Continuing Education Activity

Leukocytosis also known as elevated white blood cell count is one of the common laboratory abnormalities commonly seen in the inpatient acute care setting as well as in the outpatient practice. Leukocytosis has a variety of etiologies with which practitioners of all backgrounds should be familiar. Basic interpretation of differential white cell count in leukocytosis helps in finding the underlying pathological process. Appropriate workup for leukocytosis help in finding the cause of elevated white cell count which may help in recognizing the disease at an early stage and can potentially save the patient from comorbidities. This activity outlines the basic approach towards leukocytosis, the interpretation of differential white cell counts, workup of leukocytosis, prompt referral to the specialist, treatment options available, and their utility for the interprofessional team involved in patient care.

Objectives:

• Describe the pathophysiology of leukocytosis-related medical conditions and emergencies.
• Review the risk factors for developing leukocytosis
• Identify the indications for extended evaluation of leukocytosis
• Review the management options available for leukocytosis and its subtypes

Introduction

Leukocytosis is defined as age appropriate increase in the white blood cell count(WBC). Elevation of white cell count above 11 x 10^9/L is usually considered leukocytosis in an adult.[1] The exact value of leukocytosis varies with age. A white cell count of 30,000/L is abnormal in an adult but may be appropriate and normal in a newborn individual.[2]

The exact value of white cell count varies in different laboratories depending on the "Upper normal limit" and the type of automated hematology analyzer used. Automated hematology analyzers can quickly process the whole blood samples for complete blood count and differentials including RBC count, WBC count, platelet count, hemoglobin and RBC indices, and WBC differentials. WBC is composed of neutrophils, lymphocytes, monocytes, basophils, and eosinophils. Hematology analyzers use cytochemistry and fluorescence techniques to differentiate various types of WBC and flag them as low or high based on appropriate algorithms provided to the machine. 

A review peripheral blood smear of flagged blood sample helps to establish manual differential and confirm the findings of automated differentials. A peripheral blood smear is a qualitative examination of the blood to evaluate clinically significant abnormalities in all cell lines. Peripheral blood smear requires slide formation and staining from fresh anticoagulated blood. [1]

It is important to take an appropriate history, perform a thorough physical examination, recognize underlying risk factors for leukocytosis, interpret the automated differentials and peripheral blood smear carefully, and refer the patients to the appropriate specialists for further evaluation of leukocytosis. Appropriate ancillary tests including flow cytometric immunophenotyping, molecular testing, genetic studies, and bone marrow examination help in identifying hematological malignancies.

Etiology

In the bone marrow, stem cells differentiate into megakaryoblasts (that will become platelet-producing megakaryocytes), erythroblasts (that will become erythrocytes or red blood cells), myeloblasts (that will become eosinophils, basophils, and neutrophils), monoblasts (that will become monocytes), and lymphoid progenitor cells (that will become B or T lymphocytes). The term 'leukocyte' applies to any cells within the myeloblast, monoblast, and lymphoid lineages. Leukocytosis can be classified based on the cell line that is elevated. A complete blood count (CBC) with predominantly elevated neutrophils is termed neutrophilia, eosinophils—eosinophilia, basophils—basophilia, monocytes—monocytosis, and lymphocytes—lymphocytosis. The type of cell elevated may help to identify the trigger for leukocytosis, and a detailed history and physical exam is important to support particular differential diagnoses of the particular leukocytosis presenting itself. This article will describe the general etiologies of some of the most common presentations of leukocytosis.

