Download PDF

Disorders of Granulocytes and Monocytes¶

Part 2: Cardinal Manifestations and Presentation of Diseases · Part 2 – Cardinal Manifestations & Presentation · Chapter 67

Key Clinical Points¶

ANC <500 cells/μL impairs control of endogenous microbial flora; ANC <200/μL results in absent local inflammatory process.
LAD1 hallmark: Delayed separation of umbilical cord, sustained neutrophilia, and recurrent infections of skin and mucosa.
Pelger-Hüet anomaly: Benign inherited trait with bilobed nuclei (pince-nez appearance); distinguish from pseudo-Pelger-Hüet (acquired in myelodysplastic syndromes).
DARC gene: Null expression of Duffy antigen receptor for cytokines confers resistance to Plasmodium vivax malaria.
Toxic granulations: Immature or abnormally staining azurophil granules seen in severe acute bacterial infection.
Döhle bodies: Cytoplasmic inclusions representing aggregates of rough endoplasmic reticulum (ER) seen in infection/toxic states.
Neutrophil half-life: 6–7 hours in circulation; survival is regulated by G-CSF and IFN-γ.
Chemokine groups: C, CC, CXC, and CX3C based on cysteine structure near N terminus.
Drug-induced neutropenia: Typically occurs within 7 days of exposure; discontinuation of the offending agent usually results in recovery within 5–7 days.
Leukemoid reaction: Persistent neutrophilia with counts ≥30,000–50,000/μL involving mature, non-clonally derived cells.

DEFINITION & OVERVIEW¶

• Leukocytes: Primary cells for inflammatory/immune responses; 4.3–10.8 imes 10^9/L total count. ◦ Neutrophils: 45–74% of leukocytes. ◦ Bands: 0–4%; Lymphocytes: 16–45%; Monocytes: 4–10%; Eosinophils: 0–7%; Basophils: 0–2%. • Neutrophil Granules: ◦ Azurophil (Primary): Contain myeloperoxidase, cathepsin G, cationic proteins, and defensins; essential for killing gram-negative bacteria. ◦ Specific (Secondary): Formed during myelopoiesis (regulated by CEBPE); contain lactoferrin, vitamin B12-binding protein, NOX2 components, histaminase, and receptors for chemokines/adhesion factors (e.g., CR3). • Morphological Markers: ◦ Pelger-Hüet: Bilobed nuclei; can be a benign inherited trait or acquired in myelodysplastic syndromes. ◦ Döhle bodies: Cytoplasmic inclusions of rough endoplasmic reticulum (ER) seen in infection/toxic states. ◦ Hypersegmentation: >5 nuclear lobes; suggests vitamin B12/folate deficiency or WHIM syndrome.

Neutrophil Life Cycle & Pools¶

• Production and Distribution: ◦ 90% of the neutrophil pool is in the bone marrow. ◦ 2–3% are in circulation; remainder are in tissues. • Circulatory Compartments: ◦ Free-flowing: Not in contact with endothelium. ◦ Marginated: In physical contact with the endothelium. • Recruitment Process (Extravasation): 1. Rolling: Mediated by selectins (L-selectin [CD62L], E-selectin [CD62E], P-selectin [CD62P]). 2. Activation & Tight Adhesion: Mediated by integrins (CD11a/CD18, CD11b/CD18) binding to ICAM-1 and ICAM-2. 3. Diapedesis: Passage between endothelial cells via PECAM-1 (CD31). • Pulmonary Circulation: ◦ Movement depends on neutrophil deformability; increased rigidity leads to pulmonary trapping.

EPIDEMIOLOGY¶

• Benign Ethnic Neutropenia: ◦ Common in certain African-American groups. ◦ Range: 1500–2000/μL; generally without sequelae. ◦ Mechanism: Associated with null expression of the DARC gene (Duffy antigen receptor for cytokines). ◦ Clinical Significance: Provides resistance to Plasmodium vivax malaria.

