Leukocytosis

Leukocytosis can be a reaction to various infectious, inflammatory, and, in certain instances, physiologic processes (eg, stress, exercise). This reaction is mediated by several molecules, which are released or upregulated in response to stimulatory events that 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 in the bone marrow, (3) the rate of marginating cells out of blood vessels into the tissues, 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. 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. If the neutrophil count exceeds 30,000/μL as a reaction to extrinsic factors, such as infection, it is sometimes called a leukemoid reaction.

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.

A study by Tien et al indicated that hyperleukocytosis is an independent risk factor for poor prognosis in acute myelogenous leukemia, its impact being unassociated with a patient’s cytogenetic or mutational status. However, the detrimental effects of hyperleukocytosis were apparently reduced in study patients who underwent allogeneic hematopoietic stem cell transplantation in first complete remission, with overall and disease-free survival being significantly extended in these individuals.[2]

Spurious hyperkalemia may result from hyperleukocytosis. Claver-Belver et al described a case of T-cell acute lymphoblastic leukemia with a WBC count of 468.11 X 109/L. A biochemistry analyzer determined the patient's serum potassium level to be 7.3 mmol/L, but a blood gas analyzer determined the whole blood potassium value to be only 4.0 mmol/L. According to the investigators, the spuriously high serum potassium value was attributable to a centrifugation process for serum separation. Thus, it is important to recognize that such false findings may occur in the presence of a very high WBC count.[3]

In certain situations, leukocytosis may have a prognostic value. In a study performed mostly with adult patients, cardiac preoperative leukocytosis (defined by WBC >11,000) was found to be a strong predictor of postoperative medical complications.[4]

A study by Izhakian et al indicated that following lung transplantation, delayed leukocytosis is significantly linked to a higher mortality rate (hazard ratio = 1.52). The highest associated mortality was found when the delay was attributed to acute graft rejection.[5]

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 exceed their supplies. Therefore, young infants may have neutropenia in response to serious infection.

Table. Normal Leukocyte Counts (Open Table in a new window)

Neutrophilia

Neutrophilia (ie, neutrophil count that exceeds the reference range for age; see the Absolute Neutrophil Count calculator) 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. Other bacterial infections that are known to cause neutropenia include Staphylococcus aureus, brucellosis, tularemia, rickettsia, Mycobacterium tuberculosis, ehrlichiosis, and leishmaniasis. 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. A study by Lee and Harper 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.[6] 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 focused on febrile neonates (aged ≤28 d) who visited the emergency department.[7] 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.

  • Immunization practice with heptavalent pneumococcal conjugate vaccination (now 13-valent) 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 than an infection with S pneumoniae.[8] 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 (see below under "lymphocytosis").

• Inflammation: This includes inflammatory bowel disease, rheumatoid arthritis, and vasculitis (eg, Kawasaki syndrome).

• Extremely low birth weight: A higher frequency of leukemoid reaction (neutrophils >30,000/μL) was reported in extremely low birth weight (≤1000 g) infants without obvious causes of leukocytosis and in association with longer ventilatory support and a higher frequency of bronchopulmonary dysplasia (BPD).[9] A prospective study of preterm infants showed a significant correlation between the infant's leukemoid reaction (neutrophil count >40,000/μL) and histological evidence of chorioamnionitis.[10] In this study, the incidence of BPD was significantly higher in infants who had leukemoid reaction compared with those without leukemoid reaction.

• Prostaglandin (PGE1): In neonates with ductus-dependent congenital heart disease, administration of PGE1 caused reversible elevation in neutrophil count by an average of 6000/μL.[11] This was later confirmed in a retrospective study with more than 2 weeks of infusion of PGE1.[12] .

• Lithium: Lithium carbonate, commonly used for depression and bipolar disorder, is known to cause modest leukocytosis and neutrophilia (up to twice as many as the baseline count). The increase is due to increased production of neutrophils.[13]

• Heparin: Heparin induces leukocytosis, mainly lymphocytosis, but in some cases, neutrophilia as well. One in every 230 patients treated with heparin had leukocytosis.[14]

