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Leukocytosis, defined as an elevated white blood cell (WBC) count, is a common clinical finding with a broad differential diagnosis that includes infections, inflammatory conditions, malignancies, and hereditary disorders. Normal WBC thresholds vary by age and physiologic states such as pregnancy, and interpretation should be individualized. Evaluation of the differential count helps narrow the etiology, with patterns such as eosinophilia suggesting allergic or parasitic processes and lymphocytosis often associated with viral or autoimmune conditions. Clinical assessment should incorporate patient history, symptom duration, trends in laboratory values, and associated complete blood count abnormalities. Although many cases are transient and require no intervention, persistent or marked leukocytosis may warrant further evaluation, including peripheral smear review and, in select cases, bone marrow aspiration and biopsy to distinguish reactive processes from hematologic malignancies. Management is directed at the underlying cause. Most patients do not require specific therapy; however, serious conditions such as leukemia, lymphoma, or hyperleukocytosis with leukostasis require urgent intervention, including cytoreductive therapy, leukapheresis, and supportive care. This activity reviews the etiology, pathophysiology, and clinical evaluation of leukocytosis, with an emphasis on evidence-based diagnostic and management strategies. This activity provides clinicians with essential knowledge to optimize care for patients with leukocytosis. This activity also emphasizes differentiating benign from pathologic causes, recognizing high-risk presentations, and applying a patient-centered approach to management. In addition, this activity highlights the importance of interprofessional collaboration in evaluating leukocytosis and implementing evidence-based treatment strategies, with a focus on tailoring management to the underlying etiology. Objectives: Identify common and serious causes of leukocytosis, including reactive, inflammatory, infectious, and malignant etiologies. Implement appropriate diagnostic evaluation and evidence-based management for leukocytosis. Assess patient history, risk factors, and symptomatology to guide the evaluation and narrow the differential diagnosis.

Identify common and serious causes of leukocytosis, including reactive, inflammatory, infectious, and malignant etiologies. Implement appropriate diagnostic evaluation and evidence-based management for leukocytosis. Assess patient history, risk factors, and symptomatology to guide the evaluation and narrow the differential diagnosis. Collaborate with an interprofessional healthcare team to optimize patient care and coordinate follow-up to ensure timely diagnosis, monitoring, and management based on the underlying cause. Access free multiple choice questions on this topic.

Leukocytosis refers to an age-appropriate increase in the white blood cell (WBC) count. In adults, a WBC count exceeding 11,000 cells/µL is generally considered leukocytosis, whereas a count greater than 100,000 cells/µL is termed hyperleukocytosis.[1] However, normal thresholds vary by age and physiological state, such as pregnancy. For example, a WBC count of 30,000 cells/µL would be abnormal in adults but may fall within the normal range for a newborn.[2] Leukocytosis is a common finding with a broad differential diagnosis and is typically further classified based on the predominant WBC subtype responsible for the elevation. Increases in lymphocytes, neutrophils, eosinophils, basophils, monocytes, or immature precursor cells (blasts) may all be responsible. Common causes of leukocytosis include infection, inflammation, allergic reactions, malignancy, and hereditary disorders. Evaluation of the WBC differential can help identify the underlying etiology. For example, eosinophilia may suggest allergic or parasitic conditions, whereas lymphocytosis is often seen in viral infections, autoimmune diseases, and hyperthyroidism. Further evaluation depends on the clinical presentation, symptom duration, trends in laboratory values, the differential count, and findings on the complete blood count (CBC). In selected cases, particularly when a malignant process is suspected, additional studies such as bone marrow biopsy, flow cytometry, and molecular or genetic testing may be required. Clinicians guide treatment decisions based on the underlying pathology. Although many patients do not require treatment, severe cases such as hyperleukocytosis and leukostasis are a medical emergency and require immediate treatment.

In the bone marrow, stem cells differentiate into distinct lineages: megakaryoblasts, which give rise to platelet-producing megakaryocytes; erythroblasts, which mature into erythrocytes (red blood cells [RBCs]); myeloblasts, which develop into neutrophils, eosinophils, and basophils; monoblasts, which form monocytes; and lymphoid progenitor cells, which give rise to B and T lymphocytes. The term leukocyte encompasses cells derived from the myeloblast, monoblast, and lymphoid lineages. Leukocytosis is classified according to the predominant elevated cell type. A CBC with predominantly demonstrating a predominance of neutrophils is termed neutrophilia. Similarly, elevations in eosinophils, basophils, monocytes, and lymphocytes are referred to as eosinophilia, basophilia, monocytosis, and lymphocytosis, respectively. Neutrophilia Neutrophils account for approximately 40% to 60% of the total leukocyte count. Neutrophilia is defined as an absolute neutrophil count at least 2 standard deviations above the mean, or greater than 7700 cells/µL in adults, and represents the most common cause of leukocytosis.[2] Given the wide variation in normal values, approximately 2.5% of the healthy population may have neutrophilia. Infection, most commonly bacterial, is a frequent cause. Certain viral infections, including herpes simplex virus, varicella-zoster virus, and Epstein-Barr virus (EBV), may also produce neutrophilia in children, particularly those aged 5 or younger. Acute and chronic inflammatory conditions, such as rheumatic diseases, Kawasaki disease, adult-onset Still disease, inflammatory bowel disease, and chronic hepatitis, are also common etiologies. Additional causes include myeloproliferative neoplasms, asplenia, cigarette smoking, physiologic stress, pregnancy, obesity, thyroid disorders, Down syndrome, nonhematologic malignancies, and medications such as glucocorticoids, catecholamines, and lithium. Leukemoid Reaction

