Neutrophilic Leukocytosis - A Double-Edged Sword in the Human Immune System

Introduction

Leukocytes are white blood cells (WBCs) that are produced from bone marrow, and play a prime role in the immune mechanism of the body. Leukocytes consist of heterogeneous types of cells namely neutrophils, eosinophils, basophils, monocytes, and lymphocytes. Neutrophils are a subdivision of white blood cells that form the first line of defense against infectious agents. They are the first immune cells to get activated when a bacteria or virus enters the body. Neutrophils also enhance the immune response of other types of leukocytes.

An increase in the number of white blood cells, in general, is termed leukocytosis. Neutrophilia refers to increased neutrophil count above normal levels. Usually, neutrophilia is seen in infections, inflammations, and other conditions. These elevated levels recede when the underlying disorders are corrected. However, persistent higher levels of neutrophils or leukocytes are indicative of clinical disease pathologies and require prompt intervention to reduce further complications.

What Is Neutrophilic Leukocytosis?

Neutrophilic leukocytosis is the increase in the number of neutrophils in the circulating blood. Leukocytosis with an increase in neutrophils is a characteristic feature of several infectious and inflammatory disorders. Neutrophils travel to infection or inflammatory sites, ingest microorganisms or foreign substances and destroy them by releasing enzymes that cause oxidative stresses in the engulfed substances. Neutrophilic leukocytosis is classified into the following types -

• Physiological Neutrophilic Leukocytosis - occurs during normal physiological processes such as physical activity, pregnancy, etc.

• Primary Neutrophilic Leukocytosis - increased production of neutrophils from bone marrow due to the abnormality in the regulation of neutrophil synthesis.

• Secondary Neutrophilic Leukocytosis - the most common type that occurs as an immune response to specific stimuli, also known as reactive neutrophilic leukocytosis.

What Are the Causes of Neutrophilic Leukocytosis?

Neutrophils increase in response to diverse conditions and disorders. Some of the predominant causes of neutrophilic leukocytosis are as follows -

• Bacterial infections (pneumococci, clostridium species, tuberculosis).

• Viral infections.

• Severe physical activity or stress.

• Emotional stress.

• Burns.

• Pregnancy.

• Obesity.

• Trauma.

• Urinary tract infections.

• vasculitis.

• Meningitis.

• Pneumonia.

• Cerebral vascular accidents.

• Infectious mononucleosis is caused by the Epstein-Barr virus (EBV)

• Inflammatory conditions like autoimmune disorders.

• Rheumatoid arthritis.

• Drug-induced (corticosteroids, Heparin, Lithium carbonate, catecholamines).

• Myelocytic leukemias.

• Nonhematological neoplasms(solid tumor malignancies).

• Excessive smoking.

• Allergic reactions to medications.

• Post-splenectomy.

• Bone marrow stimulation in cases like hemolytic anemia or idiopathic thrombocytopenic purpura.

• Leukocyte adhesion deficiency (hereditary neutrophilic leukocytosis).

• Chronic Idiopathic Neutrophilia.

• Down syndrome.

• Familial Cold Urticaria.

• Chronic Myelogenous Leukemia and Other Myeloproliferative Neoplasms.

• Heat strokes.

What Are the Clinical Manifestations of Neutrophilic Leukocytosis?

• Episodic fevers.

• Conjunctivitis.

• Tenderness in muscle and skin when exposed to cold.

• Rashes and urticaria.

• Splenomegaly.

• lymphadenopathy.

• Periodontitis.

• Recurrent skin infections.

• Mucosal infections with the absence of pus formation.

• Poor or delayed wound healing.

• Delay in umbilical cord separation.

• Hyperviscosity of blood is usually seen in leukemic patients.

• Thrombotic events due to hyperviscosity of the blood.

What Are the Complications of Neutrophilic Leukocytosis?

• Hypercoagulability due to leukemoid reactions.

• Bacteremia in case of uncontrolled infections.

• Septic shock due to bacterial endotoxins.

• Multiorgan failure.

• Impaired wound healing.

• Severe periodontal infections.

• Severe mental disturbances in hereditary neutrophilic leukocytosis.

