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1004 American Family Physician www.aafp.org/afp Volume 92,
Number 11 ◆ December 1, 2015
An elevated white blood cell count has many potential
etiologies, including malignant and nonmalignant causes.
It is important to use age- and pregnancy-specific normal ranges
for the white blood cell count. A repeat complete
blood count with peripheral smear may provide helpful
information, such as types and maturity of white blood cells,
uniformity of white blood cells, and toxic granulations. The
leukocyte differential may show eosinophilia in parasitic
or allergic conditions, or it may reveal lymphocytosis in
childhood viral illnesses. Leukocytosis is a common sign of
infection, particularly bacterial, and should prompt physicians
to identify other signs and symptoms of infection. The
peripheral white blood cell count can double within hours after
certain stimuli because of the large bone marrow stor-
age and intravascularly marginated pools of neutrophils.
Stressors capable of causing an acute leukocytosis include
surgery, exercise, trauma, and emotional stress. Other
nonmalignant etiologies of leukocytosis include certain medi-
cations, asplenia, smoking, obesity, and chronic inflammatory
conditions. Symptoms suggestive of a hematologic
malignancy include fever, weight loss, bruising, or fatigue. If
malignancy cannot be excluded or another more likely
cause is not suspected, referral to a hematologist/oncologist is
indicated. (Am Fam Physician. 2015;92(11):1004-1011.
Copyright © 2015 American Academy of Family Physicians.)
Evaluation of Patients with Leukocytosis
LYRAD K. RILEY, MD, and JEDDA RUPERT, MD, Eglin Air
Force Base Family Medicine Residency, Eglin Air Force Base,
Florida
L
eukocytosis, often defined as an ele-
vated white blood cell (WBC) count
greater than 11,000 per mm3 (11.0
× 109 per L) in nonpregnant adults,
is a relatively common finding with a wide
differential. It is important for clinicians to
be able to distinguish malignant from non-
malignant etiologies, and to differentiate
between the most common nonmalignant
causes of leukocytosis.
Leukocytosis in the range of approxi-
mately 50,000 to 100,000 per mm3 (50.0 to
100.0 × 109 per L) is sometimes referred to as
a leukemoid reaction. This level of elevation
can occur in some severe infections, such as
Clostridium difficile infection, sepsis, organ
rejection, or in patients with solid tumors.1
Leukocytosis greater than 100,000 per mm3
is almost always caused by leukemias or
myeloproliferative disorders.2
Normal Variation
The normal range for WBC counts changes
with age and pregnancy (Table 1).3 Healthy
newborn infants may have a WBC count
from 13,000 to 38,000 per mm3 (13.0 to
38.0 × 109 per L) at 12 hours of life (95%
confidence interval). By two weeks of age,
this decreases to approximately 5,000 to
20,000 per mm3 (5.0 to 20.0 × 109 per L), and
gradually declines throughout childhood to
reach adult levels of 4,500 to 11,000 per mm3
(4.5 to 11.0 × 109 per L; 95% confidence
interval) by about 21 years of age.3 There is
also a shift from relative lymphocyte to neu-
trophil predominance from early childhood
to the teenage years and adulthood.4 During
pregnancy, there is a gradual increase in the
normal WBC count (third trimester 95%
upper limit = 13,200 per mm3 [13.2 × 109
per L] and 99% upper limit = 15,900 per mm3
[15.9 × 109 per L]), and a slight shift toward
an increased percentage of neutrophils.5 In
one study of afebrile postpartum patients,
the mean WBC count was 12,620 per mm3
(12.62 × 109 per L) for women after vaginal
deliveries and 12,710 per mm3 (12.71 × 109
per L) after cesarean deliveries. Of note, pos-
itive bacterial cultures were not associated
with leukocytosis or neutrophilia, making
leukocytosis an unreliable discriminator in
deciding which postpartum patients require
antibiotic therapy.6 Patients of black African
descent tend to have a lower WBC count (by
1,000 per mm3 [1.0 × 109 per L]) and lower
absolute neutrophil counts.7
Normal Leukocyte Life Cycle
and Responses
The life cycle of leukocytes includes devel-
opment and differentiation, storage in the
bone marrow, margination within the vas-
cular spaces, and migration to tissues. Stem
cells in the bone marrow produce cell lines
CME This clinical content
conforms to AAFP criteria
for continuing medical
education (CME). See
CME Quiz Questions on
page 977.
Author disclosure: No rel-
evant financial affiliations.
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Leukocytosis
December 1, 2015 ◆ Volume 92, Number 11 www.aafp.org/afp
American Family Physician 1005
of erythroblasts, which become red blood
cells; megakaryoblasts, which become plate-
lets; lymphoblasts; and myeloblasts. Lym-
phoblasts develop into various types of T
and B cell lymphocytes. Myeloblasts further
differentiate into monocytes and granulo-
cytes, a designation that includes neutro-
phils, basophils, and eosinophils (Figure 1).
Once WBCs have matured within the bone
marrow, 80% to 90% remain in storage in
the bone marrow. This large reserve allows
for a rapid increase in the circulating WBC
count within hours. A relatively small pool
(2% to 3%) of leukocytes circulate freely in
the peripheral blood1; the rest stay depos-
ited along the margins of blood vessel walls
or in the spleen. Leukocytes spend most of
their life span in storage. Once a leukocyte is
released into circulation and peripheral tis-
sues, its life span ranges from two to 16 days,
depending on the type of cell.
Differentiation by Type of White
Blood Cell
Changes in the normal distribution of
types of WBCs can indicate specific causes
of leukocytosis (Table 2).8 Although the
differential of the major types of WBCs is
important for evaluating the cause of leu-
kocytosis, it is sometimes helpful to think
in terms of absolute, rather than relative,
leukopenias and leukocytoses. To calculate
the absolute cell count, the total leukocyte
count is multiplied by the differential per-
centage. For example, with a normal WBC
count of 10,000 per mm3 (10.0 × 109 per L)
and an elevated monocyte percentage of 12,
the absolute monocyte count is 12% or 0.12
times the WBC count of 10,000 per mm3,
yielding 1,200 per mm3 (1.2 × 109 per L),
which is abnormally elevated.
The most common type of leukocytosis
is neutrophilia (an increase in the absolute
number of mature neutrophils to greater
than 7,000 per mm3 [7.0 × 109 per L]), which
can arise from infections, stressful condi-
tions, chronic inflammation, medication use,
and other causes (Table 3).1-7,9,10 Lymphocy-
tosis (when lymphocytes make up more than
40% of the WBC count or the absolute count
is greater than 4,500 per mm3 [4.5 × 109
SORT: KEY RECOMMENDATIONS FOR PRACTICE
Clinical recommendation
Evidence
rating References
Leukocytosis greater than 100,000 per mm3
(100.0 × 109 per L) is almost always caused
by leukemias or myeloproliferative disorders.
C 2
Leukocytosis is not a reliable indicator of
postpartum bacterial infection.
