Leukocytosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2] Lakshmi Gopalakrishnan, M.B.B.S. [3]

Synonyms and keywords: Elevated white blood cell count; Right-shift leukocytosis; Left-leukocytosis

Overview

Leukocytosis is an elevation of the white blood cell count above the normal range (greater than 11,000 per mm3). Leukocytosis is frequently a sign of an inflammatory response, most commonly the result of infection, but may also occur following certain parasitic infections, bone tumors, strenuous exercise, emotional stress, pregnancy, anesthesia, and epinephrine administration. Leukocytosis may be classified into 5 subtypes: neutrophilia (most common), lymphocytosis, monocytosis, eosinophilia, and basophilia. Other classification, include: Left shift or right shift leucocytosis. The pathogenesis of leukocytosis is characterized by the increase of leukocytes (primarily neutrophils), followed by the proliferation and release of granulocyte and monocyte precursors in the bone marrow which is stimulated by several products of inflammation including C3a and G-CSF.

Historical Perspective

• Leukocytosis was first discovered by Paul Kautchakoff, in 1846.

Classification

• Leukocytosis may be classified into 5 subtypes:

• Neutrophilia (most common)
• Lymphocytosis
• Monocytosis
• Eosinophilia
• Basophilia.

• Leukocytosis may also be classified into 2 groups:

• Left shift (most common)

• Immature leukocytes increase
• Proliferation and release of granulocyte and monocyte precursors in the bone marrow
• Usually stimulated by several products of inflammation including C3a and G-CSF

• Right shift

• Reduced count or lack of "young neutrophils"
• Associated with the presence of "giant neutrophils

• Other variant of leukocytosis is the leukemoid reaction.
• The image below demonstrates a graphic figure that illustrates hematopoietic growth factors in leukocytosis.

• 
  Hematopoietic growth factors in leukocytosis
  Courtesy of Wikipedia

Pathophysiology

• The pathogenesis of leukocytosis is characterized by:

• An increased release of leukocytes from bone marrow storage pools
• Decreased margination of leukocytes onto vessel walls
• Decreased extravasation of leukocytes from the vessels into tissues
• Increase in number of precursor cells in the marrow

Causes

• To see a comprehensive list of all causes of leukocytosis, please click here

Causes of leukocytosis
Neutrophilic leukocytosis (neutrophilia)	Acute bacterial infections, especially pyogenic infections Sterile inflammation Tissue necrosis Myocardial infarction Burns
Eosinophilic leukocytosis (eosinophilia)	Allergic disorders Asthma Hay fever Drug allergies Allergic skin diseases Pemphigus Dermatitis herpetiformis Parasitic infections Some forms of malignancy Hodgkin's lymphoma Some forms of Non-Hodgkin lymphoma Systemic autoimmune diseases (e.g. SLE) Some forms of vasculitis Cholesterol embolism (transiently)
Basophilic leukocytosis Basophilia	Myeloproliferative disease, e.g. Chronic myelogenous leukemia
Monocytosis	Chronic infections Tuberculosis Bacterial endocarditis Rickettsiosis Malaria Systemic autoimmune diseases, e.g. SLE Inflammatory bowel diseases, e.g. ulcerative colitis
Lymphocytosis	Chronic infections Tuberculosis Brucellosis Viral infections Hepatitis Cytomegalovirus infection Infectious mononucleosis Pertussis Some forms of malignancy, such as lymphocytic leukæmias

Epidemiology and Demographics

• Leukocytosis is very common.

Age

• Patients of all age groups may develop leukocytosis.
• Normal white blood count differential changes with age.
• Leukocytosis in neonates is more common, compared to children and adults.

Gender

• Leukocytosis affects men and women equally.

Race

• There is no racial predilection for leukocytosis.

Risk Factors

• Common risk factors in the development of leukocytosis, include:

• Physiologic processes (eg, stress, exercise, pregnancy)
• Drugs (e.g.corticosteroids, lithium, beta agonists)
• Trauma
• Stress

Natural History, Complications and Prognosis

• The majority of patients with leukocytosis are initially symptomatic.
• Early clinical features, include:

• Fever
• Hyperhidrosis
• Fatigue

• Common complications of leukocytosis, include:

• Tumor lysis syndrome
• Disseminated intravascular coagulopathy
• Acute respiratory failure
• Pulmonary hemorrhage
• CNS infarction
• Splenic infarction
• Myocardial ischemia
• Renal failure

• Prognosis is generally depends on the underlying etiologies.

