Leukocytosis

Introduction

Leukocytosis can be defined as a condition where you have an increased white blood cell (WBC) count in the blood. White blood cells, also known as leukocytes, are a critical part of the body’s immune system and help fight infection and inflammation.

Normally, the white blood cell count falls within a specific range. Leukocytosis is diagnosed when the WBC count goes above the normal range.

Normal White Blood Cell (WBC) Count Ranges

The white blood cell (WBC) count is part of a complete blood count (CBC) test, which measures various components of your blood. A CBC is frequently included in routine checkups to establish a baseline for your blood cell counts and potentially identify any underlying issues early on. Normal white blood cell (WBC) count and differential counts can vary depending on age.

Age Group	Total WBC Count (x 109/L)	Neutrophils (%)	Lymphocytes (%)	Monocytes (%)	Eosinophils (%)	Basophils (%)
Newborn (0-1 day)	9 – 34	30-60	20-60	3-10	1-6	0-2
Infant (1 day – 1 month)	5 – 19	40-70	20-50	3-10	1-6	0-2
Child (1 month – 18 years)	5 – 15	30-55	30-70	2-10	1-6	0-2
Adult (>18 years)	4.5 – 11	40-70	20-40	2-10	1-4	0-2

Significance of Leukocytosis

Leukocytosis, although not a specific diagnosis itself, holds significant importance as a diagnostic tool for several reasons:

Alerts to Potential Problems: An elevated white blood cell count is a red flag that something is going on in the body. It indicates the immune system is activated, potentially fighting off an infection, inflammation, or other underlying issue.

Guides Further Investigation:  The presence of leukocytosis prompts further investigation to determine the cause.  Doctors can consider the patient’s symptoms, medical history, and the specific type of leukocytosis (e.g., neutrophilia, lymphocytosis) to narrow down the possibilities. This can lead to a more efficient and targeted diagnostic approach.

Helps Differentiate Conditions: Leukocytosis patterns can be helpful in differentiating between different conditions.

* For example, a high neutrophil count (neutrophilia) is more suggestive of a bacterial infection, while a high lymphocyte count (lymphocytosis) might point towards a viral infection or an autoimmune disorder.

Monitors Treatment Response:  In some cases, leukocytosis can be used to monitor how well a patient is responding to treatment. For instance, a decrease in white blood cell count after starting antibiotics for an infection might indicate the treatment is working.

Limitations to Consider

• Non-Specific: Leukocytosis can occur in various situations besides infection. Inflammation, tissue injury, and even some medications can cause a high WBC count.
• Variations: The normal white blood cell count can vary slightly depending on age, ethnicity, and even diurnal – it is lower in the morning and increases through the day.
• Severity Doesn’t Correlate: The degree of leukocytosis doesn’t necessarily reflect the severity of the underlying condition. Sometimes, severe infections might not cause a significant increase in WBCs.
• Can be Transient: Leukocytosis can sometimes be transient (short-lived) due to factors like stress, exercise, or certain medications.
• Can be Absent: Not all infections or inflammatory conditions lead to leukocytosis. Some individuals, especially those with compromised immune systems, might not experience a rise in WBC count despite an infection.

Physiological Leukocytosis

Leukocytosis can occur in various patient populations, but reference ranges for what constitutes “elevated” white blood cell (WBC) counts can differ depending on age and specific circumstances. 

Newborns

• Higher Baseline WBC: Newborns naturally have higher baseline WBC counts compared to adults. This is due to their immature immune system and the stress of birth.
• Physiological Leukocytosis: In the first few days of life, newborns often experience a transient “physiological leukocytosis” with WBC counts reaching up to 30 x 10⁹/L. This is normal and doesn’t necessarily indicate an infection.
• Leukocytosis in Newborns: However, a persistently high WBC count (above 30 x 10⁹/L) or a rapid rise in WBC count can be a sign of infection, which needs prompt evaluation by a healthcare professional. The specific type of leukocytosis (neutrophilia, lymphocytosis, etc.) can offer clues about the potential type of infection.