Infection, most commonly bacterial, is a frequent cause. Certain viral infections, including herpes simplex virus, varicella-zoster virus, and Epstein-Barr virus (EBV), may also produce neutrophilia in children, particularly those aged 5 or younger. Acute and chronic inflammatory conditions, such as rheumatic diseases, Kawasaki disease, adult-onset Still disease, inflammatory bowel disease, and chronic hepatitis, are also common etiologies. Additional causes include myeloproliferative neoplasms, asplenia, cigarette smoking, physiologic stress, pregnancy, obesity, thyroid disorders, Down syndrome, nonhematologic malignancies, and medications such as glucocorticoids, catecholamines, and lithium. Leukemoid Reaction A leukemoid reaction is a transient and marked increase in WBC count, and is typically characterized by a neutrophil count greater than 50,000 cells/µL without a myeloproliferative neoplasm. Medications, asplenia, nonhematologic malignancies, and infection caused by Clostridioides difficile, tuberculosis, pertussis, and visceral larva migrans can cause a leukemoid reaction. This acute inflammatory reaction can be mistaken for leukemia; however, 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 condition must be distinguished from leukemia, which is characterized by increased blast cells and other immature leukocyte precursors and WBCs, in contrast to the predominance of mature neutrophils seen in a leukemoid reaction. A leukemoid reaction typically resolves with treatment of the underlying cause, whereas leukemia is characterized by persistently elevated WBC counts until definitive therapy is completed. Leukocytosis has also been associated with poorer outcomes in patients undergoing shoulder arthroplasty.[4] Leukoerythroblastosis

A leukemoid reaction is a transient and marked increase in WBC count, and is typically characterized by a neutrophil count greater than 50,000 cells/µL without a myeloproliferative neoplasm. Medications, asplenia, nonhematologic malignancies, and infection caused by Clostridioides difficile, tuberculosis, pertussis, and visceral larva migrans can cause a leukemoid reaction. This acute inflammatory reaction can be mistaken for leukemia; however, 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 condition must be distinguished from leukemia, which is characterized by increased blast cells and other immature leukocyte precursors and WBCs, in contrast to the predominance of mature neutrophils seen in a leukemoid reaction. A leukemoid reaction typically resolves with treatment of the underlying cause, whereas leukemia is characterized by persistently elevated WBC counts until definitive therapy is completed. Leukocytosis has also been associated with poorer outcomes in patients undergoing shoulder arthroplasty.[4] Leukoerythroblastosis Leukoerythroblastosis typically indicates a myelophthisic process, in which normal bone marrow is infiltrated and replaced by nonhematopoietic or abnormal cells. The peripheral smear characteristically shows leukocytosis with circulating immature erythroid and myeloid cells, including blast cells. Other potential causes include cytokine-mediated responses, such as those seen in SARS-CoV-2 infection, direct myelotoxic injury, and viral infections.[5][6] In most cases, this finding is associated with a poor prognosis. Lymphocytosis Lymphocytes typically comprise approximately 20% to 40% of the total leukocyte count. In children, lymphocytosis is often benign and may reflect rapid growth and development of the immune system. Potential causes include hypersensitivity reactions, leukemia, physiologic stress, asplenia, thymoma, and lymphoma.

