21/8/2020 Leukocytosis: Basics of Clinical Assessment - American Family Physician

Leukocytosis: Basics of Clinical Assessment

NEIL ABRAMSON, M.D., and BECKY MELTON, M.D., Baptist Regional Cancer Institute, Jacksonville, Florida
Am Fam Physician. 2000 Nov 1;62(9):2053-2060.

  A more recent article on leukocytosis is available (https://www.aafp.org/afp/2015/1201/p1004.html).

Leukocytosis, a common laboratory finding, is most often due to relatively benign conditions (infections or
inflammatory processes). Much less common but more serious causes include primary bone marrow
disorders. The normal reaction of bone marrow to infection or inflammation leads to an increase in the
number of white blood cells, predominantly polymorphonuclear leukocytes and less mature cell forms (the
“left shift”). Physical stress (e.g., from seizures, anesthesia or overexertion) and emotional stress can also
elevate white blood cell counts. Medications commonly associated with leukocytosis include
corticosteroids, lithium and beta agonists. Increased eosinophil or basophil counts, resulting from a variety
of infections, allergic reactions and other causes, can lead to leukocytosis in some patients. Primary bone
marrow disorders should be suspected in patients who present with extremely elevated white blood cell
counts or concurrent abnormalities in red blood cell or platelet counts. Weight loss, bleeding or bruising,
liver, spleen or lymph node enlargement, and immunosuppression also increase suspicion for a marrow
disorder. The most common bone marrow disorders can be grouped into acute leukemias, chronic leukemias
and myeloproliferative disorders. Patients with an acute leukemia are more likely to be ill at presentation,
whereas those with a chronic leukemia are often diagnosed incidentally because of abnormal blood cell
counts. White blood cell counts above 100,000 per mm3 (100 × 109 per L) represent a medical emergency
because of the risk of brain infarction and hemorrhage.

Leukocytosis, de ned as a white blood cell count greater than 11,000 per mm3 (11 ×109 per L),1 is frequently
found in the course of routine laboratory testing. An elevated white blood cell count typically reflects the normal
response of bone marrow to an infectious or inflammatory process. Occasionally, leukocytosis is the sign of a
primary bone marrow abnormality in white blood cell production, maturation or death (apoptosis) related to a
leukemia or myeloproliferative disorder. Often, the family physician can identify the cause of an elevated white
blood cell count based on the ndings of the history and physical examination coupled with basic data from the
complete blood count.

Production, Maturation and Survival of Leukocytes

Common progenitor cells, referred to as “stem cells,” are located in the bone marrow and give rise to
erythroblasts, myeloblasts and megakaryoblasts. Three quarters of the nucleated cells in the bone marrow are
committed to the production of leukocytes. These stem cells proliferate and differentiate into granulocytes
(neutrophils, eosinophils and basophils), monocytes and lymphocytes, which together comprise the absolute

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white blood cell count. Approximately 1.6 billion granulocytes per kg of body weight are produced each day, and
50 to 75 percent of these cells are neutrophils.2 An abnormal elevation in the neutrophil count (neutrophilia)
occurs much more commonly than an increase in eosinophils or basophils.

The maturation of white blood cells in the bone marrow and their release into the circulation are influenced by
colony-stimulating factors, interleukins, tumor necrosis factor and complement components.3 Approximately
90 percent of white blood cells remain in storage in the bone marrow, 2 to 3 percent are circulating and 7 to 8
percent are located in tissue compartments.

The cells within the bone marrow compartment are classi ed into two populations: those that are in the
process of DNA synthesis and maturation and those that are in a storage phase awaiting release into the
circulating pool. The storage of maturing cells allows for rapid response to the demand for increased white
blood cells, with a two- to threefold increase in circulating leukocytes possible in just four to ve hours.

The circulating pool of neutrophils is divided into two classes. One pool of cells is circulating freely, and the
second pool is deposited along the margins of blood vessel walls. When stimulated by infection, inflammation,
drugs or metabolic toxins, the deposited cells “demarginate” and enter the freely circulating pool.

Once a leukocyte is released into circulation and tissue, it remains there only a few hours, at which time cell
death occurs. The estimated life span of a white blood cell is 11 to 16 days, with bone marrow maturation and
storage comprising the majority of the cell's life.