Pregnant Women

• Physiological Leukocytosis: During pregnancy, women experience a physiological leukocytosis with WBC counts reaching up to 18 x 10⁹/L. This is a normal adaptation to support the developing fetus and prepare for childbirth.
• Leukocytosis During Pregnancy: While a mild elevation in WBC count is expected, a significant or persistent increase can indicate an underlying infection, such as a urinary tract infection (UTI) or a vaginal infection. As with newborns, the specific type of leukocytosis can provide additional information.
• Considerations in Interpretation: When interpreting WBC counts in pregnant women, healthcare professionals consider factors like gestational age and potential sources of inflammation, such as labor or delivery.

Physiology of WBC production and function

The production and function of white blood cells (WBCs) involve a complex interplay between different organs and cell types. 

WBC Production (Leukopoiesis)

• Hematopoietic Stem Cells: The journey begins with hematopoietic stem cells residing primarily in the bone marrow. These are immature “master cells” with the potential to self-renew and to differentiate into various blood cell types, including all types of WBCs.
• Differentiation and Maturation: Various factors like cytokines (signaling molecules) and growth factors influence the differentiation of hematopoietic stem cells into the myeloid progenitor and lymphoid progenitor cells. These progenitor cells then mature into different types of WBCs depending on the specific signals they receive. 
• Location of Maturation:
  • Granulocytes (neutrophils, eosinophils, basophils): Mature in the bone marrow.
  • Monocytes: Monocytes mature in the bone marrow, alongside granulocytes. Mature monocytes are released from the bone marrow into the bloodstream. Then they migrate from the bloodstream into tissues throughout the body. Once they enter the tissues, monocytes differentiate further and mature into macrophages.
  • Lymphocytes (B cells, T cells, natural killer cells): While B cells mature primarily in the bone marrow, T cells undergo maturation in the thymus gland, a specialized organ located in the chest. Natural killer cells mature in various tissues throughout the body.
• Release into Circulation: Once mature, WBCs are released from the bone marrow or thymus into the bloodstream, where they circulate and carry out their functions.

WBC Function

There are two main categories of WBCs based on their function:

• Phagocytes: These cells directly engulf and destroy pathogens (disease-causing organisms) like bacteria and fungi. Neutrophils are the most abundant phagocytes, but monocytes and macrophages (mature monocytes that migrate into tissues) also play a role in phagocytosis.
• Immune Cells: These cells are involved in the body’s adaptive immune response, which is a more targeted defense system against specific pathogens.
  • B cells: Produce antibodies, specialized proteins that can bind to specific pathogens and mark them for destruction or neutralize them.
  • T cells: Orchestrate the immune response by coordinating the activity of other immune cells and directly attacking infected cells.
  • Natural killer cells: Destroy virus-infected cells and some cancer cells.

Additional Points

• The lifespan of WBCs varies depending on the type. Neutrophils have a short lifespan, constantly patrolling for pathogens, while memory B cells and T cells can live for years, providing long-term immunity.
• The production of WBCs is a tightly regulated process that responds to the body’s needs. In response to infection or inflammation, the production of specific WBC types can be ramped up to combat the threat.

The Role of the Bone Marrow in Leukocytosis

The bone marrow microenvironment is a complex and fascinating ecosystem that plays a crucial role in leukocytosis by creating the ideal conditions for the production and maturation of white blood cells (WBCs). 

Bone Marrow Microenvironment

Regulation of HSC Function: The microenvironment regulates HSC function through various mechanisms:

• Cytokines: Cytokines like interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and stem cell factor (SCF) stimulate HSC proliferation and differentiation into specific WBC lineages.
• Extracellular Matrix: The extracellular matrix, a network of proteins and sugars, provides structural support and also influences HSC behavior through physical cues and signaling molecules.
• Mesenchymal stem cells: Act as supportive “nurse” cells, providing structural support and secreting factors that influence the survival, proliferation, and differentiation of hematopoietic stem cells into mature WBCs.
• Endothelial cells: Form the lining of blood vessels within the bone marrow, creating a specialized niche for hematopoietic stem cells and allowing mature WBCs to efficiently enter the bloodstream.
• Osteoblasts: Although their primary function is bone formation, they also contribute to leukopoiesis by secreting specific factors that influence the maturation and release of certain WBC types.

Fat Cells (Adipocytes)

The bone marrow naturally contains some fat cells, and the number can increase with age or certain medical conditions. These fat cells play a complex role in leukopoiesis.