Lymphocytosis Lymphocytes typically comprise approximately 20% to 40% of the total leukocyte count. In children, lymphocytosis is often benign and may reflect rapid growth and development of the immune system. Potential causes include hypersensitivity reactions, leukemia, physiologic stress, asplenia, thymoma, and lymphoma. Infectious causes of lymphocytosis are generally viral, including EBV, cytomegalovirus, influenza, measles, mumps, rubella, adenovirus, and Coxsackie virus. Certain bacterial infections, such as pertussis and cat scratch disease, can also cause lymphocytosis. Additional infectious causes include tuberculosis, brucellosis, babesiosis, and syphilis.[1] Eosinophilia Eosinophils account for approximately 1% to 4% of an individual's total leukocyte count, and an absolute eosinophil count (AEC) of more than 500 cells/µL defines eosinophilia. The list of potential underlying causes of eosinophilia is extensive. Common causes include allergic conditions such as allergic rhinitis and atopic dermatitis, which are typically associated with mild eosinophilia. Patients with severe eosinophilia (≥20,000 cells/µL) are more likely to be associated with a myeloid neoplasm. Besides these 2 extremes, the level of eosinophilia alone does not help to determine the underlying cause. Infectious causes of eosinophilia include helminths, fungi, protozoa, certain bacterial infections, HIV, human T-cell lymphotropic virus type 1, and scabies.[7][8] Nearly any medication reaction can cause eosinophilia. Frequently associated agents include nonsteroidal anti-inflammatory drugs (NSAIDs), allopurinol, phenytoin, penicillins, cephalosporins, and sulfasalazine, some of which are linked to specific eosinophilia-associated syndromes. Additional causes of eosinophilia include rheumatologic diseases such as eosinophilic granulomatosis with polyangiitis, adrenal insufficiency, and immunodeficiency syndromes. Monocytosis

Infectious causes of eosinophilia include helminths, fungi, protozoa, certain bacterial infections, HIV, human T-cell lymphotropic virus type 1, and scabies.[7][8] Nearly any medication reaction can cause eosinophilia. Frequently associated agents include nonsteroidal anti-inflammatory drugs (NSAIDs), allopurinol, phenytoin, penicillins, cephalosporins, and sulfasalazine, some of which are linked to specific eosinophilia-associated syndromes. Additional causes of eosinophilia include rheumatologic diseases such as eosinophilic granulomatosis with polyangiitis, adrenal insufficiency, and immunodeficiency syndromes. Monocytosis Monocytes comprise approximately 2% to 8% of an individual's total leukocyte count.[2] Monocytosis is defined as an absolute monocyte count greater than 1000 cells/µL and is most commonly associated with chronic infections and inflammatory conditions, including inflammatory bowel disease, endocarditis, tuberculosis, malaria, typhoid fever, and syphilis. Hematologic malignancies such as leukemia and lymphoma may also present with monocytosis.[9] Additional causes include pregnancy and asplenia. Emerging evidence suggests that monocyte levels may have prognostic value in emergency department settings.[10] Basophilia Basophils comprise approximately 0.5% to 1% of an individual's peripheral blood smear.[2] Basophilia is an uncommon cause of leukocytosis. Common causes include myeloproliferative disorders, hypersensitivity or inflammatory reactions, myxedema, and infections.[11][12] Transient basophilia is often a reactive response, particularly in the setting of acute viral illness. In contrast, persistent basophilia on serial CBCs for longer than 8 weeks raises concern for an underlying malignancy or myeloproliferative disorder.[13] In adults, leukemia may occur without an identifiable predisposing factor. In children, germline genetic mutations may be inherited from a parent or arise de novo. Certain familial conditions, such as Li-Fraumeni syndrome, neurofibromatosis type 1, Noonan syndrome, and Lynch syndrome, are associated with an increased risk of multiple malignancies, some of which involve the bone marrow and may present as leukocyte malignancies.[14][15]

The prevalence of leukocytosis varies widely depending on the underlying cause. Beyond its diagnostic significance, leukocytosis may also serve as a marker of morbidity and mortality risk. In patients with cardiovascular or cerebrovascular events, the degree of leukocytosis correlates with the severity of ischemic injury and clinical outcomes. Studies of patients presenting with myocardial infarction have demonstrated higher mortality rates among those with elevated WBC counts. Two such studies reported in-hospital mortality rates of 4.4% and 7.7% in patients with the lowest WBC counts, compared with 15.9% and 27.3% in those with the highest counts.[16][17] Reports also indicate that leukocytosis has been associated with hypertension, glucose intolerance, diabetes mellitus, and increased mortality risk. Similarly, most patients with sickle cell disease have elevated WBC counts, and leukocytosis is a poor prognostic indicator during vaso-occlusive events. Hyperleukocytosis occurs in approximately 20% of patients with acute myeloid leukemia (AML) and in 10% to 30% of those with acute lymphoblastic leukemia (ALL). Hyperleukocytosis also occurs in a significant number of newly diagnosed cases of chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia. Drug reaction with eosinophilia and systemic symptoms (DRESS) is a medication-related hypersensitivity syndrome characterized by lymphocytosis, often with atypical lymphocytes, and eosinophilia, which is reported in 30% to 70% of affected patients.

