Leukocytosis – Causes, Symptoms, Diagnosis, Treatment

Leukocytosis is the broad term for an elevated white blood cell (WBC) count, typically above 11.0×10^9/L, on a peripheral blood smear collection. The exact value of WBC elevation can vary slightly between laboratories depending on their ‘upper limits of normal’ as identified by their reference ranges. The WBC value represents the sum-total of white blood cell subtypes, including neutrophils, eosinophils, lymphocytes, monocytes, atypical leukocytes that are not normally present on peripheral blood smear (e.g., lymphoblasts), or any combination of these. The clinician should properly characterize the leukocytosis and determine if further evaluation and workup are indicated.

Leukocytosis is a condition in which the white cell (infection?. সহজ বাংলা: শ্বেত রক্তকণিকা।" data-rx-term="leukocyte" data-rx-definition="Leukocyte means white blood cell, which helps fight infection. সহজ বাংলা: শ্বেত রক্তকণিকা।">leukocyte? count) is above the normal range in the blood.^[rx][rx] It is frequently a sign of an inflammatory response,^[rx] most commonly the result of infection?, but may also occur following certain parasitic infections or bone tumors as well as leukemia. It may also occur after strenuous exercise, convulsions such as epilepsy, emotional stress, pregnancy and labor, anesthesia, as a side effect? of medication (e.g., lithium), and epinephrine administration

The broad differential diagnoses of leukocytosis require evaluation beyond basic laboratory workup, and clinicians should be able to perform physical examinations and targeted histories to ascertain the possible causes of the presenting lab abnormality. To evaluate for these causes, careful histories, physical examinations, medication reconciliations, family histories, and the possible need for consultants for procedures (e.g., genetic testing, hematology/oncology consultations, infectious disease, etc.) must be completed depending on what is discovered.[rx]

Types of Leukocytosis

There are five principal types of leukocytosis

• Neutrophilia (the most common form)^[rx]
• Lymphocytosis
• Monocytosis
• allergy?, parasites, and some inflammation. সহজ বাংলা: অ্যালার্জি/পরজীবী সংক্রমণে জড়িত রক্তকণিকা।" data-rx-term="eosinophil" data-rx-definition="Eosinophil is a white blood cell involved in allergy, parasites, and some inflammation. সহজ বাংলা: অ্যালার্জি/পরজীবী সংক্রমণে জড়িত রক্তকণিকা।">eosinophil? count, often linked with allergy, parasites, inflammation, or blood disease. সহজ বাংলা: ইওসিনোফিল বেশি হওয়া।" data-rx-term="eosinophilia" data-rx-definition="Eosinophilia means high eosinophil count, often linked with allergy, parasites, inflammation, or blood disease. সহজ বাংলা: ইওসিনোফিল বেশি হওয়া।">Eosinophilia?
• Basophilia?

The following is a general list of considerations that a clinician should have when evaluating a leukocytosis:

Acute? leukocytosis

• Leukemoid reaction
• Reactive causes
• Infection?
• Acute? allergies
• Tissue ischemia?
• Drugs/medications (epinephrine, corticosteroids, NSAIDs, cephalosporin antibiotics, anticonvulsants, beta-agonists, allopurinol, penicillin-derivative antibiotics, illicit substances)
• Vaccine? administration
• Myocardial infarction?/injury
• Hemorrhage
• Acute? hemolysis
• Sepsis/septic shock
• Pregnancy

Chronic? leukocytosis

• Smoking
• Obesity
• Chronic? allergies
• Autoimmune? phenomenon
• Vasculitis
• Connective tissue diseases
• Malignancy
• Pregnancy
• Chronic? infection?

Causes of Leukocytosis

In the bone marrow, stem cells differentiate into megakaryoblasts (that will become platelet?-producing megakaryocytes), erythroblasts (that will become erythrocytes or red blood cells), myeloblasts (that will become eosinophils, basophils, and neutrophils), monoblasts (that will become monocytes), and lymphoid progenitor cells (that will become B or T lymphocytes). The term ‘infection?. সহজ বাংলা: শ্বেত রক্তকণিকা।" data-rx-term="leukocyte" data-rx-definition="Leukocyte means white blood cell, which helps fight infection. সহজ বাংলা: শ্বেত রক্তকণিকা।">leukocyte?’ applies to any cells within the myeloblast, monoblast, and lymphoid lineages. Leukocytosis can be classified based on the cell line that is elevated. A complete blood count (CBC) with predominantly elevated neutrophils is termed neutrophilia, eosinophils—allergy?, parasites, and some inflammation. সহজ বাংলা: অ্যালার্জি/পরজীবী সংক্রমণে জড়িত রক্তকণিকা।" data-rx-term="eosinophil" data-rx-definition="Eosinophil is a white blood cell involved in allergy, parasites, and some inflammation. সহজ বাংলা: অ্যালার্জি/পরজীবী সংক্রমণে জড়িত রক্তকণিকা।">eosinophil? count, often linked with allergy, parasites, inflammation, or blood disease. সহজ বাংলা: ইওসিনোফিল বেশি হওয়া।" data-rx-term="eosinophilia" data-rx-definition="Eosinophilia means high eosinophil count, often linked with allergy, parasites, inflammation, or blood disease. সহজ বাংলা: ইওসিনোফিল বেশি হওয়া।">eosinophilia?, basophils—basophilia?, monocytes—monocytosis, and lymphocytes—lymphocytosis. The type of cell elevated may help to identify the trigger for leukocytosis, and a detailed history and physical exam is important to support particular differential diagnoses of the particular leukocytosis presenting itself. This article will describe the general etiologies of some of the most common presentations of leukocytosis.

