From the Guidelines
The workup for leukocytosis of unknown etiology should begin with a thorough history and physical examination, followed by initial laboratory tests including a complete blood count with differential, comprehensive metabolic panel, urinalysis, and blood cultures if infection is suspected, as recommended by the most recent guidelines 1. The initial step in evaluating leukocytosis is to identify potential causes such as infection, inflammation, stress, or malignancy through a thorough history and physical examination.
- Key elements of the history include:
- Medications that may cause leukocytosis
- Exposure to radiation or toxins
- Recent viral infections
- The physical examination should focus on signs of infection, inflammation, or malignancy. Initial laboratory tests should include:
- Complete blood count with differential to characterize the type of white blood cells elevated
- Comprehensive metabolic panel
- Urinalysis
- Blood cultures if infection is suspected Additional tests may be considered based on clinical suspicion, such as:
- Chest X-ray
- Inflammatory markers (ESR, CRP)
- Specific tests for gastrointestinal symptoms or suspected abscesses
- Viral studies, including CMV, human herpesvirus 6, EBV, parvovirus, as recommended by 1
- Nutritional assessments, including B12, folate, iron, copper, ceruloplasmin, vitamin D, as recommended by 1 If these initial investigations are unrevealing, consider hematology consultation for:
- Bone marrow examination
- Flow cytometry
- Cytogenetic studies to rule out hematologic malignancies For persistent unexplained leukocytosis, advanced imaging such as CT scans or PET scans may be warranted to identify occult infections or malignancies 1. Throughout this process, serial complete blood counts should be performed to monitor trends in white blood cell counts. The workup should be tailored to the patient's specific presentation, as leukocytosis can result from numerous conditions, including infections, inflammatory disorders, hematologic malignancies, certain medications, and physiologic stress responses. The most recent and highest quality study 1 provides a comprehensive approach to the diagnostic work-up of leukocytosis, emphasizing the importance of a thorough history, physical examination, and targeted laboratory tests.
From the Research
Initial Evaluation
The workup for leukocytosis (elevated white blood cell count) of unknown etiology typically begins with a thorough history, physical examination, and peripheral blood smear 2. This initial evaluation aims to identify potential causes of leukocytosis, which can be broadly divided into primary malignant diseases and secondary causes that are expected physiologic responses of the bone marrow.
Differential Diagnosis
The differential diagnosis of leukocytosis includes:
- Physiologic responses to infectious and inflammatory processes
- Primary hematologic disorders such as leukemias, lymphomas, and myeloproliferative neoplasms 3
- Neutrophilic leukocytosis, which can be observed physiologically after physical or mental stress 4
- Elevation of white blood cells caused by acute or chronic leukemia, or malignant lymphoma 4
Laboratory Testing
Laboratory testing, including a complete blood count and peripheral blood smear, is essential in the evaluation of leukocytosis 3. Additional testing, such as bone marrow aspiration and biopsy, imaging studies, and specialized molecular tests, may be necessary to establish a definitive diagnosis.
Clinical Features and Outcome
Patients with unexplained or persistent leukocytosis may appear to be in a state of continued inflammation, recently described as the persistent inflammation-immunosuppression and catabolism syndrome (PICS) 5. These patients often have a prolonged hospital course, extensive use of empiric broad-spectrum antibiotics, and a high risk of colonization with resistant opportunistic organisms.
Red Flags
Certain clinical features, such as extremely elevated white blood cell counts, concurrent abnormalities in red blood cell or platelet counts, weight loss, bleeding or bruising, liver, spleen or lymph node enlargement, and immunosuppression, should raise suspicion for a primary bone marrow disorder 6. White blood cell counts above 100,000 per mm3 (100 x 10(9) per L) represent a medical emergency due to the risk of brain infarction and hemorrhage 6.