Inflammatory Biomarkers in Aging

Insights from physical examination blood work data

Introduction

A defining hallmark of aging is the gradual progression toward frailty as individuals move beyond their physical prime. Frailty is characterized by declining physical resilience, impaired cognitive and mental function, and reduced physiological reserve, leaving older adults increasingly vulnerable to a wide spectrum of health conditions. These include infectious diseases, autoimmune disorders, metabolic dysfunction, neurodegenerative decline, and cancer. As frailty advances, it often leads to a substantial reduction in quality of life and increased healthcare utilization.
 
Although the biological mechanisms underlying frailty are still being actively investigated, chronic systemic inflammation has emerged as a central contributor. This persistent, low-grade inflammatory state—commonly referred to as “inflammaging”—is thought to arise from the cumulative effects of cellular senescence, genetic susceptibility, excess adiposity, gut microbiome dysbiosis, immune system remodeling, and chronic or latent infections. Together, these factors create a pro-inflammatory milieu that accelerates biological aging and disease onset.
 
In clinical practice, systemic inflammation is assessed through a panel of circulating inflammatory biomarkers, selected based on an individual’s family history, presenting symptoms, or known medical conditions. Table 1 summarizes commonly used inflammatory biomarkers and their clinical relevance. Physicians typically order these tests when specific disease symptoms are present or to monitor disease progression and treatment response. However, asymptomatic older adults, particularly those with a family history of chronic disease, may also benefit from proactively measuring select inflammatory markers during routine health evaluations.
 
Given current recommendations for annual physical examinations beginning at age 50, incorporating a complete blood count (CBC) together with key inflammatory biomarkers into standard blood work may enhance early detection of age-related pathologies. Even in individuals without a known family history of disease, tracking baseline inflammatory markers can provide valuable insight into underlying biological aging processes and support more timely preventive or lifestyle interventions.
​
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 a cornerstone of preventive medicine, particularly in older adults where the risk of chronic disease increases with age. Monitoring systemic inflammation through blood-based biomarkers offers a potential strategy for identifying biological changes that precede clinical disease. Before incorporating inflammatory marker testing into routine care, however, patients and clinicians should carefully weigh both the potential benefits and limitations.
 
Potential Benefits
 
1. Early detection of chronic inflammation
Persistent low-grade inflammation is strongly associated with many age-related conditions, including cardiovascular disease, type 2 diabetes, neurodegenerative disorders, and certain cancers. Identifying elevated inflammatory markers may reveal subclinical risk before overt symptoms develop.
2. Improved risk stratification
Inflammatory biomarkers can help distinguish individuals who may be at higher risk for developing chronic, inflammation-driven diseases. This information may complement traditional risk factors such as age, family history, and metabolic status.
3. Support for targeted interventions
Tracking inflammatory markers enables more personalized preventive strategies. Depending on the underlying drivers of inflammation, interventions may include dietary changes, physical activity, weight management, stress reduction, microbiome-directed therapies, or pharmacologic treatment when appropriate.
4. Monitoring disease progression and treatment response
In individuals with established chronic conditions, inflammatory biomarkers can provide insight into disease activity and help assess the effectiveness of therapeutic or lifestyle interventions over time.
 
Potential Limitations
 
1. Limited disease specificity
Most inflammatory biomarkers reflect generalized immune activation rather than a specific disease process. Elevated levels may result from diverse causes, complicating clinical interpretation.
2. Biological and environmental variability
Inflammatory marker levels can fluctuate due to acute infections, psychological stress, sleep deprivation, physical exertion, or medication use, potentially leading to transient elevations that do not reflect chronic disease risk.
3. Lack of assay standardization
Differences in laboratory methods, reference ranges, and cutoff values may result in variability across testing platforms, reducing comparability between measurements over time or across providers.
4. Cost and healthcare resource considerations
Routine or frequent testing of inflammatory biomarkers may increase healthcare costs and laboratory utilization, particularly when clinical utility is uncertain.
5. Uncertainty regarding intervention outcomes
Although inflammation is clearly linked to aging-related diseases, the extent to which lowering inflammatory biomarkers directly translates into reduced disease incidence or improved outcomes remains an active area of research.