• Neutrophilia: Neutrophils typically make up about 40% to 60% of total infection?. সহজ বাংলা: শ্বেত রক্তকণিকা।" data-rx-term="leukocyte" data-rx-definition="Leukocyte means white blood cell, which helps fight infection. সহজ বাংলা: শ্বেত রক্তকণিকা।">leukocyte? count, and neutrophilia is the most common type of leukocytosis.[rx] If the patient is currently undergoing a stressor, neutrophils, the most abundant infection?. সহজ বাংলা: শ্বেত রক্তকণিকা।" data-rx-term="leukocyte" data-rx-definition="Leukocyte means white blood cell, which helps fight infection. সহজ বাংলা: শ্বেত রক্তকণিকা।">leukocyte? on peripheral smear under normal circumstances, will increase.[rx] Increases occur from both upregulated bone marrow production and the demargination of existing neutrophils from the endothelium. Neutrophilia occurs most often in response to a stressor, termed reactive neutrophilia, but can also be the result of an autonomous process (e.g., chronic myeloid leukemia). Possible causes of acute elevations involve recent physical stress, emotional stress, infection, medications, trauma, and smoking. Chronic inflammation?, such as rheumatic disease, inflammatory bowel disease, chronic hepatitis, vasculitides, chronic steroid use, bone marrow stimulating processes (hemolytic anemia, immune thrombocytopenia?, colony-stimulating factors), and congenital? diseases (Down syndrome, hereditary idiopathic? neutrophilia), all have baseline neutrophilia. Pregnancy and obesity also have acute to chronic presentations of neutrophilia.

  • Leukemoid Reaction: A leukemoid reaction is a transient increase in WBC count defined as significant neutrophilia >50×10^9/L in the absence of a myeloproliferative neoplasm. This acute inflammatory reaction can be mistaken for leukemia, but careful history, physical examination, and, if necessary, further laboratory evaluation, can find that this reaction can occur in sepsis, organ rejection, solid tumors, and bacterial infections. Peripheral smears and radiological imaging may be necessary to identify the true cause of these reactive laboratory findings.[rx] This must be separated from leukemia, which is defined as increases in blast cells (precursor cells to leukocytes) and immature WBCs, rather than mature neutrophils that are seen in a leukemoid reaction. A leukemoid reaction also improves after treating the underlying cause for the neutrophilia, whereas leukemia will continue to demonstrate elevated WBCs until definitive targeted treatment is completed.
• Lymphocytosis: Lymphocytes, on average, make up approximately 20-40% of a person’s total leukocyte count. Increases in lymphocytes in children are usually benign and related to rapid growth and development of the immune system. Less benign conditions, such as viral infections, hypersensitivity reactions, leukemia, and lymphoma, can all cause lymphocytosis. A careful review of systems, history collection, and physical examination findings will help guide clinicians as to which etiology may be the cause of the presenting lymphocytosis. Evaluation of acute or chronic infection can help tailor the differential for lymphocytosis. Acute infections such as cytomegalovirus, Bordetella pertussis, hepatitis, toxoplasmosis, and Epstein-Barr, have all been implicated in acute absolute lymphocytosis. Chronic infections, such as brucellosis and tuberculosis, have also been shown to have chronic lymphocytosis.[rx] For these chronic infections, a complete review of organ systems and social history should be evaluated to identify these disease processes.
• Eosinophilia: Eosinophils are approximately 1-4% of a person’s total leukocyte count. Elevations above 0.5×10^9/L, which in the past have been identified as mild eosinophilia, is the generally accepted cut-off for eosinophilia. However, significant elevations over 1.5×10^9/L are the usual cut-off for further evaluation and consideration, especially in multiple CBCs separated in time. Eosinophilia can occur in neoplastic, inflammatory, infectious, parasitic, autoimmune, and allergic conditions.[rx] A careful review of prior CBC lab analyses, looking for persistent eosinophilia, which is defined as two abnormal CBCs collected with a minimum time interval between the two lab draws of four weeks, should be completed by the primary care provider to evaluate for the less-benign causes of this phenomenon.[rx] Medications, such as NSAIDs, common antibiotics (nitrofurantoin, quinolones, cephalosporins, penicillins, sulfa-containing drugs), have also been implicated in eosinophilia, and a careful medication reconciliation should be completed on patients presenting with this laboratory abnormality. It is most commonly elevated in allergic conditions, such as seasonal and environmental allergies, but evaluation for parasitic and infectious etiologies should be completed, especially if the patient has exposure history or other risk factors.[rx]
• Monocytes: Monocytes make up approximately 2-8% of a person’s total leukocyte count.[rx] Monocytes have been identified in patients with chronic infections, endocarditis, inflammatory conditions, autoimmune diseases, granulomatous diseases, malignancy, medication side effects, and myeloproliferative disorders. There is evidence they are a marker of poor prognostic outcomes in emergency room settings, suggested being related to coronary artery disease, atherosclerosis, and stroke. This should be considered in acute care settings when evaluating CBCs.[rx] When monocytosis is persistent, careful consideration should be done to evaluate malignancy potential.[rx]
• Basophils: Basophils compromise 0.5-1% of a person’s peripheral blood smear.[rx] Basophilia can occur in inflammatory conditions, viral infections, endocrinopathies, myeloproliferative disorders, and malignancies. Like eosinophils, it is also present in allergic or anaphylactic conditions, especially in reaction to drugs and food.[rx] It is a relatively uncommon cause of leukocytosis.[rx] Transient hyperbasophilia can occur as a reactive response, especially to an acute viral illness.  Persistent basophilia present on multiple CBCs for over eight weeks suggests an underlying malignancy or myeloproliferative disease, and leukemias associated with basophilia are extremely rare.[rx]

