Neutrophil Count

Neutrophils are the most abundant type of white blood cell in the body; they have a critical role in the body's immune response. 

Neutrophils are primarily responsible for defending the body against bacterial and fungal infections through phagocytosis, a process in which they engulf and destroy pathogens.

Neutrophils are a type of granulocyte characterized by the presence of granules in their cytoplasm, which contain enzymes and antimicrobial substances used to combat pathogens during the immune response.

This article focuses on neutrophils (%) as a biomarker, delving into their significance, variability in health and disease, and their diagnostic and prognostic implications.

Alterations from expected levels of neutrophils in the blood, both in terms of percentage and absolute count, may signal important pathological processes and plays a role in diagnosing, monitoring, and managing various health conditions.

What are Neutrophils?

Definition and Role of Neutrophils in the Immune System  [7., 8.]

Neutrophils are the most abundant type of white blood cell in the human body.  They have the following designations: myeloid cells, polymorphonuclear leukocytes and granulocytes, and they are members of the innate immune system.  

Myeloid cells are a type of white blood cell derived from the bone marrow through the process of myelopoiesis. Neutrophils, eosinophils, basophils, monocytes, dendritic cells, and megakaryocytes (which produce platelets) are all considered myeloid cells. 

Myeloid cells play essential roles in immune defense, inflammation, and tissue repair. They are characterized by their distinctive morphology and functions, which vary depending on the specific cell type and the microenvironment in which they operate.

Polymorphonuclear leukocytes, commonly abbreviated as PMNs, are a type of white blood cell in the innate immune system characterized by their multi-lobed nucleus, giving them a segmented appearance. They are also referred to as granulocytes due to the presence of granules in their cytoplasm. 

PMNs play a crucial role in the innate immune response, particularly in defending the body against bacterial and fungal infections. They are highly mobile and capable of migrating to sites of infection or tissue damage, where they engulf and destroy pathogens through phagocytosis and the release of antimicrobial substances.

Neutrophils are considered granulocytes because they contain granules filled with enzymes and antimicrobial substances, which are deployed to neutralize threats.

As part of the innate immune system, neutrophils are the first line of cells recruited at the site of infection and attack, ingest, and digest microorganisms by producing reactive oxygen species.

They also play a vital role in acute and chronic inflammatory settings and autoimmune disorders.

In adults, the approximate normal range of white blood cell (WBC) count is 4000 to 11,000 cells/microL, out of which 60% to 70% are mature neutrophils circulating in peripheral blood. 

Basic Physiology and Function of Neutrophils  [4., 6.]

The life cycle of a neutrophil is relatively short, typically ranging from a few hours to a few days. They are produced in the bone marrow and released into the bloodstream, where they circulate until they are recruited to a site of infection or injury. 

Their quick response and ability to navigate to infection sites are facilitated by chemical signals in the body. Once at the site of infection, neutrophils exert their function by phagocytosis, or engulfing pathogens and destroying them via degranulation, or the release of reactive oxygen species. This process is essential for the resolution of infection and for preventing its spread. 

Neutrophils can also deploy a defensive mechanism known as neutrophil extracellular traps (NETs), where they release nuclear material to ensnare and neutralize pathogens, thereby contributing to host defense against infections.

Additionally, neutrophils play a role in wound healing and tissue repair, clearing away debris and dead cells.

Initially perceived as short-lived and nonspecific, neutrophils are now understood to have multifaceted roles in immune defense, infection clearance, and inflammation regulation. 

Neutrophils in Disease  [6.]

Neutrophils, traditionally viewed as microbe-killing cells, are increasingly recognized for their diverse roles in disease. 

Under homeostatic conditions, various subsets of neutrophils exist in tissues but much remains unknown about their generation and recruitment. 

In pathological states like inflammation and cancer, distinct neutrophil subsets emerge with specific functions. For instance, during infection with antibiotic-resistant bacteria, subsets like PMN-1 and PMN-2 display differential cytokine production and macrophage activation potential. 

Metabolic disorders like hyperglycemia and hyperlipidemia prime neutrophils for enhanced pro-inflammatory responses, contributing to conditions like diabetes and atherosclerosis. Additionally, neutrophils play crucial roles in thrombosis, venous inflammation, and pancreatitis, where their ability to form neutrophil extracellular traps (NETs) can exacerbate or resolve inflammation. 