• Other: Medications that are known to cause leukocytosis and leukemoid reaction along with eosinophilia are antiepileptic drugs, including carbamazepine,[15] phenobarbital, and phenytoin.[16] Minocycline, which is commonly used for the treatment of acne, has been reported to cause an infectious mononucleosis-like syndrome with leukocytosis.[17] Cross-reactivity between carbamazepine and phenytoin has been associated with a severe hypersensitivity reaction called drug rash with eosinophilia and systemic symptoms (DRESS) syndrome.[15, 18] The antipsychotic drug clozapine has been known to cause agranulocytosis, but it also causes dose-related elevation in leukocytes and neutrophil counts.[19]

• Familial cold autoinflammatory syndrome (familial cold urticaria) is characterized by development of multiple purpuric raised erythema a few hours after exposure to cold, fever, chills, arthralgia, and consistent elevation of neutrophil and WBC counts. It is transmitted in autosomal dominant fashion.[20]

• 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 (myeloproliferative disorder) during the postnatal period. In most cases, this change is transient (referred to as transient myeloproliferative disorder); however, some develop acute leukemia.

  • Some solid tumors (most commonly described in carcinoma of the lung and in undifferentiated carcinoma) cause neutrophilia by the tumor cells called paraneoplastic leukemoid reaction. This is rare in children, but has been well described in adult patients. The presumed mechanism is production of cytokines, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF), by tumor cells or metastatic cells. However, in some patients, cytokines measured were not elevated.[21]

• 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. Persistent leukocytosis and thrombocytosis are commonly seen in patients postsplenectomy. Leukocyte adhesion molecule deficiency (LAD) has 3 subtypes (LAD1, LAD2, LAD3), characterized by delayed separation of umbilical cord and neutrophilia[22] with an increased susceptibility to infection. LAD 1 is caused by a mutation of ITGB2 gene coding for the β 2 (CD18) subunit responsible for membrane expression of the leukocyte integrins. Flow cytometric demonstration of the absence of CD11b/CD18 on the patient's leukocytes is diagnostic. Patients with LAD3 have abnormal bleeding in addition to increased risk of infections.

• Decreased neutrophil margination, including steroid administration, exercise, epinephrine administration, and other stressful situations (eg, trauma, severe pain)

  • Neutrophilia due to these causes is generally short lived (ie, minutes to hours, not days). Transient but significant elevation in white cell numbers and neutrophil counts have been described after a brief period of exercise, afebrile seizure including status epilepticus, and mild head trauma with Glasgow Coma Scale of 15.[23, 24, 25] See the Glasgow Coma Scale calculator.

  • A significant elevation in the leukocyte count (and lymphopenia) during the first week after isolated spinal cord injury was observed in patients with neurological impairment compared with controls who had isolated spinal cord injury without neurological impairment.[26] This elevation was not due to steroid administration. Authors speculated that alpha adrenergic stimuli, endogenous corticosteroid increase, or both may be the cause. Contrary to the simultaneous lymphopenia in this study, lymphocytosis was observed after a brief exercise.[23] Neutrophilia and leukocytosis were also observed during abdominal attack in patients with hereditary angioneurotic edema. Attacks of other organs were not associated with leukocytosis.[27]

• Increased release of neutrophils from marrow: This occurs in infection, stress, and hypoxia; it also occurs due to endotoxin stimulation and steroid administration.

• A mutation in the CSF3R gene: A familial neutrophilia (neutrophil count ≤22,900/μL) has been described due to a mutation in the transmembrane domain of G-CSF receptor (T617N).[28]

• Therapeutic repetitive injections of pegylated G-CSF or G-CSF–caused hyperleukocytosis[29]

Lymphocytosis

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). An exceedingly high lymphocyte count such as 100 X 109/L indicates poor prognosis.

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. On the other hand, some viral infection results in remarkable leukemoid reaction with a shift to left. An example is the Hantavirus pulmonary syndrome.[30] The highest WBC count during the 1993 outbreak was reported to be 65,000/μL with shift to left. The author has seen neutrophilia and leukocytosis in the early phase of Epstein-Barr virus infection in children.

Chronic lymphocytic leukemia that is routinely characterized by mature lymphocytosis is extremely rare in children and is usually not considered in the differential diagnosis of lymphocytosis.

Eosinophilia

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, atopic dermatitis and eczema, anticonvulsant hypersensitivity reaction, allergy to drugs, eosinophilic esophagitis and enteritis, and other allergic conditions (see above under the heading of neutrophilia for familial cold autoinflammatory syndrome).

• 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.

