LEUKOCYTOSIS

Resident Author: Sofia Khan, MD

Faculty Advisor: David Tannenbaum, MD, CCFP
Created: February 2013

Overview
Leukocytosis is defined as a white blood cell (WBC) count greater than 11,000/uL (11 109/L) in adults.1 It is usually due to an increase in the absolute value
of neutrophils > 7700/uL (neutrophilia), but can also be due to an increase in lymphocytes > 4000/uL (lymphocytosis), eosinophils > 450/uL (eosinophilia),
monocytes > 800/uL (monocytosis), and rarely basophils > 200/uL (basophilia).2 Because the cutoffs are set as 2 standard deviations above the mean, 2.5% of
the normal population will have leukocytosis, with no clinical significance.2

Definitions
a) Myeloid: The common myeloid progenitor gives rise to most WBCs including neutrophils, eosinophils, basophils, and macrophages.3
b) Lymphocytes (B cells and T cells): Arise from the common lymphoid progenitor.3
c) Polymorphonuclear Neutrophils (PMNs): Are the final cell type arising from the development pathway of myeloblast -> promyelocyte -> myelocyte -> meta-
myelocyte -> band -> PMN.2 The peripheral blood lab value for absolute neutrophil count (ANC) includes both PMNs and bands.4
d) Demargination: More than one-half of the neutrophils in the peripheral circulation are attached to the vascular endothelium. These "marginated" neutrophils
can be released within minutes (i.e.,"demarginated") due to physiological or psychological stress, as well as due to certain drugs, increasing the measured
ANC.4,5
e) Left shift: Band count greater than 700/uL. (i.e. increase in the precursors of the mature PMN).2
f) Leukemoid reaction: By convention, a historical term to describe WBC > 50 000/uL when due to causes other than leukemia. It is usually due to a relatively
benign cause (e.g. infection or inflammation), though leukemia must be ruled out.1,2

Diagnostic Considerations
Most often, an elevated WBC count is due to the bone marrows normal response to an external stimulus such as infection or inflammation. This leukocytosis
most commonly presents as an increase in PMNs and with a left shift (due to release of stored leukocytes). But every now and then, a leukocytosis may reflect
a primary bone marrow disorder, i.e. acute or chronic leukemia or a myeloproliferative disorder.1

Normally responding bone marrow1,4,5

Infection
Inflammation: tissue necrosis, infarction, burns, electric shock, arthritis, heat stroke, snake bite
Stress (physical/emotional): overexertion, recent vigorous exercise, seizures, anaesthesia, epinephrine, anxiety, depression, rage
Pregnancy and following uncomplicated vaginal or caesarean delivery
Drugs: corticosteroids, lithium, beta agonists.
Cigarette smoking (*most common cause of mild neutrophilia)
Trauma: post-splenectomy (transient, for weeks - months)
Hemolytic anemia (in fact, any cause of anemia can lead to secondary leukocytosis and increased platelets due to the bone marrows attempt to compensate
for low hemoglobin via increased hematopoiesis)
Solid Tumour Malignancy (the tumour stimulates bone marrow non-specifically by releasing growth factors)

Abnormal bone marrow1 Diagnostic Approach

Acute or chronic leukemias Most of the time the etiology can be found by a thorough history and physical
Myeloproliferative disorders (Polycythemia Vera, Essential Thrombocytosis, coupled with analyzing the WBC differential and peripheral blood smear.1,4
Myelofibrosis, CML) 1) History:
Assess for triggers and symptoms related to normal and abnormal bone

RED FLAGS marrow response

2) Physical:
For bone marrow disorder prompting further investigations: WBC > 30 X
Vitals: fever, hypothermia, BP, HR
10 /L, accompanying abnormal red blood cell or platelet counts, bleeding,
9

Infectious source
bruising, petechiae, enlargement of liver/spleen/lymph nodes, life threatening
Cardio/respiratory examination
infection or immunosuppression, lethargy, significant weight loss.1
Hepatosplenomegaly
Joint swelling/erythema/tenderness
Lymphadenopathy

