Nonmalignant Disorders of Leukocytes

Chapter 21: Nonmalignant Disorders - Granulocytes and Monocytes

Terms and Definitions

• Leukocytosis

  • Condition defined by a total leukocyte count exceeding $11.0 imes 10^9/L$ in adults.

• Leukopenia

  • Condition where the total leukocyte count is below $4.5 imes 10^9/L$ in adults.

• Neutrophilia

  • An increase in absolute neutrophil count greater than $7.0 imes 10^9/L$ in adults.

• Neutropenia

  • A decrease in absolute neutrophil count of less than $1.5 - 2.0 imes 10^9/L$ in adults.

• Left shift or shift to the left

  • An increased number of immature neutrophils in the peripheral blood.

• Monocytosis

  • An increase in absolute monocyte count greater than $8.0 imes 10^9/L$ in adults.

• Monocytopenia

  • A decrease in absolute monocyte count of less than $2.0 imes 10^9/L$ in adults.

• Lymphocytosis

  • An increase in absolute lymphocyte count greater than $4.8 imes 10^9/L$ in adults.

• Lymphocytopenia

  • A decrease in absolute lymphocyte count of less than $2.0 imes 10^9/L$ in adults.

Disorders Affecting Granulocytes and Monocytes

• The response to a variety of nonmalignant disease states and toxic changes.

• Changes can be qualitative or quantitative.

• Often affects one class of leukocyte more than another.

• Reflects the body's normal response to various disease or toxic processes.

Evaluating Leukocytes

Leukocytosis

• Definition: Total leukocyte count more than $11.0 imes 10^9/L$ in adults.

• Most commonly caused by an increase in neutrophils.

• Other leukocyte increases, although less common, may include lymphocytes, eosinophils, monocytes, and basophils.

• Common Causes:

  • Bacterial Infection: Increased neutrophils.

  • Viral Infection: Increased lymphocytes.

  • Parasitic Infection: Increased eosinophils.

Leukopenia

• Definition: Decrease in leukocyte count below $4.5 imes 10^9/L$ in adults.

• Most often caused by decreased neutrophils.

• Can involve other cell lines.

Disorders of Neutrophils: Quantitative

Causes of Neutrophilia

• Can be due to:

  • Malignant: Neoplastic transformation of hematopoietic stem cells (discussed later).

  • Benign: Acquired conditions leading to neutrophilia.

Neutrophilia Classification

1. Immediate Neutrophilia

   • Occurs for approximately 20-30 minutes due to redistribution from marginal pool to circulating pool.

   • Neutrophils are mature and observed during acute stress or exercise (referred to as "shift neutrophilia").

2. Acute Neutrophilia

   • Occurs 4-5 hours after a pathologic stimulus (such as a bacterial infection).

   • Increased flow of neutrophils from the bone marrow to blood; may include immature neutrophils.

3. Chronic Neutrophilia

   • Develops if the stimulus persists beyond a few days.

   • Depletion of storage pool in bone marrow and increased early neutrophil precursors ("left shift").

Conditions Associated with Neutrophilia

• Most Common Causes:

  • Bacterial infections.

  • Fungal infections.

• Inflammatory Processes:

  • Burns, trauma, and surgery.

• Metabolic Alterations:

  • Uremia, eclampsia, and gout.

• Post-hemorrhage or hemolysis recovery.

• Chemical/Drug Effects:

  • Corticosteroids, certain antibiotics (e.g., minocycline).

• Physiological Factors:

  • Strenuous exercise, stress, pain, temperature extremes, and childbirth.

Reactive Chronic Neutrophilia

• Characterized by leukocyte count less than $50 imes 10^9/L$.

• Observed left shift with presence of toxic granulation, Dohle bodies, and cytoplasmic vacuolization.

Neutrophilic Conditions and Laboratory Findings

Bacterial Infection

• Most prevalent cause of neutrophilia.

• Bone marrow increases output of storage neutrophils to fight infection.

• Lab Findings:

  • Left shift observed with increased bands, metamyelocytes, and myelocytes; blasts occasionally seen in severe cases.