Common inflammatory biomarkers encountered during annual check-ups.
​

During routine annual physical examinations, clinicians most commonly assess C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and white blood cell (WBC) count as initial indicators of systemic inflammation. These biomarkers are widely recommended by medical societies and public health agencies because they are well validated, inexpensive, broadly available, and relatively easy to interpret in clinical practice.
 
Among these, CRP and WBC are most frequently included in standard blood work, particularly in adults aged 50 and older.

 C-Reactive Protein (CRP)
 
C-reactive protein is an acute-phase protein produced by the liver in response to inflammation. Clinicians may order one of two related tests depending on the clinical context:

• Standard C-reactive protein (CRP)
• High-sensitivity C-reactive protein (hs-CRP)

Although both assays measure the same protein, they differ substantially in sensitivity and clinical application.
 
Standard C-Reactive Protein (CRP)

• Detects CRP concentrations above ~1 mg/L
• Reflects acute inflammation or infection
• Commonly used to diagnose and monitor:
  • Bacterial infections
  • Sepsis
  • Acute inflammatory or autoimmune conditions

 
High-Sensitivity C-Reactive Protein (hs-CRP)

• Detects CRP concentrations as low as 0.03 mg/L
• Identifies chronic, low-grade systemic inflammation
• Primarily used for:
  • Cardiovascular risk assessment
  • Monitoring chronic inflammatory diseases
  • Predicting long-term disease risk and progression

 
Key Differences Between CRP and hs-CRP

1. Sensitivity
   hs-CRP detects much lower CRP concentrations than standard CRP.
2. Clinical application
   • CRP: acute inflammation and infection
   • hs-CRP: chronic inflammation and cardiovascular risk stratification
3. Risk thresholds
   hs-CRP enables clinically meaningful categorization of low-grade inflammation.

 
Reference Ranges (1,2)
 
Although reference ranges may vary slightly by laboratory, commonly cited values include:

• Normal CRP / hs-CRP:
  < 1.0 mg/L (some sources cite < 0.5 mg/L)

Cardiovascular Risk Stratification (hs-CRP)

• Low risk: < 1.0 mg/L
• Average risk: 1.0–3.0 mg/L
• High risk: > 3.0 mg/L

Clinical relevance:
For older adults and geriatric populations, hs-CRP is more appropriate than standard CRP for tracking chronic, low-grade systemic inflammation associated with aging, frailty, and cardiometabolic disease.

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)
 
An elevated white blood cell count (leukocytosis) is a well-known physiological response to infection, inflammation, stress, or tissue injury. While total WBC count is routinely used as a general indicator of immune activation, its utility as a standalone inflammatory biomarker is limited.
 
Limitations of WBC Count

• Low specificity: Elevations may occur due to stress, exercise, medications, or acute illness.
• Low sensitivity for chronic inflammation: Normal WBC values do not exclude low-grade or persistent inflammatory states.
• Limited prognostic value: WBC count alone provides little insight into the severity, duration, or cause of inflammation.

 
Normal reference range:
4,000–10,000 cells/µL
* Laboratory Reference Ranges in Healthy Adults. Updated: Apr 20, 2024
Author: Abimbola Farinde, PharmD, PhD. Medscape.
 
Beyond Total WBC: The Value of CBC-Derived Ratios
In contemporary clinical practice, inflammation is rarely assessed using total WBC count alone. Instead, WBC is interpreted as part of a Complete Blood Count (CBC) with differential, which quantifies:

• Neutrophils
• Lymphocytes
• Monocytes
• Eosinophils
• Basophils
• Platelets

 
These components allow clinicians to calculate more sensitive and prognostically informative inflammatory indices, including:

• Neutrophil-to-lymphocyte (NLR) ratio
• Platelet-to-lymphocyte (PLR) ratio

 
As summarized in Table 1, these ratios have gained attention as low-cost, readily available markers of systemic inflammation and immune dysregulation, particularly relevant in aging populations. Additional biomarkers derived from routine blood work will be discussed in subsequent sections.
 
Neutrophil-to-Lymphocyte Ratio (NLR) (1)
 
The neutrophil-to-lymphocyte ratio (NLR) reflects the balance between innate immunity (neutrophils) and adaptive immunity (lymphocytes) and is considered a more sensitive and specific marker of systemic inflammation than total WBC count alone.
 