Progenitor cells, or stem cells, reside in the bone marrow and differentiate into erythroblasts, myeloblasts, and megakaryoblasts. Most nucleated cells in the bone marrow give rise to leukocytes, including granulocytes, which form neutrophils, eosinophils, and basophils. In addition, stem cells give rise to lymphocytes and monocytes. Colony-stimulating factors, interleukins, tumor necrosis factor, and complement components regulate WBC maturation in the bone marrow and the release of WBCs into the circulation. During neutrophil development, myeloblasts differentiate into promyelocytes, then myelocytes, and subsequently metamyelocytes. Metamyelocytes no longer undergo mitosis and mature into band forms. These cells may be released into the circulation, where they account for approximately 3% to 5% of circulating WBCs and complete maturation, or they may remain in the bone marrow storage pool and mature into segmented neutrophils before release. Once released, approximately 50% of neutrophils remain in circulation, whereas the remaining 50% adhere to the vessel walls, forming a marginated pool, with neutrophils shuttling between the vascular system and tissues. Maintenance of this homeostasis between circulating and adherent neutrophils is essential for an effective immune response to a pathogen. Circulating catecholamines and glucocorticoids help regulate this system, and catecholamines also influence leukocyte maturation and function through interactions with surface adrenoceptors. Eosinophils and basophils undergo similar development in the bone marrow; however, once released, eosinophils typically leave the intravascular space and migrate into tissues. They are highly concentrated in the gastrointestinal tract, lungs, and skin and do not recirculate back into the bloodstream. Neutrophils, eosinophils, and basophils are classified as polymorphonuclear leukocytes. In contrast, lymphocytes are mononuclear leukocytes originating in the bone marrow from the granulocyte-macrophage progenitor (colony-forming unit–granulocyte-macrophage [CFU-GM]). Unlike eosinophils, lymphocytes can recirculate between the bloodstream and tissues.

Eosinophils and basophils undergo similar development in the bone marrow; however, once released, eosinophils typically leave the intravascular space and migrate into tissues. They are highly concentrated in the gastrointestinal tract, lungs, and skin and do not recirculate back into the bloodstream. Neutrophils, eosinophils, and basophils are classified as polymorphonuclear leukocytes. In contrast, lymphocytes are mononuclear leukocytes originating in the bone marrow from the granulocyte-macrophage progenitor (colony-forming unit–granulocyte-macrophage [CFU-GM]). Unlike eosinophils, lymphocytes can recirculate between the bloodstream and tissues. Leukocytosis may result from increased leukocyte production, decreased removal from the circulation, demargination, or release from storage compartments. Demargination refers to the mobilization of cells, which is mediated by the effects of external factors on adhesion molecules.[18][19][20] In response to stress, infection, or inflammation, polymorphonuclear cells, band forms, and metamyelocytes enter the circulation and migrate to the necessary sites, accompanied by the release of stored leukocytes from the bone marrow. Elevated plasma concentrations of stress hormones, such as catecholamines and glucocorticoids, increase circulating levels of granulocytes, monocytes, and natural killer cells. Marrow growth factors likely contribute to leukocytosis associated with increased RBC production in conditions such as hemolytic anemia. In addition, malignant transformation of pluripotent hematopoietic stem cells leads to leukocytosis associated with leukemia.

When evaluating a peripheral blood smear under microscopy, the clinician should prepare the specimen from anticoagulated blood to prevent clotting. Slide preparation involves creating a gradient from thick to thin. The smear is then air-dried and stained using a stain such as May-Grünwald-Giemsa or Wright, which typically highlights nuclei in blue and the cytoplasm in pink. Microscopic examination begins at the feathered (thin) edge of the smear, where cells are minimally overlapping, and proceeds toward the thicker regions, where WBCs are more concentrated. Evaluation of cells under high-power magnification with an oil-immersion lens is required to assess leukocyte morphology, including abnormalities and cytoplasmic inclusions. Please see StatPearls' companion resource, "Histology, White Blood Cell," for additional information regarding the specific histopathologic appearance of the various forms of leukocytes.

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 signs or symptoms of infection, including recent exposures, sick contacts, and travel history. Additional pertinent information includes a history of hematologic malignancy or disorders (such as sickle cell disease), cigarette smoking, vigorous exercise, extreme emotional or physical stress, asplenia, pregnancy, thyroid disorders, or any family history of leukocytosis. A comprehensive medication history is also necessary. Occupational exposures to benzene, pesticides, and other industrial chemicals should be evaluated, as they are associated with an increased risk of bone marrow malignancies.[21] A personal history of malignancy is also important, particularly in patients who have received chemotherapy or radiation therapy, given their increased risk of developing leukemia or lymphoma.[22] Symptoms associated with eosinophilia depend on the organ systems involved. The clinical history should include assessment for asthma, atopy, rheumatologic disease, infections, malignancy, dietary exposures, medication use, and family history. Patients with atopic conditions may report pruritus, urticaria, angioedema, or rash. Respiratory symptoms such as nasal or sinus congestion, wheezing, cough, and chest tightness may suggest eosinophilic granulomatosis with polyangiitis. Cardiac involvement, such as eosinophilic myocarditis, may present with dyspnea, chest pain, palpitations, or signs of heart failure. Constitutional symptoms, including fever, chills, night sweats, unintentional weight loss, fatigue, and easy bruising, may indicate an underlying malignancy.[23] Significant elevations in WBC count, particularly those approaching 100,000 cells/µL, warrant immediate evaluation for leukemia or myeloproliferative disorders. These disorders can affect leukocytes or other cell lines and have 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.

