AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• References

Background

Leukocytosis refers to an increase in the total number of WBCs due to any cause. From a practical standpoint, leukocytosis is traditionally classified according to the component of white cells that contribute to an increase in the total number of WBCs. Therefore, leukocytosis may be caused by an increase in (1) neutrophil count (ie, neutrophilia), (2) lymphocyte count (ie, lymphocytosis), (3) monocyte count (ie, monocytosis), (4) eosinophilic granulocyte count (ie, eosinophilia), (5) basophilic granulocyte count (ie, basophilia), or (6) immature cells (eg, blasts). A combination of any of the above may be involved.

Neutrophilia also is divided into 4 categories based on the mechanism of neutrophilia: (1) increased production, (2) decreased egress from vascular space, (3) increased mobilization from the marrow storage pool, and (4) reduced margination into the tissue.

Clinically, dividing leukocytosis on the basis of its causes is more convenient. By dividing it according to causes, leukocytosis can be immediately applied for diagnostic purposes. Leukocytosis can be caused by infection, inflammation, allergic reaction, malignancy, hereditary disorders, or other miscellaneous causes.

Pathophysiology

Leukocytosis can be a reaction to various infectious, inflammatory, and, in certain instances, physiologic processes (eg, extreme stress). This reaction is mediated by several molecules, which are released or upregulated in response to stimulatory events and which include growth or survival factors (eg, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, c-kit ligand), adhesion molecules (eg, CD11b/CD18), and various cytokines (eg, interleukin-1, interleukin-3, interleukin-6, interleukin-8, tumor necrosis factor).

The peripheral leukocyte count is determined by several mechanisms, including (1) the size of precursor and storage pool of myeloid and lymphoid cells, (2) the rate of release of the cells from the storage pool, (3) the rate of marginating cells out of blood vessels, and (4) the rate of consumption of the cells in the tissues (ie, cell loss). The growth factors, adhesion molecules, and cytokines control all 4 mechanisms listed above. For a detailed discussion, see Robbins Pathologic Basis of Disease.¹

Hyperleukocytosis (WBC count >100 X 10⁹/L, or >100 X 10³/µL) occurs in leukemia and myeloproliferative disorders. This is certainly due to its inherent autonomous growth potential of malignant cells. Hyperleukocytosis often causes vascular occlusion, resulting in ischemia, hemorrhage, and edema of the involved organs. The problem is most commonly observed in acute myelogenous leukemia with high WBC counts. Individuals often clinically present with mental status changes, stroke, and renal or pulmonary insufficiency.

In a person with sickle cell disease, the baseline WBC count is elevated with a mean of 12-15 X 10⁹/L (12-15 X 10³/µL). This change mainly is due to a shift of granulocytes from the marginated pool to the circulating compartment. The segmented neutrophil count increases in both vaso-occlusive crisis and in bacterial infection in patients with sickle cell disease.

Mortality/Morbidity

Clinically significant morbidity and mortality are frequently observed in patients with leukemic hyperleukocytosis. Hyperleukocytosis may result in tumor lysis syndrome and disseminated intravascular coagulopathy. In addition to well-known complications (eg, acute respiratory failure, pulmonary hemorrhage, CNS infarction, hemorrhage), splenic infarction, myocardial ischemia, renal failure due to renal vessel leukostasis, and priapism have been reported.

Age

Always remember age-specific reference ranges for total WBC, neutrophil, and lymphocyte counts. The total WBC and neutrophil count in neonates younger than 1 week are physiologically higher than those of older children and adults. The proportion of lymphocytes and absolute lymphocyte count in children younger than 6 years are higher than those in adults. Failure to recognize age-specific lymphocytosis may lead to unnecessary investigations (see the table below for reference ranges of age-related leukocyte counts).

Infants (usually aged <3 mo) have small storage pools of neutrophils. In severe infections, their neutrophilic demands often exceeded their supplies. Therefore, young infants may have neutropenia in response to serious infection.

Normal Leukocyte Counts

^*Numbers of leukocytes are in X 10⁹\L or thousands per μL; ranges are estimates of 95% confidence limits; and percentages refer to differential counts.

