Selective IgA deficiency is the most common primary immunodeficiency, defined by undetectable or markedly reduced serum IgA (<7 mg/dL) with normal IgG and IgM levels in children older than 4 years, often presenting with recurrent sinopulmonary and gastrointestinal infections, allergies, or autoimmune conditions, though many affected children remain asymptomatic.

Selective IgA Deficiency — Paediatrics

Selective IgA deficiency (SIgAD) is defined as a serum IgA level < 0.07 g/L (i.e. < 7 mg/dL) in a patient aged ≥ 4 years, with normal serum IgG and IgM levels, and in whom other causes of hypogammaglobulinaemia have been excluded ^[1]^[2]^[3].

Why Age ≥ 4 Years?

IgA is the last immunoglobulin class to reach adult levels. In healthy children, serum IgA is physiologically very low at birth and rises slowly — it does not reach adult reference values until approximately 6–10 years of age. Therefore, a low IgA measured before age 4 may simply reflect normal immune maturation rather than a true deficiency. The diagnostic threshold of age 4 prevents over-diagnosis. If measured in a child aged 1–3 years and IgA is undetectable, the term "probable IgA deficiency" can be used, but definitive diagnosis requires confirmation after age 4 ^[2]^[3].

Break down the name:

"Selective" → only one immunoglobulin class (IgA) is deficient, while others (IgG, IgM) remain normal — distinguishing it from panhypogammaglobulinaemia (e.g. XLA, CVID).
"IgA" → Immunoglobulin A, the major antibody at mucosal surfaces.
"Deficiency" → quantitative reduction to undetectable or near-undetectable levels.

The most common primary immunodeficiency (PID) ^[1]^[2]^[3]. This is a universally high-yield fact for exams.

2. Epidemiology

Population	Approximate Prevalence
Caucasians (European descent)	~1 in 300–700 — making it the commonest PID by far ^[1]^[2]
East Asians (Chinese, Japanese)	~1 in 2,000–5,000 — much rarer
Blood donors (screening studies)	1 in 500 (Western literature)

Most common PID worldwide ^[1]^[2]^[3].
In Hong Kong, the prevalence is considerably lower than in Caucasian populations, reflecting the HLA-linked genetic basis (see below). However, it remains the most common antibody deficiency encountered in the local Chinese paediatric population, even if absolute numbers are small.
Sex ratio: roughly equal (M:F ≈ 1:1), though some registries report a slight male preponderance.

Many patients are never diagnosed because they are asymptomatic.
Diagnosed incidentally (e.g. during workup for coeliac disease, recurrent infections, autoimmune cytopenias, or pre-transfusion screening).
Diagnosed at any age from 4 years onward; cannot be reliably diagnosed before 4.

Risk Factor	Explanation
Family history of PID	First-degree relatives of SIgAD patients have increased risk of SIgAD and CVID — shared genetic susceptibility
HLA associations	Strong link with HLA-A1, HLA-B8, HLA-DR3, HLA-DQ2 (the "autoimmune haplotype" — same haplotype associated with coeliac disease, T1DM, SLE)
Drugs (rare, secondary cause)	Phenytoin, carbamazepine, sulfasalazine, gold, penicillamine — these can cause acquired/transient IgA deficiency; technically "secondary" but important to exclude
Chromosomal abnormalities	18q deletion syndrome, 22q11.2 deletion (some overlap with DiGeorge)
Congenital infections	Intrauterine infections (e.g. rubella, CMV, toxoplasma) may rarely impair IgA class switching

3. Anatomy & Function of IgA — Understanding What Is Lost

IgA is the most abundantly produced immunoglobulin in the body (more IgA is produced daily than all other Ig classes combined — ~3–5 g/day), yet its serum concentration is only third (after IgG and IgM) because most IgA is secreted at mucosal surfaces rather than circulating in blood.