Clinically, NLR is widely used to monitor and prognosticate outcomes in a broad range of conditions, including:

• Acute and chronic infections (e.g., sepsis, pneumonia, COVID-19)
• Cardiovascular disease
• Cancer
• Major depressive disorder and other neuropsychiatric conditions (2)
• Postoperative complications and surgical risk stratification

 
Because NLR is derived directly from a routine CBC with differential, it offers a low-cost, readily available marker for tracking immune dysregulation and inflammatory burden in aging populations.

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 et al. (3) reported an average NLR of 1.65 in healthy adults, with a 95% confidence interval of 0.78–3.53. When calculated using standard hematological reference ranges (4), a narrower expected range of approximately 1.67–2.0 has been proposed.
 
Clinical interpretation:
Persistently elevated NLR values may reflect chronic inflammation, immune imbalance, or increased disease risk, whereas stable low values are generally associated with immune homeostasis.
 
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)
 
Beyond their role in hemostasis, platelets are active participants in immune regulation and inflammation. They contribute to host defense through:

• Formation of physical barriers against pathogens
• Immune thrombosis in collaboration with neutrophils and monocytes
• Secretion of cytokines, chemokines, reactive oxygen species, and antimicrobial peptides
• Interactions with IgG-opsonized targets via Fc receptors

 
Given these functions, the platelet-to-lymphocyte ratio (PLR) has emerged as a valuable marker of inflammatory and prothrombotic states.
 
Clinical Associations of Elevated PLR
 
Elevated PLR has been linked to numerous disease categories, including:

• Cardiovascular disease: coronary artery disease (2,3), atherosclerosis, myocardial infarction, heart failure, stroke
• Rheumatic diseases: rheumatoid arthritis, systemic lupus erythematosus (4)
• Neurological and psychiatric disorders: bipolar disorder (5-7), ADHD (6), traumatic brain injury (8)
• Metabolic disorders: insulin resistance, type 2 diabetes
• Infectious diseases: severity prediction in COVID-19
• Cancer: ovarian, cervical, prostate, and advanced-stage malignancies

 
Conversely, low PLR values generally indicate the absence of a proinflammatory or prothrombotic state and may also reflect thrombocytopenia.
 
Reference Ranges

• Typical PLR in healthy individuals: < 150 (1)
• Calculated standard hematological range (9): approximately 73–150

 
PLR is particularly useful when interpreted alongside NLR, as both indices provide complementary insights into immune activation and inflammatory burden.

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 (AMC), Monocyte-to-Lymphocyte Ratio (MLR), and Lymphocyte-to-Monocyte Ratio (LMR)
 
Monocytes play a central role in both innate and adaptive immunity. After migrating into tissues, they differentiate into macrophages and dendritic cells, which are key mediators of:

• Chronic inflammation
• Antigen presentation
• Cytokine production (e.g., TNF-α, IL-1β, IL-6, IL-12)
• Tissue repair and resolution of inflammation

 
Given these functions, the absolute monocyte count (AMC) and derived ratios--MLR and its inverse, LMR—have gained prominence as diagnostic and prognostic inflammatory biomarkers.
 
Absolute Monocyte Count

• Normal reference range: 200–800 cells/µL (1)

 
Monocytosis may be observed in conditions such as chronic inflammation, sepsis, diabetes, atherosclerosis, autoimmune disease, chronic infections, stress responses, sarcoidosis, and myeloproliferative disorders.

Monocytopenia is commonly associated with immunosuppressive therapies, particularly glucocorticoids.

Monocyte-to-Lymphocyte Ratio (MLR)
 
Over the past decade, MLR has been shown to have diagnostic or prognostic value in a wide array of conditions, including:

• Cancer: solid tumors (2), prostate cancer (3), hepatocellular carcinoma (4), lung cancer (5), overall cancer mortality (6)
• Metabolic disease: type 2 diabetes (7)
• Neurodegenerative disease: Parkinson’s disease (8)
• Cardiovascular disease: coronary artery disease (9)
• Renal disease: chronic kidney disease (10)

 
Reference Ranges

• Normal MLR: 0.1–0.3
• Calculated normal range: approximately 0.17–0.20

 
Inflammation Stratification (Approximate)

• Normal: 0.1–0.3
• Mild inflammation: 0.3–0.5
• Moderate inflammation: 0.5–0.8
• Severe inflammation: > 0.8

MLR values may fluctuate due to age, sex, circadian rhythm, physical activity, infections, and medications, and should always be interpreted in clinical context.