C 6
Patients with leukocytosis and no other signs of
systemic inflammatory response syndrome do
not require blood cultures.
C 19
A = consistent, good-quality patient-oriented evidence; B =
inconsistent or limited-
quality patient-oriented evidence; C = consensus, disease-
oriented evidence, usual
practice, expert opinion, or case series. For information about
the SORT evidence
rating system, go to http://www.aafp.org/afpsort.
Table 1. White Blood Cell Count Variation with Age
and Pregnancy
Patient characteristic Normal total leukocyte count
Newborn infant 13,000 to 38,000 per mm3
(13.0 to 38.0 × 109 per L)
Infant two weeks of age 5,000 to 20,000 per mm3
(5.0 to 20.0 × 109 per L)
Adult 4,500 to 11,000 per mm3
(4.5 to 11.0 × 109 per L)
Pregnant female (third trimester) 5,800 to 13,200 per mm3
(5.8 to 13.2 × 109 per L)
Information from reference 3.
Figure 1. White blood cell maturation. The life cycle of
leukocytes
includes development and differentiation, storage in bone
marrow,
margination within vascular spaces, and migration to tissues.
Megakaryoblast
Platelets
Erythroblast
Erythrocyte
Myeloblast
Basophil Eosinophil Neutrophil Monocyte
Stem cell
Lymphoblast
Lymphocyte
B
o
n
e
m
ar
ro
w
B
lo
o
d
IL
LU
ST
R
A
TI
O
N
B
Y
D
A
V
E
K
LE
M
M
Leukocytosis
1006 American Family Physician www.aafp.org/afp Volume 92,
Number 11 ◆ December 1, 2015
per L]) can occur in patients with pertussis,
syphilis, viral infections, hypersensitivity
reactions, and certain subtypes of leukemia
or lymphoma. Lymphocytosis is more likely
to be benign in children than in adults.4
Epstein-Barr virus infection, tuberculosis or
fungal disease, autoimmune disease, sple-
nectomy, protozoan or rickettsial infections,
and malignancy can cause monocytosis
(monocytes make up more than 8% of the
WBC count or the absolute count is greater
than 880 per mm3 [0.88 × 109 per L]).8
Eosinophilia (eosinophil absolute count
greater than 500 per mm3 [0.5 × 109 per L]),
Table 3. Nonmalignant Causes of Neutrophilia
Cause Distinguishing features Evaluation
Patient
characteristics
Pregnancy, obesity, race, age Reference appropriate WBC count
by age or pregnancy trimester
Compare WBC count to recent baseline (if available)
Infection Fever, system-specific symptoms
Physical examination findings
Obtain system-specific cultures and imaging (e.g., sputum
cultures,
chest radiography)
Consider empiric antibiotics
Consider use of other biomarkers, such as CRP and
procalcitonin
Reactive
neutrophilia
Exercise, physical stress (e.g., postsurgical,
febrile seizures), emotional stress (e.g.,
panic attacks), smoking
Confirm with history
Chronic
inflammation
Rheumatic disease, inflammatory bowel
disease, granulomatous disease,
vasculitides, chronic hepatitis
Obtain personal and family medical history
Consider erythrocyte sedimentation rate and CRP levels,
specific
rheumatology laboratories
Consider subspecialist consultation (e.g., rheumatology,
gastroenterology)
Medication
induced
Corticosteroids, beta agonists, lithium,
epinephrine, colony-stimulating factors
Confirm with history; consider discontinuation of medication,
if warranted
Bone marrow
stimulation
Hemolytic anemia, immune
thrombocytopenia, bone marrow
suppression recovery, colony-
stimulating factors
Complete blood count differential; compare with baseline
values
(if available)
Examine peripheral smear
Consider reticulocyte and lactate dehydrogenase levels
Consider flow cytometry, bone marrow examination,
hematology/
oncology consultation
Splenectomy History of trauma or sickle cell disease Confirm
with history
Congenital Hereditary/chronic idiopathic
neutrophilia, Down syndrome,
leukocyte adhesion deficiency
Obtain family, developmental history
Consider hematology/oncology, genetics, and immunology
consultations
NOTE: After patient characteristics, causes are listed in
approximate order of frequency.
CRP = C-reactive protein; WBC = white blood cell.
Information from references 1 through 7, 9, and 10.
Table 2. Normal White Blood Cell
Distribution
White blood
cell line
Normal percentage of
total leukocyte count
Neutrophils 40 to 60
Lymphocytes 20 to 40
Monocytes 2 to 8
Eosinophils 1 to 4
Basophils 0.5 to 1
Information from reference 8.
Leukocytosis
December 1, 2015 ◆ Volume 92, Number 11 www.aafp.org/afp
American Family Physician 1007
although uncommon, may suggest allergic
conditions such as asthma, urticaria, atopic
dermatitis or eosinophilic esophagitis, drug
reactions, dermatologic conditions, malig-
nancies, connective tissue disease, idiopathic
hypereosinophilic syndrome, or parasitic
infections, including helminths (tissue par-
asites more than gut-lumen parasites).11,12
Isolated basophilia (number of basophils
greater than 100 per mm3 [0.1 × 109 per L])
is rare and unlikely to cause leukocytosis
in isolation, but it can occur with allergic
or inflammatory conditions and chronic
myelogenous leukemia13 (Table 4).
Nonmalignant Etiologies
A reactive leukocytosis, typically in the
range of 11,000 to 30,000 per mm3 (11.0 to
30.0 × 109 per L), can arise from a variety of
etiologies. Any source of stress can cause a
catecholamine-induced demargination of
WBCs, as well as increased release from the
bone marrow storage pool. Examples include
surgery, exercise, trauma, burns, and emo-
tional stress.9 One study showed an average
increase in WBCs of 2,770 per mm3 (2.77 ×
109 per L) peaking on postoperative day 2
after knee or hip arthroplasty.10 Medications
known to increase the WBC count include
corticosteroids, lithium, colony-stimulating
factors, beta agonists, and epinephrine. Dur-
ing the recovery phase after hemorrhage or
hemolysis, a rebound leukocytosis can occur.
Leukocytosis is one of the hallmarks of
infection. In the acute stage of many bacte-
rial infections, there are primarily mature and
immature neutrophils (Figure 2); sometimes,
as the infection progresses, there is a shift to
lymphocyte predominance. The release of less-
mature bands and metamyelocytes into the
peripheral circulation results in the so-called
“left shift” in the WBC differential. Of note,
some bacterial infections paradoxically cause
neutropenias, such as typhoid fever, rickett-
sial infections, brucellosis, and dengue.1,14
Viral infections may cause leukocytosis early
in their course, but a sustained leukocytosis
is not typical, except for the lymphocytosis in
some childhood viral infections.
