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Primary Immune Deficiency Diseases

Chapter 362 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology · Chapter 362

Key Clinical Points

  1. PIDs are genetic diseases with Mendelian inheritance involving defects in innate or adaptive immunity.
  2. Recurrent or unusually severe infections are the primary clinical indicators for PID diagnosis.
  3. Severe congenital neutropenia (SCN) is characterized by neutrophil counts <500/μL and a notable absence of pus.
  4. Chronic granulomatous disease (CGD) involves impaired ROS production, leading to abscesses from catalase-positive organisms.
  5. Severe combined immunodeficiency (SCID) features profound T-cell deficiency and lack of thymic shadow.
  6. Mendelian susceptibility to mycobacterial disease (MSMD) is a specific defect in the IL-12–IFN-γ axis.
  7. Complement deficiencies can lead to Neisseria infections and autoimmune diseases like SLE.
  8. Leukocyte adhesion deficiency (LAD) results in impaired migration of neutrophils into tissues.
  9. GATA2 deficiency leads to monocytopenia, lymphoid deficiency, and risk of myeloid malignancies.
  10. Newborn screening for SCID utilizes T-cell receptor excision circles (TREC).

DEFINITION & CLASSIFICATION

• Definition (Harrison's 22e): Primary immunodeficiencies (PIDs) are genetic diseases with primarily Mendelian inheritance. • Scope: Over 550 conditions identified; mutations in ~500 genes. • Prevalence: Estimated at 5–10 per 100,000 individuals (likely under-reported). • Clinical Spectrum: Ranges from broad (SCID) to narrow (MSMD), and may include autoimmunity, allergy, or cancer risk.

Classification of PIDs

• Categorization: Based on the immune arm affected and the specific mechanism of defect. • Table 362-1 (Classification): • Innate Immune System: SCN, Asplenia, LAD, CGD, TLR signaling defects, MSMD, Complement deficiencies. • Adaptive Immune System: SCID, Hyper-IgE syndrome, Agammaglobulinemia, CVID, IgA deficiency. • Regulatory Defects: Autoinflammatory syndromes, HLH, ALPS, IPEX, APECED.

EPIDEMIOLOGY

• General Prevalence: 5–10 per 100,000 individuals. • Innate Immunity Subset: Approximately 10% of all PIDs. • SCID Incidence: Estimated at 1 in 50,000 live births.

ETIOLOGY & PATHOPHYSIOLOGY

• Genetic Basis: Mutations in non-redundant gene products lead to clinical phenotypes. • Innate Immune System Deficiencies: (~10% of PIDs) include defects in phagocytic cells, adhesion, killing, receptors, and complement.

Severe Congenital Neutropenia (SCN)

• Definition: Inherited diseases with severely impaired neutrophil counts (<500 PMN/μL). • Clinical Presentation: Often from birth; may be cyclic (3-week period). • Pathology: Most often a block in granulopoiesis at the promyelocytic stage. • Genetics: Mutations in 21 genes; common ones include GFI1, HAX1, and ELANE (50% of cases). • ELANE mutations → can cause cyclic neutropenia or be refractory to G-CSF. • WASP mutation → X-linked SCN with monocytopenia. • CXCR4 mutation → WHIM syndrome. • Moesin deficiency → additional leukocyte motility defects.

Asplenia

• Mechanism: Primary failure of spleen development (rare, can be isolated or syndromic). • Risk: Lack of filtration leads to fulminant infections by encapsulated bacteria. • Diagnosis: Abdominal ultrasound and detection of Howell-Jolly bodies.

GATA2 Deficiency

• Mechanism: Mutation in GATA2 (transcription factor) affecting hematopoiesis. → Results in monocytopenia, dendritic cell deficiency, and lymphoid (B/NK) deficiency (DCML). • Complications: Predisposes to lymphedema, myelodysplasia, and acute myeloid leukemia.

Leukocyte Adhesion Deficiency (LAD)

• LAD I: Mutation in β2 integrin gene; impaired adhesion to inflamed endothelium. • LAD II: Defect in fucose transporter → missing selectin ligands. • LAD III: Mutation in kindlin (Fermt 3) → defective β2 integrin activation; also causes bleeding due to platelet dysfunction. • Other: Neutrophil-specific granule deficiency (C/EBPα mutation) mimics LAD.

Chronic Granulomatous Disease (CGD)

• Mechanism: Impaired phagocytic killing due to defective ROS production in the phagolysosome. • Genetics: 70% X-linked; 30% autosomal. Defects in NADPH oxidase components (gp91phox, p22phox) or regulators (p47phox, p67phox, p40phox, CYBC1). • Clinical Presentation: Deep-tissue abscesses in macrophage-rich organs (lymph nodes, liver, lungs); recurrent skin infections (folliculitis).