Lymphocyte-to-Monocyte Ratio (LMR)
 
The LMR is the inverse of MLR and is often used interchangeably in clinical studies:

• LMR = 1 / MLR

 
Approximate Reference Ranges

• Normal LMR: ~10–3.3
• Calculated normal range: ~5.9–5.0
• Mild inflammation: 3.3–2.0
• Moderate inflammation: 2.0–1.25
• Severe inflammation: < 1.25

 
Lower LMR values generally reflect heightened inflammatory activity and worse prognosis in several chronic diseases.
 
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)
 
Because clinicians rarely rely on a single biomarker in isolation, there has been growing interest in composite inflammatory indices that integrate multiple immune cell populations into a single metric. Over the past decade, researchers have developed and validated two such indices—the Systemic Inflammatory Index (SII) and the Systemic Inflammation Response Index (SIRI)—across a wide range of inflammatory, autoimmune, cardiovascular, oncologic, and infectious diseases [1].
 
Systemic Inflammatory Index (SII)
 
The Systemic Inflammatory Index (SII) integrates three key components of the immune response:

• Neutrophils (N): markers of innate immune activation
• Lymphocytes (L): indicators of adaptive immune regulation
• Platelets (P): mediators of inflammation and thrombosis

 
Formula:
SII = (Neutrophils / Lymphocytes) × Platelets
 
By combining these parameters, SII captures both immune activation and prothrombotic signaling, offering a more comprehensive picture of systemic inflammation than single ratios such as NLR or PLR alone.
 
Based on standard hematological reference ranges [2], the estimated normal SII range in healthy individuals is approximately:

• 300–583

This estimate is consistent with findings from comparative studies of healthy controls versus patients with immune-mediated and inflammatory diseases, including those summarized in the meta-analysis by Mangoni and Zinellu [3] (reproduced in the table below).
 
Clinical relevance:
Elevated SII values have been associated with worse outcomes in cardiovascular disease, cancer, autoimmune disorders, and chronic inflammatory states, making SII a promising risk stratification tool in aging populations. 

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

 

Systemic Inflammation Response Index (SIRI)
 
The Systemic Inflammation Response Index (SIRI) incorporates:

• Neutrophils (N)
• Lymphocytes (L)
• Monocytes (M)

 
Formula:
SIRI = (Neutrophils / Lymphocytes) × Monocytes
 
Initially developed as a prognostic biomarker in oncology, SIRI has since demonstrated diagnostic and prognostic utility across a broader spectrum of inflammatory diseases, including infections and immune-mediated conditions [1].
 
Unlike SII, a universally accepted normal reference range for SIRI has not yet been established, as most studies focus on patients with overt inflammatory pathology. Nevertheless, evidence suggests that low SIRI values reflect immune balance, whereas higher values indicate escalating systemic inflammation.
Based on standard hematological ranges [2], the estimated SIRI range in healthy individuals is approximately:

• 0.40–1.33

 
For practical clinical interpretation:

• SIRI < 1.0 is generally considered indicative of a non-inflammatory or low-inflammatory state
• Higher values suggest increasing inflammatory burden and immune dysregulation

Clinical Perspective on SII and SIRI
 
Together, SII and SIRI complement traditional biomarkers such as CRP, NLR, PLR, and MLR by integrating multiple immune pathways into single indices. Their calculation from routine CBC data makes them cost-effective, accessible, and well suited for longitudinal monitoring, particularly in older adults and individuals undergoing annual physical examinations.
 
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 a long-established marker of systemic inflammation. Although it is not routinely included in all annual physical exams, ESR is frequently ordered when clinicians suspect infection, autoimmune disease, malignancy, or chronic inflammatory conditions.
 
What ESR Measures
ESR quantifies the rate at which red blood cells settle at the bottom of a vertical tube over one hour. Inflammatory processes increase plasma proteins—particularly fibrinogen and immunoglobulins—that promote red blood cell aggregation, causing them to settle more rapidly [1].
 