An elevated WBC count is a suggestive,
but not definitive, marker of the presence of
significant infection. For example, the sen-
sitivity and specificity of an elevated WBC
count in diagnosing acute appendicitis are
62% and 75%, respectively.15,16 For diagnos-
ing serious bacterial infections without a
Table 4. Selected Conditions Associated with Elevations
in Certain White Blood Cell Types
White blood
cell line Conditions that typically cause elevations
Basophils Allergic conditions, leukemias
Eosinophils Allergic conditions, dermatologic conditions,
eosinophilic
esophagitis, idiopathic hypereosinophilic syndrome,
malignancies, medication reactions, parasitic infections
Lymphocytes Acute or chronic leukemia, hypersensitivity
reaction,
infections (viral, pertussis)
Monocytes Autoimmune disease, infections (Epstein-Barr virus,
fungal,
protozoan, rickettsial, tuberculosis), splenectomy
Neutrophils Bone marrow stimulation, chronic inflammation,
congenital,
infection, medication induced, reactive, splenectomy
Figure 2. Neutrophilia postsplenectomy with sepsis. An 18-
year-old
woman with distal pancreatectomy and splenectomy for benign
pancreatic pseudopapillary tumor two weeks earlier presents to
the
emergency department with a temperature of 103°F (39.4°C),
leuko-
cytosis with bandemia, tachycardia, and urinalysis results
consistent
with infection. White blood cell count = 57,100 per mm3 (57.1
× 109 per
L), hemoglobin = 12.6 g per dL (126 g per L), platelet count =
832,000
per mm3 (832 × 109 per L). White blood cell differential:
75.4% seg-
mented cells, 19.3% bands. Note neutrophils (arrows) with < 3
lobes
to nuclei (band cells).
Leukocytosis
1008 American Family Physician www.aafp.org/afp Volume 92,
Number 11 ◆ December 1, 2015
source in febrile children, the discrimina-
tory value of leukocytosis is less than that of
other biomarkers, such as C-reactive protein
or procalcitonin.17 Although a WBC count
greater than 12,000 per mm3 (12.0 × 109
per L) is one of the criteria for the systemic
inflammatory response syndrome (or sepsis
when there is a known infection), leukocy-
tosis alone is a poor predictor of bacteremia
and not an indication for obtaining blood
cultures.18,19
Other acquired causes of leukocytosis
include functional asplenia (predominantly
lymphocytosis), smoking, and obesity.
Patients with a chronic inflammatory condi-
tion, such as rheumatoid arthritis, inflam-
matory bowel disease, or a granulomatous
disease, may also exhibit leukocytosis.
Genetic causes include hereditary or chronic
idiopathic neutrophilia and Down syndrome.
Malignant Etiologies
Leukocytosis may herald a malignant dis-
order, such as an acute or chronic leukemia
(Figure 3), or a myeloproliferative disorder,
such as polycythemia vera, myelofibrosis, or
essential thrombocytosis. A previous article
on leukemia in American Family Physician
reviewed the features and differentiation of
malignant hematopoietic disorders.20 Many
solid tumors may lead to a leukocytosis in
the leukemoid range, either through bone
marrow involvement or production of gran-
ulocyte colony-stimulating or granulocyte-
macrophage colony-stimulating factors1,3,21
(Figure 4). Chronic leukemias are most com-
monly diagnosed after incidental findings
of leukocytosis on complete blood counts
in asymptomatic patients. Patients with fea-
tures suggestive of hematologic malignancies
require prompt referral to a hematologist/
oncologist (Table 5).3,22
Approach to Evaluation
A systematic approach to patients with leu-
kocytosis includes identifying historical
clues that suggest potential causes (Figure 5).
Fever and pain may accompany infections
or malignancies; other constitutional symp-
toms, such as fatigue, night sweats, weight
loss, easy bruising, or bleeding, might suggest
Figure 3. Lymphocytosis in a 70-year-old woman with a history
of
chronic lymphocytic leukemia presenting to the emergency
depart-
ment with a five-day history of subjective fevers, sore throat,
and
cough. White blood cell count = 147,500 per mm3 (147.5 × 109
per L),
hemoglobin = 8.8 g per dL (88 g per L), platelet count = 82,000
per
mm3 (82 × 109 per L). White blood cell differential: 96.6%
lympho-
cytes (monomorphic). Note many mature lymphocytes (small
nuclei
near the size of a red blood cell with thin rim cytoplasm; black
arrows)
and many smudge cells (white arrows).
Figure 4. Eosinophilia in malignancy in a 76-year-old man with
a his-
tory significant for metastatic prostate cancer presenting for
che-
motherapy. White blood cell count = 26,600 per mm3 (26.6 ×
109
per L), hemoglobin = 10.8 g per dL (108 g per L), hematocrit =
32.6%.
White blood cell differential: 51.8% eosinophils, 36.8%
neutrophils,
6% lymphocytes, 4.5% monocytes, 0.9% basophils. Note
eosinophils
(arrows).
Leukocytosis
December 1, 2015 ◆ Volume 92, Number 11 www.aafp.org/afp
American Family Physician 1009
malignancy.22 Previous diagnoses or comor-
bid conditions that cause chronic inflam-
mation should be noted, as well as recent
stressful events, medication use, smoking
status, and history of splenectomy or sickle
cell anemia. A history of an elevated WBC
count is important, because duration will
help determine the likely cause. Leukocy-
tosis lasting hours to days has a different
differential diagnosis (e.g., infections, acute
leukemias, stress reactions) than a case that
persists for weeks to months (e.g., chronic
inflammation, some malignancies).
The physical examination should note
erythema, swelling, or lung findings sug-
gestive of an infection; murmurs suggestive
of infective endocarditis; lymphadenopathy
suggestive of a lymphoproliferative disor-
der; or splenomegaly suggestive of chronic
myelogenous leukemia or a myeloprolifera-
tive disorder; petechiae or ecchymoses; or
painful, inflamed joints suggestive of con-
nective tissue disease or infection.
Initial laboratory evaluation should
include a repeat complete blood count to
confirm the elevated WBC level, with differ-
ential cell counts and a review of a peripheral
blood smear. The peripheral smear should be
examined for toxic granulations (suggestive
of inflammation), platelet clumps (which
may be misinterpreted as WBCs), the pres-
ence of immature cells, and uniformity of the
WBCs. On evaluation of a leukocytosis with
lymphocyte predominance, a monomorphic
population is concerning for chronic lym-
phocytic leukemia, whereas a pleomorphic
(varying sizes and shapes) lymphocytosis is
suggestive of a reactive process.4,23 With all
forms of leukocytosis, concurrent abnor-
malities in other cell counts (erythrocytes
or platelets) suggest a primary bone mar-
row process and should prompt hematology/
oncology evaluation.
As indicated by the history and examina-
tion findings, physicians should consider
performing cultures of blood, urine, and
joint or body fluid aspirates; rheumatol-
ogy studies; a test for heterophile antibod-
ies (mononucleosis spot test); and serologic
titers. Radiologic studies may include chest
radiography (to identify infections, some
malignancies, and some granulomatous dis-
eases) and, as indicated by history, computed
tomography or bone scan. If hematologic
malignancy is suspected, additional confir-
matory testing may include flow cytometry,
cytogenetic testing, or molecular testing of
the bone marrow or peripheral blood.