Physiologic Leukocytosis

• No left shift observed; no increase in immature cells.

• Common occurrences during birth and in the first days of life, extreme temperatures, or emotional stimuli.

Leukoerythroblastic Reaction

• Presence of NRBCs and left shift; seen with chronic neoplastic myeloproliferative conditions.

Leukemoid Reaction

• Characterized by leukocyte counts exceeding $50 imes 10^9/L$.

• Not a result of leukemia; transient and resolves when stimulus is removed.

• Numerous circulating immature leukocyte precursors noted.

• Similar blood picture to chronic myelocytic leukemia (CML).

• LAP (Leukocyte Alkaline Phosphatase) Test:

  • Increased in leukemoid reaction; decreased in CML.

Neutropenia

• Definition: Absolute neutrophil count (ANC) less than $1.5 imes 10^9/L$.

• Causes Include:

  • Increased cell loss (e.g., immune neutropenia).

  • Bone marrow inability to maintain cell production due to increased utilization (e.g., hypersplenism, megaloblastic anemia).

  • Decreased Bone Marrow Production:

    • Myeloid hypoplasia; decreased storage, circulating, and marginal pool.

Nuclear Abnormalities

Pelger-Huet Anomaly

• An inherited benign autosomal dominant condition characterized by having two segmented nuclei which do not segment beyond two.

• Morphology resembles sunglasses without ear pieces; cells function normally without increased susceptibility to infection.

Hypersegmented Neutrophils

• Defined as neutrophils containing six or more nuclear segments.

• Indicative of megaloblastic anemia.

• Typically associated with folate or vitamin B12 deficiency.

Pyknotic Nucleus

• Found in dying neutrophils, recognized by its singular, dark, round appearance.

• Important for differentiation from nucleated red blood cells (NRBCs).

Inherited Functional Abnormalities

Alder-Reilly Anomaly

• Inherited condition with large purplish granules in the cytoplasm of granulocytes.

• Rare; detected using special stains (toluidine blue).

Chediak-Higashi Syndrome

• Rare autosomal recessive disorder causing death in infancy or early childhood.

• Characterized by giant gray-green peroxidase-positive bodies and other compromised cellular functions leading to neutropenia and thrombocytopenia.

• Survivors exhibit hypopigmentation, silvery hair, and photophobia.

May-Hegglin Anomaly

• A rare inherited condition resembling an autosomal dominant trait with larger Dohle-like RNA inclusions in granulocytes.

• Frequently associated with thrombocytopenia and bleeding issues.

Chronic Granulomatous Disease

• An inherited disorder with about 65% X-linked and 35% autosomal recessive occurrence.

• Causes recurrent infections and formation of granulomas. Patients may remain asymptomatic until adulthood, but granulocytes have impaired bacterial killing.

Monocyte/Macrophage Disorders

Quantitative Disorders

• Monocytosis: Absolute monocyte count (AMC) greater than $0.8 imes 10^9/L$.

  • Seen in inflammatory conditions and malignancies.

• Monocytopenia: AMC less than $0.2 imes 10^9/L$.

  • Often seen in stem cell disorders.

Qualitative Disorders - Lysosomal Storage Diseases

• Inherited disorders that result in the accumulation of unmetabolized materials in lysosomes due to enzyme deficiencies.

• Three main disorders:

  1. Gaucher Disease

  • Enzyme deficiency: β-glucocerebrosidase; especially common in the Ashkenazi Jewish population.

  • Macrophages fail to digest cellular stroma, causing glucocerebroside accumulation, leading to splenic and hepatic enlargement.

  1. Niemann-Pick Disease

  • Enzyme deficiency: sphingomyelinase; also observed in the Jewish population.

  • Causes accumulations that lead to jaundice at birth, hepatosplenomegaly, and neurological impairment, often fatal by age 3.

  1. Tay-Sachs Disease

  • Enzyme deficiency: hexosaminidase A; prevalent in the Ashkenazi Jewish population.

  • Disease severity correlates with enzyme activity; presents with CNS and ocular deterioration, resulting in death by age 4.

