• Bacterial
  • Streptococcus
  • Staphylococcus aureus
  • Haemophilus
  • Neisseria
  • Brucella
  • Bartonella (Cat-scratch disease)
  • Pertussis
• Viral
  • Infectious mononucleosis
  • Cytomegalovirus (CMV)
  • Rubella
  • Mumps
  • Hepatitis
• Fungal
  • Aspergillus
• Parasitic
  • Toxocara
  • Toxoplasma
  • Trichinella
  • Tapeworms
  • Strongyloides
• Tuberculosis
• Syphilis
• Acute infectious lymphocytosis
  • Benign viral mediated lymphocytosis (often >25,000/mm³)
• Kawasaki disease

• Down syndrome
• Sickle cell disease
• Fanconi anemia
• Thrombocytopenia with absent radii
• Leukocyte adhesion factor deficiency

• Corticosteroids
  • Epinephrine
  • Lithium
• Granulocyte colony stimulating factor (GCSF)

• Acute hemorrhage
• Severe burns
• Inflammation

• Leukemia
• Lymphoma
• Myeloproliferative disorders
• Solid tumors

• Hyperthyroidism
• Acidosis

• Juvenile rheumatoid arthritis
• Rheumatoid arthritis
• Inflammatory bowel disease
  • Ulcerative colitis
  • Crohn disease
• Chronic granulomatous disease
• Pulmonary eosinophilic syndromes
  • Transient infiltrates associated with a peripheral eosinophilia

• Asthma
• Seasonal or drug allergies
• Eczema
• Psoriasis

• Severe hemolysis

• Nucleated RBCs
• Clumped platelets on a mechanical differential

• Next, determine which white blood cell line is elevated by reviewing the WBC differential to help direct the workup and therapy.
• The differential diagnosis for a patient with a neutrophilia can be different from a patient in whom lymphocytosis is present. For example, an elevated granulocyte count is more likely with bacterial infections and a lymphocytosis is usually associated with viral infections. Pitfall: Many laboratories provide only machine-generated differentials. If there are any abnormalities a manual differential must be obtained. It may be necessary to review the smear with a hematologist or pathologist especially if there are any significant abnormalities.

• Most elevations of WBC count are in the 10,000 to 20,000/mm³ range. A WBC count in the 30,000/mm³ range is more consistent with pertussis or pneumococcal bacteremia. Counts higher than that are worrisome for malignant processes or leukemoid reactions.

Question: Is there any evidence for infection, such as fever, rash, or swelling?
Significance: Infection is the most common etiology for leukocytosis. A thorough history should be taken for apparent or occult infections. Fever can also be a symptom of inflammatory diseases such as JRA or CGD.

Question: What other complaints has the patient had over the preceding weeks to months?
Significance: Infectious etiologies tend to present acutely. If a patient has long-term complaints one should broaden the differential or focus it based on specific complaints. A chronic cough may point to tuberculosis whereas a whooping cough may indicate pertussis.

Question: Does the patient have any other medical problems?
Significance: Patients with sickle cell disease have an elevated WBC count probably secondary to chronic inflammation or marrow expansion. Children with Down syndrome can have a benign leukemoid reaction, especially in the first few months of life, that resolves spontaneously.

Question: Is the patient on any medications?
Significance: Corticosteroids will increase the neutrophil precursors (also called a left-shifted differential). Epinephrine can cause a transitory increase in neutrophil count.

Question: Is there a familial history of any inflammatory diseases?
Significance: For example, collagen vascular disease such as RA, thyroid, Crohn disease.

Question: Has the patient lost weight, been fatigued, had night sweats, or been pale?
Significance: Malignancy such as leukemia must be ruled out.

Finding: Are there any obvious sources of infection?
Significance: Look for cellulitis, otitis, pharyngitis, or abscesses on examination. A good lung examination on a quiet child is necessary as pneumonia secondary to Streptococcus can cause a WBC count as high as 30,000 to 40,000/mm³. A murmur or gallop may be a sign of bacterial endocarditis.

Finding: Lymphadenopathy or hepatosplenomegaly?
Significance: Points toward a possible viral etiology but is also of concern for malignancy.

Finding: Are joints tender or swollen?
Significance: JRA, septic arthritis, SLE

Finding: Mongoloid features?
Significance: Down syndrome.

Test: WBC count including differential and smear.
Significance: If neutrophilia is present think of bacterial infections. One may also see Döhle bodies, toxic granulations, or vacuolization in bacteremia. A recovering or stressed marrow may have an increase in monocytes or eosinophils. Look for leukemic blasts.

Test: Hemoglobin/platelet count
Significance: If either is low, consider a marrow infiltrative process or a hyperstimulated marrow to compensate for a low hemoglobin or platelet count (Fanconi’s anemia, thrombocytopenia with absent radii).

Test: Chemistry panel
Significance: Evaluate LFTs for possible viral etiology. Uric acid and LDH are elevated in leukemia and lymphoma.

Test: Cultures
Significance: Blood, urine, stool, throat, etc.

Test: Monospot, Heterophil Ab, EBV titers
Significance: Screen for infectious mononucleosis. Monospot can be falsely negative in younger children.

Test: Leukocyte alkaline phosphatase
Significance: Elevated in infection but not in leukemia. Helps to differentiate CML from a leukemoid reaction.

Test: ANA
Significance: Screen for rheumatologic etiology.

Test: Bone marrow biopsy and aspirate
Significance: Necessary if any other blood cell line is abnormally low or if the WBCs appear dysmorphic. Need to rule out malignancy, myelodysplasia, or other marrow processes. Send cytogenetics when possible.

Test: Chest x-ray
Significance: Pneumonia, tuberculosis.

• WBC counts greater than 50,000/mm³
• Any indication of malignancy
• Any indication of a rheumatologic etiology
• Inability to find an etiology with a persistent leukocytosis

• Antibiotics if a child appears septic.
• Patient should be started on fluids containing bicarbonate and allopurinol if leukemia is suspected, and sent to a pediatric oncology center.

Q: Infectious mononucleosis (IM) and acute lymphocytic leukemia have many similar signs and symptoms. How can I differentiate them?
A: Both can present with fever, malaise, headache, prominent lymphadenopathy, organo-megaly, and suppressed hemoglobin and platelet counts. IM tends to be associated with a sore throat and children with ALL are more likely to complain of bony pain. The easiest way to differentiate the two is a careful exam of the peripheral smear. A heterophil AB or monospot can be sent and, if positive, help with the diagnosis.

Q: What does “left-shifted” mean?
A: There are early granulocyte precursors (metamyelocytes, myelocytes) seen in the peripheral smear with a bandemia and neutrophilia. Often seen with bacteremia or marrow recovery from a suppressing drug/virus.

Gin-Shaw S, Moore GP. Selected white cell disorders. Emerg Med Clin North Am 1993;11(2):495–516.

Hoffbrand AV, Pettit JE, eds. Color atlas of clinical hematology, 2nd ed. Mosby-Wolfe, 1994.

Peterson L, Hrisinko MA. Benign lymphocytosis and reactive neutrophilia. Clin Lab Med 1993;13(4):863–877.