Data Sources: The primary literature search was
completed using Essential Evidence Plus and included
searches of the Cochrane, POEM, and NICE guideline
databases using the search term leukocytosis. In addition,
PubMed searches were performed using the terms leu-
kocytosis and white blood cell. Search dates: October 31
and December 17, 2014, and September 2015.
The authors thank Melissa King, MD, Department of
Hematology/Oncology, Eglin Air Force Base Hospital, for
reviewing the manuscript, and Niquanna Perez, Eglin Air
Force Base laboratory services, for procuring peripheral
smear images.
The views expressed in this article are those of the
authors and do not reflect the official policy or position
of the U.S. government, the Department of Defense, or
the U.S. Air Force.
Table 5. Findings Suggestive
of Hematologic Malignancies
in the Setting of Leukocytosis
Symptoms
Bruising/bleeding tendency
Fatigue, weakness
Fever > 100.4°F (38°C)
Immunosuppression
Night sweats
Unintentional weight loss
Physical examination findings
Lymphadenopathy
Petechiae
Splenomegaly or hepatomegaly
Laboratory abnormalities
Decreased red blood cell count or
hemoglobin/hematocrit levels
Increased or decreased platelet count
Monomorphic lymphocytosis on peripheral
smear
Predominantly immature cells on peripheral
smear
White blood cell count > 30,000 per mm3
(30.0 × 109 per L), or > 20,000 per mm3
(20.0 × 109 per L) after initial management
Information from references 3 and 22.
Leukocytosis
Evaluation of Leukocytosis
Figure 5. Algorithm for the evaluation of leukocytosis. (ANA =
antinuclear antibodies; CRP = C-reactive protein;
ESR = erythrocyte sedimentation rate.)
Leukocytosis (white blood cell count > 11,000 per mm3 [11.0 ×
109 per L])
Repeat complete blood count
Order peripheral smear
Leukocytosis confirmed?
Obtain additional history and perform physical examination
Leukocytosis explained by history or patient characteristics
(e.g., pregnancy, newborn, splenectomy, smoking,
medications)?
No further workup necessary
No further workup necessary
Patient presents with:
Weight loss, fatigue, night sweats, fevers
Abnormal red blood cell and platelet count
Immature leukocyte forms (blasts)
Chronic duration (weeks or years)
History of or risk factors for malignancy,
splenomegaly, lymphadenopathy, bruising?
Consider malignancy:
Hematology/oncology consultation
Consider additional testing to include flow
cytometry, cytogenetic testing, or molecular
testing of the bone marrow or peripheral blood
Consider nonmalignant etiologies
Which cell line is affected?
No Yes
No Yes
No Yes
Basophilia (> 100 per mm3
[0.1 × 109 per L]; rare):
Search for malignancy
(or allergic condition,
much less likely)
Monocytosis (> 880 per mm3 [0.88 × 109 per L]):
Infections (Epstein-Barr virus, tuberculosis,
fungal, protozoan, rickettsial)
Autoimmune disease
Splenectomy
Consider:
Sick contact, surgical,
and travel history
Imaging (chest
radiography)
Pathogen-specific
testing (mononucleosis
spot test, purified
protein derivative)
ESR, CRP, and ANA
measurement
Neutrophilia (> 7,000 per
mm3 [7.0 × 109 per L]):
Infection
Chronic inflammation
Recent stressors
Medication induced
Bone marrow stimulation
Splenectomy
Tobacco use
(see Table 3)
Consider:
Medical, medication,
family, travel, sick
contact, surgical,
and social history
ESR, CRP, and ANA
measurement
Pathogen isolation
(blood cultures,
lumbar puncture)
Additional imaging
(system-specific)
Lymphocytosis (> 4,500 per
mm3 [4.5 × 109 per L]):
Infections (viral, pertussis)
Hypersensitivity reaction
Consider:
Sick contact and
immunization history
Imaging (chest
radiography)
Pathogen-specific
testing (viral panels)
Eosinophilia (> 500 per
mm3 [0.5 × 109 per L]):
Allergic conditions
Eosinophilic esophagitis
Medication reactions
Dermatologic conditions
Parasitic infections
Consider:
Medication, travel history
Full skin examination
Skin biopsy, if warranted
Allergy/immunology testing
Parasite-specific testing
(stool ova and parasites)
Upper endoscopy
Leukocytosis
December 1, 2015 ◆ Volume 92, Number 11 www.aafp.org/afp
American Family Physician 1011
The Authors
LYRAD K. RILEY, MD, is a faculty member at the U.S. Air
Force Eglin Family Medicine Residency Program, Eglin
Air Force Base, Fla., and an assistant professor in the
Department of Family Medicine at the Uniformed Services
University of the Health Sciences School of Medicine,
Bethesda, Md.
JEDDA RUPERT, MD, is a second-year resident at the U.S.
Air Force Eglin Family Medicine Residency Program.
Address correspondence to Lyrad K. Riley, MD, Eglin
AFB Family Medicine Residency, 307 Boatner Rd., Eglin
Air Force Base, FL 32542 (e-mail: [email protected]).
Reprints are not available from the authors.