White Blood Cell Count Reference Range Changes with Age

Age Appropriate Reference Range for Leukocyte Count 

Newborn: 13-38×10^9/L

Birth-2 weeks: 5-20×10^9/L

Adult: 4.5-11×10^9/L

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Diagnosis of Leukocytosis

Leukocytosis is a relatively common phenomenon on a CBC with a variety of causes. The first step is to obtain a CBC with differential, which evaluates the different cell lines. A peripheral blood smear can be helpful and is appropriate in patients with unexplained leukocytosis. It can be particularly helpful to obtain a manual differential for the analysis of abnormal cells or if there is a question of the accuracy of the automated leukocyte differential.[rx]

When evaluating the peripheral smear under microscopy, the blood should be collected from a fresh lab draw that is anticoagulated or directly from a finger stick puncture. Preparing the slide involves a gradation of blood on the slide from thick to thin. The smear is air-dried and then a stain, such as May-Grunwald-Giemsa and Wright stains, which produces cells where the nuclei are blue and the cytoplasm is pink. Under the microscope, the clinician will then begin the slide review on the feathered, or thin edge of the smear, where the cells are just barely overlapping, and work into the thicker area of the smear, where the WBC’s typically reside. High-power field viewing with an oil-immersion lens is necessary to examine leukocytes for abnormalities and inclusions.

Typical leukocytes of neutrophils, basophils, monocytes, eosinophils, and lymphocytes, are expected to be seen in the appropriate percentages as discussed in the Etiology section of this article. Immature granulocytes and precursors, such as blasts and myelocytes, and lymphoma cells are significantly abnormal findings.[rx]

History and Physical

When a patient presents with leukocytosis on initial CBC, a careful history and physical examination should be performed, as well as an evaluation of prior CBCs for trends. In an acute setting, such as an urgent care facility or emergency department, prior CBCs may not be available for evaluation and interpretation. Targeted histories and physical examination may guide the clinician in the proper direction as to the underlying cause for the leukocytosis. In these settings, stress, trauma, and infection are likely the most common cause of leukocytosis. In a less acute setting, such as primary care appointment, a routine CBC may demonstrate leukocytosis, and this may require further investigation if the patient has not had recent stress (emotional or physical), surgery, or infection. Prior CBCs, if available, are extremely useful in determining if this is an acute lab elevation, or if this is a more persistent elevated trend that needs further consideration. In persistent elevations of certain lines, such as less common cell lines (basophils and monocytes), on multiple CBCs, should prompt the clinician to ask the patient targeted historical questions to evaluate for malignancy. Typical symptoms of an underlying malignancy can include fevers, chills, night sweats, unintended weight loss, fatigue, and/or easy bruising. In women, pregnancy can increase leukocytes greater than the upper limit of the normal reference range of 11×10^9. This must also be assessed on initial evaluation.

