make diagnostic or prognostic assessments within a broader clinical context, rather than relying on a single biomarker, there has been a growing interest in combining multiple inflammatory markers into a single index. Over the past decade, pioneering researchers have developed and validated the Systemic Inflammatory Index (SII) and the Systemic Inflammatory Response Index (SIRI) for use across a wide range of medical conditions [1].
 
The Systemic Inflammatory Index (SII) integrates neutrophil (N), lymphocyte (L), and platelet (P) counts into a single metric, calculated as SII = (N/L) * P. Based on standard hematological ranges [2], the normal SII range for healthy individuals is estimated to be between 300 and 583. This range aligns with findings from studies comparing SII values in healthy controls versus those in individuals with immune-related diseases, as shown in the tables below, adapted from Table 1 of Mangoni AA & Zinellu A [3].
 

Study	Healthy Controls		Patients with RA*
	n	Mean SII+/- SD	n	Mean SII+/-SD
Satis S et al.	31	597+/-58	109	666+/-33
Choe JY et al.	80	387+/-227	123	968+/-591
Taha SI et al. (a)	100	510 ± 221	100	733 ± 493
Choe JY et al.	71	409+/-277	257	697+/-579

*RA: Rheumatoid Arthritis, SD: Standard Deviation

 

Study	Healthy Controls		Patients with Gout
	n	Mean SII+/- SD	n	Mean SII+/-SD
Jiang Y et al. (a)	194	349+/-137	474	572+/-314
Jiang Y et al. (b)	194	349+/-137	399	426 ± 185

SD: Standard Deviation

 

Study	Healthy Controls		Patients with UC*
	n	Mean SII+/- SD	n	Mean SII+/-SD
Xie Y et al., 2021, China	185	344 ± 36	187	637 ± 139
Zhang MH et al.	172	402 ± 69	172	1126 ± 301
Yan J et al.	106	449 ± 233	167	1159 ± 861

*UC: Ulcerative Colitis, SD: Standard Deviation

 

Study	Healthy Controls		Patients with AS*
	n	Mean SII+/- SD	n	Mean SII+/-SD
Wu J et al.	63	297 ± 110	136	492 ± 246
Luo Q et al.	75	413 ± 204	79	874 ± 781
Taha SI et al. (c)	100	510 ± 221	50	838 ± 408

*AS: Ankylosing Spondylitis, SD: Standard Deviation

 

Study	Healthy Controls		Patients with OA*
	n	Mean SII+/- SD	n	Mean SII+/-SD
Tarabeih N et al.	519	455 ± 314	98	615 ± 406

*OA; Osteoarthritis, SD: Standard Deviation

 

Study	Healthy Controls		Patients with PsA*
	n	Mean SII+/- SD	n	Mean SII+/-SD
Kelesoglu Dincer AB et al.	103	468 ± 188	106	616 ± 390

*PsA: Psoriatic Arthritis, SD: Standard Deviation

 

Study	Healthy Controls		Patients with Sarcoidosis
	n	Mean SII+/- SD	n	Mean SII+/-SD
Karadeniz H et al. (b)	27	484 ± 182	46	2259 ± 1556

SD: Standard Deviation

 

Study	Healthy Controls		Patients with GPA*
	n	Mean SII+/- SD	n	Mean SII+/-SD
Karadeniz H et al. (c)	27	484 ± 182	38	2533 ± 1780

*GPA : Granulomatosis Polyangiitis, SD: Standard Deviation

 

Study	Healthy Controls		Patients with IgG4-RD*
	n	Mean SII+/- SD	n	Mean SII+/-SD
Karadeniz H et al. (a)	27	484 ± 182	30	1707 ± 1343

IgG4-RD : IgG4 Related Disease, SD: Standard Deviation

 

Study	Healthy Controls		Patients with Uveitis
	n	Mean SII+/- SD	n	Mean SII+/-SD
Kurtul BE et al.	46	438 ± 122	46	680 ± 312

SD: Standard Deviation

 

The Systemic Inflammation Response Index (SIRI), on the other hand, combines neutrophil (N), lymphocyte (L), and monocyte (M) counts into a single metric, calculated as SIRI = (N/L) * M. Originally developed as a prognostic tool for cancer, SIRI's diagnostic and prognostic value has since been expanded to other diseases characterized by inflammation [1].
A universally defined "normal" reference range for SIRI in healthy individuals has yet to be established, as most studies have focused on its use in clinical settings involving abnormal inflammatory responses, such as infections, malignancies, or other inflammatory conditions. However, in healthy individuals, SIRI values tend to be low due to the balanced levels of neutrophils, monocytes, and lymphocytes. For clinical purposes, studies suggest that a SIRI value below 1 is indicative of a healthy, non-inflammatory state, while higher values signal a stronger systemic inflammatory response. Based on standard hematological ranges [2], the estimated normal range for SIRI in healthy individuals is between 0.40 and 1.33.
 