In gout, NETs can have both inflammatory and anti-inflammatory effects, depending on the context. The heterogeneity of neutrophil function underscores the need for further research into their role in disease pathology and potential therapeutic targets.

Neutrophils in Cancer  [6.] 

Neutrophils exhibit dynamic behavior in cancer, playing both supportive and inhibitory roles in tumor development. Tumors can induce an increase in circulating neutrophils, often associated with poor outcomes in many cancers.

The neutrophil to lymphocyte ratio (NLR) serves as a prognostic marker, reflecting disease severity. 

LDNs, a distinct subpopulation of neutrophils, are found in the low-density fraction of blood and are associated with cancer progression. Their precise function remains unclear, but they may play roles in inflammation and immunosuppression. 

Tumor-associated neutrophils (TANs) display phenotypic plasticity, exhibiting either antitumor (N1) or protumor (N2) properties influenced by the tumor microenvironment. While murine models have provided insights into TAN behavior, human TANs remain less understood. 

Additionally, neutrophils can exert cytotoxicity against cancer cells following immunogenic cell death induced by certain anticancer therapies, highlighting their potential as effector cells in cancer immunotherapy.

What Are Neutrophils in Blood Tests?

A neutrophil count is typically part of a complete blood count (CBC) with differential, which measures the types and numbers of cells in the blood including red blood cells, white blood cells (WBCs), and platelets. 

A complete blood count (CBC) is commonly ordered to assess overall health and detect a wide range of conditions, including infections, anemia, and various blood disorders, by providing information on the quantity and quality of different types of blood cells.

The CBC with differential provides detailed information about the total number of WBCs and breaks down the WBC count into the five major types of white blood cells including lymphocytes, monocytes, neutrophils, eosinophils, and basophils.  An elevated or decreased number of WBCs can signal a problem.

The neutrophil count can be expressed as an absolute number or as a percentage of the total white blood cell count. 

Normal Neutrophil Ranges

The evaluation of neutrophils in blood tests is a standard procedure in clinical diagnostics, providing critical information about the body's immune response and overall health status.

While it is important to consult the individual lab company regarding their reference range for neutrophils, a common reference range is given as:  [5.]

Neutrophils: 2500-8000 per mm3 (55-70%)

Neutrophils are reported as an absolute number present in a blood sample, although they may also be described as a % of total white blood cells present on a CBC.  The % neutrophils test, also known as neutrophil percentage or neutrophil count, measures the proportion of neutrophils in the total white blood cell count. 

Knowing the proportion of neutrophils relative to other types of WBCs may help to understand the relative balance of each type of WBC.  

Types of Neutrophils Seen on Peripheral Blood Smear  [2.]

Neutrophils in blood work typically present as segmented and band neutrophils.  Other forms may also be seen, often in disease processes.

Segmented Neutrophil:

• Predominant white blood cell in blood, most mature of myeloid lineage
• Round to oval shape, 10-15 micrometers in size
• Condensed nuclear chromatin; nucleus segmented or lobulated
• Increased in leukemoid reactions, infections, inflammatory disorders

Band Neutrophil:

• Typically 5%-10% of nucleated blood cells
• Round to oval shape, 10-18 micrometers in size
• Indented nucleus, specific granules predominate
• Increased in myeloproliferative neoplasms, left shift, leukemoid reaction

Metamyelocyte:

• Round to oval shape, 10-18 micrometers in size
• Condensed nuclear chromatin, nucleus begins to indent
• Predominance in left shifted neutrophilia, myeloproliferative neoplasms

Myelocyte:

• Round to oval shape, smaller than promyelocyte
• Eccentric nucleus, clumping of chromatin, presence of primary and secondary granules
• Found in left shifted neutrophilia, acute myeloid leukemia, myeloproliferative neoplasms

Promyelocyte:

• Round to oval shape, 12-24 micrometers in size
• High nucleus to cytoplasm ratio, finely reticular chromatin with nucleoli
• Blue cytoplasm with red-purple granules
• Found in left shifted neutrophilia, acute myeloid leukemia, myeloproliferative neoplasms

Clinical Significance of Elevated Neutrophils: What Do High Neutrophils Mean?

Leukocytosis refers to an increase in total WBC count.  In adults, leukocytosis is defined as white blood cell (WBC) count > 11 × 10^9/L.  [2.] 

Hyperleukocytosis is typically defined as WBC > 100 × 10^9/L and is usually found in leukemias and myeloproliferative disorders.  [2.] 

