Leukocytosis

Etiology

In the bone marrow, stem cells differentiate into megakaryoblasts that become platelet-producing megakaryocytes; erythroblasts that become erythrocytes or red blood cells (RBC); myeloblasts that become eosinophils, basophils, and neutrophils; monoblasts that become monocytes; and lymphoid progenitor cells that become B or T lymphocytes. The term leukocyte applies to any cell within the myeloblast, monoblast, and lymphoid lineages. Clinicians classify leukocytosis based on the elevated cell line.

A CBC with predominantly elevated neutrophils is termed neutrophilia. Elevated eosinophils result in eosinophilia; elevated basophils result in basophilia; elevated monocytes result in monocytosis; and elevated lymphocytes result in lymphocytosis. 

Neutrophilia

Neutrophils comprise approximately 40% to 60% of the total leukocyte count. Neutrophilia, an increased neutrophil count at least 2 standard deviations above the mean or >7700 neutrophils/µL in adults, is the most common cause of leukocytosis.[2] Given the wide variation in normal values, 2.5% of the normal population has neutrophilia. Infection, generally bacterial, is a common cause. Viral infections due to the herpes simplex virus (HSV), the varicella virus (VZV), and the Epstein-Bar virus (EBV) can also cause neutrophilia in children, especially those younger than 5. Acute and chronic inflammation due to conditions like rheumatic diseases, Kawasaki disease, adult-onset Still disease, inflammatory bowel disease, and chronic hepatitis are common causes. Additionally, myeloproliferative neoplasms, asplenia, cigarette smoking, stress, pregnancy, obesity, thyroid disorders, Down syndrome, nonhematologic malignancies, and medications like glucocorticoids, catecholamines, and lithium are potential causes. 

Leukemoid Reaction

A leukemoid reaction is a transient increase in WBC count marked by a neutrophil count of >50,000 cells/µL without a myeloproliferative neoplasm. Medications, asplenia, nonhematologic malignancies, and infection with Costridioides difficile, tuberculosis, pertussis, and visceral larva migrans can cause a leukemoid reaction. This acute inflammatory reaction can be mistaken for leukemia, but careful history, physical examination, and further laboratory evaluation can confirm the diagnosis. Peripheral smears and radiological imaging may be necessary to identify the actual cause of these reactive laboratory findings.[3] This diagnosis must be differentiated from leukemia, defined as increases in blast cells, precursor cells to leukocytes, and immature WBCs rather than mature neutrophils seen in a leukemoid reaction. A leukemoid reaction improves after treating the underlying cause of the neutrophilia, whereas leukemia continues to demonstrate elevated WBCs until the completion of definitive treatment.

Leukoerythroblastosis

Leukoerythroblastosis typically suggests a myelophthisic process, where normal marrow space is infiltrated and replaced by nonhematopoietic or abnormal cells. The peripheral smear reveals leukocytosis with immature erythroid, myeloid, and blast cells in the peripheral blood. Other potential causes are cytokine release, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), direct myelotoxicity, and viral infections.[4][5] In most cases, it portends a poor prognosis.

Lymphocytosis

Lymphocytes, on average, comprise approximately 20% to 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. Hypersensitivity reactions, leukemia, stress, asplenia, thymoma, and lymphoma may cause lymphocytosis. Infectious causes of lymphocytosis are generally viral, like EBV, cytomegalovirus, influenza, measles, mumps, rubella, adenovirus, and Coxsackie virus. Bacterial infections like pertussis and cat scratch disease cause lymphocytosis. Additional possible infectious causes are tuberculosis, brucellosis, babesiosis, and syphilis.[1] 

Eosinophilia

Eosinophils account for approximately 1% to 4% of a person's leukocytes, and an eosinophil count >500 cells/µL defines eosinophilia. The list of potential underlying causes of eosinophilia is extensive. Allergic conditions like allergic rhinitis and atopic dermatitis are common causes and are generally associated with mild eosinophilia. Patients with severe eosinophilia, ≥20,000 cells/µL, are more likely to have a myeloid neoplasm. Besides these 2 extremes, the level of eosinophilia does not help distinguish the underlying cause.

