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]; Grammar Reviewer: Natalie Harpenau, B.S.[4]

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

Overview

Leukocytosis is the 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 sub-types: neutrophilia (most common), lymphocytosis, monocytosis, eosinophilia, and basophilia. Other classifications include: Left shift or right shift leukocytosis. 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 then 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 sub-types:

• 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"

• Another 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 bone 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 auto-immune 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, in comparison 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:

• Physiological processes (e.g. 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 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 that are consistent with the diagnosis of leukocytosis involve the White blood cell count being above the normal range (greater than 11,000 per mm3).

Differentiating Leukocytosis from Other Diseases

Differential diagnosis methods of leukocytosis:

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 involvement	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	NA	↑	↑	↑	Bone marrow examination + clinical manifestation	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 involvement	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	Unknown Mutation	−	+	−	−	+	−	Autosomal dominant autoinflammatory syndrome	Positive family history	Hive-like rash without itching	+	−	Nl	−	−	−	+	Red eyes Vomiting Headache	↑	↓	↓/↑	Leukocytosis	Leukocytosis	↑	Nl	↑	Genetic tests	Blindness Hearing loss
	Rheumatoid arthritis	Immune-mediated	−	+	−	−	−	+	Any, more in young women, between 30-60 years old	Positive family history Cigarette smoking Obesity	Deformed joints Rheumatoid nodules	+	−	Nl	−	−	−	+	Weight loss Fatigue Dry eyes and mouth	↑	↓	↑	Leukocytosis	NA	↑	Nl	Nl	Clinical manifestation + positive anti-CCP antibodies	Osteoporosis Infections Carpal tunnel syndrome Multi-organ involvement Lymphoma
	Juvenile onset rheumatoid arthritis	Immune-mediated	−	+	−	−	−	+	Children under the age of 16	Positive family history	Blotchy rash on a child's arms and legs	+	−	Nl	−	−	+	+	Fatigue Dry eyes and mouth	↑	↓	↑	Leukocytosis	NA	↑	Nl	Nl	Clinical manifestation + laboratory findings	Uveitis Infections Multi-organ involvement
	Adult Still's disease	Immune-mediated	−	+	−	−	−	+	Rare autoimmune disease	NA	Nonpruritic salmon-colored rash (usually over trunk or extremities while febrile)	+	−	Nl	−	−	+	+	Headache Sore throat Weight loss Muscle pain	↑	↓	↑	Leukocytosis	NA	↑	Nl	Nl	Diagnosis of exclusion	High ferritin Negative ANA Aseptic meningitis Sensorineural hearing loss
	Kawasaki disease	Immune-mediated	−	+	−	−	−	+	Autoimmune disease, more in Asian ethnicity boys	NA	Diffuse maculopapular erythematous rash in the genital area, and red eyes, lips, palms or soles of the feet	+	+	Nl	−	−	+	+	Strawberry tongue Sore throat Diarrhea Bilateral conjunctival inflammation	↑	↓	↑	Leukocytosis	NA	↑	Nl	Nl	Diagnostic criteria	Medium-sized-vessel vasculitis Coronary artery aneurysm
