White Blood Cells Abnormalities Of

Introduction

White blood cell (WBC) abnormalities are a frequent finding in Canadian clinical practice, ranging from benign, reactive processes to life-threatening malignancies. For the MCCQE1, candidates must demonstrate the ability to interpret a Complete Blood Count (CBC) and differential, differentiate between reactive and malignant causes, and manage urgent conditions like febrile neutropenia.

Understanding the pathophysiology of leukocytes is crucial for Internal Medicine and Hematology rotations. This guide focuses on the quantitative and qualitative disorders of WBCs, aligned with the CanMEDS roles of Medical Expert and Health Advocate.

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Canadian Context: In Canada, reference ranges for WBCs are typically reported in SI units ( $x 10^9/L$ ). The standard normal range for total WBC is approximately 4.0 to 11.0 x 10⁹/L, though this may vary slightly between provincial laboratories.

Classification of WBC Abnormalities

WBC abnormalities are generally categorized by the specific cell line affected and whether the count is elevated (Leukocytosis) or decreased (Leukopenia).

Neutrophils

Neutrophils (Granulocytes)

Neutrophilia: > 7.5 x 10⁹/L (approx). Causes: Bacterial infection, inflammation, stress, steroids.
Neutropenia: < 1.5 - 2.0 x 10⁹/L. Causes: Viral infection, drugs (chemotherapy, idiosyncratic), autoimmune, ethnic neutropenia.

Neutrophil Abnormalities

Neutrophilia

Neutrophilia is the most common form of leukocytosis.

Left Shift: The presence of immature neutrophils (bands, metamyelocytes) in the peripheral blood. This usually suggests a severe acute infection or inflammation.
Leukemoid Reaction: WBC count > 50 x 10⁹/L with a left shift, mimicking leukemia but is actually a reactive process (e.g., severe C. difficile colitis).

Common Causes (MCCQE1 High Yield)

Infection: Bacterial.
Inflammation: Tissue necrosis (MI, burns), Vasculitis.
Drugs: Corticosteroids (demargination), Lithium, G-CSF.
Physiologic: Stress, exercise, pregnancy.
Malignancy: Chronic Myeloid Leukemia (CML).

Neutropenia

Neutropenia is defined as an Absolute Neutrophil Count (ANC) of less than 1.5 x 10⁹/L.

\text{ANC} = \text{Total WBC} \times (\% \text{Neutrophils} + \% \text{Bands})

Severity	ANC Range (x 10⁹/L)	Clinical Risk
Mild	1.0 – 1.5	Minimal risk of infection.
Moderate	0.5 – 1.0	Moderate risk.
Severe	< 0.5	High risk of life-threatening infection.

Febrile Neutropenia

This is a medical emergency. For MCCQE1, you must recognize the criteria and immediate management steps.

🚨 Medical Emergency: Febrile Neutropenia

Definition: Single oral temperature ≥ 38.3°C OR temperature ≥ 38.0°C sustained for >1 hour usually in a patient with ANC < 0.5 x 10⁹/L.

Action: Do not wait for cultures. Initiate empiric broad-spectrum antibiotics (e.g., Piperacillin-Tazobactam or Cefepime) within 60 minutes of presentation.

Drug-Induced Neutropenia

Several drugs commonly prescribed in Canada can cause agranulocytosis.

Clozapine: Requires mandatory monitoring via the Canadian Clozaril Support System.
Methimazole/Propylthiouracil: Patients must be educated to seek care if they develop a sore throat/fever.
Sulfonamides & NSAIDs.

Lymphocyte Abnormalities

Lymphocytosis

Viral Infections: Infectious Mononucleosis (EBV) is a classic exam topic. Look for atypical lymphocytes on the smear.
Bordetella Pertussis: Can cause massive lymphocytosis resembling leukemia.
Chronic Lymphocytic Leukemia (CLL):
- Most common leukemia in adults in Western countries.
- Smudge Cells on peripheral smear.
- Diagnosis: Flow Cytometry.

Lymphopenia

HIV: Always screen if no other cause is found.
Autoimmune: SLE (check ANA).
Iatrogenic: Chemotherapy, radiation, chronic steroid use.

Eosinophilia

Defined as an absolute eosinophil count > 0.5 x 10⁹/L.

Mnemonic for Causes: CANADA-P

Connective Tissue Diseases (Churg-Strauss/EGPA)
Allergies / Asthma / Atopy (Most common)
Neoplasm (Hodgkin Lymphoma, CML)
Adrenal Insufficiency (Addison’s disease)
Drugs (DRESS syndrome, NSAIDs, antibiotics)
Atheroembolic disease (Cholesterol emboli)
Parasites (Strongyloides - important in immigrants/travelers returning to Canada)

Approach to the Patient with WBC Abnormalities

Step 1: Detailed History

Constitutional Symptoms: Fever, weight loss, night sweats (B symptoms).
Infectious symptoms: Cough, dysuria, skin changes.
Medication History: Recent start of new drugs (antibiotics, antipsychotics, antithyroids).
Social History: Travel (parasites), sexual history (HIV), occupation.

Step 2: Physical Examination

Vitals: Fever suggests infection or malignancy.
Lymph Nodes: Palpate all chains (cervical, axillary, inguinal).
Abdomen: Check for splenomegaly (common in CML, CLL, Mono) and hepatomegaly.
Skin: Petechiae/bruising (bone marrow failure), rashes.

