Granulocytes are immune cells that fight pathogens and heal damaged cells. They play critical roles in inflammation and wound healing. High levels occur in infections, autoimmune diseases, and cancer. Low levels are most often caused by infections and drugs. Read on to find out what high and low granulocyte levels mean and what factors may decrease or increase them.
What Are Granulocytes?
Pathogen-Fighting Immune Cells
Granulocytes are white blood cells that contain small sacs called granules. The contents of these granules are released into the blood during infections, injuries, and allergic reactions. These contents include antimicrobial proteins, enzymes to digest bacteria, and reactive oxygen species .
There are four types of granulocytes :
Granulocytes are made in the bone marrow from stem cells and then released into the circulation. They are part of the innate immune system, which provides a quick response to pathogens. Granulocytes become activated by pathogens and damaged cells .
Granulocytes are also known as polymorphonuclear leukocytes (PML) or polymorphonuclear neutrophils (PMN).
The main function of granulocytes is to engulf and destroy invading pathogens and parasites. They are responsible for starting the process of inflammation as well as resolving it. Granulocytes are also involved in wound healing and tissue remodeling [1, 5].
Immune messenger molecules (eotaxin and IL-8) recruit granulocytes from the bloodstream to injured or infected tissues. They are then activated by bacteria, viruses, and fungi or damaged cells.
When they encounter a pathogen, granulocytes engulf them and release the contents of their granules to digest and destroy them. However, they also can cause damage to your own cells in the process .
After a threat has been eliminated, granulocytes destroy themselves by programmed cell death (apoptosis). However, in many inflammatory diseases like rheumatoid arthritis and asthma, granulocytes last longer than they should .
Neutrophils are the most abundant immune cells in the body. They make up 50% to 70% of all immune cells. They only survive 8-12 hours in the blood (where they normally reside) and 1-2 days in tissues (when there is an infection) [3, 6].
Neutrophils are among the first immune cells to arrive at the site of an injury or infection. They produce antimicrobial compounds called defensins, enzymes (proteases), and reactive oxygen species (superoxide and hydrogen peroxide) that break down and destroy pathogens.
However, these compounds can also cause damage to surrounding healthy tissue, which can lead to delayed healing and excess scarring .
Eosinophils were thought to primarily fight parasites such as worms. However, recent research suggests that they may also allow some parasites to live while preventing them from doing too much damage [9, 10].
- Fighting viral, bacterial, and fungal infections
- Activating acquired immunity
- Helping prepare the uterus for pregnancy
- Repairing and remodeling tissue
- Regulating blood sugar and insulin levels
Like neutrophils, they are made in the bone marrow and then released into the bloodstream. They take up residence in the gut, ovaries, and lymph nodes, where they can live for several weeks. They are usually not found in the lung, skin, or throat except in disease states [11, 14, 15].
When basophils become activated, they release the contents of their granules, which includes heparin and histamine.
Histamine expands blood vessels and increases blood flow. Heparin is an anti-clotting agent that helps maintain proper blood flow. This allows immune cells easy access to the site of inflammation [20, 21, 22].
Due to their similarity, mast cells were originally thought to be basophils. Whereas basophils mainly circulate in the bloodstream, mast cells live tissues. They are abundant in places that come into close contact with the environment, such as the skin, gut, and airways [17, 23, 24].
Mast cells are responsible for the early recognition of foreign invaders. Within seconds of encountering a pathogen, mast cells release histamine, enzymes, and heparin .
Mast cells also play key roles in asthma and allergies by overreacting to the presence of harmless substances such as pollen and pet dander. They also participate in autoimmune conditions, including rheumatoid arthritis and multiple sclerosis .
By releasing pro-inflammatory cytokines (TNF-α and IL-6), mast cells can recruit T cells and dendritic cells to help fight pathogens. This makes mast cells a crucial link between the innate and adaptive immune systems .
Immature granulocytes are normally located in the bone marrow and have not yet matured into granulocytes .
Granulocytes Normal Range
Granulocytes are measured as part of a standard complete blood count (CBC) test.