Etiology of Leukocytosis
The investigation of leukocytosis begins with an understanding of its two basic causes: (1) the appropriate
response of normal bone marrow to external stimuli and (2) the effect of a primary bone marrow disorder.
Physiologic mechanisms of leukocytosis are listed in Table 1.

View/Print Table
TABLE 1
Pathophysiologic Mechanisms of Leukocytosis

Normally responding bone marrow

Infection

Inflammation: tissue necrosis, infarction, burns, arthritis

Stress: overexertion, seizures, anxiety, anesthesia

Drugs: corticosteroids, lithium, beta agonists

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Trauma: splenectomy

Hemolytic anemia

Leukemoid malignancy

Abnormal bone marrow

Acute leukemias

Leukocytosis with Normal Bone Marrow

In most instances, increased white blood cell counts are the result of normal bone marrow reacting to
inflammation or infection. Most of these cells are polymorphonuclear leukocytes (PML). Circulating PML and
less mature forms (e.g., band cells and metamyelocytes) move to a site of injury or infection. This is followed
by the release of stored leukocytes, commonly referred to as a “left shift.” Inflammation-associated leukocytosis
occurs in tissue necrosis, infarction, burns and arthritis.

Leukocytosis may also occur as a result of physical and emotional stress.4,5 This is a transient process that is
not related to marrow production or the release of band cells or other immature cells. Causes of stress
leukocytosis include overexertion, seizures, anxiety, anesthesia and epinephrine administration. Stress
leukocytosis reverses within hours of elimination of the inciting factor.

Other causes of leukocytosis include medications, splenectomy, hemolytic anemia and malignancy.
Medications commonly associated with leukocytosis include corticosteroids, lithium and beta agonists.1,6,7
Splenectomy causes a transient leukocytosis that lasts for weeks to months. In hemolytic anemia, non-speci c
increases in leukocyte production and release occur in association with increased red blood cell production;
marrow growth factors are likely contributors. Malignancy is another recognized cause of leukocytosis (and,
occasionally, thrombocytosis); the tumor non-speci cally stimulates the marrow to produce leukocytosis.

An excessive white blood cell response (i.e., more than 50,000 white blood cells per cm3 [50 × 109 per L])
associated with a cause outside the bone marrow is termed a “leukemoid reaction.” Even this exaggerated
white blood cell count is usually caused by relatively benign processes (i.e., infection or inflammation). An
underlying malignancy is the most serious but least common cause of a leukemoid reaction.

As mentioned previously, an increase in neutrophils is the most common cause of an elevated white blood cell
count, but other sub-populations of cells (eosinophils, basophils, lymphocytes and monocytes) can also give
rise to increased leukocyte numbers.

EOSINOPHILIA

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Eosinophils are white blood cells that participate in immunologic and allergic events. Common causes of
eosinophilia are listed in Table 2. The relative frequency of each cause usually relates to the clinical setting. For
example, parasitic infections are often responsible for eosinophilia in pediatric patients, and drug reactions
commonly cause an increased eosinophil count in hospitalized patients. Dermatologists frequently nd
eosinophilia in patients with skin rashes, and pulmonologists often see elevated numbers of eosinophils in
conjunction with pulmonary in ltrates and bronchoallergic reactions.

View/Print Table
TABLE 2
Etiology of Eosinophilia

Allergic events

Parasitic infections

Dermatologic conditions

Infections: scarlet fever, chorea, leprosy, genitourinary infections

Immunologic disorders: rheumatoid arthritis, periarteritis, lupus erythematosus, eosinophilia-myalgia

syndrome

Pleural and pulmonary conditions: Löffler's syndrome, pulmonary in ltrates and eosinophilia

Malignancies: non-Hodgkin's lymphoma, Hodgkin's disease

Myeloproliferative disorders: chronic myelogenous leukemia, polycythemia vera, myelo brosis

Adrenal insuf ciency: Addison's disease

Sarcoidosis

Other causes of eosinophilia include malignancies, especially those affecting the immune system (Hodgkin's
disease and non-Hodgkin's lymphoma),8 and immunologic disorders such as rheumatoid arthritis and
periarteritis. Eosinophilia-myalgia syndrome, a recently described disorder associated with dietary supplements
of tryptophan, resembles a connective tissue disease with brosis of muscle fascial tissue and peripheral
eosinophilia.9

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BASOPHILIA
Basophilia is an uncommon cause of leukocytosis. Basophils are inflammatory mediators of substances such
as histamine. These cells, along with similar tissue-based cells (mast cells), have receptors for IgE and
participate in the degranulation of white blood cells that occurs during allergic reactions, including
anaphylaxis.10  Causes of basophilia, some of uncertain origin, are listed in Table 3.

