Disorders of Granulocytes and Monocytes¶
Chapter 67 | Part 2: Cardinal Manifestations and Presentation of Diseases
KEY CLINICAL POINTS¶
- Neutrophils are critical for host defense against bacterial infections, with defects leading to severe susceptibility to infections and granulomatous diseases.
- Chronic granulomatous disease (CGD) is an X-linked recessive disorder caused by NADPH oxidase deficiency, leading to impaired microbial killing and recurrent infections.
- Leukocyte adhesion deficiency (LAD) types 1-3 impair neutrophil migration and adhesion, resulting in recurrent infections and leukocytosis.
- Eosinophilia is associated with allergic reactions, helminthic infections, and certain malignancies, while eosinopenia occurs with stress and corticosteroid use.
- Genetic testing and bone marrow evaluation are essential for diagnosing inherited granulocyte disorders, with gene therapy and transplantation offering curative options.
1. DEFINITION & OVERVIEW¶
Granulocytes (neutrophils, eosinophils, basophils) and monocytes are key components of the innate immune system. Neutrophils are the most abundant, with a segmented nucleus and granules containing enzymes for microbial killing. Monocytes differentiate into macrophages and dendritic cells, playing roles in phagocytosis and antigen presentation. Eosinophils are involved in allergic responses and parasite defense.
Table 67-1: Causes of Neutropenia¶
| Category | Causes |
|---|---|
| Decreased Production | Drug-induced (alkylating agents, antimetabolites), Hematologic diseases (aplastic anemia), Infections (tuberculosis, HIV), Nutritional deficiency (vitamin B12, folate) |
| Peripheral Destruction | Antineutrophil antibodies, Autoimmune disorders (Felty syndrome), Drugs (aminopyrine, sulfonamides), Granulomatosis with polyangiitis |
| Peripheral Pooling | Overwhelming infection, Hemodialysis, Cardiopulmonary bypass |
Table 67-2: Causes of Neutrophilia¶
| Category | Causes |
|---|---|
| Increased Production | Infection, Inflammation, Myeloproliferative diseases |
| Category | Causes |
|---|---|
| Increased Marrow Release | Glucocorticoids, Acute infection, Stress |
| Decreased Margination | Leukocyte adhesion deficiency, Drugs (epinephrine), Stress |
1.1 Neutrophil Structure and Function¶
Neutrophils have a multilobed nucleus and granules containing enzymes like myeloperoxidase, elastase, and defensins. They undergo chemotaxis, phagocytosis, and produce reactive oxygen species (ROS) via NADPH oxidase. Neutrophil extracellular traps (NETs) are formed to immobilize pathogens.
1.2 Monocyte and Macrophage Function¶
Monocytes circulate in blood and differentiate into macrophages in tissues. They phagocytose pathogens, present antigens, and secrete cytokines. Macrophages are critical for tissue repair and immune regulation.
2. EPIDEMIOLOGY¶
Neutropenia is common in malignancy and autoimmune diseases, with iatrogenic causes (e.g., chemotherapy) being the most frequent. CGD has an incidence of 1 in 100,000–200,000, with X-linked recessive inheritance in 70% of cases. LAD1 is autosomal recessive, while LAD2 and LAD3 have distinct genetic etiologies.
2.1 Risk Factors¶
Infections (e.g., HIV, tuberculosis), autoimmune disorders (e.g., lupus), malignancies, and drug use (e.g., chemotherapy, antibiotics) increase susceptibility to granulocyte disorders.
2.2 Demographics¶
CGD is more common in males due to X-linked inheritance. Ethnic variations in neutrophil counts (e.g., African Americans with benign ethnic neutropenia) are noted.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Defects in NADPH oxidase (CGD), granule formation (e.g., specific granule deficiency), or adhesion molecules (LAD) impair immune function. Genetic mutations in genes like CYBB (CGD), ITGB2 (LAD1), or STAT3 (Job’s syndrome) underlie inherited disorders.
Table 67-3: Types of Granulocyte and Monocyte Disorders¶
| Function | Drug-Induced | Acquired | Inherited |
|---|---|---|---|
| Adherence-aggregation | Aspirin, colchicine, alcohol | Neonatal state, hemodialysis | Leukocyte adhesion deficiency types 1-3 |
| Chemokinesis-chemotaxis | Glucocorticoids, colchicine | Thermal injury, malnutrition | Chédiak-Higashi syndrome, Wiskott-Aldrich syndrome |
| Microbicidal activity | Colchicine, cyclophosphamide | Leukemia, aplastic anemia | Chronic granulomatous disease, neutrophil-specific granule deficiency |
3.1 NADPH Oxidase Deficiency¶
CGD results from mutations in NCF1, NCF2, CYBA, or CYBB, leading to impaired ROS production and microbial killing. Patients are susceptible to Staphylococcus, Aspergillus, and Burkholderia infections.