Mendelian Susceptibility to Mycobacterial Disease (MSMD)

• Mechanism: Defect in the IL-12–IFN-γ axis (e.g., IL-12p40, IL-12Rβ, IFN-γR1/R2, TYK2, STAT1, IRF8, ISG15). • Clinical Presentation: Narrow susceptibility to tuberculous and nontuberculous mycobacteria; some cases include Salmonella.

Toll-Like Receptor (TLR) Pathway Deficiencies

• Mechanism: Recessive mutations in adapter molecules IRAK4 or MYD88. • Clinical Presentation: Early-onset, invasive S. pneumoniae or S. aureus infections; susceptibility often decreases after first few years.

Complement Deficiency

• Mechanism: Deficiencies in plasma proteins leading to failed C3b deposition or lytic complex formation. • Classic Pathway (C1q, C4, C2): → Risk of tissue-invasive infections and autoimmune diseases (e.g., SLE). • Alternative Pathway (D, properdin): → Risk of invasive Neisseria infections. • Lytic Phase (C5, C6, C7, C8, C9): → Risk of systemic Neisseria infection due to failure to lyse thick cell walls.

CLINICAL FEATURES

• General: Recurrent/severe infections; recurring allergic or autoimmune manifestations. • Infection Types & Implications: • Respiratory tract (bronchi, sinuses) → Suggests defective antibody response. • Invasive bacterial → Suggests complement deficiency, innate signaling defects, or asplenia. • Viral/Candida/Opportunistic → Suggests impaired T-cell immunity. • Skin infections/Deep abscesses → Suggests innate defects (CGD) or Hyper-IgE syndrome. • Specific Syndromes: • SCN: No pus; life-threatening bacterial/fungal infections. • Asplenia: Fulminant infection by encapsulated bacteria. • LAD: Impaired wound healing, delayed umbilical cord loss; bleeding (LAD III). • CGD: Deep-tissue abscesses in macrophage-rich organs; recurrence of folliculitis. • MSMD: Susceptibility to mycobacteria and Salmonella.

DIFFERENTIAL DIAGNOSIS

• Overlaps: Many PIDs present with a combination of recurrent infections, inflammation, and autoimmunity. • Clinical Differentiation: Distinguishing between specific innate defects (e.g., CGD vs. SCN) based on the type of pathogen (e.g., catalase-positive for CGD).

DIAGNOSTIC APPROACH

  1. Initial Screening: Blood cell counts and morphology → identify SCN (neutrophils <500), LAD, or Asplenia (Howell-Jolly bodies).
  2. Specialized Assays: Dihydrorhodamine (DHR) or Nitroblue tetrazolium (NBT) → assess ROS production in PMNs to diagnose CGD.
  3. Functional Assays: CH50 and AP50 → evaluate classic and alternative complement pathways to identify specific complement deficiencies.
  4. Immunophenotyping: Lymphocyte phenotype (T, B counts) → differentiate T-cell defects from agammaglobulinemia.

MANAGEMENT & TREATMENT

  1. Severe Congenital Neutropenia (SCN): • Hygiene: Strict measures, especially in infants. • Prophylaxis: Trimethoprim/sulfamethoxazole. • Treatment: G-CSF to improve neutrophil development. • Advanced: HSCT for specific cases (e.g., certain ELANE mutations).
  2. Chronic Granulomatous Disease (CGD): • Bacterial: Combination therapy with cell-penetrating antibiotics.
  3. Fungal: Aggressive, long-term antifungals (e.g., Itraconazole).
  4. Inflammation: Steroids (caution for glucocorticoid dependence).
  5. Prophylaxis: Trimethoprim/sulfamethoxazole and Itraconazole.
  6. Mendelian Susceptibility to Mycobacterial Disease (MSMD):
  7. Treatment: IFN-γ (to bypass IL-12/IL-12R deficiency).
  8. Advanced: HSCT for severe cases.
  9. Complement Deficiency:
  10. Prophylaxis: Appropriate vaccinations and daily oral penicillin.

COMPLICATIONS & PROGNOSIS

• Infection Risk: Varies from broad (SCID) to specific (MSMD). • Autoimmunity: Linked to complement deficiencies (Classic/Lytic) and certain T-cell defects. • Cancer Risk: Some PIDs increase risk of lymphoma or other lymphocytic cancers.

SPECIAL POPULATIONS

• Newborn Screening: Use of T-cell receptor excision circles (TREC) to identify SCID early.