Step 3: Initial Investigations

CBC with Differential: Confirm the cell line involved.
Peripheral Blood Smear: Essential. Look for:
- Blasts (Acute Leukemia)
- Smudge cells (CLL)
- Atypical lymphocytes (Mono)
- Hypersegmented neutrophils (B12/Folate deficiency)
- Toxic granulation/Döhle bodies (Severe infection)

Step 4: Advanced Testing (If indicated)

Flow Cytometry: For suspected lymphoproliferative disorders.
Bone Marrow Biopsy: Unexplained cytopenias or presence of blasts.
Viral Serology: EBV, CMV, HIV.

Canadian Guidelines

Choosing Wisely Canada

Don’t order flow cytometry for patients with mild, stable lymphocytosis < 5.0 x 10⁹/L who are asymptomatic and have no other cytopenias or lymphadenopathy. Repeat CBC in 3-6 months is appropriate.
Don’t transfuse red blood cells for iron deficiency anemia without hemodynamic instability; treat with iron. (Relevant as anemia often accompanies WBC issues).

Management of Febrile Neutropenia

Based on Canadian consensus guidelines (adapted from IDSA/ASCO):

Risk Stratification: Use the MASCC Risk Index.
- Low Risk (MASCC ≥ 21): May be treated as outpatient with oral Ciprofloxacin + Amoxicillin/Clavulanate (monitor closely).
- High Risk (MASCC < 21): Admit for IV antibiotics.

Key Points to Remember for MCCQE1

Study Checklist

[ ] Steroids cause neutrophilia via demargination (neutrophils detach from vessel walls).
[ ] Benign Ethnic Neutropenia is a common, normal variant in individuals of African or Middle Eastern descent; no treatment is needed.
[ ] Viral infections usually cause lymphocytosis, but can cause neutropenia (bone marrow suppression).
[ ] CML typically presents with massive leukocytosis, basophilia, and splenomegaly. Look for the Philadelphia chromosome ( $t(9;22)$ ).
[ ] Auer Rods on a smear are pathognomonic for Acute Myeloid Leukemia (AML).
[ ] Always rule out HIV in a patient with unexplained lymphopenia.

Sample Question

Clinical Scenario

A 68-year-old man presents to his family physician for a routine check-up. He feels generally well but reports mild fatigue over the last few months. He has no fevers, night sweats, or weight loss. His past medical history is significant for hypertension. Physical examination reveals nontender, mobile cervical and axillary lymphadenopathy. The spleen is palpable 2 cm below the costal margin. There is no hepatomegaly.

Laboratory results:

Hemoglobin: 135 g/L
Platelets: 160 x 10⁹/L
WBC: 42.0 x 10⁹/L
Neutrophils: 4.0 x 10⁹/L
Lymphocytes: 37.0 x 10⁹/L
Peripheral Smear: Numerous mature-appearing small lymphocytes and smudge cells are seen.

Which one of the following is the most appropriate next step to confirm the diagnosis?

Options

A. Bone marrow aspiration and biopsy
B. Peripheral blood flow cytometry
C. Lymph node excisional biopsy
D. Serum protein electrophoresis
E. Observation and repeat CBC in 3 months

Click to reveal the answer and explanation

Explanation

The correct answer is:

B. Peripheral blood flow cytometry

Reasoning: This patient presents with isolated lymphocytosis, lymphadenopathy, and “smudge cells” on the peripheral smear. This clinical picture is highly suggestive of Chronic Lymphocytic Leukemia (CLL).

Option B: Flow cytometry of the peripheral blood is the gold standard for diagnosing CLL. It identifies the specific immunophenotype of the B-cells (typically CD5+, CD19+, CD20+, CD23+). It is less invasive than a marrow biopsy and sufficient for diagnosis in most cases.
Option A: Bone marrow biopsy is generally not required for the initial diagnosis of CLL but may be used for prognostic information or if unexplained cytopenias develop.
Option C: Lymph node biopsy is used for diagnosing lymphomas (like Hodgkin’s or Non-Hodgkin’s) but is invasive and unnecessary when leukemic cells are present in the peripheral blood.
Option D: Serum protein electrophoresis is used to screen for multiple myeloma or Waldenström macroglobulinemia. While CLL can be associated with hypogammaglobulinemia, this is not the confirmatory diagnostic test.
Option E: While early-stage CLL is often managed with “watch and wait,” the diagnosis must first be confirmed before a management plan is made. Furthermore, a count of 42.0 x 10⁹/L warrants investigation.

References

Medical Council of Canada. (2023). MCCQE Part I Clinical Decision-Making and Objectives. Retrieved from mcc.ca
Choosing Wisely Canada. (2023). Hematology: Five Things Physicians and Patients Should Question. Retrieved from choosingwiselycanada.org
Kaushansky, K., et al. (2021). Williams Hematology (10th ed.). McGraw-Hill Education.
Taplitz, R. A., et al. (2018). Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update. Journal of Clinical Oncology. (Adopted by various Canadian Provincial Oncology Groups).
Toronto Notes. (2023). Hematology Chapter. Toronto Notes for Medical Students, Inc.