Subclass	Where Found	Form	Function
IgA1	Serum (predominant) and mucosa	Monomer (serum), dimer (secretory)	Systemic immune defence; vulnerable to bacterial IgA1 proteases (e.g. from H. influenzae, S. pneumoniae, N. meningitidis)
IgA2	Predominantly mucosal (gut, respiratory)	Dimer (secretory)	Mucosal defence; resistant to IgA1 proteases

Plasma cells in lamina propria
         │
         ▼ produce dimeric IgA + J chain
         │
         ▼ binds polymeric Ig receptor (pIgR) on basolateral surface of epithelial cells
         │
         ▼ transcytosis across epithelial cell
         │
         ▼ released at apical (luminal) surface with secretory component (SC) attached
         │
         ▼ = Secretory IgA (sIgA)

Functions of sIgA at mucosal surfaces:

Immune exclusion — binds pathogens and antigens in the lumen, preventing adherence to and penetration of epithelial surfaces (the single most important function).
Neutralisation of toxins and viruses.
Intracellular neutralisation — can intercept pathogens during transcytosis.
Non-inflammatory — does NOT activate complement via classical pathway (unlike IgG/IgM), thereby preventing excessive inflammation at mucosal surfaces — this is crucial for maintaining tolerance to commensal flora and food antigens.

Respiratory tract (nasal mucosa, sinuses, trachea, bronchi)
GI tract (from stomach to rectum — highest density in small bowel lamina propria)
Genitourinary tract
Breast milk (providing passive mucosal immunity to breastfed infants)
Tears, saliva

Why SIgAD Causes Sinopulmonary and GI Infections

Sinopulmonary and GI infections are the hallmark of humoral (antibody) deficiency because these are the mucosal surfaces where IgA is the primary defender and which are in direct contact with the external environment ^[1]. Without IgA's immune exclusion function, pathogens adhere to and penetrate the mucosa more easily. This is the same principle across all humoral deficiencies (XLA, CVID, Hyper-IgM, SIgAD) — the difference is severity.

4. Aetiology & Pathophysiology

SIgAD is fundamentally a defect in B-cell class switching and/or terminal differentiation specifically towards the IgA isotype. The B cells are present and can switch to IgG and IgM, but fail to complete the switch to IgA or fail to mature into IgA-secreting plasma cells.

Step-by-step pathophysiology:

Naive B cells encounter antigen and receive T-cell help (via CD40–CD40L interaction, cytokines including TGF-β, APRIL, BAFF, IL-10, IL-21).
In germinal centres, class switch recombination (CSR) occurs — the immunoglobulin heavy chain gene rearranges from Cμ (IgM) to Cα1 or Cα2 (IgA1 or IgA2).
TGF-β is the key cytokine that drives switching to IgA.
APRIL (a proliferation-inducing ligand) and BAFF (B-cell activating factor) bind to TACI (transmembrane activator and CAML interactor, encoded by TNFRSF13B) on B cells — this signalling is critical for IgA class switching and plasma cell survival.
The switched B cell then differentiates into an IgA-secreting plasma cell that homes to mucosal tissues.

In SIgAD, step(s) 2–5 are impaired:

The B cells may fail to undergo CSR to IgA (intrinsic B-cell defect).
Or there may be defective T-cell help (e.g. inadequate TGF-β signalling).
Or there may be increased T-regulatory cell suppression of IgA production.
The exact mechanism varies — SIgAD is genetically heterogeneous.

SIgAD does not follow a simple Mendelian pattern. It is considered a polygenic/multifactorial disorder with variable penetrance.

Genetic Factor	Detail
HLA region (MHC, chromosome 6p21)	Strongest genetic association; HLA-A1, B8, DR3, DQ2 haplotype — the same "autoimmune haplotype" seen in coeliac disease, T1DM, SLE. This explains the frequent co-occurrence of SIgAD with these conditions.
*TACI (TNFRSF13B) mutations*	Found in ~5–10% of SIgAD patients; same gene implicated in CVID ^[4]. These are usually heterozygous variants with variable penetrance.
*BAFF-R (TNFRSF13C) variants*	Rare; associated with low IgG and IgM as well ^[4].
Other loci	IFIH1, CLEC16A — some overlap with type 1 diabetes susceptibility loci.

