What are the causes of neutrophilia in leukocytosis?

Updated: May 19, 2020
  • Author: Susumu Inoue, MD; Chief Editor: Jennifer Reikes Willert, MD  more...
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Answer

Neutrophilia (ie, neutrophil count that exceeds the reference range for age; see the Absolute Neutrophil Count calculator) may be due to the following conditions and interventions:

  • Infection (most common cause)

    • Most bacterial infections cause neutrophilia with bandemia (the 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, had been transferred, or had died to select a population that 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 and Prevnar 13 (a 13-valent pneumococcal conjugate vaccine) significantly reduced the 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 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"). A report describing a relationship between the severity of coronavirus disease 2019 (COVID-19) and leukocyte count indicated that leukocytosis—in particular, neutrophilia—is associated with a more severe disease. [39]

  • 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 the 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]

  • Surgery: Maxillofacial surgical procedures have been shown to raise the total leukocyte, as well as the neutrophil, count. [37] For example, a study found that the mean presurgical WBC count was 7.79 x 109/L, whereas it rose to 19.28 x 109/L on the first postoperative day, and decreased to 16.28 x 109/L on the second postoperative day.{ref d}

  • 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 a dose-related elevation in leukocytes and neutrophil counts. [19]

  • Familial cold autoinflammatory syndrome (familial cold urticaria) is characterized by the 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 the 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 the blood circulation and its destruction and departure from the circulation into the 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 three subtypes (LAD1, LAD2, LAD3), characterized by delayed separation of the umbilical cord and neutrophilia, [22] with 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 of LAD. Patients with LAD3 have abnormal bleeding in addition to increased risk for infections.

  • Decreased neutrophil margination, including steroid administration, exercise, epinephrine administration, and other stressful situations (eg, trauma, surgery, 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 an 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]


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