ETIOLOGY & PATHOPHYISIOLOGY¶

• Neutrophilia Mechanisms: ◦ Infection: Most common acute cause; involves increased production and marrow release. ◦ Inflammation: Chronic, thermal injury, tissue necrosis, myocardial/pulmonary infarction. ◦ Drug-induced: Glucocorticoids, G-CSF. ◦ Reduced Margination: Epinephrine (stress, exercise), glucocorticoids; also seen in LAD types 1, 2, and 3. ◦ Leukemoid Reaction: Persistent neutrophilia ≥30,000–50,000/μL with mature, non-clonally derived cells. • Neutropenia Mechanisms: ◦ Decreased Production: ◦ Drug-induced: Alkylating agents (e.g., cyclophosphamide), antimetabolites (e.g., methotrexate), noncytotoxic agents (e.g., penicillins, sulfonamides). ◦ Hematologic diseases: Aplastic anemia, Chédiak-Higashi syndrome. ◦ Nutritional deficiency: Vitamin B12, folate (especially in alcoholics). ◦ Infection: Tuberculosis, malaria, HIV, etc. ◦ Peripheral Destruction: ◦ Antineutrophil antibodies; splenic or lung trapping. ◦ Autoimmune disorders: Felty syndrome, systemic lupus erythematosus (SLE). ◦ Peripheral Pooling (Transient): ◦ Overwhelming bacterial infection (acute endotoxemia), hemodialysis, cardiopulmonary bypass. • Adhesion & Chemotaxis Defects: ◦ Adherence-aggregation: Affected by aspirin, colchicine, alcohol, glucocorticoids. ◦ Chemokinesis-chemotaxis: Affected by high-dose glucocorticoids, aconitifen, etc.

CLINICAL FEATURES¶

• Morphological Findings: ◦ Pelger-Hüet: Bilobed nuclei (pince-nez appearance); indicates either a benign trait or myelodysplastic syndrome. ◦ Döhle bodies: Blue-staining, non-granular areas in cytoplasm; indicate infection/toxic states. ◦ Vacuolization: Cytoplasmic vacuoles in monocytes and neutrophils; seen in severe COVID-19 cases. ◦ Hypersegmentation: >5 nuclear lobes; suggests B12/folate deficiency or WHIM syndrome.

Table 67-1 & 67-2 Summary¶

• Neutropenia (Table 67-1): ◦ Decreased Production: Drugs (alkylating agents, antimetabolites), Hematologic diseases, Nutrition (B12/folate), Infection. ◦ Peripheral Destruction: Antineutrophil antibodies, Felty syndrome, Granulomatosis with polyangiitis. ◦ Pooling: Endotoxemia, Hemodialysis. • Neutrophilia (Table 67-2): ◦ Increased Production: Infection, Inflammation, Myeloproliferative diseases. ◦ Increased Marrow Release: Glucocorticoids, Acute infection (endotoxin). ◦ Decreased Margination: Epinephrine, Stress, LAD types 1–3.

DIFFERENTIAL DIAGNOSIS¶

• Leukemoid Reaction vs. Leukemia: → Leukemoid reaction ≥30,000–50,000/μL with mature, non-clonally derived cells. → Leukemia: Characterized by clonal expansion of leukemic cells.

DIAGNOSTIC APPROACH¶

Morphological Assessment: ◦ Identify Pelger-Hüet (biled nuclei) to distinguish between benign/inherited and acquired (MDS). ◦ Identify Döhle bodies to confirm infection or toxic states. ◦ Identify Vacuolization in the context of severe COVID-19.
Specific Tests for Inherited Disorders: ◦ Chronic Granulomatous Disease (CGD): DHR or NBT test → no superoxide and H_2O_2 production; immunoblot for NADPH oxidase components; genetic detection of CYBB, CYBA, NCF1, NCF2, NCF4, or CYBC1. ◦ Leukocyte Adhesion Deficiencies (LAD): ◦ Type 1: Monoclonal antibodies against LFA-1 (CD18/CD11a), Mac-1 (CD18/CD11b), or p150,95 (CD18/CD11c); genetic detection of ITGB2. ◦ Type 2: Monoclonal antibodies against CD15s; genetic detection of SLC35C1. ◦ Type 3: Genetic detection for FERMT3. ◦ Other Disorders: ◦ GATA2 Deficiency: Genetic detection (profound monocytopenia). ◦ DOCK8 Deficiency: Genetic detection (severe eczema, high IgE).

MANAGEMENT & TREATMENT¶

Drug-Induced Neutropenia: → Identify offending agent (e.g., alkylating agents, sulfonamides). → Discontinue drug → recovery typically occurs within 5–7 days.
Congenital Phagocyte Defects: → Management: Hematopoietic stem cell transplantation and gene therapy have extended survival into adulthood.
Infection Management: → Standard protocols for bacterial/fungal infections in patients with congenital phagocyte defects (e.g., CGD, LAD).

PROGNOSIS & COMPLICATIONS¶

• Congenital Phagocyte Defects: ◦ Early life: Infections of skin, ear, respiratory tract, and bone. ◦ Sepsis/Meningitis: Rare in these patients. ◦ Management: Stem cell transplant and gene therapy have significantly improved outcomes.

SPECIAL CONSIDERATIONS¶

• Benign Ethnic Neutropenia: ◦ Common in African-Americans; no clinical sequelae; associated with DARC gene. ◦ Clinical Significance: Provides resistance to Plasmodium vivax.