Within leukocytosis it is important to understand which type of white blood cell is elevated. 

High levels of neutrophils, a condition known as neutrophilia, often point to the presence of an infection, inflammation, or stress response in the body. 

Neutrophilia can be a reaction to bacterial infections, where the body increases neutrophil production to combat the invading pathogens. It can also be seen in cases of acute stress, trauma, or inflammation. 

Chronic inflammatory conditions like rheumatoid arthritis or inflammatory bowel disease can also trigger neutrophilia. 

Moreover, stress-induced neutrophilia may occur due to the release of certain hormones like cortisol, which stimulates the production and release of neutrophils from the bone marrow into the bloodstream. 

Medications such as corticosteroids or lithium can also induce neutrophilia as a side effect.

Clinical Significance of Low Neutrophil Levels  [3.]

Conversely, low levels of neutrophils, or neutropenia, can be a cause for concern as they may indicate a weakened immune system's ability to fight infections.  Neutropenia compromises immune defenses, leading to recurrent infections.

It can stem from decreased production (marrow hypoplasia) or increased destruction (marrow hyperplasia) of neutrophils.

Causes of neutropenia are considered primary or secondary.  

Primary Causes of Neutropenia:

• Genetic disorders such as Kostmann syndrome, characterized by decreased neutrophil production, contribute to primary neutropenia.
• Conditions like chronic granulomatous disease and leukocyte adhesion deficiency exemplify primary neutropenia, affecting immune function and predisposing individuals to severe infections.

Secondary Causes of Neutropenia:

• Infections, medications (e.g., antibiotics, antiepileptics), and autoimmune diseases are common secondary causes of neutropenia.
• Chemotherapy, particularly in cancer treatment, can induce neutropenia, increasing the risk of febrile complications and impacting treatment outcomes.
• Other factors like radiation exposure, myelofibrosis, and prolonged drug exposure can also lead to secondary neutropenia.

Low Neutrophil Counts and Associations with Cancer

Neutropenia, or a decrease in neutrophil levels, can have several causes, including certain cancers. Some types of leukemia and advanced stages of other cancers can lead to low neutrophil counts either due to bone marrow involvement or as a side effect of treatments like chemotherapy. 

Neutropenia in cancer patients is a significant concern, as it increases the risk of infections, potentially complicating treatment and recovery.

Understanding Neutrophils and Lymphocytes

Neutrophils are the most abundant type of white blood cells and are part of the innate immune system. They are among the body's first responders to infection, particularly bacterial infections, and are known for their ability to quickly respond to and neutralize invading pathogens. 

Lymphocytes, in contrast, are pivotal mostly in the adaptive immune response, with roles in fighting viruses, bacteria, and cancer cells, and in maintaining immune memory.

Why Would Neutrophils Be High and Lymphocytes Be Low?

A high neutrophil count coupled with a low lymphocyte count can be indicative of several conditions:  [1.] 

• Acute Bacterial Infections: The body responds to bacterial invasions by increasing the production of neutrophils to fight off the infection, which can simultaneously cause a relative decrease in lymphocytes.
• Acute Stress Response: Stress, whether physical (such as surgery or trauma) or emotional, can lead to a surge in neutrophils as part of the body's immediate stress response. This can also result in a temporary decrease in lymphocyte levels, reflecting a shift in the body's priorities to address the immediate challenge.
• Steroid Use: Corticosteroids, used to treat a variety of conditions, can cause an increase in neutrophils and a decrease in lymphocytes due to their immunosuppressive effects.
• Chronic Inflammatory Conditions: Conditions like rheumatoid arthritis or severe inflammation can lead to elevated neutrophil levels and decreased lymphocytes over time, reflecting the body's ongoing battle with inflammation.

Lab Testing for Neutrophils

The evaluation of lymphocyte levels is a critical component of routine blood work, especially in the assessment of an individual's immune system status and in diagnosing a variety of conditions. 

The primary laboratory test used for this purpose is the Complete Blood Count (CBC) with differential.

A venipuncture is required for this test.  Fasting is not required.

Complete Blood Count (CBC) with Differential

The CBC is one of the most common blood tests and provides comprehensive information about the blood, including red cells, white cells, and platelets. 

When performed with a differential count, the test goes further to quantify the different types of white blood cells including neutrophils, lymphocytes, monocytes, eosinophils, and basophils.

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