SIgAD and CVID Are on a Spectrum — High Yield

SIgAD and CVID share genetic susceptibility (e.g. TACI mutations, HLA associations) and can occur in the same family ^[1]^[2]^[4]. Approximately 5–10% of SIgAD patients progress to CVID over time (developing falling IgG levels). Conversely, some CVID patients start with isolated IgA deficiency years before IgG drops. This is why longitudinal monitoring of immunoglobulin levels is recommended in symptomatic SIgAD patients.

This is the key to understanding the benign nature in the majority:

Secretory IgM (sIgM) upregulation: In SIgAD, mucosal B cells increase production of secretory IgM, which can partially compensate for the absent sIgA at mucosal surfaces. sIgM can also bind the polymeric Ig receptor and undergo transcytosis, performing immune exclusion — though less efficiently than sIgA.
IgG subclass compensation: Some mucosal IgG (especially IgG1 and IgG2) transudation may increase.
Innate mucosal defences: Intact epithelial barriers, antimicrobial peptides (defensins), mucus layer, and normal phagocyte function remain protective.

When compensation fails (i.e. when sIgM upregulation is insufficient, or there is a concurrent IgG subclass deficiency — especially IgG2), the patient becomes symptomatic.

Must be excluded before diagnosing primary SIgAD:

Drug	Mechanism
Phenytoin	Inhibits IgA synthesis; may impair lymphocyte function
Carbamazepine	Similar mechanism
Sulfasalazine	Direct suppression of IgA production
Penicillamine, gold	Immune modulation
Valproic acid	Rare

Drug withdrawal may lead to recovery of IgA levels (though not always).

5. Classification

Selective IgA deficiency is classified under "Predominantly Antibody Deficiencies" in the International Union of Immunological Societies (IUIS) classification of primary immunodeficiencies ^[4].

Hierarchy:

Primary Immunodeficiencies
├── Combined (T+B) deficiencies (e.g. SCID)
├── Combined with syndromic features (e.g. DiGeorge, Wiskott-Aldrich)
├── ***Predominantly Antibody Deficiencies*** ← SIgAD is here
│   ├── X-linked agammaglobulinaemia (XLA)
│   ├── Common variable immunodeficiency (CVID)
│   ├── Hyper-IgM syndromes
│   ├── ***Selective IgA deficiency*** ← most common PID
│   ├── IgG subclass deficiency
│   ├── Specific antibody deficiency with normal Ig
│   └── Transient hypogammaglobulinaemia of infancy
├── Diseases of immune dysregulation
├── Congenital defects of phagocyte number/function
├── Defects in intrinsic and innate immunity
├── Autoinflammatory disorders
├── Complement deficiencies
└── Phenocopies of PIDs

Category	Definition	Clinical Significance
Complete SIgAD	Serum IgA < 0.07 g/L (undetectable)	True deficiency; higher risk of clinical manifestations
Partial IgA deficiency	Serum IgA detectable but > 2 SD below age-matched mean (yet not < 0.07 g/L)	Less clinically significant; often asymptomatic; not formally classified as SIgAD
SIgAD + IgG subclass deficiency	Meets SIgAD criteria AND has low IgG2 (± IgG4)	More symptomatic; higher risk of sinopulmonary infections; may need Ig replacement
SIgAD evolving to CVID	Initially isolated low IgA, then IgG falls over years	Requires longitudinal monitoring

6. Clinical Features

Most patients with selective IgA deficiency are asymptomatic ^[1]^[2]^[3]. Only ~15–30% develop clinically significant disease.

The clinical spectrum ranges from completely asymptomatic (majority) to recurrent infections and autoimmune disease (minority). The severity depends on:

Whether compensatory sIgM is adequate
Co-existing IgG subclass deficiency (especially IgG2)
Presence of associated autoimmune conditions

6.2 Symptoms

Pathophysiological basis: Loss of sIgA at mucosal surfaces → failure of immune exclusion → increased pathogen adherence and invasion at mucosal interfaces exposed to the environment.

