Table 2.
Overview of common markers of inflammation—advantages and disadvantages.
| Marker | Class of Marker | Measured in: Matrix | Stability | Techniques Used | Relevance for Chronic Diseases | Comments, Advantages/Disadvantages |
|---|---|---|---|---|---|---|
| Cytokines: IL1β, IL-6, IL-8, IFγ, TNF-α, | Pro-inflammatory cytokines | Plasma, serum, or expression of mRNA in tissue | Stable for 3 freeze-thaw cycles reported for IL-6, IL-10, IFNγ, and IL-2 [309]. Stable during 1 y at −80 °C (IL-1β, IFγ, IL-6, TNF-α) [310] | ELISA, multiplex bead array assays [311], mRNA levels by PCR | IL-6: In meta-analyses related to cognitive decline in elderly without dementia [312], more severe COVID-19 complications [313], IBS [314], polymorphisms of IL-6 related to lower risk of obesity [315]. | Primary markers of inflammation, low half-lives in blood (minutes) |
| IL-8: Meta-analyses shown relations between elevated IL-8 and lupus erythematodes [316], hepato-cellular carcinoma [317], periodontitis [318], but not obesity [319]. | ||||||
| IFγ: Polymorphisms related in meta-analysis of 9 case-control studies to breast cancer [320], in a meta-analysis of 8 studies on cervical cancer [321]. No sign. association with mycoplasma caused pneumonia in meta-analysis of 6 small-medium scale studies [322]. | ||||||
| TNF-α: higher circulating conc. in individuals with obesity [323]. Meta-analysis of 5 prospective studies failed to show relation with T2D RR, unlike IL-6 and CRP [324]. Increased TNF-α (and IL-6 and 8) in breast-cancer based on meta-analysis [325]. | ||||||
| Leukocyte count | Cell counting | Whole blood | Cell counting should be done on fresh whole blood samples, within 3 h [326]. Freezing for 15 d at −70 °C resulted in sign. changes in cell counts [327] | In clinic, several automated systems, including impedance and optical systems, as well as image cytometers [328] | Increased leukocyte count (>11 × 109/L) associated with worse outcome in stable CAD and even in the general population [329], in a meta-analysis related with MetS [330] and also with T2D [331]. | Interesting proxy-marker of inflammation, as leukocytes are major secreters of cytokines |
| Lymphocyte count | Low lymphocyte count found in meta-analyses of COVID-19 [332], also used in HIV as decision-helper for starting anti-viral therapy [333]. | |||||
| Eosiniphil counts | Normally <0.5 × 109 cells/L. Eosinophils increased in allergic diseases, e.g., asthma as shown in a meta-analysis [334] and also in autoimmune diseases, such as celiac disease [335], and in IBD (both CD and UC) [336]. Elevated also in Hodgkin’s lymphoma [337]. | |||||
| Monocyte counts | Monocytosis indicated by >0.8 × 109/L in adults. Frequently associated with infections, e.g., malaria [338], autoimmune diseases such as rheumatoid arthritis [339], IBD (1020), colorectal cancer as shown in a meta-analysis [340], obesity [341], and schizophrenia as seen in a meta-analysis [342]; no elevation found in meta-analysis of T2D [331]. | |||||
| Basolphil counts | Number normally <0.20 × 109/L [343]. Elevated level (>2.0 × 109/L) associated with autoimmune inflammation and allergies [344]. Low level of basophils associated with rheumatoid arthritis [345]. | |||||
| Neutrophil-lymphocyte ratio (NLR) | High NLR reported for poor glycemic control in T2D [346]. Multiple studies showed that increased NLR was associated with poor prognosis in a variety of cancers, such as colon, pancreatic, stomach, and lung cancer. In meta-analysis of >100 studies and 40,000 patients, an NLR >4 was associated with worse solid tumor survival rates [347]. | |||||
| Lymphocyte –monocyte ratio (LMR) | LMR associated with stroke severity and poor outcome, also according to meta-analysis [348]. Low LMR was sign. associated in a meta-analysis with lower overall survival in patients with ovarian cancer [349] and with solid tumors due to meta-analysis of 29 studies [350]. | |||||
| SII | In meta-analysis of 22 articles and >7500 patients, SII proposed as good predictor for tumor progression and survival in several cancers [351]. | |||||
| CRP | Acute phase proteins/reactants | Blood, CRF, | 11 y at −80 °C [352] | ELISA and other immune-techniques [353] | Meta-analyses showed higher levels in blood of PD [354], CHD and stroke mortality [355]. Increased tyrosine-nitrated levels in subjects with CAD [356] and with hemodialysis vs. controls [357]. | Very frequently used marker |
| SAA | Serum, plasma | At least 17 d at −20 °C [358], no report on storability at −80 °C | In clinical practice automated latex agglutination immunoassay [359] | Strong relation between elevated SAA and obesity [14], coronary heart disease [15], poor overall survival in individuals with solid tumors [360] and worse outcomes in lung cancer [361] in meta-analysis. | Very frequently used marker | |