• Neutrophilia: Neutrophils typically make up about 40% to 60% of the total leukocyte count, and neutrophilia is the most common type of leukocytosis.[2] If the patient is currently undergoing a stressor, neutrophils, the most abundant leukocyte on peripheral smear under normal circumstances, will increase.[1] Increases occur from both upregulated bone marrow production and the demargination of existing neutrophils from the endothelium. Neutrophilia occurs most often in response to a stressor, termed reactive neutrophilia, but can also be the result of an autonomous process (e.g., chronic myeloid leukemia). Possible causes of acute elevations involve recent physical stress, emotional stress, infection, medications, trauma, and smoking. Chronic inflammation, such as rheumatic disease, inflammatory bowel disease, chronic hepatitis, vasculitides, chronic steroid use, bone marrow stimulating processes (hemolytic anemia, immune thrombocytopenia, colony-stimulating factors), and congenital diseases (Down syndrome, hereditary idiopathic neutrophilia), all have baseline neutrophilia. Pregnancy and obesity also have acute to chronic presentations of neutrophilia. 
  • Leukemoid Reaction: A leukemoid reaction is a transient increase in WBC count defined as significant neutrophilia >50x10^9/L in the absence of a myeloproliferative neoplasm. This acute inflammatory reaction can be mistaken for leukemia, but careful history, physical examination, and, if necessary, further laboratory evaluation can find that this reaction can occur in sepsis, organ rejection, solid tumors, and bacterial infections. Peripheral smears and radiological imaging may be necessary to identify the true cause of these reactive laboratory findings.[3] This must be separated from leukemia, which is defined as increases in blast cells (precursor cells to leukocytes) and immature WBCs, rather than mature neutrophils that are seen in a leukemoid reaction. A leukemoid reaction also improves after treating the underlying cause for the neutrophilia, whereas leukemia will continue to demonstrate elevated WBCs until definitive targeted treatment is completed. 
• Lymphocytosis: Lymphocytes, on average, make up approximately 20-40% of a person's total leukocyte count. Increases in lymphocytes in children are usually benign and related to the rapid growth and development of the immune system. Less benign conditions, such as viral infections, hypersensitivity reactions, leukemia, and lymphoma, can all cause lymphocytosis. A careful review of systems, history collection, and physical examination findings will help guide clinicians as to which etiology may be the cause of the presenting lymphocytosis. Evaluation of acute or chronic infection can help tailor the differential for lymphocytosis. Acute infections such as cytomegalovirus, Bordetella pertussis, hepatitis, toxoplasmosis, and Epstein-Barr have all been implicated in acute absolute lymphocytosis. Chronic infections, such as brucellosis and tuberculosis, have also been shown to have chronic lymphocytosis.[1] For these chronic infections, a complete review of organ systems and social history should be evaluated to identify these disease processes. 
• Eosinophilia: Eosinophils are approximately 1-4% of a person's total leukocyte count. Elevations above 0.5x10^9/L, which in the past have been identified as mild eosinophilia, is the generally accepted cut-off for eosinophilia. However, significant elevations over 1.5x10^9/L are the usual cut-off for further evaluation and consideration, especially in multiple CBCs separated in time. Eosinophilia can occur in neoplastic, inflammatory, infectious, parasitic, autoimmune, and allergic conditions.[4] A careful review of prior CBC lab analyses, looking for persistent eosinophilia, which is defined as two abnormal CBCs collected with a minimum time interval between the two lab draws of four weeks, should be completed by the primary care provider to evaluate for the less-benign causes of this phenomenon.[5] Medications, such as NSAIDs, common antibiotics (nitrofurantoin, quinolones, cephalosporins, penicillins, sulfa-containing drugs), have also been implicated in eosinophilia, and a careful medication reconciliation should be completed on patients presenting with this laboratory abnormality. It is most commonly elevated in allergic conditions, such as seasonal and environmental allergies, but evaluation for parasitic and infectious etiologies should be completed, especially if the patient has an exposure history or other risk factors.[6]
• Monocytes: Monocytes make up approximately 2-8% of a person's total leukocyte count.[2] Monocytes have been identified in patients with chronic infections, endocarditis, inflammatory conditions, autoimmune diseases, granulomatous diseases, malignancy, medication side effects, and myeloproliferative disorders. There is evidence they are a marker of poor prognostic outcomes in emergency room settings, suggested being related to coronary artery disease, atherosclerosis, and stroke. This should be considered in acute care settings when evaluating CBCs.[7] When monocytosis is persistent, careful consideration should be done to evaluate malignancy potential.[8]
• Basophils: Basophils compromise 0.5-1% of a person's peripheral blood smear.[2] Basophilia can occur in inflammatory conditions, viral infections, endocrinopathies, myeloproliferative disorders, and malignancies. Like eosinophils, it is also present in allergic or anaphylactic conditions, especially in reaction to drugs and food.[9] It is a relatively uncommon cause of leukocytosis.[10] Transient hyperbasophilia can occur as a reactive response, especially to an acute viral illness.  Persistent basophilia present on multiple CBCs for over eight weeks suggests an underlying malignancy or myeloproliferative disease, and leukemias associated with basophilia are extremely rare.[11]