References
[1] Islam MM, Satici MO, Eroglu SE. Unraveling the clinical significance and prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, systemic inflammation response index, and delta neutrophil index: An extensive literature review. Turkish Journal of Emergency Medicine. 2024; 24, 8-19. DOI: 10.4103/tjem.tjem_198_23
[2] Medscape: Laboratory Reference Ranges in Healthy Adults. Updated: Apr 20, 2024
Author: Abimbola Farinde, PharmD, PhD.
[3] Mangoni AA, Zinellu A. The diagnostic role of the systemic inflammation index in patients with immunological diseases: a systematic review and meta-analysis. Clinical and Experimental Medicine. 2024; 24, 27. https://doi.org/10.1007/s10238-024-01294-3
 
Erythrocyte Sedimentation Rate (ESR)
 
The erythrocyte sedimentation rate (ESR) is not typically included in routine physical examinations unless your healthcare provider suspects the presence of infection or inflammation. However, if your lab results include this test, the following information will help you understand its significance.
 
ESR is a widely used blood test that measures how quickly red blood cells (erythrocytes) settle at the bottom of a test tube over a given period, typically one hour. In the presence of inflammation, red blood cells tend to clump together and settle more rapidly. Clinicians use the ESR test to evaluate and monitor the presence of inflammation in the body, which can be associated with various disease states.
 
Mechanism of ESR [1]: The principle behind the ESR test is that certain proteins produced during inflammation, especially fibrinogen and immunoglobulins, promote the aggregation of red blood cells, making them fall more rapidly in a column of blood. The faster the sedimentation rate, the higher the likelihood of an inflammatory process occurring in the body. While the ESR is a non-specific test, meaning it does not pinpoint the exact cause or location of inflammation, it provides valuable information about the presence and intensity of inflammatory processes.
 
Clinical Uses of ESR: Clinicians use the ESR test to assess a range of conditions characterized by inflammation, including:

• Infections: Bacterial infections or chronic infections like tuberculosis often result in elevated ESR levels.
• Autoimmune diseases: Conditions like rheumatoid arthritis, lupus, and vasculitis are associated with increased ESR.
• Chronic inflammatory diseases: Clinicians routinely use ESR to monitor diseases like inflammatory bowel disease (IBD), polymyalgia rheumatica, and giant cell arteritis.
• Cancer: Malignancies, particularly lymphoma and multiple myeloma, may cause a high ESR.

While ESR alone does not diagnose these conditions, healthcare providers often used it alongside other tests and clinical evaluations to support a diagnosis, assess disease activity, or monitor treatment effectiveness.
 
Normal ESR Ranges: ESR values can vary based on age and sex:

• Males:
  • Under 50 years: 0–15 mm/hour
  • Over 50 years: 0–20 mm/hour
• Females:
  • Under 50 years: 0–20 mm/hour
  • Over 50 years: 0–30 mm/hour

Clinicians consider values above these ranges elevated that may warrant further investigation.
 
 Pathologically Elevated ESR: A significantly elevated ESR, particularly values above 50 mm/hour, suggests a systemic inflammatory response and may point to underlying pathology. Extreme elevations, such as over 100 mm/hour, are often associated with serious conditions like:

• Severe infections (e.g., endocarditis, osteomyelitis)
• Autoimmune diseases in active flares
• Advanced malignancies

However, a high ESR is non-specific and could be the result of various benign conditions such as pregnancy, anemia, or even during menstruation, making clinical context crucial for interpretation.
 
Low ESR: Conditions like polycythemia (increased number of red blood cells) or certain blood disorders could result in lower-than-normal ESR. However, a low ESR is less common and typically not a concern unless accompanied by other symptoms.
 
Limitations: While ESR is useful for assessing inflammation, it has a key limitation: It is a non-specific marker. Factors unrelated to inflammation, such as anemia, kidney disease, or even high cholesterol levels can influence the sedimentation rate. As a result, clinicians often use ESR in conjunction with other markers of inflammation, like C-reactive protein (CRP), which responds more quickly to acute inflammatory changes and is often more specific.
In summary, the ESR test is a valuable tool in clinical practice for assessing inflammation. Its simplicity and low cost make it an excellent initial screening test. The lack of specificity requires interpretation of the result within the context of other clinical findings and diagnostic tests.
 
Reference
[1] Fabry TL. Mechanism of Erythrocyte Aggregation and Sedimentation. Blood 1987; 70, 1572-1576. https://doi.org/10.1182/blood.V70.5.1572.1572

Case study 1

​Patient X is a 73-year-old Southeast Asian male with a BMI of 24.8 and a Waist-to-Height Ratio (WHtR) of 0.51. The patient has a history of benign hypertension, hyperlipidemias (borderline high cholesterol and high triglycerides), and periodic gout attacks starting at the age of forty. Consultation with a cardiologist resulted in the initiation of drug treatment:
 
Rx2004: Fenofibrate (Antara) 130 mg QD and Valsartan 80 mg QD initiated ca. October 2004.
 