Significant elevations in WBC count, particularly those approaching 100,000 cells/µL, warrant immediate evaluation for leukemia or myeloproliferative disorders. These disorders can affect leukocytes or other cell lines and have 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 that primarily affect the central nervous system and lungs, although other organs, such as 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 system symptoms such as visual changes, headache, dizziness, tinnitus, gait instability, confusion, somnolence, and, occasionally, coma. Management of hyperleukocytosis and leukostasis depends on the specific hematologic malignancy.[24][25]

An accurate diagnosis requires a comprehensive medical history, a thorough physical examination, and careful identification of underlying risk factors for leukocytosis. Clinicians should also meticulously interpret automated differentials and peripheral blood smears and refer patients to appropriate specialists for further assessment. Additional ancillary tests, such as flow cytometric immunophenotyping, molecular testing, genetic studies, and bone marrow examination, may be necessary to evaluate for hematologic malignancies. The absolute WBC count can vary across laboratories due to differences in the upper limit of normal and the type of hematology analyzer used. Hematology analyzers evaluate whole-blood samples to generate a CBC with differential, including RBC, WBC, and platelet counts, as well as hemoglobin level, RBC indices, and WBC differentials. Modern hematology analyzers use cytochemical and fluorescence-based techniques to differentiate WBC subtypes and categorize them as low or high using preset algorithms. Careful examination of flagged blood samples through a peripheral blood smear aids in establishing a manual differential and validating automated differential findings.[26][27] Cryoproteins such as cryoglobulins and cryofibrinogen can artificially elevate the WBC count. Hyperleukocytosis can also skew hemoglobin and hematocrit values, as well as blood cell indices. In the laboratory, blood specimens with leukocytosis may exhibit a time-dependent decline in glucose levels if left unprocessed, resulting in artifactual hypoglycemia.[28] Clinicians assess the leukocyte count using a peripheral blood sample obtained through a routine blood draw. Cell counts vary by age and, to a lesser extent, race. In general, leukocyte counts are higher in infants than in adults.[29] During childhood, lymphocytes predominate in the peripheral blood, whereas neutrophils become the predominant leukocyte subtype in adulthood Age-appropriate reference ranges for leukocytes are provided below. Newborns: 13,000 to 38,000 cells/µL Infants (from 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 (third trimester): 5800 to 13,200 cells/µL

Age-appropriate reference ranges for leukocytes are provided below. Newborns: 13,000 to 38,000 cells/µL Infants (from 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 (third trimester): 5800 to 13,200 cells/µL Leukocyte counts and differentials may vary by ancestry. Individuals of African, Middle Eastern, and West Indian descent may have lower baseline WBC counts and absolute neutrophil counts compared with those of European or Hispanic descent.[30] This condition, known as benign ethnic neutropenia, may be identified in individuals of African descent who have chronically low neutrophil counts on CBC in the absence of infectious concerns on history and physical examination. Benign ethnic neutropenia is an important consideration when evaluating a patient of African descent, as leukocytosis may fall within the normal laboratory reference range. However, values should be interpreted relative to the patient’s prior CBC results. Hereditary forms of this condition have been described.[31] The initial step in evaluating a patient with leukocytosis is to obtain a WBC differential and review prior CBCs for any noticeable trends. A peripheral smear should then be assessed, with a manual differential performed if the automated differential is abnormal. If there is concern for malignancy, referral to a hematology-oncology specialist is warranted. Neutrophilia Serial outpatient CBC monitoring may be appropriate for asymptomatic patients with modest, stable neutrophilia. Patients with a WBC count greater than 100,000 cells/µL warrant urgent hematologic consultation. In addition, patients who are clinically unstable, particularly those with neutrophilia accompanied by hypotension, high fever or hypothermia, or abdominal rebound tenderness, require hospitalization and prompt evaluation. Please see StatPearls' companion resource," Neutrophilia," for additional information. Additional testing to consider may include: Renal and liver function tests. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibody, blood and urine cultures, lumbar puncture, and sputum culture. The ESR and CRP serve as nonspecific markers of inflammation. D-dimer when evaluating for sepsis. C difficile testing in hospitalized patients with recent antibiotic exposure.