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1004 American Family Physician www.aafp.orgafp Volume 92, Num.docx

  • 1. 1004 American Family Physician www.aafp.org/afp Volume 92, Number 11 ◆ December 1, 2015 An elevated white blood cell count has many potential etiologies, including malignant and nonmalignant causes. It is important to use age- and pregnancy-specific normal ranges for the white blood cell count. A repeat complete blood count with peripheral smear may provide helpful information, such as types and maturity of white blood cells, uniformity of white blood cells, and toxic granulations. The leukocyte differential may show eosinophilia in parasitic or allergic conditions, or it may reveal lymphocytosis in childhood viral illnesses. Leukocytosis is a common sign of infection, particularly bacterial, and should prompt physicians to identify other signs and symptoms of infection. The peripheral white blood cell count can double within hours after certain stimuli because of the large bone marrow stor- age and intravascularly marginated pools of neutrophils. Stressors capable of causing an acute leukocytosis include surgery, exercise, trauma, and emotional stress. Other nonmalignant etiologies of leukocytosis include certain medi- cations, asplenia, smoking, obesity, and chronic inflammatory conditions. Symptoms suggestive of a hematologic malignancy include fever, weight loss, bruising, or fatigue. If malignancy cannot be excluded or another more likely cause is not suspected, referral to a hematologist/oncologist is indicated. (Am Fam Physician. 2015;92(11):1004-1011. Copyright © 2015 American Academy of Family Physicians.) Evaluation of Patients with Leukocytosis LYRAD K. RILEY, MD, and JEDDA RUPERT, MD, Eglin Air Force Base Family Medicine Residency, Eglin Air Force Base,
  • 2. Florida L eukocytosis, often defined as an ele- vated white blood cell (WBC) count greater than 11,000 per mm3 (11.0 × 109 per L) in nonpregnant adults, is a relatively common finding with a wide differential. It is important for clinicians to be able to distinguish malignant from non- malignant etiologies, and to differentiate between the most common nonmalignant causes of leukocytosis. Leukocytosis in the range of approxi- mately 50,000 to 100,000 per mm3 (50.0 to 100.0 × 109 per L) is sometimes referred to as a leukemoid reaction. This level of elevation can occur in some severe infections, such as Clostridium difficile infection, sepsis, organ rejection, or in patients with solid tumors.1 Leukocytosis greater than 100,000 per mm3 is almost always caused by leukemias or myeloproliferative disorders.2 Normal Variation The normal range for WBC counts changes with age and pregnancy (Table 1).3 Healthy newborn infants may have a WBC count from 13,000 to 38,000 per mm3 (13.0 to 38.0 × 109 per L) at 12 hours of life (95% confidence interval). By two weeks of age, this decreases to approximately 5,000 to 20,000 per mm3 (5.0 to 20.0 × 109 per L), and gradually declines throughout childhood to
  • 3. reach adult levels of 4,500 to 11,000 per mm3 (4.5 to 11.0 × 109 per L; 95% confidence interval) by about 21 years of age.3 There is also a shift from relative lymphocyte to neu- trophil predominance from early childhood to the teenage years and adulthood.4 During pregnancy, there is a gradual increase in the normal WBC count (third trimester 95% upper limit = 13,200 per mm3 [13.2 × 109 per L] and 99% upper limit = 15,900 per mm3 [15.9 × 109 per L]), and a slight shift toward an increased percentage of neutrophils.5 In one study of afebrile postpartum patients, the mean WBC count was 12,620 per mm3 (12.62 × 109 per L) for women after vaginal deliveries and 12,710 per mm3 (12.71 × 109 per L) after cesarean deliveries. Of note, pos- itive bacterial cultures were not associated with leukocytosis or neutrophilia, making leukocytosis an unreliable discriminator in deciding which postpartum patients require antibiotic therapy.6 Patients of black African descent tend to have a lower WBC count (by 1,000 per mm3 [1.0 × 109 per L]) and lower absolute neutrophil counts.7 Normal Leukocyte Life Cycle and Responses The life cycle of leukocytes includes devel- opment and differentiation, storage in the bone marrow, margination within the vas- cular spaces, and migration to tissues. Stem cells in the bone marrow produce cell lines CME This clinical content
  • 4. conforms to AAFP criteria for continuing medical education (CME). See CME Quiz Questions on page 977. Author disclosure: No rel- evant financial affiliations. Downloaded from the American Family Physician website at www.aafp.org/afp. Copyright © 2015 American Academy of Family Physicians. For the private, noncom- mercial use of one individual user of the website. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests. Leukocytosis December 1, 2015 ◆ Volume 92, Number 11 www.aafp.org/afp American Family Physician 1005 of erythroblasts, which become red blood cells; megakaryoblasts, which become plate- lets; lymphoblasts; and myeloblasts. Lym- phoblasts develop into various types of T and B cell lymphocytes. Myeloblasts further differentiate into monocytes and granulo- cytes, a designation that includes neutro- phils, basophils, and eosinophils (Figure 1). Once WBCs have matured within the bone marrow, 80% to 90% remain in storage in the bone marrow. This large reserve allows for a rapid increase in the circulating WBC count within hours. A relatively small pool
  • 5. (2% to 3%) of leukocytes circulate freely in the peripheral blood1; the rest stay depos- ited along the margins of blood vessel walls or in the spleen. Leukocytes spend most of their life span in storage. Once a leukocyte is released into circulation and peripheral tis- sues, its life span ranges from two to 16 days, depending on the type of cell. Differentiation by Type of White Blood Cell Changes in the normal distribution of types of WBCs can indicate specific causes of leukocytosis (Table 2).8 Although the differential of the major types of WBCs is important for evaluating the cause of leu- kocytosis, it is sometimes helpful to think in terms of absolute, rather than relative, leukopenias and leukocytoses. To calculate the absolute cell count, the total leukocyte count is multiplied by the differential per- centage. For example, with a normal WBC count of 10,000 per mm3 (10.0 × 109 per L) and an elevated monocyte percentage of 12, the absolute monocyte count is 12% or 0.12 times the WBC count of 10,000 per mm3, yielding 1,200 per mm3 (1.2 × 109 per L), which is abnormally elevated. The most common type of leukocytosis is neutrophilia (an increase in the absolute number of mature neutrophils to greater than 7,000 per mm3 [7.0 × 109 per L]), which can arise from infections, stressful condi- tions, chronic inflammation, medication use, and other causes (Table 3).1-7,9,10 Lymphocy-
  • 6. tosis (when lymphocytes make up more than 40% of the WBC count or the absolute count is greater than 4,500 per mm3 [4.5 × 109 SORT: KEY RECOMMENDATIONS FOR PRACTICE Clinical recommendation Evidence rating References Leukocytosis greater than 100,000 per mm3 (100.0 × 109 per L) is almost always caused by leukemias or myeloproliferative disorders. C 2 Leukocytosis is not a reliable indicator of postpartum bacterial infection. C 6 Patients with leukocytosis and no other signs of systemic inflammatory response syndrome do not require blood cultures. C 19 A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited- quality patient-oriented evidence; C = consensus, disease- oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort. Table 1. White Blood Cell Count Variation with Age
  • 7. and Pregnancy Patient characteristic Normal total leukocyte count Newborn infant 13,000 to 38,000 per mm3 (13.0 to 38.0 × 109 per L) Infant two weeks of age 5,000 to 20,000 per mm3 (5.0 to 20.0 × 109 per L) Adult 4,500 to 11,000 per mm3 (4.5 to 11.0 × 109 per L) Pregnant female (third trimester) 5,800 to 13,200 per mm3 (5.8 to 13.2 × 109 per L) Information from reference 3. Figure 1. White blood cell maturation. The life cycle of leukocytes includes development and differentiation, storage in bone marrow, margination within vascular spaces, and migration to tissues. Megakaryoblast Platelets Erythroblast Erythrocyte Myeloblast Basophil Eosinophil Neutrophil Monocyte