^† Neutrophils include band cells at all ages and a small number of metamyelocytes and myelocytes in the first few days of life.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• References

Causes

• Neutrophilia (ie, neutrophil count that exceeds the reference range for age) may be due to the following conditions:
• • Infection (most common cause)
  • • Most bacterial infections cause neutrophilia with bandemia (number of bands exceeds the reference range). Some bacterial infections do not cause neutrophilia. For example, typhoid fever causes leukopenia, neutropenia, or both. Infants, preterm infants in particular, have small storage pools of neutrophils in the bone marrow. Therefore, neutropenia develops in severe or chronic infections because the neutrophilic demand is greater than the supply.
    • Neutrophilia alone or with an increased band count had variable sensitivity and specificity in numerous studies as a possible predictor of bacteremia in young children with fever. The study by Lee and Harper (1998) was unique in that they selected infants and toddlers aged 3-36 months with fever (>39°C) who appeared well and who were sent home from the emergency department.² They excluded patients who were admitted, transferred, or died to select a population who potentially had truly occult bacteremia. The study showed a significantly positive correlation between the frequency of blood cultures positive for Streptococcus pneumoniae and the WBC and absolute neutrophil counts.
    • In another study, Brown et al (2005) focused on febrile neonates (aged £28 d) who visited the emergency department.³ They calculated the sensitivity and specificity of various WBCs for the detection of bacterial infection. They found modest discriminatory power of the WBC count; the (area under the receiver operator characteristic [ROC] curve) was 0.7231.
    • Recent immunization practice with heptavalent pneumococcal conjugate vaccination seems to have reduced incidence of bacteremia with this organism in infants aged 2-6 months. Accordingly, extreme leukocytosis, which is a common characteristic of pneumococcal bacteremia, has decreased in frequency.
    • Urinary tract infection and pneumonia due to other organisms are more prevalent in infants with fever and typically cause less leukocytosis.⁴ Therefore, the algorithm that uses the total white cell count to gauge bacteremia risk in infants may not apply to the new generation of children with fever.
    • In general, the WBC and neutrophil counts alone are not sensitive or specific enough to accurately predict bacterial infection. Although viral infections generally do not cause neutrophilia, it can occur during the early phases of infection.
  • Inflammation: This includes inflammatory bowel disease, rheumatoid arthritis, and vasculitis (eg, Kawasaki syndrome).
  • Malignancy and myeloproliferative disorders
  • • These are rare causes of neutrophilia in children.
    • Hodgkin lymphoma typically causes mild-to-moderate neutrophilia.
    • Patients with chronic phase of adult-type chronic myelocytic leukemia and a positive Philadelphia chromosome present with neutrophilia with immature forms, eosinophilia, basophilia, and thrombocytosis.
    • Juvenile myelomonocytic leukemia causes leukocytosis and monocytosis with bizarre-shaped monocytes rather than neutrophilia alone.
    • Infants with Down syndrome frequently have leukocytosis, neutrophilia, differential shift to the left, and immature forms (blasts) in the blood. In most cases, this change is transient (referred to as transient myeloproliferative disorder); about 20-30% of infants with Down syndrome develop leukemia.
    • Some solid tumors (most commonly described in carcinoma of the lung), cause neutrophilia by the tumor cells producing granulocyte colony-stimulating factor.
  • Decreased egress from circulation
  • • The neutrophil count is a balance between its production and release into blood circulation and its destruction and departure from circulation into tissue. Anything that affects any component of this balance affects the neutrophil count.
    • Decreased egress from circulation may occur with the administration of corticosteroids, splenectomy, or congenital leukocyte adhesion molecule deficiency. Leukocyte adhesion molecule deficiency is a congenital condition. In babies born with this disorder, the umbilical stump may not fall off in a normal period, and they may have persistent neutrophilia in the absence of clinical signs of infection, with an increased susceptibility to infection. Flow cytometric demonstration of the absence of CD11b/CD18 on the patient's leukocytes may assist in establishing the diagnosis.