3.2 Leukocyte Adhesion Deficiency¶
LAD1 (ITGB2 mutations) impairs integrin function, preventing neutrophil migration. LAD2 (SLC35C1) affects fucosylation, while LAD3 (FERMT3) disrupts integrin signaling.
4. CLINICAL FEATURES¶
Patients present with recurrent infections (skin, respiratory, gastrointestinal), abscesses, and granulomas. CHS patients may have nystagmus, partial albinism, and neurological complications. Eosinophilia is associated with allergies, helminths, and certain cancers.
4.1 Infections¶
CGD: S. aureus, Aspergillus, Burkholderia. LAD1: Skin, mucosal, and respiratory tract infections. CHS: Broad-range bacterial and fungal infections.
4.2 Autoimmune and Inflammatory Complications¶
CGD: Autoimmune thrombocytopenia, juvenile arthritis. LAD1: Chronic inflammation, granulomas. Job’s syndrome: Eczema, cold abscesses, and lung disease.
5. DIFFERENTIAL DIAGNOSIS¶
Distinguish neutropenia from drug-induced causes (e.g., chemotherapy), autoimmune disorders (Felty syndrome), or infections (HIV, tuberculosis). Eosinophilia differentiates from allergic reactions, helminthic infections, and malignancies.
5.1 Neutropenia¶
Drug-induced, autoimmune, infections, nutritional deficiencies, or bone marrow failure.
5.2 Eosinophilia¶
Allergic reactions, helminthic infections, malignancies (e.g., Hodgkin disease), or hypereosinophilic syndromes.
6. INVESTIGATIONS & DIAGNOSIS¶
CBC with differential, peripheral blood smear for Döhle bodies or Pelger-Hüet anomaly, bone marrow biopsy, and genetic testing. DHR test for CGD, flow cytometry for LAD, and imaging for granulomas.
Table 67-4: Inherited Disorders of Phagocyte Function¶
| Clinical Features | Cellular Defects | Diagnosis |
|---|---|---|
| Chronic Granulomatous Disease | NADPH oxidase deficiency | DHR test, genetic analysis |
| Chédiak-Higashi Syndrome | Lysosomal transport defect (LYST) | Wright stain, genetic testing |
| Leukocyte Adhesion Deficiency | Integrin dysfunction (ITGB2, SLC35C1, FERMT3) | Flow cytometry, gene panel |
6.1 Diagnostic Tests¶
Nitroblue tetrazolium (NBT) test, DHR assay, bone marrow evaluation, and genetic sequencing for inherited disorders.
6.2 Imaging¶
CT/MRI for granulomas, abscesses, or organ involvement in CGD. Skin window tests for leukocyte migration.
7. MANAGEMENT & TREATMENT¶
Antibiotics (e.g., trimethoprim-sulfamethoxazole), antifungals (itraconazole), G-CSF for neutropenia, and bone marrow transplantation for severe cases. Gene therapy is emerging for CGD and LAD.
7.1 Pharmacologic Therapy¶
Prophylactic antibiotics, antifungals, and IFN- γ for CGD. Corticosteroids for inflammation, but caution in CGD due to infection risk.
7.2 Bone Marrow Transplantation¶
Curative for severe CGD, LAD, and specific granule deficiency. Gene therapy trials for LAD1 and CGD.
8. PROGNOSIS & COMPLICATIONS¶
CGD and LAD require lifelong management with antibiotics and antifungals. Complications include sepsis, granulomas, and organ damage. Hypereosinophilic syndromes may cause heart failure or CNS involvement.
8.1 Long-Term Outcomes¶
CGD: Improved with IFN- γ and prophylaxis. LAD: Variable, with some patients surviving into adulthood. Job’s syndrome: Chronic, with progressive complications.
8.2 Organ Damage¶
CGD: Cardiac and CNS complications. Hypereosinophilic syndromes: Myocardial fibrosis, endomyocardial disease.
9. SPECIAL CONSIDERATIONS¶
Pregnancy: Monitor for neutropenia in women with WHIM syndrome. Pediatrics: Early diagnosis of LAD and CGD is critical. Elderly: Increased risk of infections and drug-induced neutropenia.
9.1 Pregnancy¶
Neutropenia may occur in maternal-fetal immune interactions. Avoid certain drugs (e.g., sulfonamides) in pregnancy.
9.2 Pediatrics¶
Early recognition of LAD and CGD is vital for bone marrow transplantation. Neonatal neutropenia may be benign or congenital.
10. KEY POINTS & CLINICAL PEARLS¶
- Neutropenia and neutrophilia have diverse etiologies, including drug-induced, infectious, and genetic causes.
- CGD and LAD require lifelong management with antibiotics and antifungals.
- Genetic testing is essential for diagnosing inherited granulocyte disorders.
- Bone marrow transplantation and gene therapy offer curative options for severe cases.
- Monitor for complications like sepsis, granulomas, and organ damage in chronic disorders.