Mechanism of ESR
During inflammation, elevated acute-phase proteins reduce the repulsive forces between erythrocytes, leading to rouleaux formation and faster sedimentation. Thus, higher ESR values correlate with greater inflammatory activity, although the test does not identify the source or cause of inflammation.

Clinical Uses of ESR
ESR is commonly used to support diagnosis, assess disease activity, and monitor treatment response in:

• Infections: bacterial infections, tuberculosis
• Autoimmune diseases: rheumatoid arthritis, systemic lupus erythematosus, vasculitis
• Chronic inflammatory conditions: inflammatory bowel disease, polymyalgia rheumatica, giant cell arteritis
• Malignancies: lymphoma, multiple myeloma

 
Because of its non-specific nature, ESR is almost always interpreted alongside other biomarkers and clinical findings.

Normal ESR Reference Ranges
 
ESR values vary by age and sex:
Males

• < 50 years: 0–15 mm/hr
• ≥ 50 years: 0–20 mm/hr

Females

• < 50 years: 0–20 mm/hr
• ≥ 50 years: 0–30 mm/hr

Values above these ranges are considered elevated and may warrant further evaluation.

Pathologically Elevated ESR

• > 50 mm/hr: suggests significant systemic inflammation
• > 100 mm/hr: often associated with serious underlying pathology, including:
  • Severe infections (e.g., endocarditis, osteomyelitis)
  • Active autoimmune disease flares
  • Advanced malignancy

 
However, elevated ESR may also occur in non-pathologic states, such as pregnancy, anemia, or menstruation, underscoring the importance of clinical context.

Low ESR
 
Low ESR values are uncommon and usually benign. They may be observed in conditions such as polycythemia or certain red blood cell disorders and typically do not require intervention unless accompanied by symptoms.

Limitations of ESR
 
While ESR remains valuable due to its simplicity, low cost, and long clinical history, it has notable limitations:

• Non-specific to disease type or location
• Influenced by non-inflammatory factors (e.g., anemia, kidney disease, lipid levels)
• Slower to respond to acute changes compared with CRP

 
For these reasons, ESR is most effective when combined with CRP, CBC-derived ratios, and clinical assessment.
​
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 Profile
Patient X is a 73-year-old Southeast Asian male with a body mass index (BMI) of 24.8 and a waist-to-height ratio (WHtR) of 0.51.
 
Medical History
The patient’s medical history is notable for:

• Benign hypertension
• Dyslipidemia, characterized by borderline elevated total cholesterol and hypertriglyceridemia
• Recurrent gout flares beginning in his early forties

 
Pharmacologic History
Following cardiology consultation, pharmacologic management was initiated and subsequently modified over time as follows:

• October 2004 (Rx2004):
  Fenofibrate (Antara) 130 mg once daily (QD) and valsartan 80 mg QD were initiated for lipid management and blood pressure control.
• November 2007 (Rx2007):
  Ezetimibe/simvastatin (Vytorin) 10/20 mg QD was added to the treatment regimen.
• 2011–2012 (Rx2012):
  In the third quarter of 2011, the patient was diagnosed with cholelithiasis and subsequently underwent cholecystectomy in April 2012. Following this, a newly established primary care physician discontinued both fenofibrate and Vytorin.
• July 2015 (Rx2015):
  Atorvastatin 10 mg QD was introduced for ongoing lipid management.
• 2017 (Rx2017):
  After consultation with a rheumatologist, allopurinol 200 mg QD was prescribed for gout prophylaxis.

Following initiation of allopurinol therapy, the patient reported complete resolution of gout flares.
 
Laboratory Data
The patient provided complete blood count (CBC) data spanning from 1989 to the present. Longitudinal analyses were performed, and the following inflammatory and hematologic indices were plotted over time:

• Neutrophil-to-lymphocyte ratio (NLR)
• Platelet-to-lymphocyte ratio (PLR)
• Platelet count
• Monocyte-to-lymphocyte ratio (MLR)
• Systemic Immune-Inflammation Index (SII)
• Systemic Inflammation Response Index (SIRI)

​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 Profile
Patient Y is a 74-year-old Southeast Asian male with a body mass index (BMI) of 27.8 and a waist-to-height ratio (WHtR) of 0.59.
 