Epidemiology

Leukocyte count is evaluated by collecting a peripheral blood smear through a routine blood draw. The cell count ranges vary depending on age and race. In general, leukocyte counts are significantly higher in infants than adults.[12] Through adolescence, lymphocytes predominate the peripheral smear. By adulthood, the peripheral blood smear shifts towards neutrophils being the predominant cell line. See Table 1 for general reference ranges.Black African, Middle Eastern, and West Indian descent also play a role in WBC count and differential. Patients of these backgrounds can have reduced WBC counts and lower absolute neutrophil counts compared to patients of Hispanic and European descent.[13] This has been termed benign ethnic neutropenia (BEN) and can be identified in a patient of African descent with no infectious concerns on history and physical examination and with chronically low neutrophils on CBC. This is an important consideration when evaluating a patient of African descent with BEN, as their presentation of leukocytosis may be within the normal laboratory reference range for CBCs, but be elevated in comparison to their prior CBCs.

Table 1: White Blood Cell Count Reference Range Changes with Age

Age Appropriate Reference Range for Leukocyte Count 

• Newborn: 13-38x10^9/L
• Birth-2 weeks: 5-20x10^9/L
• Adult: 4.5-11x10^9/L

Pathophysiology

Leukocytosis can occur acutely and often transiently or chronically in response to an inflammatory stressor/cytokine cascade or as part of an autonomous myeloproliferative neoplasm. Neutrophilia is the most common presentation, but clinicians should be aware of the other cell lines that can be involved in acute and chronic presentations. A detailed history, physical examination, medication reconciliation, full evaluation of a CBC with differential, and comparison to prior CBCs can help clinicians elucidate the underlying cause of leukocytosis and guide appropriate treatment.

Histopathology

Leukocytosis is a relatively common phenomenon on a CBC with a variety of causes. The first step is to obtain a CBC with differential, which evaluates the different cell lines. A peripheral blood smear can be helpful and is appropriate in patients with unexplained leukocytosis. It can be particularly helpful to obtain a manual differential for the analysis of abnormal cells or if there is a question of the accuracy of the automated leukocyte differential.[14]

When evaluating the peripheral smear under microscopy, the blood should be collected from a fresh lab draw that is anticoagulated or directly from a finger stick puncture. Preparing the slide involves a gradation of blood on the slide from thick to thin. The smear is air-dried and then a stain, such as May-Grunwald-Giemsa and Wright stains, which produces cells where the nuclei are blue, and the cytoplasm is pink. Under the microscope, the clinician will then begin the slide review on the feathered or thin edge of the smear, where the cells are just barely overlapping, and work into the thicker area of the smear, where the WBC's typically reside. High-power field viewing with an oil-immersion lens is necessary to examine leukocytes for abnormalities and inclusions.

Typical leukocytes of neutrophils, basophils, monocytes, eosinophils, and lymphocytes are expected to be seen in the appropriate percentages, as discussed in the Etiology section of this article. Immature granulocytes and precursors, such as blasts and myelocytes, and lymphoma cells are significantly abnormal findings.[15]

History and Physical

When a patient presents with leukocytosis on initial CBC, a careful history and physical examination should be performed, as well as an evaluation of prior CBCs for trends. In an acute setting, such as an urgent care facility or emergency department, prior CBCs may not be available for evaluation and interpretation. Targeted histories and physical examination may guide the clinician in the proper direction as to the underlying cause for the leukocytosis. In these settings, stress, trauma, and infection are likely the most common cause of leukocytosis. In a less acute setting, such as primary care appointment, a routine CBC may demonstrate leukocytosis, and this may require further investigation if the patient has not had recent stress (emotional or physical), surgery, or infection. Prior CBCs, if available, are extremely useful in determining if this is an acute lab elevation, or if this is a more persistent elevated trend that needs further consideration. In persistent elevations of certain lines, such as less common cell lines (basophils and monocytes), on multiple CBCs, should prompt the clinician to ask the patient targeted historical questions to evaluate for malignancy. Typical symptoms of an underlying malignancy can include fevers, chills, night sweats, unintended weight loss, fatigue, and/or easy bruising. In women, pregnancy can increase leukocytes greater than the upper limit of the normal reference range of 11x10^9. This must also be assessed on initial evaluation. 