  • 9. B Y D A V E K LE M M Leukocytosis 1006 American Family Physician www.aafp.org/afp Volume 92, Number 11 ◆ December 1, 2015 per L]) can occur in patients with pertussis, syphilis, viral infections, hypersensitivity reactions, and certain subtypes of leukemia or lymphoma. Lymphocytosis is more likely to be benign in children than in adults.4 Epstein-Barr virus infection, tuberculosis or fungal disease, autoimmune disease, sple- nectomy, protozoan or rickettsial infections, and malignancy can cause monocytosis (monocytes make up more than 8% of the WBC count or the absolute count is greater than 880 per mm3 [0.88 × 109 per L]).8 Eosinophilia (eosinophil absolute count
  • 10. greater than 500 per mm3 [0.5 × 109 per L]), Table 3. Nonmalignant Causes of Neutrophilia Cause Distinguishing features Evaluation Patient characteristics Pregnancy, obesity, race, age Reference appropriate WBC count by age or pregnancy trimester Compare WBC count to recent baseline (if available) Infection Fever, system-specific symptoms Physical examination findings Obtain system-specific cultures and imaging (e.g., sputum cultures, chest radiography) Consider empiric antibiotics Consider use of other biomarkers, such as CRP and procalcitonin Reactive neutrophilia Exercise, physical stress (e.g., postsurgical, febrile seizures), emotional stress (e.g., panic attacks), smoking Confirm with history
  • 11. Chronic inflammation Rheumatic disease, inflammatory bowel disease, granulomatous disease, vasculitides, chronic hepatitis Obtain personal and family medical history Consider erythrocyte sedimentation rate and CRP levels, specific rheumatology laboratories Consider subspecialist consultation (e.g., rheumatology, gastroenterology) Medication induced Corticosteroids, beta agonists, lithium, epinephrine, colony-stimulating factors Confirm with history; consider discontinuation of medication, if warranted Bone marrow stimulation Hemolytic anemia, immune thrombocytopenia, bone marrow suppression recovery, colony- stimulating factors Complete blood count differential; compare with baseline values (if available)
  • 12. Examine peripheral smear Consider reticulocyte and lactate dehydrogenase levels Consider flow cytometry, bone marrow examination, hematology/ oncology consultation Splenectomy History of trauma or sickle cell disease Confirm with history Congenital Hereditary/chronic idiopathic neutrophilia, Down syndrome, leukocyte adhesion deficiency Obtain family, developmental history Consider hematology/oncology, genetics, and immunology consultations NOTE: After patient characteristics, causes are listed in approximate order of frequency. CRP = C-reactive protein; WBC = white blood cell. Information from references 1 through 7, 9, and 10. Table 2. Normal White Blood Cell Distribution White blood cell line Normal percentage of total leukocyte count
  • 13. Neutrophils 40 to 60 Lymphocytes 20 to 40 Monocytes 2 to 8 Eosinophils 1 to 4 Basophils 0.5 to 1 Information from reference 8. Leukocytosis December 1, 2015 ◆ Volume 92, Number 11 www.aafp.org/afp American Family Physician 1007 although uncommon, may suggest allergic conditions such as asthma, urticaria, atopic dermatitis or eosinophilic esophagitis, drug reactions, dermatologic conditions, malig- nancies, connective tissue disease, idiopathic hypereosinophilic syndrome, or parasitic infections, including helminths (tissue par- asites more than gut-lumen parasites).11,12 Isolated basophilia (number of basophils greater than 100 per mm3 [0.1 × 109 per L]) is rare and unlikely to cause leukocytosis in isolation, but it can occur with allergic or inflammatory conditions and chronic myelogenous leukemia13 (Table 4). Nonmalignant Etiologies
  • 14. A reactive leukocytosis, typically in the range of 11,000 to 30,000 per mm3 (11.0 to 30.0 × 109 per L), can arise from a variety of etiologies. Any source of stress can cause a catecholamine-induced demargination of WBCs, as well as increased release from the bone marrow storage pool. Examples include surgery, exercise, trauma, burns, and emo- tional stress.9 One study showed an average increase in WBCs of 2,770 per mm3 (2.77 × 109 per L) peaking on postoperative day 2 after knee or hip arthroplasty.10 Medications known to increase the WBC count include corticosteroids, lithium, colony-stimulating factors, beta agonists, and epinephrine. Dur- ing the recovery phase after hemorrhage or hemolysis, a rebound leukocytosis can occur. Leukocytosis is one of the hallmarks of infection. In the acute stage of many bacte- rial infections, there are primarily mature and immature neutrophils (Figure 2); sometimes, as the infection progresses, there is a shift to lymphocyte predominance. The release of less- mature bands and metamyelocytes into the peripheral circulation results in the so-called “left shift” in the WBC differential. Of note, some bacterial infections paradoxically cause neutropenias, such as typhoid fever, rickett- sial infections, brucellosis, and dengue.1,14 Viral infections may cause leukocytosis early in their course, but a sustained leukocytosis is not typical, except for the lymphocytosis in some childhood viral infections. An elevated WBC count is a suggestive,
  • 15. but not definitive, marker of the presence of significant infection. For example, the sen- sitivity and specificity of an elevated WBC count in diagnosing acute appendicitis are 62% and 75%, respectively.15,16 For diagnos- ing serious bacterial infections without a Table 4. Selected Conditions Associated with Elevations in Certain White Blood Cell Types White blood cell line Conditions that typically cause elevations Basophils Allergic conditions, leukemias Eosinophils Allergic conditions, dermatologic conditions, eosinophilic esophagitis, idiopathic hypereosinophilic syndrome, malignancies, medication reactions, parasitic infections Lymphocytes Acute or chronic leukemia, hypersensitivity reaction, infections (viral, pertussis) Monocytes Autoimmune disease, infections (Epstein-Barr virus, fungal, protozoan, rickettsial, tuberculosis), splenectomy Neutrophils Bone marrow stimulation, chronic inflammation, congenital, infection, medication induced, reactive, splenectomy Figure 2. Neutrophilia postsplenectomy with sepsis. An 18- year-old woman with distal pancreatectomy and splenectomy for benign
  • 16. pancreatic pseudopapillary tumor two weeks earlier presents to the emergency department with a temperature of 103°F (39.4°C), leuko- cytosis with bandemia, tachycardia, and urinalysis results consistent with infection. White blood cell count = 57,100 per mm3 (57.1 × 109 per L), hemoglobin = 12.6 g per dL (126 g per L), platelet count = 832,000 per mm3 (832 × 109 per L). White blood cell differential: 75.4% seg- mented cells, 19.3% bands. Note neutrophils (arrows) with < 3 lobes to nuclei (band cells). Leukocytosis 1008 American Family Physician www.aafp.org/afp Volume 92, Number 11 ◆ December 1, 2015 source in febrile children, the discrimina- tory value of leukocytosis is less than that of other biomarkers, such as C-reactive protein or procalcitonin.17 Although a WBC count greater than 12,000 per mm3 (12.0 × 109 per L) is one of the criteria for the systemic inflammatory response syndrome (or sepsis when there is a known infection), leukocy- tosis alone is a poor predictor of bacteremia and not an indication for obtaining blood cultures.18,19 Other acquired causes of leukocytosis
  • 17. include functional asplenia (predominantly lymphocytosis), smoking, and obesity. Patients with a chronic inflammatory condi- tion, such as rheumatoid arthritis, inflam- matory bowel disease, or a granulomatous disease, may also exhibit leukocytosis. Genetic causes include hereditary or chronic idiopathic neutrophilia and Down syndrome. Malignant Etiologies Leukocytosis may herald a malignant dis- order, such as an acute or chronic leukemia (Figure 3), or a myeloproliferative disorder, such as polycythemia vera, myelofibrosis, or essential thrombocytosis. A previous article on leukemia in American Family Physician reviewed the features and differentiation of malignant hematopoietic disorders.20 Many solid tumors may lead to a leukocytosis in the leukemoid range, either through bone marrow involvement or production of gran- ulocyte colony-stimulating or granulocyte- macrophage colony-stimulating factors1,3,21 (Figure 4). Chronic leukemias are most com- monly diagnosed after incidental findings of leukocytosis on complete blood counts in asymptomatic patients. Patients with fea- tures suggestive of hematologic malignancies require prompt referral to a hematologist/ oncologist (Table 5).3,22 Approach to Evaluation A systematic approach to patients with leu- kocytosis includes identifying historical clues that suggest potential causes (Figure 5). Fever and pain may accompany infections