• Secreting Signaling Molecules: Fat cells can secrete cytokines that can both stimulate and inhibit leukopoiesis depending on the specific type of cytokine and the overall needs of the body.
• Potential Niche for Specific WBCs: Emerging research suggests that fat cells might create specialized niches within the bone marrow that support the development of specific WBC types, like eosinophils.
• Potential Detrimental Effects: Excessive fat accumulation in the bone marrow (increased adiposity) can disrupt the delicate balance of the microenvironment and potentially hinder leukopoiesis.

Trabecular Bone

The bone marrow is interspersed with a network of bony structures called trabecular bone. This intricate network provides a large surface area for the bone marrow microenvironment to function effectively.

• Osteoblasts on Bone Surfaces: As mentioned earlier, osteoblasts lining the trabecular bone surfaces secrete factors that influence leukopoiesis.
• Physical Support: The trabecular bone provides a physical scaffold that supports the delicate network of blood vessels and other cells within the bone marrow microenvironment.
• Vascular Network: The trabecular bone houses a rich network of blood vessels that are essential for delivering nutrients and oxygen to the bone marrow and for the release of mature WBCs into circulation.

The Role of Bone Marrow in Leukocytosis

The bone marrow has a finely tuned regulatory system that controls the production of different WBC types. In leukocytosis, this system is upregulated to generate more of the specific WBCs needed to address the underlying condition.

• Increased Production in Response to Signals: During leukocytosis, the body needs more WBCs to combat infection, inflammation, or other stressors. The bone marrow responds to various signals, such as cytokines released by immune cells, to increase the production of specific WBC types.
  • Infection: In response to bacteria, the bone marrow ramps up production of neutrophils, the most abundant phagocytic WBCs that engulf and destroy bacteria.
  • Viral Infection: During a viral infection, the bone marrow might ramp up B and T lymphocyte production, crucial for the adaptive immune response against viruses.
• The bone marrow can also store mature WBCs to be readily released into circulation when needed, allowing for a quicker response during leukocytosis.
• In severe leukocytosis, the bone marrow might release immature WBCs into the bloodstream, sometimes observed in blood tests and providing diagnostic clues.
• While the bone marrow is the primary site for WBC production, the spleen can also play a supplementary role in some situations.

The Role of Cytokines in Leukocytosis

Cytokines are like the chemical messengers within the bone marrow microenvironment, playing a central role in orchestrating leukocyte production during leukocytosis. 

• Stimulating HSC Proliferation: Certain cytokines, like granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), stimulate the proliferation of HSCs. This increases the pool of precursor cells available for WBC development.
• Directing Differentiation: Other cytokines, such as interleukin-3 (IL-3) and stem cell factor (SCF), influence the differentiation of HSCs and progenitor cells towards specific WBC lineages (e.g., neutrophils, lymphocytes) depending on the body’s needs.
• Maturation and Release: Additional cytokines, like IL-6 and IL-1, support the maturation of WBCs and their subsequent release from the bone marrow into the bloodstream.
• Regulating Production:  Cytokines also play a crucial role in regulating leukocyte production during leukocytosis:
  • Increased Production During Infection: During an infection, immune cells release cytokines like IL-1 and tumor necrosis factor-alpha (TNF-α). These cytokines stimulate the bone marrow to ramp up production of neutrophils, the type of WBCs that engulf and destroy bacteria.
  • Decreased Production in Certain Cases: In some situations, specific cytokines might suppress the production of certain WBC types while promoting others, depending on the specific needs of the immune response.

Types of Leukocytosis

Leukocytosis can be classified based on two main factors:

Predominant Cell Type

This classification focuses on the specific type of white blood cell that is predominantly elevated in the blood count.

• Neutrophilia: An increased number of neutrophils, the most common type of WBC. This often suggests a bacterial infection.
• Lymphocytosis: An elevated level of lymphocytes, which are involved in the immune response against viruses and other pathogens. This can be seen in viral infections, autoimmune diseases, or certain cancers.
• Monocytosis: An increase in monocytes, which are phagocytic WBCs and can indicate chronic infections, inflammatory conditions, or some cancers.
• Eosinophilia: An elevated number of eosinophils, which are involved in allergic reactions and parasite infections.
• Basophilia: The least common type of leukocytosis, characterized by an increase in basophils. This can be associated with allergic reactions, certain infections, or some bone marrow disorders.