Renal and liver function tests. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibody, blood and urine cultures, lumbar puncture, and sputum culture. The ESR and CRP serve as nonspecific markers of inflammation. D-dimer when evaluating for sepsis. C difficile testing in hospitalized patients with recent antibiotic exposure. Based on the initial evaluation, possible testing may include: Bone marrow biopsy Flow cytometry Molecular and genetic testing Imaging, guided by the suspected source and organ system involvement. Lymphocytosis No specific threshold of lymphocytosis warrants emergent evaluation. However, patients with hemodynamic instability or respiratory compromise require immediate assessment. Reactive lymphocytosis may result in an absolute lymphocyte count (ALC) of 20,000 to 30,000 cells/µL and typically resolves within 1 to 2 months following the inciting event. If the initial evaluation does not identify an underlying cause for lymphocytosis, patients with an ALC greater than 50,000 cells/µL should be referred to a hematology-oncology specialist to determine the need for and timing of further evaluation. As with other forms of leukocytosis, evaluation includes review of a peripheral blood smear. Atypical lymphocytes, which appear as large lymphocytes with abundant basophilic cytoplasm and a large, irregularly shaped nucleus that may exhibit nucleoli, are commonly associated with infectious mononucleosis and other viral illnesses. In contrast, infections such as pertussis, as well as monoclonal B-cell lymphocytosis and CLL, may demonstrate small or normal-appearing lymphocytes. Characteristic morphologic findings can aid diagnosis. "Smudge lymphocytes" are typical of CLL; lymphocytes with hair-like cytoplasmic projections are seen in hairy cell leukemia, and lymphocytes with cerebriform nuclei (Sézary cells) are associated with mycosis fungoides and Sézary syndrome. Additional testing may include: Renal and liver function tests ESR CRP Flow cytometry Bone marrow biopsy Viral panels, blood cultures, and urine and sputum cultures Chest radiography or additional imaging, depending on the suspected organ system involved

Characteristic morphologic findings can aid diagnosis. "Smudge lymphocytes" are typical of CLL; lymphocytes with hair-like cytoplasmic projections are seen in hairy cell leukemia, and lymphocytes with cerebriform nuclei (Sézary cells) are associated with mycosis fungoides and Sézary syndrome. Additional testing may include: Renal and liver function tests ESR CRP Flow cytometry Bone marrow biopsy Viral panels, blood cultures, and urine and sputum cultures Chest radiography or additional imaging, depending on the suspected organ system involved Flow cytometry is necessary in patients with suspected acute leukemia to distinguish between B cells, T cells, and natural killer cells. Molecular and genetic testing can identify clonal cell populations, while chromosomal analyses, such as fluorescence in situ hybridization (FISH) and karyotyping, help differentiate acquired from inherited causes of lymphocytosis. Please see StatPearls' companion resource, "Lymphocytosis," for additional information. Eosinophilia Generally, the need for emergent evaluation is determined by the severity of the illness rather than the AEC. Evidence of life-threatening or disabling conditions, particularly those suggesting eosinophil-mediated damage to the heart, lungs, nervous system, or other organs, warrants urgent intervention. Patients with an AEC greater than 1500 cells/µL, including those with incidentally identified eosinophilia, should undergo repeat CBC testing within 1 to 2 weeks. Persistent or rising AEC elevations should prompt evaluation for hypereosinophilic syndromes. If the AEC is less than 1500 cells/µL, a repeat CBC in approximately 1 month may be appropriate, provided there is no evidence of eosinophilic end-organ damage (eg, eosinophilic myocarditis, cerebral thromboembolism, encephalopathy, or peripheral neuropathy). The patient should also have no history of travel to or residence in helminth-endemic areas and no clinical features suggestive of malignancy. Please see StatPearls' companion resource, "Eosinophilia," for additional information. Additional testing may include: Allergy testing Stool ova and parasite evaluation [32][33][34] Cardiac evaluation, including troponin, electrocardiogram, and echocardiography, in patients with chest pain, dyspnea, new murmur, or fatigue; endomyocardial biopsy may be required in selected cases [35][36][37][38]