View/Print Table
TABLE 3
Etiology of Basophilia

Infections: viral infections (varicella), chronic sinusitis

Inflammatory conditions: inflammatory bowel disease, chronic airway inflammation, chronic dermatitis

Myeloproliferative disorders: chronic myelogenous leukemia, polycythemia vera, myelo brosis

Alteration of marrow and reticuloendothelial compartments: chronic hemolytic anemia, Hodgkin's

disease, splenectomy

Endocrinologic causes: hypothyroidism, ovulation, estrogens

LYMPHOCYTOSIS
Lymphocytes normally represent 20 to 40 percent of circulating white blood cells. Hence, the occurrence of
lymphocytosis often translates into an increase in the overall white blood cell count. Increased numbers of
lymphocytes occur with certain acute and chronic infections (Table 4). Malignancies of the lymphoid system
may also cause lymphocytosis.

View/Print Table
TABLE 4
Etiology of Lymphocytosis

Absolute lymphocytosis

Acute infections: cytomegalovirus infection, Epstein-Barr virus infection, pertussis, hepatitis,

toxoplasmosis

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Chronic infections: tuberculosis, brucellosis

Lymphoid malignancies: chronic lymphocytic leukemia

Relative lymphocytosis

Normal in children less than 2 years of age

Acute phase of several viral illnesses

Connective tissue diseases

Thyrotoxicosis

ddi ' di
Relative, rather than absolute, leukocytosis occurs in a number of clinical situations, such as infancy, viral
infections, connective tissue diseases, thyrotoxicosis and Addison's disease. Splenomegaly causes relative
lymphocytosis as a result of splenic sequestration of granulocytes.

Leukocytosis with Primary Bone Marrow Disorders

Clinical factors that increase suspicion of an underlying bone marrow disorder are listed in Table 5. Bone
marrow disorders are generally grouped into leukemias and myeloproliferative disorders.

View/Print Table
TABLE 5
Clinical Factors Increasing Suspicion of an Underlying Bone Marrow Disorder

Leukocytosis: white blood cell count greater than 30,000 per mm3 (30 × 109 per L)*

Concurrent anemia or thrombocytopenia

Organ enlargement: liver, spleen or lymph nodes

Life-threatening infection or immunosuppression

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Bleeding, bruising or petechiae

Lethargy or signi cant weight loss

* —If the white blood cell count is greater than 100,000 per mm3 (100 × 109 per L), a hematology consultation
should be promptly obtained.

Marrow abnormalities may occur with stem cells (acute leukemia) or more differentiated cells (chronic
leukemia). Delineating acute leukemias from chronic leukemias is clinically important because the acute forms
are more often associated with rapidly life-threatening complications such as bleeding, brain infarction and
infection. Differences in the clinical presentations of acute and chronic leukemias are provided in Table 6.

View/Print Table
TABLE 6
Differential Characteristics of Acute and Chronic Leukemias

PATIENT GROUP AND TYPE OF

SYMPTOMS SIGNS LABORATORY FINDINGS
LEUKEMIA

Children: acute Infection, Enlarged Variable white blood cell

lymphocytic leukemia bleeding, liver, spleen count, anemia,
weakness or lymph thrombocytopenia, blast
Adults: acute nodes cells
nonlymphocytic
leukemia (acute myeloid
leukemia)

Adults: chronic None, or Enlarged Leukocytosis (myeloid

myelogenous leukemia malaise and spleen precursors), normal or
abdominal increased platelet count
discomfort

Older adults: chronic None, or Enlarged Leukocytosis

lymphocytic leukemia nonspeci c spleen or (lymphocytes)
symptoms lymph
nodes

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ACUTE LEUKEMIAS
Patients with an acute leukemia often present with signs and symptoms of bone marrow failure, such as
fatigue and pallor, fever, infection and/or bleeding with purpura and petechiae. In acute leukemias, the marrow
is typically overpopulated with blast cells. These cells are indistinguishable from stem cells by light microscopy,
but the term “blast” implies an acute leukemic clone. The maturing normal marrow cellular elements are
decreased or absent. Peripheral leukemic cell counts may range from leukocytosis to leukopenia, but, as
anticipated, anemia and thrombocytopenia are common.