KEY PEARLS & CLINICAL TRAPS¶

• ANC Thresholds: ◦ ANC < 500 → impaired control of flora. ◦ ANC < 200 → absent local inflammation. • Döhle Bodies: Represent aggregates of rough endoplasmic reticulum (ER). • LAD Type 1: Characterized by delayed separation of umbilical cord and sustained neutrophilia. • Chédiak-Higashi Syndrome: Identified by giant lysosomal granules due to β-tubulin mutation.

Reference Tables¶

TABLE 67-1 Causes of Neutropenia Decreased Production Drug-induced—alkylating agents (nitrogen mustard, busulfan…¶

Harrison's 22e, p.457

Decreased Production
Drug-induced—alkylating agents (nitrogen mustard, busulfan, chlorambucil,
cyclophosphamide); antimetabolites (methotrexate, 6-mercaptopurine,
5-flucytosine); noncytotoxic agents (antibiotics [chloramphenicol, penicillins,
sulfonamides], phenothiazines, tranquilizers [meprobamate], anticonvulsants
[carbamazepine], antipsychotics [clozapine], certain diuretics, anti-inflammatory
agents, antithyroid drugs, many others)
Hematologic diseases—idiopathic, cyclic neutropenia, Chédiak-Higashi
syndrome, aplastic anemia, infantile genetic disorders (see text)
Tumor invasion, myelofibrosis
Nutritional deficiency—vitamin B , folate (especially alcoholics)
12
Infection—tuberculosis, typhoid fever, brucellosis, tularemia, measles, infectious
mononucleosis, malaria, viral hepatitis, leishmaniasis, AIDS
Peripheral Destruction
Antineutrophil antibodies and/or splenic or lung trapping
Autoimmune disorders—Felty syndrome, rheumatoid arthritis, lupus
erythematosus
Drugs as haptens—aminopyrine, α-methyldopa, phenylbutazone, mercurial
diuretics, some phenothiazines
Granulomatosis with polyangiitis (Wegener)
Peripheral Pooling (Transient Neutropenia)
Overwhelming bacterial infection (acute endotoxemia)
Hemodialysis
Cardiopulmonary bypass

TABLE 67-2 Causes of Neutrophilia Increased Production Idiopathic Drug-induced—glucocorticoids, G-CSF…¶

Harrison's 22e, p.458

Increased Production
Idiopathic
Drug-induced—glucocorticoids, G-CSF
Infection—bacterial, fungal, sometimes viral
Inflammation—thermal injury, tissue necrosis, myocardial and pulmonary
infarction, hypersensitivity states, collagen vascular diseases
Myeloproliferative diseases—myelocytic leukemia, myeloid metaplasia,
polycythemia vera
Increased Marrow Release
Glucocorticoids
Acute infection (endotoxin)
Inflammation—thermal injury
Decreased or Defective Margination
Drugs—epinephrine, glucocorticoids, nonsteroidal anti-inflammatory agents
Stress, excitement, vigorous exercise
Leukocyte adhesion deficiency type 1 (CD18); leukocyte adhesion deficiency
type 2 (selectin ligand, CD15s); leukocyte adhesion deficiency type 3 (FERMT3)
Miscellaneous
Metabolic disorders—ketoacidosis, acute renal failure, eclampsia, acute
poisoning
Drugs—lithium
Other—metastatic carcinoma, acute hemorrhage or hemolysis

TABLE 67-3 Types of Granulocyte and Monocyte Disorders FUNCTION Adherence-aggregation¶

Harrison's 22e, p.458

CAUSE OF INDICATED DYSFUNCTION
FUNCTION	DRUG-INDUCED	ACQUIRED	INHERITED
Adherence-aggregation	Aspirin, colchicine, alcohol, glucocorticoids, ibuprofen, piroxicam	Neonatal state, hemodialysis	Leukocyte adhesion deficiency types 1, 2, and 3
		Leukemia, neonatal state, diabetes mellitus, immature neutrophils
Chemokinesis- chemotaxis	Glucocorticoids (high dose), auranofin, colchicine (weak effect), phenylbutazone, naproxen, indomethacin, interleukin 2	Thermal injury, malignancy, malnutrition, periodontal disease, neonatal state, systemic lupus erythematosus, rheumatoid arthritis, diabetes mellitus, sepsis, influenza virus infection, herpes simplex virus infection, acrodermatitis enteropathica, AIDS	Chédiak-Higashi syndrome, neutrophil-specific granule deficiency, WDR1 deficiency, Job’s syndrome (in some patients), Down syndrome, α-mannosidase deficiency, leukocyte adhesion deficiencies, Wiskott-Aldrich syndrome
	Colchicine, cyclophosphamide, glucocorticoids (high dose), TNF- α-blocking antibodies	Leukemia, aplastic anemia, certain neutropenias, tuftsin deficiency, thermal injury, sepsis, neonatal state, diabetes mellitus, malnutrition, AIDS

