Basics
Description
Leukocytosis refers to a total white blood cell (WBC) count above the normal range for age. ‚
Risk Factors
- Very low-birth-weight neonates
- Immunodeficiencies or immunocompromised states
- Inflammatory disorders
- Autoimmune disorders
Alert
Children with trisomy 21 (Down syndrome) have an increased risk of developing transient myeloproliferative disorder (TMD) or leukemoid reactions. ‚
Pathophysiology
Leukocytosis results from increased marrow production, demargination, prolonged cell survival, and/or defective extravasculation in response to external stimuli or, less commonly, from an underlying marrow disorder. ‚
Diagnosis
Differential Diagnosis
- Atopy
- Allergies
- Asthma
- Eczema
- Psoriasis
- Congenital/genetic
- Down syndrome
- Hereditary neutrophilia
- Leukocyte adhesion deficiency (LAD)
- Sickle cell anemia
- Hemolysis
- Hemolytic anemia
- Transfusion reaction
- Infectious
- Bacterial
- Brucella
- Bartonella
- Bordetella pertussis
- Clostridium difficile
- Francisella tularensis
- Haemophilus
- Mycobacterium tuberculosis (TB)
- Neisseria
- Rickettsia
- Streptococcuspneumoniae
- Staphylococcus aureus
- Viral
- Cytomegalovirus (CMV)
- Epstein-Barr virus (EBV)
- Hantavirus (Hantavirus pulmonary syndrome)
- Hepatitis
- Respiratory syncytial virus
- Parasitic
- Toxocara canis
- Toxoplasma
- Trichinella
- Plasmodium spp
- Fungal
- Spirochetal
- Immunologic/inflammatory/reactive
- Appendicitis
- Addison disease
- Asplenia
- Chronic granulomatous disease
- Hypereosinophilic syndrome (HES)
- Inflammatory bowel disease (IBD)
- Juvenile idiopathic arthritis (JIA)
- L ƒ ¶ffler syndrome
- Sarcoidosis
- Smoking
- Thyrotoxicosis
- Vasculitis including Kawasaki disease
- Malignancy
- Acute leukemias
- Chronic leukemias
- Lymphomas
- Solid tumors
- Medications
- Antiepileptics
- Beta agonists
- Corticosteroids
- Epinephrine
- Granulocyte or granulocyte " “macrophage colony-stimulating factor
- Heparin
- Lithium
- Minocycline
- Prostaglandin
- Myeloproliferative disorders
- Polycythemia vera
- Essential thrombocytopenia
- Myelofibrosis (but more often associated with cytopenias)
- Poisons
- Stress
- Anesthesia
- Anxiety
- Emotional stress
- Overexertion
- Seizures
- Trauma
- Acute hemorrhage
- Severe burns
- Nonaccidental trauma
Diagnostic Tests & Interpretation
- Step 1: Confirm that the leukocytosis is real.
- Etiologies of spurious leukocytosis by automated analyzers of whole blood include nucleated or partially lysed RBCs, cryoglobulin or cryofibrinogen, or platelet clumps.
- Confirmation includes review of peripheral smear via consultation of a pathologist or hematologist.
- Step 2: Obtain a differential of the WBC count.
- A manual differential may be required.
- Distinguishing between myeloid and lymphoid or even blasts contributes to identifying the correct etiology.
- Myeloid leukocytosis include (1) neutrophilia, which commonly results from bacterial infections; (2) monocytosis; (3) eosinophilia, typically reactive; (4) basophilia, which is rare and suggestive of myeloproliferative neoplasms; and (5) increased blasts, concerning for underlying marrow abnormality.
- Lymphoid leukocytosis results from viral infections.
- Step 3: Distinguish between reactive and clonal populations.
- Reactive leukocytosis is heterogenous " ”pleomorphic, polyclonal, and/or large granular cells are present.
- Neoplasms such as leukemia/lymphoma are homogenous.
- May need to use flow cytometry with immunophenotyping and/or cell receptor gene rearrangements to rule out malignancy, especially in lymphoproliferative disorders
- Step 4: Evaluate other cell lines.
- Concurrent presence of anemia and/or thrombocytopenia suggests an underlying marrow disorder such as leukemia.
- Leukocytosis and thrombocytosis may be associated with iron deficiency anemia, sickle cell anemia, LAD type III, and pregnancy.
- Step 5: Use this information in clinical context.
Alert
Beware of any differential that has a high percentage of monocytes or atypical lymphocytes, whether machine generated or manual. Leukemic blasts can be mistaken for these cell types. ‚
History
- Evaluate for history or signs of infection.
- Acute infection is the most common cause of leukocytosis.
- Fever is nonspecific and may be present in infectious, inflammatory, rheumatoid, or malignant diseases.
- Obtain thorough past medical history.