Medical History and Treatment
The patient’s medical history includes:

• Recurrent syncope
• Hypertension
• Hyperlipidemia
• Type 2 diabetes mellitus
• Benign prostatic hypertrophy, with a prostate-specific antigen (PSA) level of 14 ng/mL

 
Pharmacologic management was initiated and escalated over time as follows:

• 2003: Metoprolol initiated for blood pressure control and syncope management
• 2011: Atorvastatin initiated for lipid management
• 2018: Metformin initiated for glycemic control
• March 2024: Semaglutide (Ozempic) initiated as adjunctive therapy for diabetes and weight management

 
Laboratory Findings
A differential white blood cell count obtained on August 24, 2024 (with eosinophils and basophils excluded) was within standard reference ranges for all measured cell types:

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

 

Despite these values falling within conventional laboratory reference ranges, derived inflammatory indices revealed elevations relative to both calculated norms and clinically reported values from apparently healthy controls.

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

 

Interpretation
Although Patient Y’s absolute leukocyte and platelet counts were within conventional reference limits, all five composite inflammatory biomarkers—NLR, PLR, MLR, SII, and SIRI—were elevated relative to expected values. This discordance suggests the presence of low-grade systemic inflammation that may not be captured by standard differential counts alone and may reflect ongoing or unresolved inflammatory disease processes.

Case Study 3

Patient Profile
Patient Z was a 69-year-old male with no prior oncologic history until age 67, when he was diagnosed with a poorly differentiated peritoneal adenocarcinoma, initially suspected to be of hepatic origin.
 
Oncologic History and Treatment Course
In the year of diagnosis, the patient underwent aggressive multimodal therapy. Cytoreductive surgery was performed, followed by hyperthermic intraperitoneal chemotherapy (HIPEC). Postoperative histopathological evaluation confirmed hepatocellular carcinoma (HCC) with peritoneal metastases.
Four months after surgery, residual unresectable hepatic tumor masses were treated with two rounds of transarterial chemoembolization (TACE) using doxorubicin. The patient remained clinically stable and functionally independent for approximately six months. Disease relapse was subsequently indicated by a marked rise in serum alpha-fetoprotein (AFP) levels.
 
Over the following six months, the patient underwent five additional rounds of TACE. However, treatment efficacy progressively declined as tumor neovascularization increased and lesions became refractory to embolization.
 
Given disease progression, locoregional therapy was discontinued and systemic biologic therapy was initiated. The patient received combination immunotherapy and anti-angiogenic treatment with atezolizumab (Tecentriq) and bevacizumab (Avastin). A total of six infusions were administered over an 18-week period. Despite therapy, imaging and clinical findings demonstrated continued slow tumor growth, accompanied by worsening abdominal pain, gastrointestinal symptoms, and progressive peritoneal ascites. Biologic therapy was discontinued due to lack of clinical benefit and increasing treatment-related morbidity.
 
The patient was transitioned to palliative care and died nine months later at age 69.
 
Laboratory Monitoring and Biomarker Analysis
For a continuous 12-month period encompassing the initiation of biologic therapy through end-of-life care, the patient underwent regular laboratory monitoring, including:

• Complete blood counts with differential
• Comprehensive metabolic panels
• Tumor biomarkers (including AFP)
• C-reactive protein (CRP)

 
This longitudinal dataset enabled a direct comparison between CRP, a conventional acute-phase inflammatory biomarker, and systemic inflammatory indices derived from differential white blood cell counts, including NLR, PLR, MLR, SII, and SIRI.

Results and Interpretation
Time-series analyses demonstrated that all five inflammation indices derived from differential blood counts tracked closely with CRP trends over the observation period. While NLR, PLR, and SII showed high sensitivity in detecting elevations above normal reference thresholds, MLR and SIRI exhibited comparatively lower sensitivity, as indicated by delayed or attenuated excursions above reference limits (denoted by horizontal arrows on the corresponding y-axes).
 
These differences likely reflect the distinct biological contributions of neutrophils, platelets, and monocytes to tumor-associated inflammation, angiogenesis, and immune modulation, particularly in the context of advanced malignancy and biologic 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