Leukocytosis

Leukocytosis is an elevation in the white blood cell (WBC) count (> 11,000/mm³) and can be further defined by the primary WBC type that is elevated (i.e., neutrophils, lymphocytes, eosinophils, monocytes, basophils). Neutrophilia and lymphocytosis are the most common forms of leukocytosis and can be caused by numerous factors, including infection, hematologic abnormalities, malignancy, and autoimmune or inflammatory disorders. Reactive leukocytosis may also result from physiological causes. Diagnosis involves obtaining a CBC with differential and a peripheral blood smear. Further studies (e.g., infectious workup) should be obtained based on the suspected cause. Management depends on the underlying cause of leukocytosis.

Eosinophilia is discussed in a separate article.

See “Overview of WBC parameters” for further details on reference ranges.

• Leukocytosis: an elevation in WBCs (> 11,000/mm³), which can be further characterized by the predominating cell type, e.g., neutrophilia, lymphocytosis, eosinophilia
• Absolute cell count: the differential percentage multiplied by the total leukocyte count ^[1]
• Reactive leukocytosis: an elevation in WBCs (usually 11,000–30,000/mm³) resulting from stress (e.g., due to surgery, burns, vigorous exercise), medications (e.g., corticosteroids, lithium), or rebound after severe anemia (e.g., following hemorrhage) ^[1]
• Leukemoid reaction: an exaggerated reactive leukocytosis (WBC elevation 50,000–100,000/mm³) in response to often benign etiologies such as inflammation (e.g., organ rejection) or infection (e.g., sepsis) or, less commonly, solid malignant tumors ^[2][3]

Normal WBC count ranges vary based on an individual's age, pregnancy status, sex, and ethnicity, and on the laboratory performing the study. ^[4][5]

Neutrophilia ^[1][3]

• Infection
  • Bacterial infections
  • Fungal infections
• Malignancy
  • Acute myeloid leukemia
  • Chronic myeloid leukemia (CML)
  • Cytokine-releasing cancers, e.g., lung cancer, renal cell carcinoma
  • Bone marrow metastasis
• Hematologic
  • Myeloproliferative neoplasms, e.g., polycythemia vera, idiopathic fibrosis
  • Primary hematologic conditions, e.g., congenital neutrophilia
  • Bone marrow stimulation, e.g., due to hemolytic anemia, recovery after marrow suppression
• Medications
  • Corticosteroids (demargination)
  • Lithium
  • Beta-adronergic agonists
  • Colony-stimulating factors, e.g., G-CSF injections
  • Epinephrine
• Physiologic
  • Obesity
  • Pregnancy
• Autoimmune or inflammatory
  • Rheumatic diseases (e.g., rheumatoid arthritis)
  • Inflammatory bowel disease
• Other
  • Splenectomy
  • Cigarette smoking
  • Stress response, e.g., to trauma or vigorous exercise

Neutrophilia is the most common form of leukocytosis. ^[1]

Lymphocytosis ^[1][2][3][6]

• Infection
  • Viral infections (e.g., EBV, CMV, hepatitis)
  • Bacterial infections (e.g., pertussis, tuberculosis, brucellosis)
  • Protozoal infection (e.g., malaria, babesiosis, toxoplasmosis)
• Malignancy
  • Acute lymphoblastic leukemia
  • Chronic lymphocytic leukemia
  • Lymphoma (e.g., NHL)
• Hematologic: monoclonal B-cell lymphocytosis
• Autoimmune or inflammatory
  • Drug hypersensitivity reaction
  • Serum sickness
• Endocrine
  • Thyrotoxicosis
  • Primary adrenal insufficiency
  • Hypopituitarism
• Other
  • Vaccines
  • Connective tissue diseases
  • Asplenia
  • Cigarette smoking
  • Stress response, e.g., to trauma or vigorous exercise

Eosinophilia ^[1][2][3]

See “Etiology” in “Eosinophilia” for a more extensive list.

• Autoimmune or inflammatory
  • Asthma
  • Allergic rhinitis
  • Eosinophilic esophagitis
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Sarcoidosis
• Medications: drug hypersensitivity reactions
• Dermatological diseases
  • Dermatitis herpetiformis
  • Erythema multiforme
  • Bullous pemphigoid ^[7]
• Infections
  • Bacterial (e.g., scarlet fever, leprosy, genitourinary infections, chlamydial infections)
  • Helminth infections
• Malignancy
  • Non-Hodgkin lymphoma
  • Hodgkin lymphoma
  • CML
  • T-cell lymphoproliferative disorders
• Hematologic
  • Polycythemia vera
  • Myelofibrosis
• Other: primary adrenal insufficiency

Eosinophilia is most commonly caused by allergic or drug reactions. ^[3]

Monocytosis ^[1][3]