Infectious causes of eosinophilia include helminths, fungi, protozoa, some bacteria, HIV, human T-cell lymphotropic virus type 1, and scabies.[6][7] Nearly any medication reaction can cause eosinophilia. However, nonsteroidal anti-inflammatory (NSAID) medications, allopurinol, phenytoin, penicillins, cephalosporins, and sulfasalazine are some of the more commonly known medications associated with specific syndromes involving eosinophilia. Additional causes of eosinophilia are rheumatologic diseases like eosinophilic granulomatosis with polyangiitis, adrenal insufficiency, and immunodeficiency syndromes.

Monocytosis

Monocytes comprise approximately 2% to 8% of a person's leukocyte count.[2] Monocytosis is a monocyte count of >1000 cells/µL commonly associated with chronic infections and inflammatory conditions like inflammatory bowel disease, endocarditis, tuberculosis, malaria, typhoid fever, syphilis, leukemia, and lymphoma.[8] Pregnancy and asplenia are additional causes. A recent study reveals that monocytes may predict prognostic outcomes in emergency room settings.[9]  

Basophils

Basophils compromise 0.5% to 1% of a person's peripheral blood smear.[2] Basophilia is an uncommon cause of leukocytosis. Common causes are myeloproliferative disorders, hypersensitivity or inflammatory reactions, myxedema, and infections.[10][11] Transient basophilia is a reactive response, especially to an acute viral illness. Persistent basophilia on serial CBCs for longer than 8 weeks suggests an underlying malignancy or myeloproliferative disease.[12] 

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.[13][14]

Epidemiology

The prevalence of leukocytosis varies by cause. In addition, leukocytosis can indicate morbidity and mortality risk. In cardiovascular or cerebrovascular events, leukocytosis severity correlates with ischemic damage severity and outcomes. Studies involving patients who present with a myocardial infarction show higher mortality rates in patients with elevated WBC counts. Two studies analyzing the in-hospital mortality rate following myocardial infarction reveal mortality rates of 4.4% and 7.7% for patients within the lowest range of WBC count and 15.9% and 27.3% for those in the highest WBC count group.[15][16] Reports also associate leukocytosis with hypertension, glucose intolerance, diabetes, and mortality risk. Similarly, most patients with sickle cell disease have an elevated WBC count. Leukocytosis is a poor prognostic indicator during vaso-occlusive events.

Hyperleukocytosis occurs in 20% and 10% to 30% of cases, respectively, in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Hyperleukocytosis also occurs in a significant number of newly diagnosed cases of chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML). Drug reaction with eosinophilia and systemic symptoms (DRESS) is a hypersensitivity reaction to medications presenting with lymphocytosis, including atypical lymphocytes, and eosinophilia noted in 30% to 70% of affected patients.  

Pathophysiology

Progenitor cells, or stem cells, reside in the bone marrow and give rise to erythroblasts, myeloblasts, and megakaryoblasts. Most nucleated cells in the bone marrow will produce leukocytes, including granulocytes, which form neutrophils, eosinophils, and basophils. In addition, stem cells form lymphocytes and monocytes. 

Colony-stimulating factors, interleukins, tumor necrosis factor, and complement components regulate WBC maturation in the bone marrow and their release into the circulation. In the evolution of the neutrophilic granulocyte, the myeloblast forms a promyelocyte, then a myelocyte, and finally a metamyelocyte. The metamyelocyte is unable to undergo further mitosis but transforms into a band. This cell is either released into circulation, comprising 3% to 5% of WBCs, and completes its maturation, or it enters a storage compartment in the marrow where it becomes a neutrophil and is later released. Once released, approximately 50% of the neutrophil cells circulate, and the remaining 50% adhere to vessel walls with neutrophils shuttling between the vascular system and tissues. Maintaining this homeostasis of circulating and adherent neutrophils is essential for tissues that need an immune response to a pathogen. Circulating catecholamines and glucocorticoids help regulate this system. Catecholamines also regulate the maturation and function of leukocytes via adrenoceptors on their surface. 