Patients with an AEC greater than 1500 cells/µL, including those with incidentally identified eosinophilia, should undergo repeat CBC testing within 1 to 2 weeks. Persistent or rising AEC elevations should prompt evaluation for hypereosinophilic syndromes. If the AEC is less than 1500 cells/µL, a repeat CBC in approximately 1 month may be appropriate, provided there is no evidence of eosinophilic end-organ damage (eg, eosinophilic myocarditis, cerebral thromboembolism, encephalopathy, or peripheral neuropathy). The patient should also have no history of travel to or residence in helminth-endemic areas and no clinical features suggestive of malignancy. Please see StatPearls' companion resource, "Eosinophilia," for additional information. Additional testing may include: Allergy testing Stool ova and parasite evaluation [32][33][34] Cardiac evaluation, including troponin, electrocardiogram, and echocardiography, in patients with chest pain, dyspnea, new murmur, or fatigue; endomyocardial biopsy may be required in selected cases [35][36][37][38] Vitamin B12 and tryptase levels, as elevated levels may suggest an underlying malignancy [39] Upper endoscopy [40] Chest radiography and pulmonary function tests in patients with respiratory symptoms [41] High-resolution computed tomography (CT) for patients with possible eosinophilic granulomatosis with polyangiitis [42][43][44] Additional imaging, as warranted, on the suspected organ system involved Basophilia As with other cell lines, evaluation of basophilia begins with review of a peripheral blood smear. Additional studies may include bone marrow aspiration and biopsy, FISH, karyotyping, and molecular genetic analysis.[2][45] Please see StatPearls' companion resource, "Basophilia," for additional information. Monocytosis Potential additional evaluations for monocytosis may include ESR, CRP, antinuclear antibody testing, a mononucleosis spot test, tuberculosis testing with a tuberculin skin test, and an interferon-gamma release assay. Imaging studies may also be obtained based on the suspected organ system involved. Hyperleukocytosis

Monocytosis Potential additional evaluations for monocytosis may include ESR, CRP, antinuclear antibody testing, a mononucleosis spot test, tuberculosis testing with a tuberculin skin test, and an interferon-gamma release assay. Imaging studies may also be obtained based on the suspected organ system involved. Hyperleukocytosis Hyperleukocytosis is defined as a WBC count of 100,000 cells/µL or higher, and patients may be asymptomatic or present with clinical manifestations. Leukostasis is diagnosed when hyperleukocytosis is accompanied by signs of tissue hypoxia; this remains a clinical diagnosis. Blasts are more likely to contribute to leukostasis than smaller, more mature cells (eg, those seen in CLL). Blasts are more adhesive than mature leukocytes because they release inflammatory cytokines (eg, tumor necrosis factor and interleukin-1β) that, together with integrins, increase cellular adhesion to the vascular endothelium.[46][47] In addition, blasts are larger and less deformable, making them more likely to obstruct the microvasculature.

Management of leukocytosis is guided by the underlying cause. Many patients do not require specific therapy. Some patients can be treated with observation and serial CBCs, whereas others may require treatment for infections, autoimmune conditions, endocrine disorders, or malignancies. Hyperleukocytosis may constitute a medical emergency when accompanied by symptoms and evidence of tissue hypoxia. Leukostasis is most commonly associated with AML, but can rarely occur in CLL and ALL. Clinicians use chemotherapy, leukapheresis, and supportive medications to treat leukostasis and prevent decompensation.[48][49] Patients with hyperleukocytosis are at an increased risk for disseminated intravascular coagulation due to increased thrombin formation and excessive fibrinolysis. Clinicians should monitor the patient's coagulation profile closely and provide supportive management, including fibrinogen replacement and platelet transfusion as indicated.

The differential diagnoses for leukocytosis are extensive. Clinicians need to distinguish acute from chronic leukocytosis and assess its degree. The higher the WBC count, the more likely a malignancy or acute reaction is the underlying cause. A systematic approach involving healthcare professionals is essential when evaluating affected patients. Acute Leukocytosis Leukemoid reaction Reactive causes Infection [50] Acute allergies Tissue ischemia Medications, including epinephrine, corticosteroids, PEG-rhG-CSF, medroxyprogesterone (progestin), NSAIDs, cephalosporin antibiotics, anticonvulsants, beta-agonists, allopurinol, penicillin-derivative antibiotics, opioids, and metformin [51][52][53][54] Recent vaccination Myocardial infarction [55] Hemorrhage Acute hemolysis Sepsis or septic shock Pregnancy Cushing disease [56] Severe emotional stress (eg, fear or rage) [57] Asphyxia [57] Vigorous exercise [57] Seizures [57] Chronic Leukocytosis Smoking Obesity Chronic allergies Autoimmune disorders Vasculitis Connective tissue disorders Malignancy Pregnancy Chronic infection Asplenia Genetic syndromes (eg, leukocyte adhesion deficiency and chronic granulomatous disease) [58]

Leukocytosis secondary to benign, nonmalignant, and treatable conditions generally carries a favorable prognosis. In contrast, leukocytosis associated with malignant lymphoproliferative disorders and lymphomas is associated with poorer outcomes. Prognosis is influenced by factors such as age, comorbidities, prior myelodysplastic syndrome or myeloproliferative neoplasm, history of exposure to cytotoxic agents or radiation, and underlying cytogenetic and molecular abnormalities. A WBC count greater than 35,000 cells/µL has also been associated with a poor prognosis.[59] As a marker of inflammation, leukocytosis may also serve as a prognostic indicator in patients without infection. Increased morbidity and mortality have been observed in patients with leukocytosis in the absence of infection who have experienced myocardial infarction, stroke, or require intensive care unit admission. Studies also demonstrate that elevated WBC counts are positively correlated with worsening glucose tolerance and inversely correlated with insulin sensitivity.