Cell Maturity

This classification looks at the maturity of the white blood cells present in the blood.

• Shift to the Left (Leukocyte Left Shift): This indicates the presence of immature white blood cells (blasts and precursors) in the bloodstream. This can occur when the bone marrow is under stress and needs to rapidly increase WBC production, often seen in severe infections or chronic leukemia.
• Shift to the Right: A less common finding, a shift to the right indicates an increased number of mature white blood cells compared to immature ones. This is not typically associated with leukocytosis and might be seen in some vitamin B12 deficiencies.

Signs and Symptoms

Leukocytosis itself is often asymptomatic. However, the underlying cause of leukocytosis can manifest through various signs and symptoms. 

General Symptoms

• Fever: An elevated body temperature is a common indicator of the body’s inflammatory response, potentially associated with infection.
• Fatigue: Increased metabolic demands during leukocytosis and the underlying condition can lead to tiredness and weakness.
• Malaise: A general feeling of discomfort, illness, or uneasiness can accompany leukocytosis.

Symptoms Depending on the Cause

• Infection:
  • Localized pain, swelling, or redness at the infection site (e.g., sore throat with tonsillitis, urinary urgency with UTI).
  • Cough, shortness of breath (respiratory infection).
  • Diarrhea, nausea, vomiting (gastrointestinal infection).
• Inflammation:
  • Joint pain, swelling, and stiffness (rheumatoid arthritis).
  • Skin rash (inflammatory skin conditions).
• Autoimmune Diseases:
  • Fatigue, weight loss, widespread pain (lupus).
• Cancer:
  • Unexplained weight loss, night sweats, easy bleeding or bruising (depending on the specific cancer).

Physical Examination Findings

• Lymphadenopathy: Enlarged lymph nodes, which are part of the immune system and can become palpable during leukocytosis, especially when infection is the cause.
• Splenomegaly: An enlarged spleen, another immune organ, can sometimes be felt on physical examination in some cases of leukocytosis.

Approach to Leukocytosis

Points to consider when evaluating a patient with leukocytosis.

• Detailed History: A thorough history, including current symptoms, past medical history, medications, recent exposures (infectious agents, allergens), and social habits, is crucial.
• Physical Examination: A comprehensive physical exam can reveal signs suggestive of the underlying cause, such as fever, lymphadenopathy (swollen lymph nodes), rash, or organ-specific findings.
• Correlation with WBC Count and Type: The specific type of leukocytosis (neutrophilia, lymphocytosis, etc.) can offer clues about the potential cause. For example, neutrophilia is more suggestive of a bacterial infection, while lymphocytosis might point towards a viral infection.
• Other Laboratory Tests: Additional tests like blood cultures, urinalysis, chest X-ray, or other investigations might be necessary depending on the suspected cause.

Additional Considerations

• Shift to the Left: The presence of immature WBCs in the peripheral blood smear (shift to the left) can indicate a more severe infection and the body’s rapid attempt to produce more WBCs.
• Specific Leukocytosis Types: The type of leukocytosis (neutrophilia, lymphocytosis, etc.) can offer clues about the underlying cause.

Complications of Leukocytosis

Leukocytosis itself isn’t necessarily a disease, but rather an indicator of an underlying condition. However, depending on the severity and type of leukocytosis, there can be potential complications. 

Vascular Occlusion

• Hyperleukocytosis: Extremely high WBC counts (>100 x 10⁹/L) can lead to a condition called hyperleukocytosis.
• Increased Blood Viscosity: In hyperleukocytosis, the massive number of WBCs can thicken the blood, increasing its viscosity. This can impair blood flow and potentially lead to:
  • Ischemic Organ Damage: Reduced blood flow to organs like the brain, lungs, kidneys, or heart can cause tissue damage and organ dysfunction.
  • Stroke: If blood flow to the brain is compromised, a stroke can occur.
  • Pulmonary Edema (Fluid in the Lungs): In severe cases, impaired blood flow to the lungs can lead to fluid buildup.