Infection Type	Specific Examples	Pathophysiological Link
Recurrent upper respiratory tract infections	Otitis media, sinusitis, rhinitis	Upper airway mucosa lacks sIgA → encapsulated bacteria (S. pneumoniae, H. influenzae) adhere and invade
Recurrent lower respiratory tract infections	Pneumonia, bronchitis	Lower airway mucosa lacks sIgA; if recurrent → risk of bronchiectasis
GI infections	Giardiasis (Giardia lamblia), bacterial gastroenteritis	Gut mucosa lacks sIgA → failure to prevent Giardia trophozoite adherence to small bowel epithelium → chronic diarrhoea, malabsorption

Encapsulated Organisms and Antibody Deficiency — High Yield

Humoral (antibody) deficiencies predispose to infections with encapsulated bacteria — Streptococcus pneumoniae, Haemophilus influenzae (type b and non-typeable), Moraxella catarrhalis. Why? Because the polysaccharide capsule resists phagocytosis; opsonisation by antibodies (IgG2 for polysaccharide antigens, IgA at mucosa) is required to facilitate clearance. Giardia lamblia is also characteristic because sIgA is the primary defence against luminal parasites ^[1].

Important nuance for paediatrics:

Recurrent URTI is extremely common in healthy children (6–8 per year is normal for a child in daycare). SIgAD should only be suspected when infections are disproportionately frequent, severe, or prolonged (the "SPUR" infections concept from GC lecture) ^[5].

Pathophysiological basis: sIgA normally prevents uptake of environmental allergens across mucosal surfaces (immune exclusion). Without sIgA, increased allergen penetration across the respiratory and GI mucosa → enhanced allergen presentation to immune cells → increased IgE sensitisation → atopic disease.

Condition	Frequency in SIgAD
Allergic rhinitis	Increased
Asthma	Increased
Atopic dermatitis / eczema	Increased
Food allergy	Increased
Drug allergy	Increased

Up to ~30–40% of SIgAD patients have atopic manifestations — higher than the general population.

Pathophysiological basis: The mechanism is multifactorial:

Shared HLA susceptibility: HLA-A1, B8, DR3, DQ2 predisposes to both SIgAD and autoimmune disease.
Increased mucosal permeability: Without sIgA, the gut barrier is more permeable → increased exposure to luminal antigens → molecular mimicry and immune activation.
Immune dysregulation: Defective B-cell class switching may be part of a broader immune regulatory defect.

Autoimmune Condition	Specific Link
Coeliac disease	Strong association — up to 2–3% of SIgAD patients have coeliac disease (10–20× general population risk) ^[6]. The shared HLA-DQ2 link explains this. Critical clinical point: IgA anti-tTG (the standard coeliac screening test) will be falsely negative in SIgAD because the patient cannot make IgA → must use IgG-based serology (IgG anti-tTG or IgG anti-deamidated gliadin peptide) ^[6].
Autoimmune cytopenias	ITP (immune thrombocytopenia) ^[7], autoimmune haemolytic anaemia (AIHA), Evans syndrome
SLE	Increased prevalence of SIgAD in SLE cohorts
Rheumatoid arthritis / JIA	Increased
Type 1 diabetes mellitus	Shared HLA susceptibility
Thyroid autoimmunity	Hashimoto's, Graves' disease
Inflammatory bowel disease	Particularly ulcerative colitis
Pernicious anaemia	Anti-intrinsic factor antibodies

Autoimmune disease may be the presenting feature of SIgAD — always check immunoglobulins when a child presents with autoimmune cytopenias or coeliac disease.

Condition	Mechanism
Chronic diarrhoea	Giardiasis, coeliac disease, IBD, or non-specific mucosal inflammation due to lack of sIgA
Nodular lymphoid hyperplasia (NLH) of small bowel	Compensatory lymphoid proliferation in the gut mucosa in response to chronic antigenic stimulation in the absence of sIgA
Malabsorption	Secondary to coeliac disease, Giardia, or chronic mucosal inflammation

Pathophysiological basis: Some SIgAD patients develop anti-IgA antibodies (usually IgG class directed against IgA). When they receive blood products containing IgA (present in donor plasma, even in packed red cells and platelets), the donor IgA binds the patient's anti-IgA antibodies → immune complex formation and/or direct mast cell activation → anaphylactic or severe allergic transfusion reaction ^[8].