Significant elevations, such as leukocytosis close to 100x10^9, should always prompt immediate evaluation for leukemia or myeloproliferative disorders. Myeloproliferative disorders are a group of disease processes characterized by cell dysplasia. There are several categories, some involving leukocytes and some involving other cell lines. Regardless, malignant transformation is possible. A review of symptoms should focus on evaluation for shortness of breath, anemia, pallor, unusual bleeding, petechiae, frequent infections, and fatigue. Physical examination should look for pallor (indicative of possible underlying anemia), petechiae, bruises, tachycardia, palpable lymphadenopathy, and splenomegaly. Frequent follow-up with CBC collections should be arranged with the assistance of a hematology and oncology consultant to monitor for any sort of malignant transformation. 

The past medical history should be reviewed, especially for the history of prior malignancies. Patients who have undergone chemotherapy and/or radiation therapy are at increased risk of leukemia or lymphoma.[16] Family history is also important, as some leukemias have a genetic predisposition. In adults, leukemia can occur without any identifiable predisposing factor. In children, germline genetic mutations can be inherited from a parent or appear de novo. Familial conditions, such as Li-Fraumeni syndrome, Neurofibromatosis Type 1, Noonan syndrome, and Lynch syndrome, among others, are characterized by a predisposition for multiple malignancies, some of which have bone marrow involvement and associated leukocyte malignancies.[17][18] Down syndrome has also been linked to a higher tendency for myeloproliferative disorders and leukemia. A careful family history, including siblings, parents, and grandparents, will help identify children and adolescents at risk for these possible malignancies.

Lastly, social history is critical in the evaluation of leukocytosis. Smoking history and job exposure to chemicals, including benzene, pesticides, and industrial chemicals, have all been linked to higher chances of bone marrow malignancy.[19]

Evaluation

As discussed under the Histopathology section of this article, the first step in any patient with leukocytosis is to obtain a CBC with differential. Prior CBCs should be reviewed and evaluated for any particular trends. The next step is to evaluate a peripheral smear and perform a manual differential if abnormalities are collected on the automatic differential. If immature or lymphoma cells are present, an oncology service should be consulted and the patient should undergo bone marrow aspiration and biopsy with appropriate flow cytometry and molecular genetic studies as indicated. Depending on the results of the bone marrow biopsy, more laboratory testing and imaging may be necessary, as guided by the oncology service.

In the absence of concerning findings on peripheral smear, the following laboratory tests and imaging may be a part of the work-up (adapted from[2]):

• Neutrophilia: consider smoking history, infection, chronic inflammation, stressors, medication, bone marrow stimulation, splenectomy
  • Next step: history collection, medication review, recent surgery review, recent illness, travel history, sick contacts
  • Possible lab tests to collect: ESR, CRP, ANA, blood cultures, urine cultures, lumbar punctures, sputum cultures
  • Possible imaging depending on the suspected source and system involvement on presentation
• Lymphocytosis: consider infections, hypersensitivity reactions
  • Next step: history collection, sick contacts, immunization history, recent travel
  • Possible lab testing: viral panels, blood cultures, urine cultures, sputum cultures
  • Possible imaging: chest radiography, imaging depending on the suspected system involved
• Monocytosis: consider viral illness (EBV), rickettsial infection, tuberculosis, autoimmune disease, splenectomy[20]
  • Next step: history collection, family history (especially for autosplenectomy causing diseases like Sickle Cell disease), travel history, sick contacts, surgical history
  • Possible lab testing: ESR, CRP, ANA, mononucleosis spot test, tuberculosis testing (PPD, interferon-gamma release assay)
  • Possible imaging: chest radiography, imaging depending on the suspected system involved
• Eosinophilia: consider allergic reaction, parasitic infection, dermatologic conditions, medication reaction/hypersensitivity, eosinophilic esophagitis
  • Next step: history collection, perform skin examination for rashes/lesions, travel history, social history to include home environment and animal exposure, medication review, chronic health condition review.
  • Possible lab testing: allergy testing, parasite-specific testing (ex. stool ova and parasite evaluation), skin biopsy of lesions
  • Possible imaging: upper endoscopy, imaging as warranted on the suspected system involved
• Basophilia: consider a malignancy or possible allergic condition
  • Next step: history collection, ask malignancy symptom-specific questions (examples include fatigue, weight loss, unexplained fevers/chills, etc.)
  • Possible lab testing: inflammatory markers
  • Possible imaging: imaging depending on the suspected system involved[21]