Disseminated Intravascular Coagulopathy (DIC)

• This is a serious condition where abnormal blood clotting occurs throughout the bloodstream.
• Certain types of leukocytosis, particularly those associated with some cancers, can increase the risk of DIC.
• DIC can lead to:
  • Bleeding complications
  • Blockage of blood vessels by clots

Tumor Lysis Syndrome (TLS)

• In certain cancers, particularly leukemias, aggressive treatment can lead to the rapid death of a large number of cancer cells.
• The breakdown products can overwhelm the body’s ability to handle them, leading to:
  • Electrolyte imbalances (e.g., high potassium, low calcium)
  • Kidney failure
  • Heart rhythm disturbances

Increased Risk of Infection (Paradoxical)

• While leukocytosis indicates the body’s attempt to fight infection, very high WBC counts can sometimes impair the function of certain white blood cells, making the body paradoxically more susceptible to opportunistic infections.

Organ Infiltration

• In some cases of leukemias, the abnormal white blood cells can infiltrate organs like the liver, spleen, and lymph nodes, causing:
  • Enlargement of these organs
  • Disruption of their normal function

Laboratory Investigations for Leukocytosis

Leukocytosis is often identified through a complete blood count (CBC). However, a thorough evaluation often requires additional laboratory investigations to pinpoint the underlying cause. 

Complete Blood Count (CBC) with Differential

This is the cornerstone of diagnosing leukocytosis.

• WBC Count: It measures the total number of WBCs per liter (L) of blood.
• Differential: This provides a breakdown of the different types of WBCs (neutrophils, lymphocytes, monocytes, eosinophils, basophils) as percentages or absolute numbers.
• Interpretation: The specific type of leukocytosis (neutrophilia, lymphocytosis, etc.) offers valuable clues about the potential cause.

Peripheral Blood Smear

A blood smear allows for visualization of individual blood cells under a microscope.

• Shift to the Left: The presence of immature WBCs (blasts and precursors) can indicate a more severe infection and the body’s rapid attempt to produce more WBCs.
• Abnormal Cell Morphology: Certain abnormalities in the appearance of WBCs can suggest specific causes, such as leukemia.

Additional Tests Based on Suspected Cause

• Blood Cultures: If infection is suspected, blood cultures are crucial to identify the specific causative organism.
• Urinalysis and Urine Culture: These tests can help diagnose urinary tract infections (UTIs), a common cause of leukocytosis.
• Chest X-Ray: Useful for evaluating potential lung infections like pneumonia, which can cause neutrophilia.
• Sputum Culture: If a respiratory infection is suspected, a sputum culture can help identify the causative organism.
• Viral Serology: Blood tests can be performed to detect specific viruses that can cause lymphocytosis.
• Bone Marrow Aspiration and Biopsy: In some cases, particularly when there’s suspicion of a bone marrow disorder or certain cancers, a bone marrow examination might be necessary.
• Autoimmune Disease Workup: If an autoimmune condition is suspected as the cause of leukocytosis, specific autoantibody tests might be ordered.
• Imaging Studies: Depending on the suspected cause, imaging studies like X-rays, CT scans, or MRIs might be used to visualize potential sources of infection or inflammation.
• Other Tests: Depending on the clinical scenario, additional tests like coagulation studies or electrolyte panels might be necessary.

Choosing the Right Tests

The specific laboratory investigations will be guided by the patient’s clinical presentation, medical history, and the type of leukocytosis identified on the CBC. A targeted approach is crucial to ensure a cost-effective and efficient evaluation.

Differential Diagnosis of Leukocytosis

Category	Examples
Infection	Bacterial infections (pneumonia, urinary tract infection)  Viral infections (mononucleosis, cytomegalovirus)  Parasitic infections (malaria) F ungal infections (aspergillosis)
Inflammation	Inflammatory bowel disease (IBD)  Rheumatoid arthritis  Systemic lupus erythematosus (SLE)  Vasculitis
Autoimmune Diseases	Rheumatoid arthritis  Systemic lupus erythematosus (SLE)  Inflammatory bowel disease (IBD)  Psoriasis
Tissue Injury	Burns  Trauma  Surgery
Neoplasms (Cancers)	Leukemias (acute and chronic)  Lymphomas  Multiple myeloma  Solid tumors (in some cases)
Allergic Reactions	Drug allergies  Food allergies  Insect bites and stings  Anaphylaxis
Stress Response	Major surgery  Burns  Severe emotional stress
Other Causes	Splenomegaly (enlarged spleen)  Dehydration  Smoking

Treatment and Management

Leukocytosis generally is a sign of the body fighting an infection or inflammation and does not require specific treatment. Doctors typically focus on addressing the underlying cause of the high white blood cell count.