  • Decreased neutrophil margination, including steroid administration, exercise, epinephrine administration, and other stressful situations (eg, trauma, severe pain): Neutrophilia due to this cause is short lived (ie, minutes to hours, not days, in duration). Furlan et al reported a significant elevation in the leukocyte count (and lymphopenia) during the first week after isolated spinal cord injury in patients with neurological impairment compared with controls who had isolated spinal cord injury without neurological impairment.⁵ This elevation was not due to steroid administration. Similar leukocytosis was observed in patients with acute brain injury. Authors speculated that alpha adrenergic stimuli, endogenous cortical increase, or both may be the cause for the leukocytosis.
  • Increased release of neutrophils from marrow: This occurs in infection, stress, and hypoxia; it also occurs due to endotoxin stimulation and steroid administration.
• Lymphocytosis conventionally refers to a lymphocyte count greater than 4 X 10⁹/L (4000/µL); however, a lymphocyte count that exceeds this is physiologically present in infants and young children. The upper normal limit of lymphocyte count in this age group has not been well defined in a healthy population.
• • Marked lymphocytosis is observed in individuals infected with pertussis (total leukocyte count of 40-50 X 10⁹/L, or X 40-50 X 10³/µL).
  • Viral infection generally causes lymphocytosis (relative or absolute) with or without neutropenia. Typical examples include infectious mononucleosis or cytomegalovirus infection, respiratory syncytial virus infections, and infectious hepatitis.
  • Chronic lymphocytic leukemia is extremely rare in children and is usually not considered in the differential diagnosis of lymphocytosis.
• An increase in absolute eosinophil count greater than 0.5 X 10⁹/L (500/µL) is generally considered eosinophilia. The following are common causes of eosinophilia.
• • Allergy and drug hypersensitivity: This includes asthma, hay fever, angioneurotic edema, urticaria, anticonvulsant hypersensitivity reaction, allergy to drugs, and other allergic conditions.
  • Parasitic infections: The most commonly observed parasitic infection causing marked eosinophilia in the United States is caused by visceral larva migrans due to Toxocara canis. Toxocara cati also causes visceral larva migrans, but this is rare. Other parasitic infections that cause tissue invasion also cause marked eosinophilia.
  • Other infections: Scarlet fever (recovery phase), viral infections (recovery phase), and chlamydial infection cause an absolute increase in eosinophils but generally do not cause leukocytosis.
  • Dermatologic disorders: Dermatitis herpetiformis, pemphigus, and erythema multiforme cause eosinophilia.
  • Hypereosinophilic syndrome
  • Other conditions: Most other conditions that cause eosinophilia rarely lead to leukocytosis and, therefore, are not listed. However, other rare disorders that should be considered include eosinophilia associated with malignant disease. Pulmonary infiltration with eosinophilia (PIE) and a combination of eosinophilia, leukocytosis, and hepatosplenomegaly may be noteworthy. PIE is characterized by bilateral pulmonary infiltrates and eosinophilia. The symptoms are similar to those of chronic pneumonia. The etiologies are multiple and include various infections (bacterial, viral, fungal, and parasitic) and neoplastic conditions (eg, Hodgkin lymphoma). The combination of leukocytosis, eosinophilia, and hepatosplenomegaly could be true eosinophilic leukemia (with blasts observed in the peripheral blood) or marked eosinophilia with a chronic indolent course.
  • Hyperleukocytosis: This disorder refers to a WBC count 100 X 10⁹/L (100 X 10³/µL). It is observed almost exclusively in leukemia and myeloproliferative disorders. Hyperleukocytosis may cause life-threatening complications (eg, cerebral infarct, cerebral hemorrhage, pulmonary insufficiency). The frequency of complications is higher in acute myelocytic leukemia than in acute lymphoblastic leukemia because myeloblasts are larger and more adhesive than lymphoblasts.
• Monocytosis is defined as a monocyte count that exceeds the upper limit of the reference range of 0.95 X 19⁹/L (950/µL). Monocytosis is commonly caused by the following conditions:
• • Bacterial infections: These include tuberculosis, subacute bacterial endocarditis, and brucellosis.
  • Other infections: Syphilis, viral infections (eg, infectious mononucleosis), and many protozoal and rickettsial infections (eg, kala azar, malaria, Rocky Mountain spotted fever) are included.
  • Malignancies: Malignancies include chronic myelomonocytic leukemia, monocytic leukemia, Hodgkin disease, and myeloproliferative disorders; in adults, they include metastatic carcinoma, particularly lung cancer.
  • Recovery phase of neutropenia or an acute infection
  • Autoimmune disease and vasculitis: These include systemic lupus erythematous, rheumatoid arthritis, ulcerative colitis, and inflammatory bowel disease.
  • Miscellaneous causes: Sarcoidosis and lipid storage disease are included.
• A basophil count that exceeds 0.10-0.15 X 10⁹/L (100-150/µL) that leads to leukocytosis is rare. Chronic myelogenous leukemia (adult type) typically exhibits basophilia and leukocytosis as described above (see Malignancy and myeloproliferative disorder).