Treatment / Management

Leukocytosis is treated based on the underlying process. For example, a neutrophilia may be produced from an underlying infection, in which case the clinician will need to perform a detailed history and physical examination and obtain other relevant lab tests and imaging to determine an infectious source and treat, respectively. Medication reconciliation, such as any recent steroid use, should also be completed to investigate drug-induced leukocytosis. Recent physical stress leading to a leukocytosis can also be ascertained from history. Both of these examples, if diagnosed, do not require further intervention. More alarming causes, such as leukemias and lymphomas, should prompt immediate hematology and oncology specialty service involvement for specific imaging and laboratory examination needed to help guide treatment. 

Clinicians should be able to recognize hyperleukocytosis, which is a WBC count > 100x10^9/mL. This is seen in patients with acute or chronic leukemias and can be a medical emergency if the patient is symptomatic, at which point they are in leukostasis. Organ failure and hemorrhage is a complication of this disorder, which requires prompt identification and treatment to reduce the number of abnormal cells. Hematology and oncology services should be involved in this patient's care, but the use of chemotherapy, leukapheresis, and medications like hydroxyurea, are all current treatment methods to prevent decompensation.[22]

Differential Diagnosis

The differential diagnosis for leukocytosis is broad. It is helpful for clinicians to be able to separate acute versus chronic leukocytosis, as well as to evaluate the degree of leukocytosis. The higher the WBC count, the more likely a significant acute reaction is occurring, or malignancy is the underlying cause. The following is a general list of considerations that a clinician should have when evaluating a leukocytosis:

• Acute leukocytosis
• Leukemoid reaction
• Reactive causes
• Infection
• Acute allergies
• Tissue ischemia
• Drugs/medications (epinephrine, corticosteroids, NSAIDs, cephalosporin antibiotics, anticonvulsants, beta-agonists, allopurinol, penicillin-derivative antibiotics, illicit substances)
• Vaccine administration
• Myocardial infarction/injury
• Hemorrhage 
• Acute hemolysis
• Sepsis/septic shock
• Pregnancy
• Chronic leukocytosis
• Smoking
• Obesity
• Chronic allergies
• Autoimmune disorders
• Vasculitis
• Connective tissue disorders
• Malignancy
• Pregnancy
• Chronic infection
• Asplenia
• Genetic syndromes

Treatment Planning

Treatment of underlying infection and follow-up CBC to confirm resolution of leukocytosis

Treatment of underlying allergic or stress disorder and follow to confirm resolution of abnormal counts

Medical Oncology

Prompt workup for acute leukemia if increased blasts are seen on differentials

Prompt referral to ER for highly elevated lymphocytes>400,000/uL or elevated cells of myeloid lineage>100,000/uL

Prognosis

Leukocytosis secondary to benign non-malignant treatable disorders carries a good prognosis. For example, acute neutrophilia secondary to acute infection, inflammation or stress disorders improves once underlying disorder is well controlled or treated. Such acute reversible causes of leukocytosis carry a good prognosis.

Leukocytosis secondary to malignant lymphoproliferative disorders and lymphomas carries a poor prognosis and requires urgent referral to Hematology/Oncology office and requires chemoimmunotherapy. 