The acute leukemias are broadly divided into two classes based on the cell of origin: acute lymphocytic
leukemia and acute non-lymphocytic leukemia. The previous designation of “acute myeloid leukemia” has been
replaced by “acute nonlymphocytic leukemia” to appropriately encompass the full variety of possible abnormal
cells (undifferentiated, myeloid, monocytic and megakaryocytic).

Acute lymphocytic leukemia most commonly occurs in children less than 18 years of age. Adults usually have
acute nonlymphocytic leukemia. Occasionally, patients with acute lymphocytic leukemia have a mediastinal
mass or central nervous system involvement at the onset of illness.

Blast cells are often seen in the peripheral blood smears of patients with acute leukemia. Auer rods, as shown
in Figure 1, are a marker of acute nonlymphocytic leukemia. Because Auer rods do not appear frequently,
precise distinction between acute lymphocytic leukemia and acute nonlymphocytic leukemia usually cannot be
accomplished based on the peripheral smear alone; histochemistry, immunotyping and chromosome analysis
are usually required.

View/Print Figure

FIGURE 1.

Peripheral blood smear from a patient with acute nonlymphocytic leukemia. Note the presence of
immature cells containing large nuclei and little cytoplasm. Note, also, the linear red inclusions, or Auer
rods (arrows), in the cytoplasm of several blast cells. Auer rods are markers of acute nonlymphocytic
leukemia. (Oil immersion, 1,000×)

All patients with acute leukemia require prompt attention and therapy. White blood cell counts in excess of
100,000 per mm3 (100 × 109 per L) constitute a medical emergency because patients with this degree of
leukocytosis are predisposed to brain infarction or hemorrhage.

CHRONIC LEUKEMIAS
Patients with a chronic leukemia typically present with much less severe illness than those with an acute
leukemia. Chronic leukemia is usually diagnosed incidentally based on high white blood cell counts. The
chronic leukemias are divided into two groups according to the cell of origin: chronic lymphocytic leukemia and
chronic myelogenous leukemia.

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Chronic lymphocytic leukemia results from the proliferation and persistence (lack of apoptosis) of relatively
mature-appearing lymphocytes (Figure 2). The spleen and lymph nodes are enlarged because of the excessive
accumulation of lymphocytes. Despite the increased number of lymphocytes, this disease is associated with
impaired immunity as a result of the scarcity of normal lymphocytes.

View/Print Figure

FIGURE 2.

Peripheral blood smear from a patient with chronic lymphocytic leukemia. Note the presence of many
mature-appearing “normal” lymphocytes. The degenerated nuclei (arrows) are called “smudge cells.”
Blast cells are not present. (Oil immersion, 1,000×)

Unless complications are present, patients with chronic lymphocytic leukemia do not require urgent referral to a
hematologist. In the absence of symptoms, such as fever, sweats, weight loss, anemia, moderate
thrombocytopenia or organ enlargement, the leukocytosis usually does not require treatment.

Chronic myelogenous leukemia, which affects myeloid cells (polymorphonuclear cells and less mature cell
forms), is frequently diagnosed after the incidental nding of a high white blood cell count. A peripheral blood
smear from a patient with this form of leukemia is shown in Figure 3. In some situations, the smear can also
show increases in basophils or eosinophils.

View/Print Figure

FIGURE 3.

Peripheral blood smear from a patient with chronic myelogenous leukemia. Note the presence of
polymorphonuclear leukocytes and earlier cell forms (metamyelocytes and myelocytes). As in most
patients with this type of leukemia, blast cells are absent. (Oil immersion, 1,000×)

Middle-aged adults more commonly develop chronic myelogenous leukemia. Some patients describe fatigue,
bleeding or weight loss. Splenomegaly is frequently present, and the markedly enlarged spleen sometimes
causes abdominal discomfort, indigestion or early satiety. Lymphadenopathy is uncommon.