• Infection
  • Bacterial (e.g., tuberculosis, endocarditis, syphilis, rickettsia)
  • Fungal
  • Viral (e.g., EBV)
  • Protozoal infections (e.g., malaria)
• Malignancy
  • Lymphoma
  • Multiple myeloma ^[4]
  • Acute or chronic myelomonocytic leukemia ^[6]
• Autoimmune or inflammatory
  • IBD
  • Sarcoidosis
  • SLE
• Hematologic
  • Recovery from bone marrow suppression
  • Neutropenia
• Other: splenectomy

Monocytosis is most commonly caused by bacterial infections. ^[6]

Basophilia ^[2]

• Malignancy
  • CML
  • Hodgkin lymphoma
• Hematologic
  • Myeloproliferative neoplasms (e.g., polycythemia vera, myelofibrosis)
  • Chronic hemolytic anemia
• Autoimmune or inflammatory:
  • Allergy
  • IBD
  • Chronic airway inflammation
  • Chronic dermatitis
• Infections
  • Viral infections (e.g., varicella)
  • Chronic sinusitis
• Endocrine
  • Hypothyroidism
  • Ovulation
• Other: splenectomy

Basophilia is most commonly caused by malignancy (e.g., CML). ^[2]

Blasts on peripheral blood smear ^[4]

• Infection
• Acute leukemia
• Chronic myeloid neoplasms (e.g., MDS)
• Excessive G-CSF stimulation (iatrogenic or endogenous)

Focused history ^[1][3]

• Systemic symptoms (e.g., fever, fatigue, weight loss)
• Infectious symptoms
• Autoimmune or inflammatory symptoms (e.g., joint pains, fever, rash)
• Detailed medication list

Focused physical examination ^[3]

• Signs of infection, e.g.:
  • Clinical features of sepsis
  • Clinical features of tonsillopharyngitis
  • Clinical features of pneumonia
  • Clinical features of UTI
  • Clinical features of cellulitis, e.g., erythema, warmth, tenderness, lymphangitis, lymphadenitis
  • Clinical features of intraabdominal abscess, lung abscess, or cerebral abscess
  • Clinical features of infective endocarditis
  • Clinical features of septic arthritis
• Skin changes, e.g., ecchymoses, petechiae, rash
• Signs of malignancy, e.g.:
  • Lymphadenopathy
  • Splenomegaly
  • Hepatomegaly

Approach

• Consult oncology for patients with red flags for malignancy.
• Rapidly evaluate and treat nonmalignant life-threatening causes of leukocytosis.

Red flags for malignancy ^[1]

• B symptoms
• Fatigue
• Easy bruising and/or bleeding
• Petechiae
• Lymphadenopathy
• Splenomegaly, hepatomegaly
• Concurrent anemia or thrombocytopenia ^[2]
• WBCs > 30,000/mm^{3 [2]}

Nonmalignant life-threatening causes of leukocytosis

• Sepsis
• Severe trauma or burns
• Hemorrhage
• Acute hemolysis
• Acute coronary syndrome
• Acute pancreatitis
• Tissue necrosis
• Acute respiratory distress syndrome
• Anaphylaxis
• Severe cutaneous adverse reactions

Initial studies ^[1]

Obtain the following to confirm the presence and type of leukocytosis:

• CBC with differential
  • Assess for predominant WBC type.
  • Concurrent RBC and platelet abnormalities suggest a bone marrow process.
  • Review prior CBC results to determine the chronicity. ^[1]
• Peripheral blood smear
  • Band cells are common during the acute phase of bacterial infections and/or inflammation.
  • Platelet clumping may be misinterpreted as WBCs.
  • Toxic granulations suggest inflammation.
  • Morphology
    • Monomorphic WBCs are concerning for malignancy.
    • Pleomorphic WBCs suggest reactive leukocytosis.

Additional studies ^[1][3]

Further evaluation is based on the clinical suspicion and may include the following:

Infection

• Cultures: blood, urine, and other sources (e.g., joint fluid, CSF)
• Viral studies (e.g., monospot test, CMV or EBV titers)
• Inflammatory markers (e.g., CRP, procalcitonin)
• Transaminases to assess for liver injury
• Imaging (e.g., CXR in suspected pneumonia)

Malignancy

• Bone marrow biopsy
• Molecular or cytogenetic testing and/or flow cytometry on peripheral blood or bone marrow
• Tissue biopsy
• Imaging (e.g., CXR, CT, or bone scan to assess for malignancy)

Inflammatory conditions

• ESR and CRP
• Serologies (e.g., ANA)

Common causes of neutrophilia

Common causes of lymphocytosis

• Treatment depends on the underlying cause of leukocytosis.
• Provide reassurance in physiological causes.
• Provide immediate inpatient care as indicated, e.g.:
  • Stabilize patients and provide sepsis management in severe infections.
  • Consult hematology and provide directed care in oncologic emergencies (e.g., hyperleukocytosis, leukostasis, tumor lysis syndrome).