Complications

Hyperleukocytosis is defined as white cell count above 50,000 per microliter. Usually hyperleukocytosis can be managed as an outpatient with prompt initiation of treamtent of underlying disorder.

If blast count is above 100,000 per microliter, there is an increased risk of hyperviscosity and leukostasis resulting hypoxia with end organ damage especially brain and lungs. Patient can suffer from intracranial bleed and multiple neurological deficits. Patient can also develop diffuse alveolar hemorrhage and severe hypoxia. Leukostasis should be promptly addressed with hydration, leukopharesis,phlebotomy and initiation of hydroxyurea or remission induction chemotherapy. 

Patients with hyperleukocytosis are at increased risk for disseminated intravascular coagulation due to increased thrombin formation and excessive fibrinolysis. It is important to monitor patient coagulation profile and replete fibrinogen and transfuse platelets as needed. 

Patients cans uffer from sever etumor lysis syndrome due ot cell lysis in the setting of excessive blast cell coutn burden. This results in severe hyperkalemia, high uric acid levels, hypocalcemia, elevated phosphate levles. Tumor lysis syndrome can cause acute renal failure, seizures, muscles cramps, weakness, nasuea and vomiting. It should be promptly addressed with hydration, rasburicase and repletion of deficient electorlytes. 23,24,25,26

Consultations

Clinicians should consult specialties revolving around the underlying cause of the presenting leukocytosis. In stress-induced leukocytosis, the assessing clinician can usually treat the patient without the need for any consultants. Infectious etiologies may involve the need for an infectious disease specialist, depending on the infection. Hematology and oncology specialists should be involved in malignancy management. Other services may be consulted depending on the inflammatory disease process presenting itself.

Deterrence and Patient Education

Leukocytosis is a common laboratory finding that may be transient or chronic. It often resolves with little to no treatment but should be properly assessed by a clinician to evaluate for the cause of the inflammatory response. More laboratory tests and imaging may be a part of the work-up for the cause of leukocytosis. Routine and regular follow-up with a primary care clinician is crucial for any patient's healthcare.

Pearls and Other Issues

Here are some important considerations regarding leukocytosis:

• Prompt identification of leukocytosis should be performed by clinicians obtaining a CBC, along with chart review for previous CBCs for evaluation of trends.
• Obtain a careful physical examination and history to ascertain the underlying force driving the presenting leukocytosis.
• Consider the patient's ethnicity, place of birth, geographical location, family, and social history when evaluating a new or chronic leukocytosis. This can help target risk factors for various etiologies for the presenting WBC count. 
• Perform a medication reconciliation, as many common medications have been linked to nonspecific leukocytosis.
• Involve appropriate specialists as needed to treat the leukocytosis (i.e., infectious disease vs. hematology and oncology depending on the underlying cause for the CBC abnormality).
• Be aware of severe complications related to malignancy-associated leukocytosis receiving treatment, to include hyperviscosity syndrome and tumor lysis syndrome.

Enhancing Healthcare Team Outcomes

Leukocytosis is a common presentation for both benign and more concerning disease processes. Physical examination, evaluation, review of all body systems, and careful history taking are crucial to identify possible causes of this common laboratory finding. A prior CBC should be used to confirm acute or chronic leukocytosis, as well as to identify trends. The outcomes of a laboratory finding of leukocytosis depend on the underlying cause.

Consultation should be obtained based on the identification of the driving force for the leukocytosis, and an interprofessional team is often needed. Primary care clinicians should be able to obtain the necessary workup for acute or chronic leukocytosis and involve the appropriate specialty consultants. Initial workup, depending on history and physical examination findings, should include cultures of blood, urine, sputum, and body fluid if indicated, rheumatologic laboratory studies, radiological imaging if needed, and the necessary confirmatory testing. Specialty consultants and their interdisciplinary teams, including infectious disease, oncology and hematology, radiation oncology, and an array of other professionals, should be involved to assist with the treatment course for the underlying condition. 

Based on clinical recommendations, leukocytosis over 100x10^9 is almost always caused by an underlying malignancy, leukemia, or myeloproliferative disorder (Evidence Rating C), and patients with leukocytosis and no evidence of systemic inflammatory process do not need blood cultures (evidence rating C).[2]