Eosinophils and basophils develop similarly, except once released from the bone marrow, eosinophils leave the intravascular space and enter tissues. They are highly concentrated in the gastrointestinal tract, lungs, and skin and cannot return to the intravascular space. Neutrophils, eosinophils, and basophils are polymorphonuclear leukocytes, and lymphocytes are mononuclear leukocytes originating in the bone marrow from the granulocyte-macrophage progenitor (CFU-GM). They can exit and reenter circulation. 

Leukocytosis occurs due to increased production, decreased removal from the circulation, demargination, and release from storage compartments. Exposure to stress, infection, or inflammation causes circulating polymorphonuclear cells, bands, and metamyelocytes to move to the necessary site. As a result, stored leukocytes are also released. Increased plasma concentrations of stress hormones such as catecholamines and glucocorticoids cause an increase in circulating numbers of granulocytes, monocytes, and natural killer cells. Marrow growth factors likely cause leukocytosis associated with increased RBC production in hemolytic anemia. Malignant transformation of pluripotent hematopoietic stem cells causes leukocytosis associated with leukemia.

Histopathology

When evaluating the peripheral smear under microscopy, the clinician should use blood that has not been allowed to clot. Preparing the slide involves grading blood from thick to thin. Clinicians allow the smear to air dry and then stain the sample. A stain, such as the May-Grunwald-Giemsa or Wright stain, highlights the nuclei blue and the cytoplasm pink. Review of the specimen begins on the feathered or thin edge of the smear, where the cells barely overlap, and works into the thicker area, where the WBCs typically reside. Viewing under a high-power field with an oil-immersion lens is necessary to examine leukocytes for abnormalities and inclusions. See StatPearls' companion reference, "Histology, White Blood Cell," for additional information regarding the specific histopathologic appearance of the various forms of leukocytes.

History and Physical

In patients with leukocytosis, the patient history should focus on identifying any evidence of underlying reactive, inflammatory, or malignant conditions. Healthcare professionals should inquire about any recent or current evidence of infection, including sick contacts and recent travel. Additional pertinent information includes a history of any hematologic malignancy or disorders like sickle cell disease, cigarette smoking, vigorous exercise, extreme emotional or physical stress, asplenia, pregnancy, thyroid disorders, or a family history of leukocytosis. A thorough medication history is also necessary. Clinicians should inquire about job exposure to benzene, pesticides, and industrial chemicals, all known to increase the risk of bone marrow malignancy.[17] A personal history of malignancy is significant because patients who have undergone chemotherapy or radiation therapy are at increased risk of leukemia or lymphoma.[18] 

Symptoms specific to eosinophilia involve the organ systems affected by eosinophils. Clinicians should inquire about asthma, atopy, rheumatologic conditions, infections, malignancy, diet, potential medication exposure, and family history. Expected symptoms may include pruritus, urticaria, angioedema, and rash for patients with atopy. Nasal or sinus symptoms, wheezing, cough, and chest congestion may signify eosinophilic granulomatosis with polyangiitis, and eosinophilic myocarditis may present with dyspnea, chest pain, palpitations, and symptoms of heart failure. Typical symptoms of an underlying malignancy can include fevers, chills, night sweats, unintentional weight loss, fatigue, or easy bruising.[19]

Significant elevations in WBC count, such as those nearing 100,000 cells/µL, warrant immediate evaluation for leukemia or myeloproliferative disorders. These disorders can affect leukocytes or other cell lines, with the potential for malignant transformation. Symptom review should prioritize assessment for shortness of breath, anemia, pallor, abnormal bleeding, petechiae, recurrent infections, and fatigue. Physical examination should include checks for pallor, petechiae, bruises, tachycardia, palpable lymphadenopathy, and splenomegaly.