Chapter 22: Nonmalignant Lymphocyte Disorders

Overview of Lymphocyte Origin

• Lymphocytes primarily arise from bone marrow and thymus.

• Secondary lymphoid organs include spleen, lymph nodes, tonsils, and Peyer’s patches in the gastrointestinal tract.

• General lymphocyte populations:

  • B lymphocytes: 10-20%

  • T lymphocytes: 60-80%

  • NK (Natural Killer) cells: < 10%

Characteristic Cell Types in Lymphocyte Disorders

• Reactive Lymphocytes

  • Also known as transformed lymph, atypical lymph, virocyte, immunoblast, or Downey cell.

  • Appears after activation by infections or inflammatory conditions, often presenting morphological signs of activation (e.g., large irregular shape, basophilia).

  • Immunoblasts: Large cells with prominent nucleoli, engaged in mitosis.

  • Plasmacytoid Lymphocytes: Daughters of immunoblasts, with eccentric nuclei and deep blue cytoplasm.

  • Plasma Cells: Fully differentiated B cells characterized by unique nuclear appearances and prominent basophilic cytoplasm, responsible for Ig secretion.

Introduction to Lymphocytosis

• Lymphocytosis: An excess of lymphocytes in the blood, defined as an absolute lymphocyte count > $4.8 imes 10^9/L$ or a relative count > 35-45%.

• Reactive process that is usually self-limited and often emerges following infection or inflammation, implicating both B and T cell activation.

Causes of Reactive Lymphocytosis

• Infectious Mononucleosis (IM)

  • Caused by the Epstein-Barr Virus (EBV), known as the "kissing disease."

  • Pathophysiology: EBV binds to B lymphocytes via CD21; triggers activation and immortalization of EBV-infected B cells, resulting in characteristic reactive lymphocyte proliferation.

Clinical Presentation of Infectious Mononucleosis

• Classic symptoms: fever, pharyngitis, lymphadenopathy, dysphagia, malaise, fatigue, and splenomegaly.

• Commonly observed in ages 14-24.

Laboratory Findings for Infectious Mononucleosis

• CBC Findings:

  • Relative lymphocytosis peaking at 2-3 weeks, remaining elevated for 2-8 weeks, leukocyte count between $12-25 imes 10^9/L$.

  • Peripheral Smear: Reactive lymphocytes, historically referred to as Downey cells, characterized by increased cytoplasm and irregular borders.

  • Serologic Test: Heterophil antibody test (Monospot).

Other Causes of Reactive Lymphocytosis

• Toxoplasmosis: Infection with Toxoplasma gondii, acquired from cat feces or undercooked meat; can transmit via placenta, causing neurological damage in newborns.

• Cytomegalovirus (CMV): Affects immunocompromised individuals severely; transmitted through contact or blood.

• Infectious Lymphocytosis: Primarily in children; includes infections like adenovirus and Bordetella pertussis, presenting similar to viral lymphocytosis.

Lymphocytopenia

• Definition: Absolute lymphocyte count < $1.0 imes 10^9/L$.

• Causes:

  • Decreased lymphocyte production or increased destruction; changes in circulation.

  • Also associated with corticosteroid therapy.

Immune Deficiency Disorders

• Defined by impaired function of components of the immune system, such as T, B, or NK lymphocytes.

• These disorders can be acquired or congenital.

Acquired Deficiencies

• AIDS (Acquired Immune Deficiency Syndrome):

  • Caused by HIV-1; transmitted sexually or through blood products, leading to T lymphocyte cell lysis due to binding CD4 antigens.

Congenital Deficiencies

• General Characteristics of Congenital Deficiencies:

  • Decrease in lymphocytes with impaired cell-mediated (T cells), humoral (B cells) immunity, or both.

  • Lymphocytes in peripheral smear appear normal.

• Severe Combined Immunodeficiency Syndrome: A major defect involving both humoral and cellular immunity, often fatal by age 2 if untreated.

• Wiskott-Aldrich Syndrome: A sex-linked recessive disorder characterized by recurrent infections, thrombocytopenia, and eczema. Fatality risks if not treated by bone marrow transplant or supportive measures.