A study by Drago et al indicated that the presence of peripheral eosinophilia may be associated with greater severity of adverse cutaneous drug reactions (ACDRs). The report included 63 ACDR patients, including 11 with peripheral eosinophilia, with ACDRs in the latter marked by longer recovery times and diffuse severe cutaneous reactions. In addition, all 11 patients with peripheral eosinophilia required systemic therapy, while just 41% of the other patients did.[31]

Monocytosis

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 (erg, kala azar, malaria, Rocky Mountain spotted fever).

• Malignancies: Malignancies include chronic myelomonocytic leukemia, monocytic leukemia, Hodgkin disease, and myeloproliferative disorders; in adults, they include metastatic carcinoma, lung cancer, and other malignant neoplasms (paraneoplastic leukemoid reaction).

• Recovery phase of neutropenia or an acute infection.

• Autoimmune disease and vasculitis: These include systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, and inflammatory bowel disease.

• Miscellaneous causes: Sarcoidosis and lipid storage disease are included.

A study by Cherfane et al indicated that a finding of monocytosis, along with a low lymphocyte/monocyte ratio, can identify the presence of active ulcerative colitis, as opposed to ulcerative colitis in remission. According to the investigators, a monocyte count of 483 and a lymphocyte/monocyte ratio of 3.1 had a sensitivity of 60% for active ulcerative colitis, along with a specificity of 61% and 53%, respectively. It was also found that a monocyte count of greater than 860 and a lymphocyte/monocyte ratio of less than 1.6 had a positive predictive value of 75% for active ulcerative colitis.[32]

Basophilia

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).

COVID-19

A literature review by Huang et al suggested that in contrast to patients with mild cases of coronavirus disease 2019 (COVID-19), those with severe cases tend to have leukocytosis and lymphopenia.[33]

In interpreting leukocytosis on the complete blood count (CBC), consider the following:

• Clinical features

• Duration

• Differential

• Remainder of the CBC

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 with differential.

Bone marrow aspiration and biopsy may be necessary to differentiate leukemia from a benign condition (leukemoid reaction), if the patient has persistent leukocytosis.

Leukocyte alkaline phosphatase (LAP) score was used to differentiate chronic myelocytic leukemia from benign leukocytosis in the past. Currently, few laboratories use this technique. Molecular determination of bcr-abl rearrangement is a more direct and specific test to make the diagnosis.

In most cases, treatment for leukocytosis is not necessary.

In extreme instances 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 reduce the WBC count are advisable. However, a decrease in leukocyte count that is too rapid carries a risk of severe tumor lysis syndrome and should be avoided.

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.

A study by Nguyen et al indicated that supportive care and conservative management can discourage early hyperleukocytosis-related morbidity and mortality in children with acute lymphoblastic leukemia, possibly negating the need for leukapheresis.[34]  A study by Choi et al, meanwhile, found no evidence that in patients with acute leukemia (myelogenous or lymphoblastic) and hyperleukocytosis, leukapheresis improves early mortality rates or reduces the incidence of either tumor lysis syndrome or disseminated intravascular coagulopathy.[35]

Promptly institute definitive treatment with appropriate chemotherapy. A study by Mamez et al indicated that the administration of oral hydroxyurea before chemotherapy can lower the rate of early death in hyperleukocytic patients with acute myelogenous leukemia. The study, which involved 160 patients, found the hospital mortality rate for patients who received pre-chemotherapy hydroxyurea to be 19%, compared with 34% for those who received no hydroxyurea prior to chemotherapy. However, the two treatment groups did not differ with regard to disease-free survival.[36]

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.

Class Summary

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

Allopurinol (Aloprim, Zyloprim)

Inhibits xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine. Reduces synthesis of uric acid without disrupting biosynthesis of vital purines. Reduces plasma concentration and urine excretion of uric acid; simultaneously increases plasma concentration and urine excretion of more soluble oxypurine precursors.

Rasburicase (Elitek)

Recombinant form of urate oxidase (derived from Saccharomyces cerevisiae -synthesized Aspergillus flavus), which oxidizes uric acid to allantoin (soluble and inactive). Indicated for treatment and prophylaxis of severe hyperuricemia associated with treatment of malignancy. Hyperuricemia causes precipitant in kidneys, leading to acute renal failure. Unlike uric acid, allantoin soluble and easily excreted by kidneys. Elimination half-life is 18 h.

Prognosis totally depends on the underlying etiologies.