  • 18. or malignancies; other constitutional symp- toms, such as fatigue, night sweats, weight loss, easy bruising, or bleeding, might suggest Figure 3. Lymphocytosis in a 70-year-old woman with a history of chronic lymphocytic leukemia presenting to the emergency depart- ment with a five-day history of subjective fevers, sore throat, and cough. White blood cell count = 147,500 per mm3 (147.5 × 109 per L), hemoglobin = 8.8 g per dL (88 g per L), platelet count = 82,000 per mm3 (82 × 109 per L). White blood cell differential: 96.6% lympho- cytes (monomorphic). Note many mature lymphocytes (small nuclei near the size of a red blood cell with thin rim cytoplasm; black arrows) and many smudge cells (white arrows). Figure 4. Eosinophilia in malignancy in a 76-year-old man with a his- tory significant for metastatic prostate cancer presenting for che- motherapy. White blood cell count = 26,600 per mm3 (26.6 × 109 per L), hemoglobin = 10.8 g per dL (108 g per L), hematocrit = 32.6%. White blood cell differential: 51.8% eosinophils, 36.8% neutrophils, 6% lymphocytes, 4.5% monocytes, 0.9% basophils. Note eosinophils (arrows).
  • 19. Leukocytosis December 1, 2015 ◆ Volume 92, Number 11 www.aafp.org/afp American Family Physician 1009 malignancy.22 Previous diagnoses or comor- bid conditions that cause chronic inflam- mation should be noted, as well as recent stressful events, medication use, smoking status, and history of splenectomy or sickle cell anemia. A history of an elevated WBC count is important, because duration will help determine the likely cause. Leukocy- tosis lasting hours to days has a different differential diagnosis (e.g., infections, acute leukemias, stress reactions) than a case that persists for weeks to months (e.g., chronic inflammation, some malignancies). The physical examination should note erythema, swelling, or lung findings sug- gestive of an infection; murmurs suggestive of infective endocarditis; lymphadenopathy suggestive of a lymphoproliferative disor- der; or splenomegaly suggestive of chronic myelogenous leukemia or a myeloprolifera- tive disorder; petechiae or ecchymoses; or painful, inflamed joints suggestive of con- nective tissue disease or infection. Initial laboratory evaluation should include a repeat complete blood count to confirm the elevated WBC level, with differ-
  • 20. ential cell counts and a review of a peripheral blood smear. The peripheral smear should be examined for toxic granulations (suggestive of inflammation), platelet clumps (which may be misinterpreted as WBCs), the pres- ence of immature cells, and uniformity of the WBCs. On evaluation of a leukocytosis with lymphocyte predominance, a monomorphic population is concerning for chronic lym- phocytic leukemia, whereas a pleomorphic (varying sizes and shapes) lymphocytosis is suggestive of a reactive process.4,23 With all forms of leukocytosis, concurrent abnor- malities in other cell counts (erythrocytes or platelets) suggest a primary bone mar- row process and should prompt hematology/ oncology evaluation. As indicated by the history and examina- tion findings, physicians should consider performing cultures of blood, urine, and joint or body fluid aspirates; rheumatol- ogy studies; a test for heterophile antibod- ies (mononucleosis spot test); and serologic titers. Radiologic studies may include chest radiography (to identify infections, some malignancies, and some granulomatous dis- eases) and, as indicated by history, computed tomography or bone scan. If hematologic malignancy is suspected, additional confir- matory testing may include flow cytometry, cytogenetic testing, or molecular testing of the bone marrow or peripheral blood. Data Sources: The primary literature search was completed using Essential Evidence Plus and included
  • 21. searches of the Cochrane, POEM, and NICE guideline databases using the search term leukocytosis. In addition, PubMed searches were performed using the terms leu- kocytosis and white blood cell. Search dates: October 31 and December 17, 2014, and September 2015. The authors thank Melissa King, MD, Department of Hematology/Oncology, Eglin Air Force Base Hospital, for reviewing the manuscript, and Niquanna Perez, Eglin Air Force Base laboratory services, for procuring peripheral smear images. The views expressed in this article are those of the authors and do not reflect the official policy or position of the U.S. government, the Department of Defense, or the U.S. Air Force. Table 5. Findings Suggestive of Hematologic Malignancies in the Setting of Leukocytosis Symptoms Bruising/bleeding tendency Fatigue, weakness Fever > 100.4°F (38°C) Immunosuppression Night sweats Unintentional weight loss Physical examination findings
  • 22. Lymphadenopathy Petechiae Splenomegaly or hepatomegaly Laboratory abnormalities Decreased red blood cell count or hemoglobin/hematocrit levels Increased or decreased platelet count Monomorphic lymphocytosis on peripheral smear Predominantly immature cells on peripheral smear White blood cell count > 30,000 per mm3 (30.0 × 109 per L), or > 20,000 per mm3 (20.0 × 109 per L) after initial management Information from references 3 and 22. Leukocytosis Evaluation of Leukocytosis Figure 5. Algorithm for the evaluation of leukocytosis. (ANA = antinuclear antibodies; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate.) Leukocytosis (white blood cell count > 11,000 per mm3 [11.0 ×
  • 23. 109 per L]) Repeat complete blood count Order peripheral smear Leukocytosis confirmed? Obtain additional history and perform physical examination Leukocytosis explained by history or patient characteristics (e.g., pregnancy, newborn, splenectomy, smoking, medications)? No further workup necessary No further workup necessary Patient presents with: Weight loss, fatigue, night sweats, fevers Abnormal red blood cell and platelet count Immature leukocyte forms (blasts) Chronic duration (weeks or years) History of or risk factors for malignancy, splenomegaly, lymphadenopathy, bruising? Consider malignancy: Hematology/oncology consultation Consider additional testing to include flow cytometry, cytogenetic testing, or molecular
  • 24. testing of the bone marrow or peripheral blood Consider nonmalignant etiologies Which cell line is affected? No Yes No Yes No Yes Basophilia (> 100 per mm3 [0.1 × 109 per L]; rare): Search for malignancy (or allergic condition, much less likely) Monocytosis (> 880 per mm3 [0.88 × 109 per L]): Infections (Epstein-Barr virus, tuberculosis, fungal, protozoan, rickettsial) Autoimmune disease Splenectomy Consider: Sick contact, surgical, and travel history Imaging (chest radiography)
  • 25. Pathogen-specific testing (mononucleosis spot test, purified protein derivative) ESR, CRP, and ANA measurement Neutrophilia (> 7,000 per mm3 [7.0 × 109 per L]): Infection Chronic inflammation Recent stressors Medication induced Bone marrow stimulation Splenectomy Tobacco use (see Table 3) Consider: Medical, medication, family, travel, sick contact, surgical, and social history ESR, CRP, and ANA measurement
  • 26. Pathogen isolation (blood cultures, lumbar puncture) Additional imaging (system-specific) Lymphocytosis (> 4,500 per mm3 [4.5 × 109 per L]): Infections (viral, pertussis) Hypersensitivity reaction Consider: Sick contact and immunization history Imaging (chest radiography) Pathogen-specific testing (viral panels) Eosinophilia (> 500 per mm3 [0.5 × 109 per L]): Allergic conditions Eosinophilic esophagitis Medication reactions Dermatologic conditions
  • 27. Parasitic infections Consider: Medication, travel history Full skin examination Skin biopsy, if warranted Allergy/immunology testing Parasite-specific testing (stool ova and parasites) Upper endoscopy Leukocytosis December 1, 2015 ◆ Volume 92, Number 11 www.aafp.org/afp American Family Physician 1011 The Authors LYRAD K. RILEY, MD, is a faculty member at the U.S. Air Force Eglin Family Medicine Residency Program, Eglin Air Force Base, Fla., and an assistant professor in the Department of Family Medicine at the Uniformed Services University of the Health Sciences School of Medicine, Bethesda, Md. JEDDA RUPERT, MD, is a second-year resident at the U.S. Air Force Eglin Family Medicine Residency Program.