Lab results are commonly shown as a set of values known as a reference range, which is sometimes referred to as a “normal range.” A reference range includes upper and lower limits of a lab test based on a group of otherwise healthy people.
Your healthcare provider will compare your lab test results with reference values to see if any of your results fall outside the range of expected values. By doing so, you and your healthcare provider can gain clues to help identify possible conditions or diseases.
The normal range of granulocytes is 1.5 – 8.5 x 10^9/L or between 1,500 and 8,500 cells per microliter (µL) of blood.
Levels below this range are referred to as granulopenia or neutropenia (low neutrophil levels). Severely low levels (below 500 cells/µL) are referred to as agranulocytosis. Low levels of granulocytes reduce the body’s ability to fight infections .
Levels above this range are referred to as granulocytosis or neutrophilia.
High Granulocytes (Granulocytosis)
The causes we discuss here are commonly associated with granulocytosis. Do not attempt to self-diagnose with any medical condition based on this single symptom! Work with your doctor to find an accurate diagnosis and appropriate treatment or management plan.
- Lymphoma (cancer of the lymphatic system)
- Chronic myeloid leukemia (cancer of the bone marrow)
3) Bone Marrow Disorders
Bone marrow produces blood cells, including granulocytes. When the process of blood cell production is disordered, granulocytosis may arise. A variety of bone marrow disorders have been associated with granulocytosis, including [38, 39]:
- Chronic myeloid leukemia (bone marrow cancer, as mentioned above)
- Essential thrombocytosis
- Primary myelofibrosis
4) Autoimmune Disorders
Some autoimmune disorders are associated with granulocytosis, most notably rheumatoid arthritis .
5) Blood Disorders
A few blood disorders may produce granulocytosis as a symptom, though not always. The most common of these include platelet clumping, cryoglobulinemia, and anemia .
Granulocyte counts are normally elevated during pregnancy due to a higher sympathetic nervous system activity. This increased activity helps the developing fetus get enough oxygen and nutrients .
7) Cushing’s Syndrome
Granulocyte levels increased in ten patients who underwent elective spine surgery due to an increase in cortisol .
Granulocyte levels were substantially higher in patients with appendicitis in a study of 456 people .
9) Heart Attack
Associated Diseases and Conditions
1) High Blood Pressure
In a 40-year observational study of 9,400 people, high neutrophil levels increased the risk of developing high blood pressure .
2) Fatigue and Stress
Higher neutrophil levels were linked to fatigue due to stressful work in 213 people .
3) Heart Disease
Neutrophils can accumulate in plaques in the artery walls and contribute to hardened arteries (atherosclerosis) .
The causes we discuss here are commonly associated with low granulocytes. Do not attempt to self-diagnose with any medical condition based on this single symptom! Work with your doctor to find an accurate diagnosis and appropriate treatment or management plan.
1) Cancer Treatment
Certain bacterial, viral, protozoan and fungal infections can cause low granulocyte levels. The flu, Epstein-Barr virus (EBV), cytomegalovirus (CMV), and hepatitis A, B and C are common viruses that can lead to low granulocyte levels [31, 61, 60, 62].
3) Certain Drugs
Some medications, including antibiotics, strong anti-inflammatories (sulfasalazine), and antipsychotics (clozapine), are associated with low granulocytes. If your doctor prescribes one such medication, you may be asked to come in for regular blood tests to ensure that your white blood cells are healthy [63, 64, 65].
4) Autoimmune Diseases
Low granulocyte levels are also a common feature of Sjögren’s syndrome, an autoimmune disease that causes dry eyes and mouth .
5) Bone Marrow Disorders
Bone marrow disorders can decrease granulocytes by interfering with their production. Examples of bone marrow disorders include :
- Leukemia (bone marrow cancer)
- Aplastic anemia
6) Vitamin B9, Vitamin B12, and Iron Deficiencies
7) Inborn Neutropenia
Congenital (inborn) neutropenia is a condition of low neutrophil levels from birth due to genetic disorders .
Benign ethnic neutropenia (BEN) is caused by a small genetic mutation and it’s found in 25% to 50% of people of African descent. However, it is not associated with an increased risk of infections commonly seen in other forms of congenital neutropenia [76, 77].