Platelet counts are usually normal to increased. In fact, chronic myelogenous leukemia is the only leukemic
process that is associated with thrombocytosis. Another laboratory feature that distinguishes this disease from
other leukemias and myeloproliferative disorders is the presence of the Philadelphia chromosome, an
abnormality of translocation between chromosome 22 and chromosome 9.

Chronic myelogenous leukemia eventually develops an accelerated phase and subsequently transforms into
acute leukemia. The accelerated phase is characterized by fever, sweats, weight loss, bone pain, bruising and
hepatosplenomegaly. During this time, thrombocytopenia and anemia develop. The median time for

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transformation of chronic myelogenous leukemia to acute leukemia is two to ve years. After the development
of acute leukemia, median survival is short.

MYELOPROLIFERATIVE DISORDERS
The myeloproliferative disorders include chronic myelogenous leukemia, polycythemia vera, myelo brosis and
essential thrombocythemia (Table 7). Because all of these entities may present with leukocytosis,
differentiation can be dif cult and usually requires special laboratory studies and bone marrow examinations.11

View/Print Table
TABLE 7
Characteristic Features of Myeloproliferative Diseases

DISEASE RED BLOOD CELLS WHITE BLOOD CELLS PLATELETS MARROW

Polycythemia vera Increased Normal or Normal or Hypercellular

increased increased

Chronic Normal or Increased Normal or Hypercellular

myelogenous increased increased
leukemia

Myelo brosis Normal or Variable Variable Fibrosis

decreased

Essential Normal or Slightly Increased Hypercellular

thrombocythemia decreased increased or
normal

Polycythemia vera usually presents with excessive numbers of erythroid cells, but increased white blood cell
and platelet counts may also be evident. Symptoms resulting from hypervolemia and hyperviscosity, such as
headache, dizziness, visual disturbances and paresthesias, are sometimes present. Less frequently, patients
with polycythemia vera develop myocardial infarction, stroke, venous thrombosis and congestive heart failure.
Overall survival is long (10 to 20 years).

Myelo brosis is a bone marrow disorder in which broblasts replace normal elements of the marrow. Patients
with myelo brosis are usually 50 years or older and have a median survival of less than 10 years. As bone
marrow brosis develops, patients can present with leukocytosis, although decreased white blood cell, red
blood cell and platelet counts are more common. Patients are asymptomatic early in the course of the disease

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and are usually diagnosed incidentally based on changes in blood cell counts. Symptomatic patients have
fatigue, shortness of breath, weight loss, bleeding or abdominal discomfort related to splenomegaly. Acute
leukemia can develop over time and, when it occurs, progresses rapidly.

Leukocytosis is also found in patients with essential thrombocythemia (primary thrombocythemia). Although
elevated platelet counts occur in all myeloproliferative disorders, essential thrombocythemia is distinguished by
the singular prominence of platelets. Markers of other disorders, such as the Philadelphia chromosome and
bone marrow brosis, are absent. It is important to exclude secondary thrombocytosis caused by nonmarrow
disorders (e.g., iron de ciency or bleeding). Most patients with essential thrombocythemia are asymptomatic
and require little, if any, therapy, although some patients develop thrombosis or hemorrhage secondary to
increased numbers of dysfunctional platelets.

Final Comment
Excessive numbers of white blood cells are most often due to the response of normal bone marrow to infection
or inflammation. In some instances, leukocytosis is a sign of more serious primary bone marrow disease
(leukemias or myeloproliferative disorders). Attention to clinical factors associated with marrow disorders, such
as extremely elevated white blood cell counts, abnormalities in red blood cell or platelet counts, weight loss,
bleeding and organ enlargement, can help the family physician decide which patients require further
investigation and consultation.

The Authors show all author info

NEIL ABRAMSON, M.D., is clinical professor of medicine at the University of Florida–Jacksonville and medical
director of education and research at Baptist Regional Cancer Institute, Baptist Medical Center, also in
Jacksonville. Dr. Abramson founded the hematology and medical oncology division at the University of Florida–
Jacksonville 29 years ago and continues to be the principal supervisor of the program at Baptist Medical
Center....

REFERENCES show all references

1. Shapiro MF, Green eld S. The complete blood count and leukocyte differential count. An approach to their
rational application. Ann Intern Med. 1987;106:65–74....

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