The complications of leukocytosis extend beyond its diagnostic significance. In severe cases, markedly elevated WBC counts can contribute to tissue injury through inflammatory mechanisms, impair organ function, and lead to systemic complications such as sepsis or organ failure. Prompt identification and management of the underlying cause are essential to prevent further complications. Complications specific to hyperleukocytosis include: Myocardial ischemia [60][61] Right ventricular overload [62] Renal insufficiency Priapism [63] Acute limb ischemia [64] Bowel infarction [65][66] Coma Respiratory failure [67] Disseminated intravascular coagulation [68] Intracranial hemorrhage [69][70] Tumor lysis syndrome [68] Tumor lysis syndrome, which results from rapid cell lysis often after initiation of treatment, is associated with several complications, including the following: Hyperkalemia, hyperphosphatemia, and hypocalcemia, which may lead to heart failure, cardiac dysrhythmias, seizures, muscle cramps, tetany, syncope, and, in severe cases, sudden death Hyperuricemia Acute renal failure

All patients with acute leukemia and WBC counts greater than 100,000 cells/µL require prompt medical evaluation and consultation with a hematology specialist. Patients with chronic leukemia also require hematology involvement; however, evaluation is typically not emergent. Depending on the underlying cause and clinical presentation, additional consultation, such as with an infectious disease specialist, may be appropriate.

Leukocytosis, defined as an elevated WBC count, can arise from various underlying factors, including infections, medications, physiological stress, and serious conditions such as leukemia or lymphoma. Understanding the potential etiologies and clinical implications of leukocytosis is important for both patients and healthcare professionals. Patients should be advised to seek medical evaluation if they experience symptoms such as fever, fatigue, unintentional weight loss, or recurrent infections, as these may indicate an underlying condition requiring prompt assessment and treatment. Education should also emphasize the importance of medication reconciliation and reporting any recent changes or additions to medications, as certain agents can contribute to leukocytosis. Regular health maintenance and appropriate monitoring, particularly in individuals with chronic conditions or a history of hematologic disorders, support early detection and management of leukocytosis. Increased awareness and proactive engagement in care can help reduce complications and facilitate timely intervention.

Key facts to keep in mind about leukocytosis include: Leukocytosis should be promptly identified, and prior CBC results should be reviewed to assess trends. The need for urgent interventions, such as leukapheresis, should be evaluated when indicated. A thorough history and physical examination are essential to determine the underlying cause of leukocytosis. Evaluation of new or chronic leukocytosis should consider factors such as ethnicity, place of birth, geographic exposure, family history, and social history. Medication reconciliation is critical, as many commonly used medications can cause nonspecific leukocytosis. Management should be guided by the underlying etiology, with appropriate involvement of specialists such as infectious disease, hematology, oncology, or other relevant disciplines. Clinicians should remain vigilant for serious complications associated with malignancy-related leukocytosis and its treatment, including hyperviscosity syndrome and tumor lysis syndrome.

Leukocytosis, defined as an elevated WBC count, is a common finding with a broad range of potential etiologies, including infection, inflammation, malignancy, and hereditary disorders. Effective evaluation requires a comprehensive approach that integrates a detailed medical history, thorough physical examination, and appropriate laboratory studies. Interpretation of leukocyte counts should consider patient-specific factors such as age, ethnicity, and pregnancy status. Although many cases of leukocytosis are self-limited and resolve without intervention, some require further evaluation, particularly when malignancy is suspected; in such cases, bone marrow biopsy may be indicated. Symptom-directed assessment can help identify underlying etiologies, such as eosinophilia associated with allergic or parasitic conditions. Marked elevations in WBC count may require urgent evaluation for leukemia or myeloproliferative disorders, necessitating coordinated care to facilitate timely diagnosis, appropriate management, and smooth transitions across care settings. Seamless interprofessional communication among healthcare providers is essential, as it facilitates the exchange of information, shared insights, and collaborative decision-making. A coordinated, multidisciplinary approach involving physicians, advanced practice providers, nurses, pharmacists, and other healthcare professionals improves outcomes and reduces morbidity and mortality. Physicians apply diagnostic expertise to accurately identify leukocytosis, develop evidence-based treatment plans, and guide overall patient care. Advanced practice providers contribute through comprehensive assessments, clinical decision-making, and collaboration in care planning. Nurses play a critical role in patient monitoring, treatment administration, education, and ensuring continuity and safety of care. Pharmacists optimize medication management by evaluating regimens, identifying potential drug interactions, and promoting safe and effective therapy. Through coordinated, patient-centered care, interprofessional teams can enhance clinical outcomes and overall quality of life by leveraging the collective skills and expertise of clinicians.