Diagnosis

Symptoms

• Leukocytosis is usually symptomatic.
• Symptoms of leukocytosis are often unspecific, such as:

• Weight loss
• Fevers of unknown origin
• Hyperhidrosis
• Chronic pain
• Fatigue
• Dyspnea
• Malaise

• Obtain history of the following:

• Clinical features
• Duration (e.g. days, weeks, months)
• Remainder of complete blood count

Laboratory Findings

• Laboratory findings consistent with the diagnosis of leukocytosis, include:

• White blood cell count above the normal range

• Greater than 11,000 per mm3

Differentiating Leukocytosis from Other Diseases

Category	Condition	Etiology	Mechanism				Congenital	Acquried	Clinical manifestations											Para−clinical findings								Gold standard	Associated findings
									Demography	History	Symptoms			Signs
																				Lab Findings
			Physiologic	Increased bone marrow production		Demargination of peripheral blood neutrophils					Appearance	Fever	Abdominal pain	BP	Asplenia	Hepatosplenomegaly	Lymphadenopathy	Joint redness	Other	CBC			PBS	Bone marrow exam	ESR/CRP	BUN/Cr	LFT
				Autonomous	Reactive															WBC	HB	Plt
Hematologic	Hereditary neutrophilia	Unknown Germline mutation in CSF3R	−	+	−	−	+	−	Rare autosomal dominant genetic disorder	Positive family history	Normal	−	−	Nl	−	+	−	−	−	↑	Nl	Nl	Normal granulocytes Histiocytes of Gaucher type	Nl	Nl	Nl	Nl	Molecular testing	High leukocyte alkaline phosphatase Progress to leukemia
	Myeloproliferative neoplasms	Unknown Mutation	−	+	−	−	+	+	Elderly	Exposure to Chemotherapy Radiation therapy Tobacco smoke	Petechiae Purpura Diffuse erythematous rash	±	+	Nl	−	+	−	−	Shortness of breath Fatigue	↑/↓	↓	↑/↓	Large platelets Ovalomacrocytosis Basophilic stippling Howell-Jolly body Pelger-Huet anomaly Ring sideroblasts	Impaired myeloid maturation Dyserythropoiesis Dysgranulopoiesis Dysmegakaryocytopoiesis Hypercellular bone marrow Fibrosis	↑	Nl	Nl	Bone marrow examination + clinical manifestation	Thrombosis at unusual sites Thrombosis in younger patients Might transformed to acute leukemia
	Polycythemia vera	Autonomous erythrocyte production JAK2 mutation (> 95%)	−	+	−	−	+	−	Mean age >60 years old	Stroke Visual disturbance	Facial plethora	−	−	↑	−	+	+	−	Painful erythema	Nl to ↑	↑	↑	Elevated normochromic, normocytic RBCs Thrombocytosis ≥ 10% immature myeloid precursors Leukoerythroblastic picture	Increased myeloid:erythroid ratio due to granulocytic proliferation	Nl	Nl	Nl	Bone marrow examination + clinical manifestation	Stroke Venous thrombosis Myelofibrosis Acute leukemia
	Microangiopathic hemolytic anemia (MAHA)	Microangiopathy Leukemoid reaction	−	+	−	−	+	+	Any	Bleeding disorder Positive family history	Pallor	+	+	↓	−	+	−	−	Shortness of breath Fatigue	↑	↓	↑	Fragmented RBCs Schistocytes		↑	↑	↑		Non-immune hemolysis Elevated LDH Elevated alkaline phosphatase Negative direct Coomb's test Thrombosis
	Leukoerythroblastosis	Space-occupying lesions in the bone marrow Infection	-	+	-	-	-	+	Any	Bleeding disorder	Pallor	−	+	Nl	−	+	−	−	Early satiety Fatigue	↑	↓	↓	Nucleated red cells Reticulocytosis Poikilocytes Circulating immature white cells, generally myelocytes and promyelocytes	Circulating immature white cells, generally myelocytes and promyelocytes Myelofibrosis	↑	Nl	↑	Bone marrow biopsy	Marrow infiltrative disorders Trauma Septicemia Massive hemolysis Megaloblastic anemia extramedullary hematopoiesis.