TABLE 67-4 Inherited Disorders of Phagocyte Function: Differential Features¶

Harrison's 22e, p.459

CLINICAL MANIFESTATIONS	CELLULAR OR MOLECULAR DEFECTS	DIAGNOSIS
Chronic Granulomatous Diseases (70% X-Linked, 30% Autosomal Recessive)
Severe infections of skin, ears, lungs, liver, and bone with microorganisms such as Staphylococcus aureus, Burkholderia cepacia complex, Aspergillus spp., Chromobacterium violaceum; often hard to culture organism; excessive inflammation with granulomas, frequent lymph node suppuration; granulomas can obstruct GI or GU tracts; gingivitis, aphthous ulcers	No respiratory burst due to impaired of NADPH oxidase in neutrophils, monocytes, and eosinophils. Mutations in CYBB, CYBA, NCF1, NCF2, NCF4, or CYBC1	DHR or NBT test; no superoxide and HO 2 2 production by neutrophils; immunoblot for NADPH oxidase components; genetic detection
Chédiak-Higashi Syndrome (Autosomal Recessive)
Specific Granule Deficiency (Autosomal Recessive and Dominant)
Recurrent infections of skin, ears, and sinopulmonary tract; delayed wound healing; decreased inflammation; bleeding diathesis	Abnormal chemotaxis, impaired respiratory burst and bacterial killing, failure to upregulate chemotactic and adhesion receptors with stimulation, defect in transcription of granule proteins. Mutations in CEBPE or SMARCD2	Lack of secondary (specific) granules in neutrophils (Wright stain), no neutrophil- specific granule contents (i.e., lactoferrin), no defensins, platelet α granule abnormality; genetic detection
Myeloperoxidase Deficiency (Autosomal Recessive)
Leukocyte Adhesion Deficiency
Type 1: Delayed separation of umbilical cord, sustained neutrophilia, recurrent infections of skin and mucosa, gingivitis, periodontal disease	Impaired phagocyte adherence, aggregation, spreading, chemotaxis, phagocytosis of C3bi-coated particles; defective production of CD18 subunit common to leukocyte integrins. Mutations in ITGB2	Reduced phagocyte surface expression of the CD18-containing integrins with monoclonal antibodies against LFA-1 (CD18/CD11a), Mac-1 or CR3 (CD18/ CD11b), p150,95 (CD18/CD11c); genetic detection
Type 2: Cognitive impairment, short stature, Bombay (hh) blood phenotype, recurrent infections, neutrophilia	Impaired phagocyte rolling along endothelium; due to defects in fucose transporter. Mutations in SLC35C1	Reduced phagocyte surface expression of Sialyl-Lewisx, with monoclonal antibodies against CD15s; genetic detection
Type 3: Petechial hemorrhage, recurrent infections	Impaired signaling for integrin activation resulting in impaired adhesion. Mutations in FERMT3	Reduced signaling for adhesion through integrins; genetic detection
Phagocyte Activation Defects (X-Linked and Autosomal Recessive)
Impaired phagocyte activation by IL-1, IL-18, TLR, CD40L, TNF-α leading to problems with inflammation and antibody production. Mutations in IKBKG
Impaired phagocyte activation by endotoxin through TLR and other pathways; TNF-α signaling preserved. Mutations in IRAK4 or MYD88
Hyper IgE–Recurrent Infection Syndrome (Autosomal Dominant) (Job’s Syndrome)
Eczematoid or pruritic dermatitis, “cold” skin abscesses, recurrent pneumonias with S. aureus with bronchopleural fistulae and cyst formation, mild eosinophilia, mucocutaneous candidiasis, characteristic facies, restrictive lung disease, scoliosis, delayed primary dental deciduation	Reduced chemotaxis in some patients, reduced memory T and B cells. Mutations in STAT3	Somatic and immune features involving lungs, skeleton, and immune system; serum IgE >2000 IU/mL; genetic testing
DOCK8 deficiency (autosomal recessive), severe eczema, atopic dermatitis, cutaneous abscesses, HSV, HPV, and molluscum infections, severe allergies, cancer	Impaired T-cell proliferation to mitogens. Mutations in DOCK8	Severe allergies, viral infections, high IgE, eosinophilia, low IgM, progressive lymphopenia, genetic detection
Mycobacterial Susceptibility (Autosomal Dominant and Recessive Forms)
GATA2 Deficiency (Autosomal Dominant)
Persistent or disseminated warts, disseminated mycobacterial disease, low monocytes, NK cells, B cells; hypoplastic myelodysplasia, leukemia, cytogenetic abnormalities, pulmonary alveolar proteinosis	Impaired macrophage activity, cytopenias. Mutations in GATA2	Profound circulating monocytopenia, NK and B-cell cytopenias; genetic detection