Transfusion Anaphylaxis in IgA Deficiency — Must Know for Exams

IgA-deficient patients can develop anaphylaxis upon transfusion due to anti-IgA antibodies reacting with donor IgA in blood products ^[8]. This is a classic exam scenario. When a patient develops anaphylaxis after transfusion:

Check for IgA deficiency and anti-IgA antibodies.
Future transfusions must use washed cellular products (to remove plasma containing IgA) or IgA-deficient donor products (rare).
Also check for haptoglobin deficiency (another rare cause of transfusion anaphylaxis).

Prevalence of anti-IgA antibodies in SIgAD: ~30–40% of SIgAD patients have detectable anti-IgA antibodies, but clinically significant anaphylaxis is rare (most with anti-IgA antibodies tolerate transfusions).

Slightly increased risk of GI malignancies (gastric carcinoma, lymphoma) — though far less than in CVID.
Chronic immune stimulation and mucosal inflammation may play a role.
The risk is modest and routine screening is not standard.

Most patients with SIgAD have no specific physical signs because the majority are asymptomatic. When signs are present, they reflect the associated conditions:

Sign	Pathophysiological Basis
Nasal mucosal congestion/oedema	Chronic allergic rhinitis secondary to increased allergen penetration
Tonsillar hypertrophy	Compensatory lymphoid hyperplasia at mucosal sites
Signs of atopic dermatitis (eczema — flexural lichenification, excoriations)	Increased allergen sensitisation through leaky mucosal barrier
Wheezing / prolonged expiratory phase	Co-existing asthma
Abdominal distension, mouth ulcers, dermatitis herpetiformis	Associated coeliac disease
Petechiae, purpura, pallor	Associated autoimmune cytopenias (ITP, AIHA)
Joint swelling/tenderness	Associated JIA or SLE
Clubbing, coarse crackles	Bronchiectasis from recurrent LRTI (late/severe cases)
Hepatosplenomegaly	Rare; if present, consider evolution toward CVID or associated lymphoproliferation

No Pathognomonic Sign

There is no single pathognomonic physical sign for SIgAD. The diagnosis is serological (undetectable serum IgA with normal IgG/IgM in a patient ≥ 4 years). Clinical suspicion arises from the pattern of recurrent mucosal infections, atopy, autoimmune disease, or incidental finding on blood work.

Using the "SPUR" framework from the GC lectures ^[5]:

Severe infections (disproportionate to what is expected)
Persistent infections (prolonged, slow to respond)
Unusual organisms (e.g. Giardia causing chronic diarrhoea)
Recurrent infections (especially sinopulmonary)

Combined with:

Family history of PID or consanguinity ^[5]
Adverse reaction to live vaccines (though SIgAD does not cause live vaccine complications — this is more for T-cell defects; still part of the general PID screen) ^[5]
Autoimmune disease in a child
Coeliac disease with negative IgA-based serology but positive IgG-based serology
Anaphylaxis to blood transfusion

Association	Mechanism
Coeliac disease	Shared HLA-DQ2; increased mucosal permeability
Autoimmune cytopenias (ITP, AIHA)	Immune dysregulation
SLE, RA/JIA, T1DM, thyroid disease	Shared autoimmune haplotype
Atopy (asthma, eczema, allergic rhinitis)	Loss of mucosal immune exclusion → increased allergen uptake
Giardiasis	Loss of luminal sIgA
Transfusion anaphylaxis	Anti-IgA antibodies vs donor IgA
Progression to CVID	Shared genetic basis (TACI mutations, HLA)
Bronchiectasis	End-organ damage from recurrent LRTI