Other forms of congenital neutropenia include Kostmann’s syndrome and cyclic neutropenia .
8) Enlarged Spleen
9) Organ Transplants
Low neutrophil levels occur in up to 28% of kidney transplants and 24% of liver transplant recipients during the first year. They are associated with more infections, organ rejection and increased mortality .
10) Thyroid Disorders
Hypothyroidism and hyperthyroidism are found in up to 43% of people with low granulocytes. Both low and high thyroid hormones are thought to destroy granulocyte precursors. People with thyroid disorders also have high levels of antibodies to granulocytes [80, 81].
Hemodialysis is the use of a filter to clean the blood of people whose kidneys are not working properly. The process changes neutrophils so that they get stuck in the blood vessels, leading to low levels in the bloodstream [82, 83].
12) Severe Burns
Associated Diseases and Conditions
Type 1 Diabetes
Type 1 diabetes is an autoimmune disorder that causes the destruction of the cells that produce insulin (beta cells). Low neutrophil levels were associated with an increased risk of developing type 1 diabetes in a study of 436 people .
Effects of Drugs on Granulocytes Levels
Drugs associated with increased granulocyte levels include:
Drugs associated with decreased granulocyte levels include:
- ACE inhibitors [91, 92]
- Allopurinol 
- Pain-relieving drugs 
- Antibiotics 
- Anticoagulants 
- Antidepressants 
- Antidiabetics 
- Antiepileptics [96, 97, 98]
- Antihistamines 
- Antimalarial 
- Antipsychotics [99, 100]
- Antithyroid medication [101, 102, 103]
- Chemotherapy [104, 105]
- Cimetidine 
- Cocaine 
- Colchicine 
- Dapsone 
- Diuretics 
- Griseofulvin 
- Immunosuppressives 
- Levodopa 
- Levamisole 
- NSAIDs 
Genetics of Granulocytes
Gene Mutations and Neutropenia Risk
People with Kostmann’s disease have neutrophil levels lower than 0.2 ×109/l. Some of the patients have mutations in ELA2 or HAX-1. Additionally, Kostmann’s patients can also acquire CSF3R gene mutations .
Chediak-Higashi patients have CHS1 gene mutations, which can cause neutropenia .
Shwachman-Diamond is a rare disorder, where the patients have defective neutrophil movement in the blood. An SBDS gene mutation is associated with neutropenia .
Gene Mutations and Neutrophilia Risk
A mutation in the CSF3R gene promotes neutrophil formation. This can lead to higher susceptibility for hereditary chronic neutrophilia .
PSTPIP1 mutation can play a role in neutrophilic dermatoses susceptibility .
People with the GPSM3 SNP rs204989 may have decreased GPSM3 production and be protected against rheumatoid arthritis. This specific variation reduces neutrophil movement to the inflammation site, which prevents long-term inflammation that is associated with arthritis .
A mutation in the RAC2 gene is associated with neutrophil dysfunction and can cause a person to be predisposed to bacterial infections. It is also associated with human immunodeficiency syndrome .
Pelger-Huët anomaly is a genetic disorder where the nucleus of neutrophils is in odd shapes. However, patients with this disorder are mostly healthy and neutrophils still function normally. A mutation in the LBR gene causes Pelger-Huët anomaly .
Eosinophils and Basophils
Granulocytes (polymorphonuclear leukocytes) are white blood cells that fight pathogens and recycle damaged cells. They include neutrophils (the main ones), eosinophils, basophils, and mast cells. They can harm healthy cells and trigger inflammatory conditions by becoming over-active.
The normal range of granulocytes is 1.5 – 8.5 x 10^9/L. Values below indicate granulopenia (neutropenia) and values above – granulocytosis or neutrophilia. IG (immature granulocytes) above 1% may indicate infections or chronic inflammation.
Low granulocytes can occur due to nutrient deficiency, autoimmune and bone marrow disorders, viral infections, genetic mutations, thyroid disorders, and severe burns.
Talk to your doctor for an accurate diagnosis and effective treatment of the underlying causes of high or low granulocytes.
Irregular Granulocyte Levels?
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