Leukostasis refers to symptoms associated with hyperleukocytosis, mainly impacting the central nervous system and lungs, though other organs like the heart and kidneys can also be affected. Symptom severity depends on the type of leukemia, WBC count, and any accompanying conditions. Patients often present with fever, dyspnea, hypoxia, and central nervous symptoms like visual changes, headache, dizziness, tinnitus, gait instability, confusion, somnolence, and, occasionally, coma. Management of hyperleukocytosis and leukostasis depends on the specific hematologic malignancy.

Evaluation

An accurate diagnosis requires gathering a comprehensive medical history, conducting a thorough physical examination, identifying underlying risk factors for leukocytosis, meticulously interpreting automated differentials and peripheral blood smears, and referring patients to relevant specialists for further assessment. Additional ancillary tests such as flow cytometric immunophenotyping, molecular testing, genetic studies, and bone marrow examination can aid in pinpointing hematological malignancies.

The precise WBC count can differ across laboratories due to variations in the upper limit of normal and the type of hematology analyzer employed. Hematology analyzers analyze whole blood samples for a CBC and differential, encompassing the RBC count, WBC count, platelet count, hemoglobin, RBC indices, and WBC differentials. These analyzers utilize cytochemistry and fluorescence techniques to distinguish between various WBC types and categorize them as low or high using preset algorithms.

A careful examination of flagged blood samples through a peripheral blood smear aids in establishing a manual differential and validating automated differentials' findings. Cryoproteins like cryoglobulins and cryofibrinogen can artificially inflate the WBC count. Hyperleukocytosis can also skew hemoglobin and hematocrit values along with the indices.

Clinicians evaluate the leukocyte count 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 in adults.[20] Through adolescence, lymphocytes predominate the peripheral smear. By adulthood, neutrophils are the predominant cell line.

Age-appropriate values for leukocytes are as follows: 

• Newborns: 13,000 to 38,000 cells/µL                                
• Babies birth to 2 weeks: 5000 to 20,000 cells/µL
• Children at 1 year: 6000 to 17,500 cells/µL
• Children at 10 years: 4500 to 13,500 cells/μL
• Adults: 4500 to 11,000 cells/μL
• Pregnant females in the third trimester: 5800 to 13,200 cells/µL

Black African, Middle Eastern, and West Indian descent also influence the WBC count and differential. Patients of these backgrounds can have reduced WBC counts and lower absolute neutrophil counts (ANCs) compared to patients of Hispanic and European descent.[21] Known as benign ethnic neutropenia, clinicians may identify this condition in a patient of African descent with no infectious concerns on history and physical examination with chronically low neutrophils on CBC. Benign ethnic neutropenia is an important consideration when evaluating a patient of African descent, as their presentation of leukocytosis may be within the normal laboratory reference range. However, the value must be elevated compared to their prior CBCs.       

The initial step for any patient with leukocytosis is obtaining the WBC differential and reviewing prior CBCs for any noticeable trends. The next step is to assess a peripheral smear and perform a manual differential if the automated differential is abnormal. If a concern exists about malignancy, referral to a hematology and oncology specialist is necessary.

Neutrophilia

Serial CBCs as an outpatient may be appropriate for asymptomatic patients with modest, stable neutrophilia. Patients with a WBC count of >100,000 cells/µL may warrant urgent hematologic consultation. Additionally, patients who are clinically unstable with neutrophilia accompanied by hypotension, high fever, hypothermia, or abdominal rebound tenderness warrant hospitalization and urgent evaluation. See StatPearls' companion topic," Neutrophilia," for additional information.

