Leukocytosis Clinical Presentation

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]