Biomarkers of Immunity: Total White Blood Cells (WBCs)

Optimal Takeaways

White blood cells are considered protective and participate in the frontline defense against infection and the complex response to injury. An acute spike in WBCs often indicates active infection, while a dramatic decrease may indicate bone marrow failure. However, WBCs are also part of an inflammatory response that can be detrimental if unbridled or prolonged, and elevations are associated with increased risk of cardiovascular disease and type 2 diabetes, fundamentally inflammatory conditions. A low WBC reflects compromised immunity and may lead to systemic infection and vulnerability.

Standard Range: 3.8 - 10.8 k/cumm (3.8-10.8 giga/L)

The ODX Range: 3.8 – 6.0 k/cumm (3.8 – 6.0 giga/L)

Low WBCs (leukopenia) may be associated with bone marrow failure or infiltration, chemotherapy, radiation, autoimmune disease, overwhelming infection, nutrition deficiency, pregnancy, drug toxicity, and drugs including antihistamines, antibiotics, anticonvulsants, antithyroid drugs, arsenic-containing drugs, barbiturates, chemotherapy, diuretics, and sulfonamides (Pagana 2022).

High WBCs (leukocytosis) are associated with inflammation, tissue necrosis, infection, leukemia, trauma, post-splenectomy, physical activity, and stress (physical and emotional). Drugs, including epinephrine, allopurinol, aspirin, chloroform, heparin, quinine, steroids, and triamterene, may increase WBCs (Pagana 2022).

Elevated WBCs are also associated with adrenergic stimulation (Anderson 2007), hypertension, hyperinsulinemia, obesity, hypertriglyceridemia, decreased HDL (Huang 2007), smoking (Touil 2012), increased risk of type 2 diabetes (Gkrania-Klotsas 2010), thrombosis (Sooriyaarachchi 2023), increased risk of cardiovascular disease, decreasing lung function, increased all-cause mortality (Leng 2005), ischemic stroke, obesity, hypertension, dyslipidemia, and metabolic syndrome (Kim 2008).

Overview

White blood cells (WBCs), also called leukocytes, are immune cells produced in the bone marrow for the primary purpose of fighting infections, promoting an inflammatory immune response to pathogens, and regulating the cellular response to injury (Tigner 2021). The total WBC count includes granulocytes (neutrophils, eosinophils, and basophils) and nongranulocytes (lymphocytes and monocytes). Neutrophils and lymphocytes are the most abundant WBCs and comprise 75-90% of the total WBC count. Although primarily associated with an immune response to invading pathogens, elevated WBCs can also be associated with increased physical or emotional stress. A decreased WBC count may indicate bone marrow failure, severe infection, autoimmunity, or malnutrition (Pagana 2022).

The total white blood cell count is considered a non-specific marker of inflammation (Gkrania-Klotsas 2010). Using data from a health check program, a retrospective study found a significant association between white blood cell (WBC) counts and C-reactive protein, confirming that higher WBCs are associated with increased inflammation. The study found that the lowest CRP value (below 1 mg/L) was associated with a WBC mean of 5.97 k/cumm (Huang 2007). The total WBC count may help predict mortality risk as well. The Women’s Health and Aging Studies cohort study observed a significantly increased mortality risk among women with WBCs above 7.0 versus the lowest mortality in those with the lowest WBCs, i.e., below 5.6 k/cumm (Leng 2005).

Excess white blood cells aggregate within artery walls, obstruct blood flow, promote thrombosis, and increase cardiovascular risk (Sooriyaarachchi 2023). Meta-analysis of 7 large long-term prospective studies revealed that higher WBC count, with a mean of 8.4 versus 5.6 k/cumm, was associated with increased CHD risk in a highly significant association (Danesh 1998). Subsequent research confirms an association between elevated WBCs and atherosclerosis, primarily an inflammatory disorder. One prospective observational study of 3,277 coronary angiography patients in the Intermountain Heart Collaborative Study revealed a mean baseline WBC count of 7.82 k/cumm. Elevated WBCs above 9.4 k/cumm, neutrophils above 6.6 k/cumm, and neutrophil to lymphocyte ratio above 4.71 were independent predictors of myocardial infarction and death in this high-risk cohort (Horne 2005).

A large prospective study of 29,526 subjects who had undergone coronary angiography found the lowest incidence of mortality in those with a mean total WBC of 6.0 k/cumm or below. Researchers also note that an elevated WBC count independently predicts cardiovascular events, even in healthy individuals (Anderson 2007).