Additional testing to consider includes the following:

• Renal and liver function tests
• Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibody (ANA), blood cultures, urine culture, lumbar puncture, sputum culture
• D-dimer in the evaluation of sepsis
• Clostridioides difficile in a hospitalized patient who recently received antibiotics
• Based on the initial evaluation, possible testing may include the following:
• Bone marrow biopsy
• Flow cytometry
• Molecular and genetic testing
• Possible imaging depending on the suspected source and system involvement in the presentation

Lymphocytosis 

No specific level of lymphocytosis exists that warrants emergent evaluation. Patients with hemodynamic instability or respiratory compromise require immediate evaluation. Reactive lymphocytosis can cause an absolute lymphocyte count (ALC) of 20,000 to 30,000 cells/µL and should resolve within 1 to 2 months of the inciting event. If the initial assessment does not reveal a cause for the lymphocytosis, patients with an ALC >50,000 cells/µL should receive an evaluation from a hematology and oncology specialist to determine the timing and need for further evaluation.

As with other forms of leukocytosis, a peripheral smear is necessary. Atypical lymphocytes, which appear as large lymphocytes with abundant basophilic cytoplasm and a large, irregularly shaped nucleus that may exhibit nucleoli, are often associated with infectious mononucleosis and viral illnesses. Infections like pertussis, monoclonal B cell lymphocytosis, and CLL may have normal or small-appearing lymphocytes. "Smudge" lymphocytes are a characteristic finding in CLL, "hair-like" projections are characteristic in hairy cell leukemia, and lymphocytes with "cerebriform" nuclei or Sézary cells are associated with mycosis fungoides or Sézary syndrome.

 Additional testing to consider includes the following:

• Renal and liver function tests
• ESR
• CRP
• Flow cytometry
• Bone marrow biopsy
• Viral panels, blood cultures, urine culture, sputum culture
• Possible chest radiography or additional imaging, depending on the suspected system involved

Flow cytometry is necessary for patients with suspected acute leukemia to distinguish between B cells, T cells, and natural killer (NK) cells. Molecular and genetic testing can detect a dominant clone of cells, and chromosomal analysis like fluorescence in situ hybridization (FISH) and a karyotype can distinguish acquired and inherited causes of lymphocytosis. See StatPearls' companion topic, "Lymphocytosis," for additional information.

Eosinophilia

Generally, the severity of the illness, not the actual eosinophil count, determines the need for emergent evaluation. Any evidence of life-threatening or disabling conditions that may reflect irreversible eosinophil-associated tissue damage to the heart, lungs, nervous system, or other organs warrants emergent intervention. Patients with an absolute eosinophil count (AEC) >1500 cells/µL should have a repeat CBC in 1 to 2 weeks, including incidentally discovered eosinophilia. If the AEC remains elevated or increases, clinicians should evaluate the patient for hypereosinophilic syndromes. If the AEC is <1500 cells /µL, patients can repeat the CBC in 1 month if no evidence of eosinophilic end-organ damage like eosinophilic myocarditis, cerebral thromboemboli, encephalopathy, or peripheral neuropathy exists. Also, patients should have no history of travel or residence in helminth-endemic areas and no features suggesting malignancy present. See StatPearls' companion topic, "Eosinophilia," for additional information.

Additional testing may include the following:

• Allergy testing
• Stool ova and parasite evaluation
• Cardiac troponin, electrocardiogram, and echocardiogram for patients with chest pain, dyspnea, a new heart murmur, or fatigue
• Vitamin B12 and tryptase: Elevated levels may suggest an underlying malignancy
• Upper endoscopy
• Chest radiograph and pulmonary function tests for patients with respiratory symptoms
• High-resolution computed tomography (CT) for patients with possible eosinophilic granulomatosis with polyangiitis
• Additional imaging, as warranted on the suspected system involved

Basophilia

As with other cell lines, clinicians begin the evaluation of basophilia with a peripheral smear. Bone marrow aspiration and biopsy, FISH analysis, karyotyping, and genetic analysis may also follow.[2][19] See StatPearls' companion reference, "Basophilia," for additional information.

Monocytosis 

Potential additional evaluations for monocytosis may include ESR, CRP, antinuclear antibody, a mononucleosis spot test, tuberculosis testing with a tuberculin skin test, and an interferon-gamma release assay with imaging studies, depending on the suspected system involved.

