Disorders of Phagocyte Function in Children
Introduction to Phagocyte Function Disorders
Definition & Significance
- Primary immunodeficiencies affecting neutrophil and macrophage function
- Part of innate immune system disorders
- Estimated incidence: 1:200,000 live births
- Significant cause of morbidity and mortality in pediatric populations
Historical Perspective
- First described by Janeway in 1954
- CGD first characterized in 1957
- Molecular basis understood in 1980s
- Recent advances in genetic understanding and treatment options
Normal Phagocyte Function
1. Cell Types Involved:
- Neutrophils (primary responders)
- Monocytes/Macrophages
- Dendritic cells
2. Key Functions:
- Pattern recognition
- Chemotaxis
- Phagocytosis
- Microbial killing
- Cytokine production
- Antigen presentation
3. Defense Mechanisms:
- Oxygen-dependent killing (respiratory burst)
- Oxygen-independent killing (defensins, lysozyme)
- NETs (Neutrophil Extracellular Traps)
Pathophysiology & Basic Mechanisms
Cellular Mechanisms
1. Adhesion Process:
- Selectin-mediated rolling
- Integrin-dependent firm adhesion
- Transendothelial migration
2. Chemotaxis Components:
- Chemokine receptors
- Signal transduction
- Cytoskeletal rearrangement
3. Phagocytosis Steps:
- Recognition of opsonins
- Membrane invagination
- Phagosome formation
- Phagolysosome fusion
Molecular Pathways
1. NADPH Oxidase Complex:
- gp91phox, p22phox, p47phox, p67phox, p40phox
- Rac2 GTPase
- Assembly and activation
2. Granule Formation:
- Primary (azurophilic) granules
- Secondary (specific) granules
- Tertiary granules
- Secretory vesicles
The ingestion of mycobacteria by the macrophage leads to the elaboration of IL-12. This stimulates T and natural killer lymphocytes through IL-12 receptors β1 and β2 to signal through STAT4 to produce IFN-γ.IFN-γ acts on its receptors 1 and 2 to signal through STAT1 for the upregulation of TNF-α, the killing of mycobacteria, and the upregulation of IL-12. Mutations in either chain of the IFN-γR lead to severe susceptibility to mycobacteria and are very difficult to treat.
Mutations in IL-12p40 or IL-12Rβ1 are milder clinically and can be treated with IFN-γ because that receptor is still intact. Complete recessive mutations in STAT1 are more severe than any of the others because they affect both IFN-γ and IFN-α signaling (not shown).
Not shown is the sharing of IL-12Rβ1 with the IL-23 receptor, a complex that also signals through STAT4 and upregulates IFN-γ. (source)
T cells become polarized toward Th1 by macrophages activated by microbes. T cells generally can be categorized as Th1 or Th2 depending on the cytokines produced by the individual cell. Th1 cells predominantly activate macrophages to enhance killing through the release of gamma interferon and TNF-α. Th2 cells predominantly activate B cells through the secretion of IL-4 and IL-5. They can also activate eosinophils and are important in defense against parasites. The infected macrophage acts to determine the fate of the naive T cell by producing IL-12, which is produced in response to engagement of TLRs by microbes. In the absence of IL-12, IL-4 from other cells can direct a Th2 response. The response then ultimately directs effector functions listed at the bottom of the figure. (source)
Classification of Phagocyte Disorders
1. Disorders of Oxidative Killing
1.1 Chronic Granulomatous Disease:
- X-linked (CYBB gene - 70%)
- Most common form
- Affects males predominantly
- Carrier females may show symptoms
- Autosomal recessive forms:
- p47phox deficiency (NCF1)
- p67phox deficiency (NCF2)
- p22phox deficiency (CYBA)
- p40phox deficiency (NCF4)
2. Adhesion Defects
2.1 Leukocyte Adhesion Deficiency:
- Type I:
- ITGB2 gene mutations
- CD18 deficiency
- Severe infections
- Type II:
- SLC35C1 gene mutations
- Fucose metabolism defect
- Bombay blood phenotype
- Type III:
- FERMT3 gene mutations
- Kindlin-3 deficiency