Rx2007: Vytorin 10/20 QD added ca. November 2007.
 
Rx2012: In the third quarter of 2011the patient was diagnosed with cholelithiasis and underwent cholecystectomy April 2012. A new primary care doctor withdrew both Fenofibrate and Vytorin.
 
Rx2015: 10 mg atorvastatin QD introduced ca. July 2015.
 
Rx 2017: Consultation with a Rheumatologist resulted in the prescription of 200 mg allopurinol QD.
 
The gout flares stopped after treatment with allopurinol.
 
The patient provided CBC data for studies from 1989 to present time. Below are the plots of NLR, PLR, Platelet counts, MLR, SII and SIRI over time.
 
 

​Please note the drop in platelet counts after cholecystectomy and withdrawal of fenofibrate and Vytorin (Rx2012). Administration of atorvastatin (Rx2015) and allopurinol (Rx2017) further lowered the platelet counts over time, likewise for the PLR and SII. MLR and SIRI were unremarkable except for four outliers possibly due to seasonal cold/flu infections.

Case study 2

Patient Y, is a 74-year-old Southeast Asian male with a BMI of 27.8 and a Waist-to-Height Ratio (WHtR) of 0.59. The patient has a history of syncope, hypertension, hyperlipidemia, diabetes and prostatic hypertrophy (PSA level: 14 ng/mL) and was treated with metoprolol starting in 2003, atorvastatin in 2011, metformin in 2018 and Ozempic in March 2024. His most recent (8/24/2024) differential white blood cell count (eosinophils and basophils excluded) was unremarkable with all counts falling within normal range:

Differential white cell counts	Results (x10E-3)	Normal range (x10E-3)
Neutrophils	4.67	2.00-8.00
Platelets	212.00	150-350
Monocytes	0.67	0.20-0.80
Lymphocytes	1.16	1.00-4.80

 

​The corresponding NLR, PLR, MLR, SII and SIRI inflammatory biomarkers are shown below: 

Patient Y		Normal Range
Inflammatory biomarkers	Results	Calculated*	Healthy Control**
NLR	4.03	1.67-2.00	0.78-3.53
PLR	183	73-150	<150
MLR	0.58	0.17-0.20	0.1-0.3
SII	853	300-583	<406 (62***)
SIRI	2.70	0.40-1.33	<1

*Calculated from hematological standards

** Clinically reported from apparently healthy patient controls

***Standard Deviation shown in parentheses

 

​All five inflammatory biomarkers, NLR, PLR, MLR, SII and SIRI, from Patient Y were higher than expected from normal ranges, potentially supporting systemic inflammation from unresolved disease state.

Case Study 3

​Patient Z is a 69-year-old male. At age 67 he was diagnosed with poorly differentiated peritoneal adenocarcinoma, possibly of hepatic origin. That same year he was treated by cytoreductive surgery followed by HIPEC (hyperthermic intraperitoneal chemotherapy). Post surgery pathology work-up confirmed the diagnosis of hepatocellular carcinoma with peritoneal metastases. Unresectable hepatic tumor masses were treated four months later by two rounds of chemoembolization with doxorubicin. The patient was stable and functional for at least 6 months when relapse was evidenced by a strong resurgence in blood level of alpha-fetoprotein (AFP). He subsequently underwent five additional rounds of chemoembolization over a 6-month period, with gradual decreasing level of effectiveness as the tumors gained additional vascularization and became refractory to the procedure. Chemoembolization was then replaced by biologics treatment with a combination of Tecentriq and Avastin to boost immune response and block angiogenesis. Six infusions were performed over an 18-week period. Therapy was then discontinued since the tumor continued to grow slowly while the patient developed serious abdominal discomfort, gastrointestinal distress, and profuse peritoneal ascites. The patient was placed under palliative care and succumbed to the disease nine months later at age 69.

For a year from the beginning of biologics therapy to the end, the patient was continuously monitored for Complete Blood Count including differential white cell counts, Comprehensive Metabolic Panel, tumor biomarkers, and C-Reactive Protein. The data set allowed for a side-by-side comparison of the performance of the inflammatory C-Reactive Protein biomarker against the systemic inflammatory biomarkers derived from differential white cell counts. The results are summarized in the time plots shown below:

​All five biomarkers derived from differential white cell counts trended similarly as C-Reactive Protein albeit the sensitivity of MLR and SIRI were weaker compared to the others in detecting higher than normal levels (indicated by horizontal arrow on the corresponding Y-axes). This distinction could reflect the separate roles of neutrophils, platelets, and monocytes in response to tumor growth and biologics therapy.

Article about "Inflammaging" in the news media
Inflammaging is chronic, stealthy and can be a serious threat to your health
Wall Street Journal, Health/Wellness section, October 7, 2024