Dr. Michael Evans developed the One-Pager concept to provide clinicians with useful clinical information on primary care topics.
 3) Bloodwork:
LEUKOCYTOSIS
Consider variant or lab error if clinical picture inconsistent:
CBC + differential o Repeat prior to launching extensive investigations4,5
o (NB WBC > 100 x 109/L represents a medical emergency because of o Consider normal variant
the risk of brain infarction and haemorrhage Needs urgent haematological o Examining the parents or siblings CBC may demonstrate a normal
consult)1 genetic variant4
o Other clues:
neutrophilia + polycythemia consider 4) Bone Marrow Biopsy
polycythemia vera4 Rarely indicated in the workup of simple neutrophilia6
leukocytosis + thrombocytopenia consider Would consider in some cases of leukemoid reactions, or when there
sepsis (+/- DIC), TTP-HUS4 is an abnormal peripheral blood smear, which warrants a bone marrow
unexplained WBC > 15 consider C. difficile biopsy as well as fungal and mycobacterial cultures to rule out tubercu-
even without diarrhea8,9 losis or fungal infection, tumour, or marrow fibrosis,4,6 +/- cytogenic and
Peripheral blood smear molecular studies6
+/- ESR and CRP elevated in occult inflammation or infection; can be help-
ful in an asymptomatic patient with leukocytosis4

Supplementary Tables Differential Diagnosis by Selected Subtypes

Adapted with permission from Leukocytosis: Basics of Clinical Assessment, November 1, 2000, Vol 62, No 9, issue of American Family Physician Copyright
2000 American Academy of Family Physicians. All Rights Reserved.

EOSINOPHILIA1,6 Drug reactions

Parasitic Infections (often in paediatrics)
Allergic diseases: drugs, asthma, atopy, urticaria
Infections: scarlet fever, chorea, leprosy, GU infections
Immunologic disorders: RA, periarteritis, SLE, eosinophilia-myalgia syndrome
Pulmonary: Lffler's syndrome, pulmonary infiltrates, bronchoallergic reactions, Churg-Strauss
Malignancies: non-Hodgkins lymphoma, Hodgkins disease
Myeloproliferative disorders: CML, polycythemia vera, myelofibrosis
Adrenal insufficiency (Addisons disease)
Sarcoidosis
BASOPHILIA 1,2
Inflammatory conditions: allergic reactions (+/- anaphylaxis), inflammatory bowel disease, chronic airway inflammation, chronic
dermatitis
Infections: varicella, chronic sinusitis
Myeloproliferative disorders: CML, polycythemia vera, myelofibrosis, essential thrombocytosis
Alteration of marrow and reticuloendothelial compartments: chronic haemolytic anemia, Hodgkins disease, splenectomy
Endocrine: hypothyroidism, ovulation, estrogens
LYMPHOCYTOSIS 1,2,7
Absolute lymphocytosis:
Acute infections: CMV, EBV, pertussis, hepatitis, toxoplasmosis
Chronic infections: tuberculosis, brucellosis
Lymphoid malignancies: ALL, CLL
Relative lymphocytosis:
Acute phase of viral illnesses (infectious lymphocytosis in children is benign and can have total WBC ranging from 20 000/uL
100 000/uL)
o The presence of significant lymphadenopathy or splenomegaly is suggestive of EBV infection, where atypical lymphocytes peak
in week 2-37
Connective tissue disorders
Thyrotoxicosis
Addisons disease
Splenomegaly (due to splenic sequestration of granulocytes)
Normal state in children less than 2 years of age

Bottom Line
Most often, an elevated WBC count is due to the bone marrows normal response to an external stimulus such as infection or inflammation. The etiology can
usually be found by a thorough history and physical coupled with analyzing the WBC differential and peripheral blood smear. However make sure to inquire
about red flags. Consider referral to a specialist if there are red flags or an abnormal blood smear.

References can be found online at http://www.dfcm.utoronto.ca/programs/postgraduateprograme/One_Pager_Project_References.htm