Metabolic syndrome is another condition associated with inflammation and cardiovascular risk. A review of routine medical checkups in 15,654 individuals found that as WBC counts increased, so did blood pressure, BMI, fasting glucose, lipids, uric acid, AST, ALT, GGT, fibrinogen, alcohol intake, and smoking, while HDL-C and income decreased. The highest tertile of WBCs (6.46-10,000 k/cumm) was associated with the greatest cardiometabolic dysfunction (Kim 2008).

Elevated total WBCs were also associated with an increased risk of type 2 diabetes, as revealed in a systematic review and meta-analysis of 20 cross-sectional and prospective studies. The highest risk of T2DM was observed in the highest tertile of 7.1 k/cumm or above, with a mean of 8.5 k/cumm, while the lowest risk was observed in the lowest tertile of 5.7 k/cumm or below, with a mean of 4.9 k/cumm (Gkrania-Klotsas 2010).

Evaluation of NHANES data found that increasing WBCs were associated with metabolic acidosis characterized by low bicarbonate and increased anion gap. A WBC count of 7 k/cumm was associated with an anion gap above 13 mEq/L, while a WBC count of 6.6 was associated with an anion gap below 10 mEq/L (Farwell 2010).

The 44-year Baltimore Longitudinal Study of Aging found that the lowest mortality risk was associated with a WBC count of 3.5-6. Individuals with WBCs above 10 had a 2-fold increased mortality, while those with WBCS below 3.5 had a 3-fold increased mortality. Those who died were more apt to smoke, be less physically active, and have a worse cardiovascular health profile than survivors (Ruggiero 2007).

References

Anderson, Jeffrey L et al. “Usefulness of a complete blood count-derived risk score to predict incident mortality in patients with suspected cardiovascular disease.” The American journal of cardiology vol. 99,2 (2007): 169-74. doi:10.1016/j.amjcard.2006.08.015

Danesh, J et al. “Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies.” JAMA vol. 279,18 (1998): 1477-82. doi:10.1001/jama.279.18.1477

Farwell, Wildon R, and Eric N Taylor. “Serum anion gap, bicarbonate and biomarkers of inflammation in healthy individuals in a national survey.” CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne vol. 182,2 (2010): 137-41. doi:10.1503/cmaj.090329

Gkrania-Klotsas, Effrossyni et al. “Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies.” PloS one vol. 5,10 e13405. 18 Oct. 2010, doi:10.1371/journal.pone.0013405

Horne, Benjamin D et al. “Which white blood cell subtypes predict increased cardiovascular risk?.” Journal of the American College of Cardiology vol. 45,10 (2005): 1638-43. doi:10.1016/j.jacc.2005.02.054

Huang, Zei-Shung et al. “Revision in reference ranges of peripheral total leukocyte count and differential leukocyte percentages based on a normal serum C-reactive protein level.” Journal of the Formosan Medical Association = Taiwan yi zhi vol. 106,8 (2007): 608-16. doi:10.1016/S0929-6646(08)60017-0

Kim, Dong-Jun et al. “The associations of total and differential white blood cell counts with obesity, hypertension, dyslipidemia and glucose intolerance in a Korean population.” Journal of Korean medical science vol. 23,2 (2008): 193-8. doi:10.3346/jkms.2008.23.2.193

Leng, Sean X et al. “Baseline total and specific differential white blood cell counts and 5-year all-cause mortality in community-dwelling older women.” Experimental gerontology vol. 40,12 (2005): 982-7. doi:10.1016/j.exger.2005.08.006

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 16th ed., Mosby, 2022.

Ruggiero, Carmelinda et al. “White blood cell count and mortality in the Baltimore Longitudinal Study of Aging.” Journal of the American College of Cardiology vol. 49,18 (2007): 1841-50. doi:10.1016/j.jacc.2007.01.076

Sooriyaarachchi, Piumika et al. “Shift Work is Associated with an Elevated White Blood Cell Count: A Systematic Review and Meta-Analysis.” Indian journal of occupational and environmental medicine vol. 27,4 (2023): 278-285. doi:10.4103/ijoem.ijoem_326_22

Tigner, Alyssa, et al. “Histology, White Blood Cell.” StatPearls, StatPearls Publishing, 19 November 2021.

Touil, N et al. “Range-reference determination of lymphocyte subsets in Moroccan blood donors.” African health sciences vol. 12,3 (2012): 334-8. doi:10.4314/ahs.v12i3.14