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• References

Other Problems to be Considered

Chronic granulocytic (myelogenous) leukemia

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• References

Lab Studies

• In interpreting leukocytosis on the CBC count, consider the following:
• • Clinical features
  • Duration
  • Differential
  • Remainder of the CBC count
• An isolated WBC count is often ordered to minimize cost. However, most of the time, the WBC count cannot be accurately interpreted without the rest of the CBC differential. Therefore, if any question of interpretation is noted, obtain the entire CBC count with differential.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• References

Medical Care

In most cases, treatment for leukocytosis is not necessary.

• In extreme incidents of hyperleukocytosis syndrome (eg, acute leukemia), leukapheresis, hydration, and urine alkalinization to facilitate uric acid excretion are indicated; however, perform these treatments only in consultation with a hematologist, oncologist, or both. Direct treatment toward the underlying etiology.
• Leukemic hyperleukocytosis may cause clinically significant complications when the WBC count exceeds 100,000/μL in acute myelogenous leukemia and 300,000/μL in acute lymphoblastic leukemia.
• • Therefore, in patients with these findings, measures to rapidly reduce the WBC count are advisable.
  • Leukapheresis or exchange blood transfusion is a treatment of choice for this purpose, with hydration, urine alkalinization, and administration of allopurinol or rasburicase (uric acid oxydase) to reduce serum uric acid and minimize tumor lysis syndrome. When rasburicase is used, urine alkalinization is not recommended.
  • Promptly institute definitive treatment with appropriate chemotherapy.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• References

Hyperleukocytosis in leukemia is often complicated by a tumor lysis syndrome, which includes a high serum uric acid and uric acid nephropathy. Prompt measures to reduce serum uric acid and prevent uric acid nephropathy are required.

Drug Category: Uric acid inhibitors

These drugs are used to prevent acute uric acid nephropathy associated with leukocytosis in myeloproliferative disease and leukemia.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• References

Medical/Legal Pitfalls

• Because leukocytosis is diagnostic information based on laboratory findings and because it does not indicate any specific prognosis or management of the patient's condition, medicolegal pitfalls are not applicable.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Miscellaneous
• References

1. Cotran RS, Kumar V, Collins T. Robbins Pathologic Basis of Disease. 6^th ed. Philadelphia, PA: WB Saunders; 1999:644-96.
2. Lee GM, Harper MB. Risk of bacteremia for febrile young children in the post-Haemophilus influenzae type b era. Arch Pediatr Adolesc Med. Jul 1998;152(7):624-8. [Medline].
3. Brown L, Shaw T, Wittlake WA. Does leucocytosis identify bacterial infections in febrile neonates presenting to the emergency department?. Emerg Med J. Apr 2005;22(4):256-9. [Medline].
4. Hsiao AL, Chen L, Baker D. Incidence and predictors of serious bacterial infections among 57- to 180-day-old infants. Pediatrics. May/2006;117:1695-1701.
5. Furlan JC, Krassioukov AV, Fehlings MG. Hematologicl abnormalities within the first week after acute isolated traumatic cervical spinal cord injury: a case-control cohort study. Spine. Nov/2006;31:2674-83. [Medline].
6. Bonadio WA. Evaluation and management of serious bacterial infections in the febrile young infant. Pediatr Infect Dis J. Dec 1990;9(12):905-12. [Medline].
7. Dinauer MC. The phagocyte system and disorders of granulopoiesis and granulocyte function. In: Nathan and Oski's Hematology of Infancy and Childhood. Vol 1. 5^th ed. Philadelphia, PA: WB Saunders; 1998:889.
8. Izbicki G, Rudensky B, Na'amad M, Hershko C, Huerta M, Hersch M. Transfusion-related leukocytosis in critically ill patients. Crit Care Med. Feb 2004;32(2):439-42. [Medline].
9. Lichtman MA, Rowe JM. Hyperleukocytic leukemias: rheological, clinical, and therapeutic considerations. Blood. Aug 1982;60(2):279-83. [Medline].
10. Shah SS, Shofer FS, Seidel JS, Baren JM. Significance of extreme leukocytosis in the evaluation of febrile children. Pediatr Infect Dis J. Jul 2005;24(7):627-30. [Medline].
11. Wang, CW, Lukens JN. Sickle cell anemia and other sickling syndromes. In: Wintrobe's Clinical Hematology. Vol 1. 10^th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999:1346-97.
12. Wright IM, Skinner AM. Post-transfusion white cell count in the sick preterm neonate. J Paediatr Child Health. Feb 2001;37(1):44-6. [Medline].

Article Last Updated: Apr 24, 2008