I. Problem/Condition.

Leukocytosis refers to an elevation in the total white blood cell count (WBC). Although each laboratory should establish its own normal range, the upper limit of normal for the WBC tends to be approximately 10-11 x1000 cells/uL, two standard deviations above the mean. The elevation can be due to one specific cell type, such as neutrophilia or lymphocytosis, or a mixture of cell types, and therefore a WBC differential is imperative to understanding its implications. Also important in understanding normal ranges is that slightly more than 2% of the normal population, based on the normal distribution in which the range was established, will have a chronic leukocytosis that is “normal” for them.

Leukemoid reaction is defined as an extremely elevated WBC (>30 x1000 cells/uL) in conjunction with a left-shift. A left shift signifies that there are immature white blood cells present such as bands, metamyelocytes, myelocytes, promyelocytes, and blasts. Also implicit in this definition is that although a leukemoid reaction appears like leukemia, it is not.

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II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

The two most familiar diagnostic categories are infection or primary hematologic disease. Infection is often self evident after a thorough history and physical examination. Note that some severe infections can result in extremely high WBCs, particularly Clostridium and Streptococcus pneumoniae.

Hematologic causes of leukocytosis include acute or chronic leukemias and myeloproliferative diseases. Typically, leukocytosis is not seen in myelodysplastic syndrome (MDS) unless MDS is transforming into acute leukemia or the MDS overlaps with a myeloproliferative syndrome. Myeloproliferative diseases include chronic myelogenous leukemia (CML), polycythemia vera, essential thrombocythemia, and primary myelofibrosis (previously known as myelofibrosis with myeloid metaplasia). Although CML typically elevates the WBC, polycythemia vera elevates the red blood cell count, and essential thrombocythemia raises the platelet count, all four myeloproliferative diseases overlap and each often results in a leukocytosis (less commonly with essential thrombocythemia).

In addition to infection and primary hematologic disease, the following other etiologies can lead to leukocytosis: Trauma and burns can cause a high WBC, sometimes very high (leukemoid reaction), as can non-hematologic neoplasms such as pancreatic cancer. Certain drugs lead to leukocytosis. These include filgrastim (G-CSF, granulocyte-colony stimulating factor), sargramostim (GM-CSF, granulocyte-macrophage colony stimulating factor), corticosteroids, epinephrine, beta-agonists, and notably lithium (while other psychiatric medications can cause neutropenia). Other autoimmune and inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, and pancreatitis, can cause a leukocytosis (or neutropenia).

Common causes, yet often forgotten, include smoking, exercise, pregnancy, and other types of stress. These frequently increase a WBC by 25%. However, that 25% increase usually does not surpass the WBC upper limit of normal. So keep in mind these causes result in only a mild leukocytosis when present.

Rare causes include thyroid storm, diabetic ketoacidosis, familial Mediterranean fever, asplenia, hereditary neutrophilia, and leukocyte adhesion defect.

Patients with acute promyelocytic leukemia (APL) can develop a leukocytosis during treatment as the promyelocytes begin to differentiate and mature into neutrophils. This is referred to as differentiation or leukocytosis syndrome and occurs with treatment using either tretinoin (ATRA) or arsenic.

B. Describe a diagnostic approach/method to the patient with this problem.

The cause of a leukocytosis can almost always be determined by history and physical exam. Vigilance for infection is essential, including assessment for sinus tenderness, neck stiffness, and a thorough skin evaluation for cellulitis.

1. Historical information important in the diagnosis of this problem.

Essential history taking for a patient with leukocytosis revolves around a thorough review of systems. Only by covering every organ system will the puzzle pieces come together. Do not stop after the first positive finding as infectious syndromes can involve multiple organ systems. Ask about B-symptoms (fever, night sweats, and weight loss), key for hematologic malignancies, frequent and recent infections, symptoms of anemia (fatigue, dizziness, dyspnea), and easy bruising.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Apart from hunting for signs of infection (erythema, respiratory crackles, abdominal tenderness, etc.), careful attention must be given to Traube’s space, the left upper quadrant where splenomegaly might be palpable in any myeloproliferative disease.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

In addition to the complete cell count, white blood cell differential, and peripheral blood smear, microbiologic tests (blood, sputum, urine, stool, Clostridium difficile toxin, etc.) and a chest x-ray are routinely helpful. Peripheral blood flow cytometry can spot a monoclonal proliferation of white blood cells while a bone marrow biopsy would be the definitive means of finding primary hematologic disease. If CML is suspected, BCR/ABL 9;21 translocation (Philadelphia chromosome) can be tested by polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) using peripheral blood.

In polycythemia vera, JAK2 mutation (also tested using peripheral blood) is positive in nearly 95% of patients. JAK2 should also be sent when essential thrombocythemia and primary myelofibrosis is suspected, but is positive in only 50% of these cases. Recently, calreticulin (CALR) was found to be mutated in roughly one-third of cases of essential thrombocythemia and primary myelofibrosis. Myeloproliferative leukemia (MPL) gene is mutated in 5% of these patients. Panels containing all three genes can now be sent for rapid gene sequencing and diagnosis of myeloproliferative diseases.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.


D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) will rarely help to clarify the diagnosis. ESR and CRP can be elevated in virtually every diagnosis noted above with the exception of drug-induced or hereditary causes. These markers of inflammation are helpful when tracking treatment response in chronic infections, particularly osteomyelitis.

Flow cytometry is the test of choice when evaluating a lymphocytosis. It is rarely helpful when evaluating a leukocytosis comprised mostly of neutrophils.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem Leukocytosis.

If the suspicion for bacterial infection is high, empiric antibiotic coverage should be started promptly after cultures are drawn. Steroids should be avoided until after biopsy in hematologic malignancies. If the diagnosis is unclear and the patient is stable, the leukocytosis can be monitored to ensure resolution or at minimum stability.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

CML is a diagnosis that should not be missed. A low threshold to send testing for BCR-ABL should be standard.

IV. What's the evidence?

Chakraborty, S, Keenportz, B, Woodward, S. “Paraneoplastic leukemoid reaction in solid tumors”. . vol. 38. 2015. pp. 326-30.

Granger, JM, Kontoyiannis, DP. “Etiology and outcome of extreme leukocytosis in 758 nonhematologic cancer patients: a retrospective, single-institution study”. . vol. 115. 2009. pp. 3919-23.

Kawada, T. “Smoking-induced leukocytosis can persist after cessation of smoking”. . vol. 35. 2004. pp. 246-50.

Wanahita, A, Goldsmith, EA, Musher, DM. “Conditions associated with leukocytosis in a tertiary care hospital, with particular attention to the role of infection caused clostridium difficile”. . vol. 34. 2002. pp. 1585-92.

This article originally appeared on Hematology Advisor