	IBD	Immune-mediated Mutation	−	+	−	−	−	+	Autoimmune disease, more in young	Stress Positive family history	Pyoderma gangrenosum	+	+	Nl	−	+	+	+	Vomiting Diarrhea Rectal bleeding	↑	↓	↑	Leukocytosis	NA	↑	Nl	Nl	Colonoscopy and biopsy	Primary sclerosing cholangitis Non-thyroidal illness syndrome DVT Bronchiolitis obliterans organizing pneumonia
	Sarcoidosis	Immune-mediated Unknown	−	+	−	−	−	+	Autoimmune disease, more in young African American women	Positive family history	Rashes Erythema nodosum Granuloma annulare Lupus pernio	+	+	Nl	−	+	+ Bilateral hilar adenopathy	+	Fatigue Weight loss Blurry vision Shortness of breath Cough	↑	↓	↑	Leukocytosis	NA	↑	Nl	Nl	Diagnosis of exclusion	Interstitial lung disease Systemic inflammatory disease
	Chronic hepatitis	Infection Autoimmune Ischemic	−	+	−	−	−	+	Elderly	Alcohol use Acute infection	Jaundice Ascites and peripheral edema	+	+	↓	−	+	+	+	Fatigue Weight loss Nausea and vomiting	↑	↓	↑	Leukocytosis	NA	↑	↑	↑	Liver biopsy	Hirsutism Amenorrhea Coagulopathy Hepatic encephalopathy Esophageal varices Hepatorenal syndrome Liver cancer
	Sweet syndrome	Immune-mediated Unknown	−	+	−	−	−	+	Rare	Relapse and remission	Tender, red, well-demarcated papules and plaques on the head, neck, legs, and arms	+	+	Nl	−	−	+	+	Conjunctivitis Iridocyclitis Oral aphthae	↑	↓	↑	Leukocytosis	Papillary and mid-dermal mixed infiltrate of polymorphonuclear leukocytes with nuclear fragmentation and histiocytic cells	↑	Nl	Nl	Diagnostic criteria	Cutaneous marker of systemic disease Acute myelogenous leukemia Immunologic disease Slight increase in alkaline phosphatase
	Acute gout	Elevated levels of uric acid in the blood Diet Genetic	−	+	−	−	−	+	Older males	Alcohol use Acute infection	Tophi	+	−		−	−	−	+	Fatigue	↑	↓	↑	Leukocytosis	NA	↑	↑	Nl	Clinical manifestation	Arthritis Urate nephropathy
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 involvement	Other signs	WBC	HB	Plt	PBS	Bone marrow exam	ESR/CRP	BUN/Cr	LFT	Gold standard	Associated findings
	Steroid	Release of granulocytes from the bone marrow	−	−	+	+	−	+	Any	Steroid use Autoimmune disease Malignancy	Obese	−	+	Nl to ↓	−	−	−	−	Abdominal pain Muscle weakness Growth failure Pubertal delay	↑	Nl to ↓	↑	Megakaryocyticfragments Large numbers of microspherocytes	Proliferation of megakaryocytes	↑	↑	Nl	Clinical manifestation + history of drug consumption	Thromboemboliccomplications Cushing syndrome Diabetes mellitus
	Filgrastim (Myeloid growth factor)	Release of granulocytes from the bone marrow	−	−	+	+	−	+	Any	Malignancy Neutropenia	Hair loss Local skin reactions at the site of injection	+	−	Nl to ↓	−	−	−	+	Cough Chest pain Vomiting	↑	Nl to ↓	↑	NA	NA	↑	Nl	Nl	Clinical manifestation + history of drug consumption	Alveolar hemorrhage Acute respiratory distress syndrome
	Lithium	Unknown	−	−	+	+	−	+	Any	Bipolar disorder	Weight gain Acne Hand tremor	−	−	Nl	−	−	−	−	Confusion Constipation or diarrhea Decreased memory Dry mouth Muscle weakness	↑	Nl to ↓	↑	NA	NA	Nl	↑	Nl	Clinical manifestation + history of drug consumption	Extrapyramidal side effects Euthyroid goitre Hypothyroidism Kidney damage