Significant elevations, such as leukocytosis close to 100×10^9, should always prompt immediate evaluation for leukemia or myeloproliferative disorders. Myeloproliferative disorders are a group of disease processes characterized by cell dysplasia. There are several categories, some involving leukocytes and some involving other cell lines. Regardless, malignant transformation is possible. A review of symptoms should focus on evaluation for shortness of breath, anemia, pallor, unusual bleeding, petechiae, frequent infections, and fatigue. Physical examination should look for pallor (indicative of possible underlying anemia), petechiae, bruises, tachycardia, palpable lymphadenopathy, and splenomegaly. Frequent follow up with CBC collections should be arranged with the assistance of a hematology and oncology consultant to monitor for any sort of malignant transformation.

The past medical history should be reviewed, especially for the history of prior malignancies. Patients who have undergone chemotherapy and/or radiation therapy are at increased risk of leukemia or lymphoma.[rx] Family history is also important, as some leukemias have a genetic predisposition. In adults, leukemia can occur without any identifiable predisposing factor. In children, germline genetic mutations can be inherited from a parent or appear de novo. Familial conditions, such as Li-Fraumeni syndrome, Neurofibromatosis Type 1, Noonan syndrome, and Lynch syndrome, among others, are characterized by a predisposition for multiple malignancies, some of which have bone marrow involvement and associated leukocyte malignancies.[rx][rx] Down syndrome has also been linked to a higher tendency for myeloproliferative disorders and leukemia. A careful family history, including siblings, parents, and grandparents, will help identify children and adolescents at risk for these possible malignancies.

Lastly, social history is critical in the evaluation of leukocytosis. Smoking history and job exposure to chemicals, including benzene, pesticides, and industrial chemicals, have all been linked to higher chances of bone marrow malignancy.[rx]

Evaluation

As discussed under the Histopathology section of this article, the first step in any patient with leukocytosis is to obtain a CBC with differential. Prior CBCs should be reviewed and evaluated for any particular trends. The next step is to evaluate a peripheral smear and perform a manual differential if abnormalities are collected on the automatic differential. If immature or lymphoma cells are present, an oncology service should be consulted and the patient should undergo bone marrow aspiration and biopsy with appropriate flow cytometry and molecular genetic studies as indicated. Depending on the results of the bone marrow biopsy, more laboratory testing and imaging may be necessary, as guided by the oncology service.

In the absence of concerning findings on peripheral smear, the following laboratory tests and imaging may be a part of the work-up (adapted from[rx]):

Treatment of Leukocytosis

Leukocytosis is treated based on the underlying process. For example, a neutrophilia may be produced from an underlying infection, in which case the clinician will need to perform a detailed history and physical examination and obtain other relevant lab tests and imaging to determine an infectious source and treat, respectively. Medication reconciliation, such as any recent steroid use, should also be completed to investigate drug-induced leukocytosis. Recent physical stress leading to a leukocytosis can also be ascertained from history. Both of these examples, if diagnosed, do not require further intervention. More alarming causes, such as leukemias and lymphomas, should prompt immediate hematology and oncology specialty service involvement for specific imaging and laboratory examination needed to help guide treatment.

Clinicians should be able to recognize hyperleukocytosis, which is a WBC count > 100×10^9/mL. This is seen in patients with acute or chronic leukemias and can be a medical emergency if the patient is symptomatic, at which point they are in leukostasis. Organ failure and hemorrhage is a complication of this disorder, which requires prompt identification and treatment to reduce the number of abnormal cells. Hematology and oncology service should be involved in this patient’s care, but the use of chemotherapy, leukapheresis, and medications like hydroxyurea, are all current treatment methods to prevent decompensation.[rx]

Complications

If acute leukocytosis is identified quickly with the underlying process treated appropriately, there are few, if any, complications. Complications are usually associated with treatment rather than the leukocyte elevation, which represents the natural immune system response to the stress being put on the patient. Chronic leukocytosis is not itself fatal but may be an ominous sign of a significant underlying process that must be appropriately identified and treated.[rx]

Acute or chronic significant leukocytosis above 25×10^9/mL, however, can have severe complications and potentially be fatal. WBC counts 25×10^9/mL and above, can cause a hyperviscosity type syndrome, which can be seen in patients with leukemia, lymphoma, and myeloproliferative disorders. Presenting symptoms of this oncological emergency include vision changes, bleeding, stroke or neurological changes, infarction, ischemia, and/or multi-organ failure.[rx][rx] The hyperviscosity syndrome can have complications related to the severity of the organ system involvement with long-lasting effects. Appropriate recognition and prompt treatment, including rehydration, phlebotomy, and plasmapheresis, can prevent death and reduce long term complications.

Notably, tumor lysis syndrome (TLS) is an extremely dangerous complication of patients receiving treatment for malignancy, especially hematologic malignancies that may be the cause of leukocytosis. This syndrome presents when the patient receives appropriate treatment that causes a dramatic number of cancer cells to die quickly. The metabolic abnormalities that arise can cause a symptom.

References