• Thrombosis.

• Hemorrhage.

• Transformation to malignancies (acute leukemia).

• Fibrosis.

What Are the Laboratory Investigations for Neutrophilic Leukocytosis?

Neutrophilic leukocytosis is a clinical phenomenon that arises due to multiple factors and requires a comprehensive diagnostic approach to identify the underlying disease pathogenesis. A thorough clinical examination with laboratory screening tests aids in the accurate interpretation of neutrophilic leukocytosis.

• Complete blood count (CBC) is used to detect an elevated number of white blood cells ( WBC count more than 100 x 10^9/mL).

• Peripheral blood smear helps in identifying more neutrophils in the blood films under light microscopy.

• Evaluation for neutrophilia is reviewed for CBC with differential (fractions of white blood cells).

• An increased number of neutrophils is confirmed by automated differential and manual examination of peripheral blood smears.

• Analyzing peripheral blood smears also helps in identifying the causes of neutrophilic leukocytosis.

Specific Laboratory Studies

Specific laboratory studies distinguish between various types of neutrophilic leukocytosis. Some of these tests are -

• Estimation of inflammatory markers (ESR, CRP, LDH, ferritin).

• Liver function tests.

• Renal function tests.

• Coagulation profile (APTT, PT, fibrinogen, D dimer) to differentiate from idiopathic thrombocytopenic purpura.

• Histopathological studies of body fluids to detect infections (blood culture, sputum culture, urine culture, wound culture, stool culture, and cerebrospinal fluid analysis).

• Testing for bacterial toxins (Clostridium species).

Tests to Differentiate Malignant Causes

Confirmatory tests such as bone marrow biopsy, genetic (molecular) testing, and flow cytometry help in the diagnosis of neutrophilic leukocytosis after assessing the CBC and peripheral smear results.

• Bone marrow biopsy differentiates hematological causes from non-hematological malignancies that invade the bone marrow.

• Morphological analysis under electron microscopy detects malignant changes.

• Flow cytometry detects various types of myeloblastic neutrophilia like chronic myeloid leukemia.

• Molecular testing is used to diagnose hereditary neutrophilic leukocytosis.

• Immunophenotyping of peripheral blood identifies essential thrombocythemia (ET) and polycythemia vera (PV).

Imaging Techniques

Appropriate imaging studies correlated with laboratory findings help in the confirmatory diagnosis of the causes that result in neutrophilic leukocytosis.

• Computed tomography (CT) of the head, neck, abdomen, chest, and pelvis to detect lymphadenopathy or lymph node enlargement.

• Magnetic resonance imaging if CT reports are inconclusive.

• Positron emission test (PET) scan.

• Chest radiography.

• Diagnostic ultrasonography.

How Is Neutrophilic Leukocytosis Treated?

There is no specific treatment for neutrophilic leukocytosis. Treating the underlying cause eventually reduces neutrophil levels. However, symptomatic treatment interventions are recommended in severe conditions.

• In the case of leukemoid reaction WBC count is more than 50,000) leukapheresis (removal of leukocytes) is conducted.

• Massive hydration is administered.

• Cytotoxic therapy with hydroxyurea is administered to prevent complications related to hypercoagulability.

• Anti-inflammatory agents and antibiotic regimes are recommended for inflammations and infections associated with neutrophilic leukocytosis.

• In the case of drug-induced neutrophilic leukocytosis, the dosage of medications is strictly monitored and is temporarily discontinued till normalcy is achieved.

• Cytoreductive drugs such as hydroxyurea are administered to reduce neutrophil levels and are frequently monitored with CBC.

• Specific anti-leukemic therapies are recommended in case of chronic myeloid leukemia.

• Allogeneic hematopoietic stem cell transplant (HCT) is recommended for primary neutrophilic leukocytosis.

Conclusion

Generally, neutrophilic leukocytosis occurs as a transient reaction in infections and inflammatory conditions. It is resolved effectively with the treatment of the underlying causes. The prognosis of neutrophilic leukocytosis improves with accurate diagnosis and treatment interventions of the related clinical conditions.