KEY PEARLS & HIGH-YIELD POINTS

• SCN Hallmark: Absence of pus in infections. • CGD Pathogens: Primarily catalase-positive bacteria (e.g., S. aureus, Serratia) and filamentous molds (e.g., Aspergillus). • Complement & Neisseria: Lytic phase deficiency specifically predisposes to Neisseria due to inability to breach thick cell walls. • MSMD Specificity: Highly specific for mycobacteria; consider in any patient with persistent mycobacterial infection. • LAD Differentiation: LAD I (β2), LAD II (fucose), and LAD III (kindlin) have distinct molecular defects but similar clinical presentations.

FLOWCHARTS

• Pathway A: Neutrophil Lineage • HSC → CMP → GM prog. → MB → Promyelo → Myelo. • Defect at Myelo stage → SCN (Severe Congenital Neutropenia). • Defect in migration/adhesion → WHIM or LAD (Leukocyte Adhesion Deficiency). • Defect in ROS production → CGD (Chronic Granulomatous Disease). • Pathway B: Monocyte/Macrophage Lineage • HSC → CMP → GM prog. → Monoblast → Promono → Monocyte → Tissue Macrophages. • Defect in Progenitor expansion → GATA2 deficiency. • Defect in ROS production → CGD or MSMD (Mendelian Susceptibility to Mycobacterial Disease).

• Normal Development: HSC → CLP → proB → preB → Immature B → Mature B → Plasma Cell. • Agammaglobulinemia: Block at proB/preB stage (lack of all antibodies). • Hyper-IgM Syndrome: Failure at CSR/SHM step (high IgM, low IgG/IgA). • CVID: Mature B cells present but failure in plasma cell differentiation or multi-class antibody production. • IgA Deficiency: Specific lack of IgA antibodies.

Reference Tables

TABLE 361-5 Monoclonal Antibodies Approved for Clinical Use in Autoimmune Disease, Some of Which Are Also Used in…

Harrison's 22e, p.2793

TARGET
MOLECULE		 FUNCTION FDA-APPROVED mAbs, TRAPS,
AND BISPECIFIC mAbs		 AUTOIMMUNE/
INFLAMMATORY		 MALIGNANCY OTHER/COMMENTS
IL-5 Induces differentiation and
survival of eosinophils		 Reslizumab (Cinqair)
Mepolizumab (Nucala)		 Asthma Both IgG1k mAbs
Inflammatory cytokine Lebrikizumab (Ebglyss)
Tralokinumab (Adtralza; Adbry)		 Atopic dermatitis
IL-17A Inflammatory cytokine Ixekizumab (Taltz)
Secukinumab (Cosentyx)		 Plaque psoriasis,
ankylosing spondylitis		 Ixekizumab is an IgG4;
secukinumab is an IgG1k
Mirikizumab (Omvoh)
Risankizumab (Skyrizi)
Guselkumab (Tremfya)		 Ulcerative colitis
Plaque psoriasis
Plaque psoriasis
362 Primary Immune
Deficiency Diseases
Alain Fischer

TABLE 362-1 Classification of Primary Immune Deficiency Diseases Deficiencies of the Innate Immune System • Phagocytic…

Harrison's 22e, p.2794

  • Deficiencies of the Innate Immune System
  • • Phagocytic cells:
    • Impaired production: severe congenital neutropenia (SCN)
    • Asplenia
    • Impaired adhesion: leukocyte adhesion deficiency (LAD)
    • Impaired killing: chronic granulomatous disease (CGD)
    • Innate immunity receptors and signal transduction:
    • Defects in Toll-like receptor signaling
    • Mendelian susceptibility to mycobacterial disease
    • Complement deficiencies:
    • Classical, alternative, and lectin pathways
    • Lytic phase
  • Deficiencies of the Adaptive Immune System

TABLE 362-2 Tests Most Frequently Used to Diagnose a Primary Immunodeficiency

Harrison's 22e, p.2795

TEST INFORMATION PID DISEASE
Blood cell counts and
cell morphology		 Neutrophil countsa
Lymphocyte countsa
Eosinophilia
Howell-Jolly bodies		 ↓ Severe congenital
neutropenia, ↑↑ LAD
T-cell ID
WAS, hyper-IgE syndrome
Asplenia
Thymic shadow
Costochondral junctions
Bone x-ray Metaphyseal ends Cartilage hair hypoplasia
IgG, IgA, IgM
IgE
Lymphocyte phenotype T, B lymphocyte counts T-cell ID,
agammaglobulinemia
Reactive oxygen species
production by PMNs
CH50, AP50 Classic and alternative
complement pathways		 Complement deficiencies
Spleen size