Hyperleukocytosis

Hyperleukocytosis is defined as a WBC count of 100,000 cells/ µL or higher, and patients may or may not exhibit accompanying symptoms. Clinicians diagnose leukostasis when a patient with hyperleukocytosis shows signs of tissue hypoxia. The diagnosis is primarily clinical.

Treatment / Management

Clinicians tailor treatment for leukocytosis to the underlying cause. Many patients do not require treatment. Some patients can undergo monitoring with serial CBCs, while others may require treatment for infections, autoimmune conditions, endocrinopathies, or malignancies.

Hyperleukocytosis can be a medical emergency if the patient becomes symptomatic and develops evidence of tissue hypoxia. Leukostasis is most commonly associated with AML but can rarely occur with CLL and ALL. Clinicians use chemotherapy, leukapheresis, and medications to treat leukostasis and prevent decompensation.[22]

Patients with hyperleukocytosis are at increased risk for disseminated intravascular coagulation due to increased thrombin formation and excessive fibrinolysis. Clinicians should monitor the patient's coagulation profile, replete fibrinogen, and transfuse platelets as needed. 

Differential Diagnosis

The differential diagnoses for leukocytosis are extensive. Clinicians need to distinguish acute versus chronic leukocytosis and evaluate the degree of leukocytosis. The higher the WBC count, the more likely a malignancy or acute reaction is the underlying cause. A general list healthcare professionals should consider when evaluating a patient with leukocytosis is as follows:

• Acute leukocytosis
• Leukemoid reaction
• Reactive causes
• Infection
• Acute allergies
• Tissue ischemia
• Medications such as epinephrine, corticosteroids, NSAIDs, cephalosporin antibiotics, anticonvulsants, beta-agonists, allopurinol, penicillin-derivative antibiotics, opioids, and metformin [23]
• Vaccine administration
• Myocardial infarction
• Hemorrhage 
• Acute hemolysis
• Sepsis or septic shock
• Pregnancy                                                                                                                                                           
• Chronic leukocytosis
• Smoking
• Obesity
• Chronic allergies
• Autoimmune disorders
• Vasculitis
• Connective tissue disorders
• Malignancy
• Pregnancy
• Chronic infection
• Asplenia
• Genetic syndromes

Prognosis

Leukocytosis secondary to benign, nonmalignant, treatable disorders carries a good prognosis. Leukocytosis secondary to malignant lymphoproliferative disorders and lymphomas carries a poorer prognosis, with age, medical comorbidities, prior myelodysplastic syndrome or myeloproliferative neoplasm, history of exposure to cytotoxic agents or radiation, and cytogenetic and molecular features all contributing to survival. Patients with conditions associated with a WBC count of>35,000 cells/µL have a poor prognosis.[24]

As a marker of inflammation, leukocytosis can also serve as a prognostic indicator in patients without infection. Increased morbidity and mortality occur in patients with leukocytosis without infection who have experienced a myocardial infarction or stroke or are admitted to the intensive care unit. Studies reveal an increased WBC count positively correlates with deterioration in glucose tolerance and negatively with insulin sensitivity. 

Complications

The complications of leukocytosis extend beyond diagnostic implications. In severe cases, excessive white blood cells can lead to tissue damage due to inflammation, impairing organ function and potentially causing systemic complications such as sepsis or organ failure. Moreover, the underlying cause of leukocytosis must be addressed promptly to prevent further complications.

Complications specific to hyperleukocytosis are as follows:

• Myocardial ischemia
• Right ventricular overload
• Renal Insufficiency
• Priapism
• Acute limb ischemia
• Bowel infarction
• Coma
• Respiratory failure
• Disseminated intravascular coagulation
• Intracranial hemorrhage
• Tumor lysis syndrome

Tumor lysis syndrome, due to cell lysis often after beginning treatment, carries its own set of complications, including the following:

• Hyperkalemia, hyperphosphatemia, and hypocalcemia leading to heart failure, cardiac dysrhythmias, seizures, muscle cramps, tetany, syncope, and possibly sudden death
• Hyperuricemia
• Acute renal failure