- Associated bleeding disorder
3. Granule Abnormalities
3.1 Specific Granule Deficiency:
- C/EBPε mutations
- Secondary granule formation defects
- Recurrent bacterial infections
3.2 Chédiak-Higashi Syndrome:
- LYST gene mutations
- Giant granule formation
- Associated features:
- Partial albinism
- Neurological manifestations
- Bleeding tendency
Clinical Features and Presentation
1. Age-Specific Manifestations
1.1 Neonatal Period:
- Delayed umbilical cord separation
- Omphalitis
- Early-onset severe infections
- Poor wound healing
1.2 Infancy and Early Childhood:
- Recurrent bacterial/fungal infections
- Failure to thrive
- Chronic inflammatory conditions
- Developmental delay
2. System-Specific Manifestations
2.1 Respiratory System:
- Recurrent pneumonia
- Lung abscesses
- Empyema
- Granuloma formation
2.2 Gastrointestinal System:
- Chronic colitis
- Perianal abscesses
- Oral ulcers
- Hepatic abscesses
2.3 Skin and Soft Tissues:
- Recurrent abscesses
- Delayed wound healing
- Dermatitis
- Granuloma formation
Diagnostic Approach
1. Initial Evaluation
1.1 History Taking:
- Age of onset
- Pattern of infections
- Family history
- Growth parameters
1.2 Physical Examination:
- Growth assessment
- Skin examination
- Lymph node evaluation
- Organ system review
2. Laboratory Studies
2.1 First-Line Tests:
- Complete blood count
- Differential count
- Inflammatory markers
- Basic metabolic panel
2.2 Specific Tests:
- DHR test for CGD
- NBT test
- Flow cytometry
- Genetic testing
Treatment and Management
1. Preventive Measures
1.1 Antimicrobial Prophylaxis:
- TMP-SMX for bacterial prophylaxis
- Antifungal prophylaxis
- Regular monitoring
1.2 Immunizations:
- Routine vaccinations
- Annual influenza vaccine
- Avoiding live vaccines in specific cases
2. Therapeutic Approaches
2.1 Acute Management:
- Broad-spectrum antibiotics
- Antifungal therapy
- Surgical drainage when needed
2.2 Definitive Treatment:
- Hematopoietic stem cell transplantation
- Gene therapy (experimental)
- Novel therapeutic approaches
Complications and Monitoring
1. Short-term Complications
- Severe infections
- Organ dysfunction
- Growth delays
- Treatment-related effects
2. Long-term Complications
- Chronic organ damage
- Developmental issues
- Psychological impact
- Quality of life concerns
Prognosis and Outcomes
1. Disease-Specific Outcomes
- Varies by condition type
- Impact of early diagnosis
- Treatment response
- Long-term survival rates
2. Quality of Life
- Physical limitations
- Educational impact
- Social integration
- Family considerations
Disorders of Phagocyte Function: Objective Q&A
- What is the primary function of phagocytes in the immune system?
The primary function of phagocytes is to engulf and destroy foreign particles, including microorganisms. - Which cells are considered professional phagocytes?
Neutrophils, monocytes, macrophages, and dendritic cells are considered professional phagocytes. - What is the most common inherited disorder of phagocyte function?
Chronic granulomatous disease (CGD) is the most common inherited disorder of phagocyte function. - What is the underlying defect in chronic granulomatous disease?
The underlying defect in CGD is the inability to generate reactive oxygen species due to a defect in the NADPH oxidase enzyme complex. - Which test is used to diagnose chronic granulomatous disease?
The dihydrorhodamine (DHR) flow cytometry test is commonly used to diagnose chronic granulomatous disease. - What are the most common pathogens causing infections in patients with CGD?
Staphylococcus aureus, Burkholderia cepacia, Serratia marcescens, and Aspergillus species are common pathogens in CGD patients. - What is leukocyte adhesion deficiency (LAD)?
Leukocyte adhesion deficiency is a rare inherited disorder characterized by the inability of leukocytes to adhere to blood vessel walls and migrate to sites of infection. - What is the underlying defect in LAD type 1?