| Haptoglobin | Serum, plasma | Stability of haptoglobin in bovine plasma at least 3 weeks at −20 °C and −80 °C [362] and 120 d in saliva at −20 °C [363] | Nephelometric methods in plasma on different automated laboratory systems [364], spectrophotometry, immunological methods, gel electrophorosis | In a recent meta-analysis, the haptoglobin genotype was associated with cardiovascular outcomes [365]. Haptoglobin also increases in inflammatory diseases, in cigarette smokers, during nephrotic syndrome [366] and in rheumatoid arthritis [367] | Interesting though less frequently employed marker | |
| Mannose-binding lectin (MBL) | Serum, plasma | Pure protein can be stored for 1 y at −80 °C [368], no data on plasma. | ELISA | In meta-analysis of MBL and polymorphisms, significant associations were found to sepsis [369], and vulvovaginal infections [370], but not to hepatitis B infection risk (though severity) [371] | Interesting but less frequently employed marker | |
| Acute phase reactant -procalcitonin | Serum, plasma | Small losses of 10% with several year storage at −80 °C [372] | ELISA | Meta-analysis of pneumonia [373] did not suggest that marker was useful to differentiate between viral and bacterial diseases, while it allowed to differentiate in another meta-analysis between infection and IBD [374] | Marker of bacterial, not viral infection or general inflammation marker | |
| ICAM-1, VCAM-1 | Endothelial marker | Soluble forms in serum, plasma | Some months in lyophilized form in kits at −20 °C, no published data on stability in samples | ELISA | In meta-analysis of 15 prospective studies with T2D, increased ICAM-1 but not VCAM-1 related to higher risk of T2D [375]. In meta-analysis of 18 case-control studies of cancer risk, ICAM-1 polymorphism was related to cancer risk [376], similar to meta-analysis of 12 case-control studies on T2D [377] and CHD in meta-analysis of 11 case-control studies [378].VCAM-1, but not ICAM-1 associated with preeclampsia in a meta-analysis of 21 studies [379]. | Marker of endothelial health, rather not general inflammation |
| PGE2 | COX-2 related marker | Serum, plasma | Unclear, but likely short, even at −80 °C | ELISA, mRNA measurement, MS-MS. | Elevated PGE2 levels in women with obesity [380], cancer, including colorectal cancer [381] and ovarian cancer [382], T2D patients [383], contribution to neurological disorders assumed [384]. | As stimulated by cytokines interesting marker of systemic inflammation |
| NF-κB | Pro-inflammatory transcription factor | Leukocytes, body tissue | 2 months at −80 °C in isolated protein extract [385] | ELISA, transcriptomics. Extraction of nuclear fraction advised. | In meta-analysis, increased expression of NF-kB in individuals with worse solid tumor outcomes [25], both in cytosol and nucleus. Increased expression in meta-analysis of non-small cell lung cancer [386], but only when determined in nuclear fraction. Isolated mycocytes from subjects with obesity showed elevated NF-kB expression [387]. | Difficult to interpret, time and tissue dependency of measures |
| Neopterin | Macrophage product | Plasma, urine | 3 d at RT, 3 months at −20 °C [111] | Fluorescence, HPLC, ELISA | Plasma levels were related to homocysteine and risk of CVD [388], and as well as to cancer such as oviaran cancer [389]. It was also shown to be modulated by age, gender, and BMI [390]. | Rather marker of immune cell activation |
| GlycA | Composite marker of glycosylation | Plasma, serum | Unclear, glycosy-lation increases protein stability [391], some months at −80 °C assumed | NMR | Strong relation to total mortality and cancer mortality [392], exercise and visceral fat [393] | Promising novel marker, expensive equipment needed (NMR) |
| HDL inflammatory marker (HII) | Lipoprotein marker | Plasma, serum | Based on stability of HDL in plasma, approx. 1–4 weeks at −80 °C, with cryo-preservants possibly longer [394] | Oxidation of LDL standard and protection by HDL fraction from individuals, dichloro-fluorescein fluorescence measurement | Higher HII associated with sepsis and shock in individuals with organ failure [395], poor outcome in subjects with hemodialysis [396] and diabetes [397]. | Analytically challenging |
| Dietary inflammatory index (DII) | Dietary marker | dietary intake | n.a. | FFQ | Higher DII related in meta-analyses to mortality of cancer, CVD, and total mortality [398], obesity [399] and cancer [400] | Only including dietary aspects, not further host-factors |
AD: Alzheimer’s disease, COX-2: cyclo-oxygenase 2, CRP: c-reactive protein, CVD: cardiovascular disease, ELISA: Enzyme-linked immune assay, FFQ: food frequency questionnaire, HDL: high density lipoproteins, IBD: inflammatory bowel diseases, ICAM-1: intercellular adhesion molecule 1, na: not applicable, NF-κB: nuclear factor kappa B, NMR: nuclear magnetic resonance, PCR: polymerase-chain reaction, PD: Parkinson’s disease, PGE2: prostaglandin E2, SAA: serum amyloid alpha, T2D: type 2 diabetes, VCAM-1: vascular adhesion molecule 1.