Immunology/ Rheumatology	Condition	Etiology	Physiologic	Autonomous increased bone marrow production	Reactive increased bone marrow production	Demargination of peripheral blood neutrophils	Congenital	Acquried	Demography	History	Appearance	Fever	Abdominal pain	BP	Asplenia	Hepatosplenomegaly	Lymphadenopathy	Joint redness	Other signs	WBC	HB	Plt	PBS	Bone marrow exam	ESR/CRP	BUN/Cr	LFT	Gold standard	Associated findings
	Leukocyte adhesion deficiency	Primary immunodeficiency Failure to express CD18	-	+	-	-	+	-	Rare autosomal recessive, LAD II more in Middle East and Brazil	Positive family history	Characteristic facial appearance, short stature, limb malformations, and severe developmental delay in LAD II	+	-	Nl	-	-	-	-	Signs of different infections	↑	↓	↓/↑	Leukocytosis	Leukocytosis	Nl	Nl	Nl	Flow cytometry	Recurrent bacterial infections Delay in umbilical cord sloughing Inability to form abscesses
	Cryopyrin-associated periodic syndromes
	Rheumatoid arthritis
	Juvenile onset rheumatoid arthritis
	Adult Still's disease
	Kawasaki disease
	IBD
	Sarcoidosis
	Chronic hepatitis
	Sweet syndrome
	Acute gout
Infection	Condition	Etiology	Physiologic	Autonomous increased bone marrow production	Reactive increased bone marrow production	Demargination of peripheral blood neutrophils	Congenital	Acquried	Demography	History	Appearance	Fever	Abdominal pain	BP	Asplenia	Hepatosplenomegaly	Lymphadenopathy	Joint redness	Other signs	WBC	HB	Plt	PBS	Bone marrow exam	ESR/CRP	BUN/Cr	LFT	Gold standard	Associated findings
	Acute bacterial																						toxic granulations, Döhle bodies, and cytoplasmic vacuoles in neutrophils
	Chronic infection
	Viral infection
	Granulomatous infections
	Bronchiectasis
Metabolic	Diabetic coma
	Acidosis
	Thyroid storm
	Hypercortisolism
	Seizures
Medication	Condition	Etiology	Physiologic	Autonomous increased bone marrow production	Reactive increased bone marrow production	Demargination of peripheral blood neutrophils	Congenital	Acquried	Demography	History	Appearance	Fever	Abdominal pain	BP	Asplenia	Hepatosplenomegaly	Lymphadenopathy	Joint redness	Other signs	WBC	HB	Plt	PBS	Bone marrow exam	ESR/CRP	BUN/Cr	LFT	Gold standard	Associated findings
	Steriod	Release of granulocytes from the bone marrow
	Myeloid growth factors
	Lithium
	Cytokines
	Catecholamines (epinephrine)	Stimulation of bone marrow myelopoiesis Egress into the circulation
	ATRA
Other	Condition	Etiology	Physiologic	Autonomous increased bone marrow production	Reactive increased bone marrow production	Demargination of peripheral blood neutrophils	Congenital	Acquried	Demography	History	Appearance	Fever	Abdominal pain	BP	Asplenia	Hepatosplenomegaly	Lymphadenopathy	Joint redness	Other signs	WBC	HB	Plt	PBS	Bone marrow exam	ESR/CRP	BUN/Cr	LFT	Gold standard	Associated findings
	Allergy
	Post splenectomy
	Down syndrome
	Cigarette smoking
	Stress/exercise
	Infancy
	Pregnancy
	Platelet clumping	Spurious
	Mixed cryoglobulinemia	Spurious
Category	Condition	Etiology	Physiologic	Autonomous increased bone marrow production	Reactive increased bone marrow production	Demargination of peripheral blood neutrophils	Congenital	Acquried	Demography	History	Appearance	Fever	Abdominal pain	BP	Asplenia	Hepatosplenomegaly	Lymphadenopathy	Joint redness	Other signs	WBC	HB	Plt	PBS	Bone marrow exam	ESR/CRP	BUN/Cr	LFT	Gold standard	Associated findings

Treatment

Medical Therapy

• The treatment for leukocytosis will depend on the underlying condition.

References

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