LAD type 1 is caused by mutations in the gene encoding the β2 integrin CD18. - What is the characteristic finding in the complete form of LAD type 1?
Persistent leukocytosis with neutrophil counts often exceeding 30,000/μL is characteristic of the complete form of LAD type 1. - What is Chediak-Higashi syndrome?
Chediak-Higashi syndrome is a rare autosomal recessive disorder characterized by partial albinism, recurrent infections, and the presence of giant granules in leukocytes. - What is the underlying genetic defect in Chediak-Higashi syndrome?
Mutations in the LYST gene, which encodes a protein involved in lysosomal trafficking, cause Chediak-Higashi syndrome. - What is the accelerated phase of Chediak-Higashi syndrome?
The accelerated phase is a life-threatening complication characterized by hemophagocytic lymphohistiocytosis-like symptoms. - What is cyclic neutropenia?
Cyclic neutropenia is a rare disorder characterized by regular fluctuations in neutrophil counts, with periods of severe neutropenia occurring approximately every 21 days. - What gene is mutated in cyclic neutropenia?
Mutations in the ELANE gene, which encodes neutrophil elastase, cause cyclic neutropenia. - What is the most common inherited neutropenia in children?
Severe congenital neutropenia (SCN), also known as Kostmann syndrome, is the most common inherited neutropenia in children. - What is the characteristic finding in severe congenital neutropenia?
Persistent severe neutropenia with absolute neutrophil counts below 500/μL is characteristic of severe congenital neutropenia. - What is the risk of developing acute myeloid leukemia in patients with severe congenital neutropenia?
Patients with SCN have an approximately 20% lifetime risk of developing acute myeloid leukemia or myelodysplastic syndrome. - What is the primary treatment for severe congenital neutropenia?
Granulocyte colony-stimulating factor (G-CSF) is the primary treatment for severe congenital neutropenia. - What is specific granule deficiency?
Specific granule deficiency is a rare disorder characterized by the absence of secondary granules in neutrophils, leading to recurrent bacterial infections. - What is the underlying genetic defect in specific granule deficiency?
Mutations in the C/EBPε gene, which encodes a transcription factor essential for neutrophil maturation, cause specific granule deficiency. - What is myeloperoxidase deficiency?
Myeloperoxidase deficiency is a common inherited disorder of neutrophil function characterized by the absence or reduced activity of the myeloperoxidase enzyme. - Why do most patients with myeloperoxidase deficiency not have increased susceptibility to infections?
Most patients with myeloperoxidase deficiency have normal neutrophil counts and other intact microbicidal mechanisms, which compensate for the enzyme deficiency. - What is the characteristic finding in the nitroblue tetrazolium (NBT) test for patients with CGD?
Patients with CGD show no or very low reduction of NBT dye, indicating impaired oxidative burst function. - What is the role of interferon-gamma in the management of CGD?
Interferon-gamma is used as prophylaxis to reduce the frequency and severity of infections in patients with CGD. - What is the characteristic feature of neutrophils in Pelger-Huët anomaly?
Neutrophils in Pelger-Huët anomaly have bilobed nuclei with coarse chromatin, giving them a "pince-nez" appearance. - What is the underlying genetic defect in glycogen storage disease type 1b that affects neutrophil function?
Mutations in the SLC37A4 gene, which encodes the glucose-6-phosphate transporter, cause neutropenia and impaired neutrophil function in glycogen storage disease type 1b. - What is the characteristic finding in patients with LAD type 2?
Patients with LAD type 2 have the Bombay blood phenotype and mental retardation in addition to recurrent infections. - What is the role of granulocyte transfusions in the management of phagocyte disorders?
Granulocyte transfusions may be used as a temporary measure to treat severe infections in patients with phagocyte disorders, particularly in CGD. - What is the underlying defect in WHIM syndrome?
WHIM syndrome is caused by gain-of-function mutations in the CXCR4 chemokine receptor, leading to impaired neutrophil release from the bone marrow. - What is the characteristic triad of symptoms in hyper-IgE syndrome (Job syndrome)?
The characteristic triad of hyper-IgE syndrome includes recurrent skin abscesses, pneumonia with pneumatocele formation, and elevated serum IgE levels.