  • 28. Address correspondence to Lyrad K. Riley, MD, Eglin AFB Family Medicine Residency, 307 Boatner Rd., Eglin Air Force Base, FL 32542 (e-mail: [email protected]). Reprints are not available from the authors. REFERENCES 1. Cerny J, Rosmarin AG. Why does my patient have leu- kocytosis? Hematol Oncol Clin North Am. 2012;26(2): 303-319, viii. 2. Jain R, Bansal D, Marwaha RK. Hyperleukocytosis: emergency management. Indian J Pediatr. 2013;80(2): 144-148. 3. Hoffman R, Benz EJ Jr, Silberstein LE, Heslop H, Weitz J, Anastasi J. Hematology: Basic Principles and Practice. 6th ed. Philadelphia, Pa.: Elsevier/Saunders; 2013:table 164-20. 4. Chabot-Richards DS, George TI. Leukocytosis. Int J Lab Hematol. 2014;36(3):279-288. 5. Lurie S, Rahamim E, Piper I, Golan A, Sadan O. Total and differential leukocyte counts percentiles in normal pregnancy. Eur J Obstet Gynecol Reprod Biol. 2008; 136(1):16-19. 6. Dior UP, Kogan L, Elchalal U, et al. Leukocyte blood count during early puerperium and its relation to puer- peral infection. J Matern Fetal Neonatal Med. 2014; 27(1):18-23. 7. Lim EM, Cembrowski G, Cembrowski M, Clarke G. Race-specific WBC and neutrophil count reference
  • 29. intervals. Int J Lab Hematol. 2010;32(6 pt 2):590-597. 8. Berliner N. Leukocytosis and leukopenia. In: Goldman L, Schafer AI, eds. Goldman’s Cecil Medicine. 24th ed. Philadelphia, Pa.: Elsevier/Saunders; 2012. 9. Iskandar JW, Griffeth B, Sapra M, Singh K, Giugale JM. Panic-attack-induced transient leukocytosis in a healthy male: a case report. Gen Hosp Psychiatry. 2011; 33(3):302.e11-302.e12. 10. Deirmengian GK, Zmistowski B, Jacovides C, O’Neil J, Parvizi J. Leukocytosis is common after total hip and knee arthroplasty. Clin Orthop Relat Res. 2011; 469(11):3031-3036. 11. Ustianowski A, Zumla A. Eosinophilia in the returning traveler. Infect Dis Clin North Am. 2012;26(3):781-789. 12. Cormier SA, Taranova AG, Bedient C, et al. Pivotal Advance: eosinophil infiltration of solid tumors is an early and persistent inflammatory host response. J Leu- koc Biol. 2006;79(6):1131-1139. 13. Munker R. Leukocytosis, leukopenia, and other reactive changes of myelopoiesis. In: Munker R, Hiller E, Glass J, Paquette R, eds. Modern Hematology: Biology and Clinical Management. 2nd ed. Totowa, N.J.; Humana Press; 2007. 14. Potts JA, Rothman AL. Clinical and laboratory features that distinguish dengue from other febrile illnesses in endemic populations. Trop Med Int Health. 2008;13(11): 1328-1340. 15. Yu CW, Juan LI, Wu MH, Shen CJ, Wu JY, Lee CC.
  • 30. Systematic review and meta-analysis of the diagnostic accuracy of procalcitonin, C-reactive protein and white blood cell count for suspected acute appendicitis. Br J Surg. 2013;100(3):322-329. 16. Van den Bruel A, Thompson MJ, Haj-Hassan T, et al. Diagnostic value of laboratory tests in identifying seri- ous infections in febrile children: systematic review. BMJ. 2011;342:d3082. 17. Yo CH, Hsieh PS, Lee SH, et al. Comparison of the test characteristics of procalcitonin to C-reactive protein and leukocytosis for the detection of serious bacterial infec- tions in children presenting with fever without source: a systematic review and meta-analysis. Ann Emerg Med. 2012;60(5):591-600. 18. Dellinger RP, Levy MM, Rhodes A, et al.; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: interna- tional guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637. 19. Coburn B, Morris AM, Tomlinson G, Detsky AS. Does this adult patient with suspected bacteremia require blood cultures? [published correction appears in JAMA. 2013;309(4):343]. JAMA. 2012;308(5):502-511. 20. Davis AS, Viera AJ, Mead MD. Leukemia: an overview for primary care. Am Fam Physician. 2014;89(9):731-738. 21. Granger JM, Kontoyiannis DP. Etiology and outcome of extreme leukocytosis in 758 nonhematologic cancer patients: a retrospective, single-institution study. Can- cer. 2009;115(17):3919-3923.
  • 31. 22. Racil Z, Buresova L, Brejcha M, et al. Clinical and labora- tory features of leukemias at the time of diagnosis: an analysis of 1,004 consecutive patients. Am J Hematol. 2011;86(9):800-803. 23. George TI. Malignant or benign leukocytosis. Hema- tology Am Soc Hematol Educ Program. 2012;2012: 475-484.