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Leukocytosis, Pediatric

Basics

Description

- Atopy - Allergies - Asthma - Eczema - Psoriasis

- Hemolysis - Hemolytic anemia - Transfusion reaction

- Parasitic - Toxocara canis - Toxoplasma - Trichinella - Plasmodium spp

- 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

- Myeloproliferative disorders - Polycythemia vera - Essential thrombocytopenia - Myelofibrosis (but more often associated with cytopenias)

- Trauma - Acute hemorrhage - Severe burns

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

  • AtopyAllergiesAsthmaEczemaPsoriasis
  • Congenital/geneticDown syndromeHereditary neutrophiliaLeukocyte adhesion deficiency (LAD)Sickle cell anemia
  • HemolysisHemolytic anemiaTransfusion reaction
  • InfectiousBacterialBrucellaBartonellaBordetella pertussisClostridium difficileFrancisella tularensisHaemophilusMycobacterium tuberculosis (TB)NeisseriaRickettsiaStreptococcuspneumoniaeStaphylococcus aureusViralCytomegalovirus (CMV)Epstein-Barr virus (EBV)Hantavirus (Hantavirus pulmonary syndrome)HepatitisRespiratory syncytial virusParasiticToxocara canisToxoplasmaTrichinellaPlasmodium sppFungalSpirochetal
  • Immunologic/inflammatory/reactiveAppendicitisAddison diseaseAspleniaChronic granulomatous diseaseHypereosinophilic syndrome (HES)Inflammatory bowel disease (IBD)Juvenile idiopathic arthritis (JIA)L ƒ ¶ffler syndromeSarcoidosisSmokingThyrotoxicosisVasculitis including Kawasaki disease
  • MalignancyAcute leukemiasChronic leukemiasLymphomasSolid tumors
  • MedicationsAntiepilepticsBeta agonistsCorticosteroidsEpinephrineGranulocyte or granulocyte " “macrophage colony-stimulating factorHeparinLithiumMinocyclineProstaglandin
  • Myeloproliferative disordersPolycythemia veraEssential thrombocytopeniaMyelofibrosis (but more often associated with cytopenias)
  • Poisons
  • StressAnesthesiaAnxietyEmotional stressOverexertionSeizures
  • TraumaAcute hemorrhageSevere 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 1p34LAD: rare autosomal recessive disorder characterized by recurrent bacterial infectionsSickle 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

  • CardiopulmonaryA 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/lymphIf hepatosplenomegaly and/or lymphadenopathy is present, consider acute viral hepatitis, infectious mononucleosis from either EBV or CMV, malignancy, malaria, or lysosomal storage disease.
  • Musculoskeletal/dermatologicArthritis 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.