	Catecholamines (epinephrine)	Stimulation of bone marrow myelopoiesis Egress into the circulation	−	−	+	+	−	+	Any	Anaphylaxis Respiratory diseases	Acutely ill Diaphoretic	−	−	Nl to ↓	−	−	−	−	Dizziness Tremor Anxiety Dyspnea	↑	↑	↑	Megakaryocyticfragments	Proliferation of megakaryocytes	↑	Nl	Nl	Clinical manifestation + history of drug consumption	Thromboemboliccomplications
	ATRA	Differentiating promyelocytes	−	−	+	+	−	+	Any	Acne Acute promyelocytic leukemia	Skin dryness Hair loss	−	−	Nl	−	−	−	−	Shortness of breath Headache Numbness Depression Itchiness Vomiting Muscle pain	↑	Nl	Nl	NA	NA	↑	Nl	↑	Clinical manifestation + history of drug consumption	Teratogen Thrombosis Benign intracranial hypertension Hypercholesterolemia Liver damage
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 involvement	Other signs	WBC	HB	Plt	PBS	Bone marrow exam	ESR/CRP	BUN/Cr	LFT	Gold standard	Associated findings
	Infections	Infection	−	+	+	+	−	+	Any	Close contact Immunodeficiency	Acutely ill	+	+	Nl to ↓	−	±	±	±	Fatigue Nausea and vomiting	↑	↓	↑	Howell-Jolly bodies Nucleated RBCs	Proliferation of megakaryocytes	↑	Nl	Nl	Clinical manifestation+ culture	Depends on etiology
	Allergy	Unknown Activation of chloride transport	−	+	+	+	−	+	Any	Anaphylaxis Respiratory diseases	Acutely ill Diaphoretic	−	−	Nl to ↓	−	−	−	−	Dizziness Tremor Anxiety Dyspnea	↑	↑	↑	Megakaryocyticfragments	Proliferation of megakaryocytes	↑	Nl	Nl	Clinical manifestation	−
	Post splenectomy	Unknown	−	−	+	+	−	+	Any	Prior surgical removal of the spleen Sickle cell disease	Normal	±	−	Nl	+	−	−	−	−	↑	↓	↑	Howell-Jolly bodies Nucleated RBCs	Proliferation of megakaryocytes	↑	Nl	Nl	Clinical manifestation	Incidental laboratory finding Thrombosis
	Cigarette smoking	Reduced plasma volume Accelerated erythropoiesis	−	−	+	+	−	+	Any	Cigarette smoking	Cyanosis	−	−	Nl	−	−	−	−	Cough Dyspnea	↑	↑	↑	NA	NA	Nl	Nl	Nl	Clinical manifestation	−
	Stress/exercise	Reduced plasma volume	+	−	+	−	−	+	Athlete	Exercise	Normal	−	−	Nl	−	−	−	−	−	↑	↑	↑	Howell-Jolly bodies Nucleated RBCs	Proliferation of megakaryocytes	↑	Nl	Nl	Clinical manifestation	−
	Infancy	Physiologic	+	−	−	−	−	+	Infancy	−	Normal	−	−	Nl	−	−	−	−	−	↑	↑	↑	NA	NA	Nl	Nl	Nl	Clinical manifestation	−
	Pregnancy	Physiologic	+	−	−	−	−	+	Pregnancy	−	Normal	−	−	Nl	−	−	−	−	−	↑	↓	↑	NA	NA	Nl	Nl	Nl	Clinical manifestation	−
	Platelet clumping	Spurious	−	−	−	−	−	+	Any	−	Normal	−	−	Nl	−	−	−	−	−	↑	Nl	↑	Cytoplasmic fragments	Nl	Nl	Nl	Nl	Clinical manifestation	−
	Mixed cryoglobulinemia	Spurious	−	−	−	−	−	+	Any	Malignancy Autoimmune disease Infection	Atypical cutaneous ulcers Palpable purpura	−	−	Nl	−	−	−	+	Headache Confusion Blurry or loss of vision Generalized weakness	↑	Nl to ↓	↑	Cytoplasmic fragments	Nl	Nl	Nl	Nl	Skin biopsy	Vasculitis Neuropathy Raynaud phenomenon
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 involvement	Other signs	WBC	HB	Plt	PBS	Bone marrow exam	ESR/CRP	BUN/Cr	LFT	Gold standard	Associated findings

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