• Targeting the Root Cause:  This is the main approach. If it’s an infection, antibiotics for bacteria, antifungals for fungus, or antivirals for viruses might be prescribed. For allergies, antihistamines could be helpful. In cases of inflammatory diseases, steroids or other anti-inflammatory drugs might be used.
• Management for Specific Conditions:  Leukemia or other blood cancers would require specialized treatment plans like chemotherapy or radiation therapy.
• Addressing Hyperleukocytosis Syndrome: In rare instances of extremely high white blood cell counts, interventions like leukapheresis (filtering white blood cells from blood) along with hydration and medication to manage uric acid levels might be necessary. 
• Symptom Relief: Medications to manage fever, pain, or inflammation caused by the underlying condition might be prescribed.

Key Points of Leukocytosis

Definition

• Increase in white blood cell (WBC) count above the reference range.

Significance

• Not a disease itself, but a marker of underlying infection, inflammation, or blood cancers.

Diagnosis

• Requires a thorough history, physical exam, and complete blood count (CBC) with differential to identify the specific type of WBC elevated and potential causes.

Management

• Focuses on treating the underlying cause:
  • Infections: Antibiotics, antifungals, or antivirals.
  • Inflammation: Corticosteroids or immunosuppressants.
  • Blood Cancers: Chemotherapy, radiation, or bone marrow transplant.
• Hyperleukocytosis Syndrome (HLS): Rare complication in some leukemias with extremely high WBC counts (>100,000/μL).
  • Management involves:
    • Hydration and urine alkalinization.
    • Allopurinol or Rasburicase for uric acid control.
    • Leukapheresis to remove excess WBCs (cautiously to avoid TLS).
    • Hemodialysis in severe cases.

Frequently Asked Questions (FAQs)

How long does it take for WBC to return to normal?

The time it takes for your WBC to return to normal after leukocytosis depends on the underlying cause:

• Infections: For common bacterial infections, WBC count usually normalizes within 5 to 25 days after starting antibiotics and as the infection resolves.
• Viral infections: WBC can take longer to return to normal after viral illnesses, sometimes up to several weeks.
• Inflammation: If caused by an inflammatory condition, WBC will normalize as the inflammation is controlled with medication.
• Blood Cancers: In blood cancers, the timeframe for WBC normalization depends on the type and severity of the cancer and the treatment plan.

Why does leukocytosis occur after splenectomy?

Leukocytosis after a splenectomy is a well-documented phenomenon and is generally considered physiologic (normal response) rather than a sign of infection. 

The Spleen’s Role

• The spleen is a vital organ in the lymphatic system that acts as a filter for blood.
• It removes old or damaged blood cells, including some white blood cells.
• It also serves as a reservoir for white blood cells, storing them until they’re needed to fight infection.

Splenectomy and White Blood Cells

• After a splenectomy, this storage pool for white blood cells is removed. The body compensates by increasing production of white blood cells in the bone marrow to maintain adequate levels in circulation.
• This leads to a temporary elevation in circulating white blood cells, a condition known as post-splenectomy leukocytosis.

Types of Leukocytosis after Splenectomy

• Early: Immediately after surgery, there’s a transient rise in neutrophils (a type of white blood cell). This usually peaks within a day or two and gradually returns to near normal within a week.
• Long-term: A mild to moderate elevation in white blood cells, including lymphocytes and monocytes (other types of white blood cells), can persist for months or even years after a splenectomy. This is considered a normal physiological response.

Disclaimer: This article is intended for informational purposes only and is specifically targeted towards medical students. It is not intended to be a substitute for informed professional medical advice, diagnosis, or treatment. While the information presented here is derived from credible medical sources and is believed to be accurate and up-to-date, it is not guaranteed to be complete or error-free. See additional information.

References 

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