- Down syndrome: TMD occurs in ¢ ˆ ¼10% infants and spontaneously resolves in 1 month, although 20 " “30% of these patients progress to AML. This is a medical emergency if there is organomegaly with cardiopulmonary compromise.
- Hereditary neutrophilia: autosomal dominant disorder with heterozygous mutation in the CSF3R gene on chromosome 1p34
- LAD: rare autosomal recessive disorder characterized by recurrent bacterial infections
- Sickle cell anemia: Leukocytosis likely reflects chronic inflammation and may be associated with increased vasoocclusive events.
- Comprehensive review of symptoms may indicate malignancy.
- B symptoms include fever, drenching night sweats, and weight loss of ≥10% over 6 months.
- Persistent bone pain may indicate leukemia and be initially diagnosed as growing pains or worked up for osteomyelitis or JIA.
- Do not forget to obtain history of travel or unusual exposures.
- Shigellosis enteritis may be seen after travel to areas with suboptimal sanitation and present with leukocytosis and even seizures.
- Nursing home residents, incarcerated individuals, and health care professionals are at higher risk for developing and transmitting TB.
- Reptiles commonly carry Salmonella and rodents commonly carry Hantavirus.
- Obtain complete family history.
- Family histories positive for autoimmune disorders may raise suspicion for IBD, JIA, HES, thyroid disease, vasculitis, etc.
Physical Exam
- Cardiopulmonary
- A careful lung examination is necessary, as pneumonia is a common cause of leukocytosis.
- A new murmur or gallop may be an early sign of bacterial endocarditis.
- Abdominal/lymph
- If hepatosplenomegaly and/or lymphadenopathy is present, consider acute viral hepatitis, infectious mononucleosis from either EBV or CMV, malignancy, malaria, or lysosomal storage disease.
- Musculoskeletal/dermatologic
- Arthritis or joint pain and/or rashes may be one manifestation in a constellation that may suggest JIA, rheumatic fever, or Lyme disease.
Imaging
Although universal vaccination with Prevnar (pneumococcal conjugate vaccine [PCV]) has decreased the incidence of pneumonia, clinicians should still strongly consider chest radiography in young, highly febrile children with leukocytosis and no obvious source of infection. ‚
Treatment
General Measures
- Isolated leukocytosis may be monitored without intervention.
- If ill-appearing, age-appropriate empiric antibiotics are indicated.
- Consultation with other subspecialties may be necessary.
- Prognosis depends on diagnosis.
Ongoing Care
In the setting of bacterial infection with appropriate microbial coverage, anticipate resolution of leukocytosis within 4 days. ‚
Alert
If malignancy is in the differential, consult hematology/oncology prior to initiating steroids. ‚
Additional Reading
- Abramson ‚ N, Melton ‚ B. Leukocytosis: basis of clinical assessment. Am Fam Physician. 2000;62(9):2053 " “2060. ‚ [View Abstract]
- Cerny ‚ J, Rosmarin ‚ AG. Why does my patient have leukocytosis? Hematol Oncol Clin North Am. 2012;26(2):303 " “319. ‚ [View Abstract]
- George ‚ TI. Malignant or benign leukocytosis. Hematology Am Soc Hematol Educ Program. 2012; 2012:475 " “484. ‚ [View Abstract]
Codes
ICD09
- 288.60 Leukocytosis, unspecified
- 288.2 Genetic anomalies of leukocytes
- 288.69 Other elevated white blood cell count
ICD10
- D72.829 Elevated white blood cell count, unspecified
- D72.0 Genetic anomalies of leukocytes
- D72.828 Other elevated white blood cell count
SNOMED
- 111583006 Leukocytosis (disorder)
- 129639005 Hereditary neutrophilia (disorder)
- 77358003 Congenital leukocyte adherence deficiency (disorder)
FAQ
- Q: Does the degree of leukocytosis correlate to the severity of infection?
- A: Just as the height of fever does not always correlate to the severity of infection, the same is true for the degree of leukocytosis. Even a normal WBC does not rule out bacteremia.
- Q: What is a leukemoid reaction?
- A: A leukemoid reaction is a physiologic response to a stress or infection and is characterized by a WBC of ≥50 ƒ — 109/L with peripheral blood myeloid precursors at all stages of maturity rather than proliferation of an immature WBC clonal population, which is characteristic of malignancies.
- Q: When is an elevated WBC a clinical emergency?
- A: Leukocytosis or hyperleukocytosis is a clinical emergency when the patient is symptomatic from leukostasis. Hyperleukocytosis is a total WBC count of ≥100 ƒ — 109/L. Clinically significant hyperleukocytosis usually occurs at WBC ≥200 ƒ — 109/L or ≥300 ƒ — 109/L in patients with acute myeloid or lymphoblastic leukemia and chronic myeloid leukemia in blast crisis, respectively; however, symptoms may present with a WBC as low as 50 ƒ — 109/L. Refer to hyperleukocytosis chapter for more information.