Feature	Selective IgA Deficiency	CVID	XLA (Bruton)	Hyper-IgM Syndrome
Inheritance	Polygenic/sporadic	Variable/polygenic	XLR	XLR (CD40L) or AR
Defective Component	IgA class switch/differentiation only	Broad B-cell differentiation failure	Btk gene → no B-cell maturation	CD40L or AID → failure of class switch from IgM
IgG	Normal	↓↓↓	↓↓↓ (all Ig)	↓
IgA	↓↓↓ (< 0.07 g/L)	↓	↓↓↓	↓
IgM	Normal	↓ or normal	↓↓↓	↑↑↑
IgE	Normal or ↑	↓	↓↓↓	↓
B cells (CD19+)	Normal	Normal or ↓	Absent/severely ↓	Normal
Severity	Usually mild/asymptomatic	Moderate-severe	Severe	Severe (also opportunistic infections ∵ T-cell component)
Tonsils	Present	May be small	Absent (no B-cell follicles)	Present
Typical age of presentation	Any (often incidental in childhood/adulthood)	Childhood to young adulthood	After 4–6 months (maternal IgG wanes)	After 4–6 months
A/I disease	Common (~25%)	Common (~25%)	Less common	Less common
Malignancy risk	Slightly ↑ (GI)	Significantly ↑ (lymphoma, GI)	Slightly ↑	↑ (lymphoma, hepatobiliary)

From GC 096 "Why do I always get sick" — this framework is directly examinable:

Exclude secondary immunodeficiency: Diabetes, HIV, protein-losing states, CKD, malignancy, immunosuppression, drugs, structural defects ^[5].
Identify "SPUR" infections: Disproportionate frequency, disproportionate severity, unusual microbes, unusual sites of infection, unusual clinical presentation ^[5].
Salient history: Identify phenotype, age of presentation, progression of symptoms, pattern of pathogens, location of infections, features of immune dysregulation, family history and consanguinity, immunisation history and adverse reactions, plot 3-generation family tree ^[5].
First-line investigations ^[5]:
- CBC and differentials
- Absolute lymphocyte count
- Liver and renal function tests
- Protein and globulin level
- Acute phase reactants (ESR/CRP) — ↓ ESR if low globulin/fibrinogen ^[5]
- Immunoglobulin profile (including IgE)
- Serum and urine electrophoresis
- C3/C4
- ANA ± autoimmune serologies
- HIV status (antigen or PCR)
- CXR / CT thorax / lung function

GC Lecture High-Yield Point

A low ESR in the context of suspected immunodeficiency may be a clue to low globulin/fibrinogen (because ESR depends on rouleaux formation, which requires adequate globulins). Don't dismiss a low ESR as "normal" — in a child with recurrent infections, it may paradoxically point to hypogammaglobulinaemia ^[5].

These are the Jeffrey Modell Foundation warning signs adapted for paediatrics:

Patient factors:

Family history of immunodeficiency or unexplained early death (before age 30)
Failure to thrive
Persistent lymphopenia (< 2500 cells/µL in young children; < 1500 cells/µL in > 5 years) ^[3]

Infection-related factors:

≥ 6 new infections within 1 year
≥ 2 serious sinus infections or pneumonias within 1 year
≥ 4 new ear infections within 1 year
≥ 2 episodes of sepsis or meningitis in a lifetime
Recurrent or resistant candidiasis
Recurrent tissue or organ abscesses
Infection with an opportunistic organism
Unexplained autoimmunity or fever
Chronic diarrhoea
Granuloma, non-healing wounds, extensive skin lesions

Treatment-related factors:

≥ 2 months of antibiotics with little effect
Need for IV antibiotics or hospitalisation to clear infections
Complications from a live vaccine ^[3]

High Yield Summary

Definition: Serum IgA < 0.07 g/L in patient ≥ 4 years, with normal IgG and IgM, other causes excluded.

Epidemiology: Most common PID (~1:500 in Caucasians, rarer in Chinese). Most patients asymptomatic.

Pathophysiology: Failure of B-cell class switching/terminal differentiation to IgA-secreting plasma cells. Polygenic (HLA-DR3/DQ2 association). Shared genetic basis with CVID — ~5–10% progress to CVID.

Compensatory mechanism: Secretory IgM partially substitutes at mucosal surfaces — explains why most are asymptomatic.

Clinical features (symptomatic minority):

Recurrent sinopulmonary + GI infections (encapsulated bacteria, Giardia)
Atopy (asthma, eczema, allergic rhinitis, food allergy)
Autoimmune disease (coeliac disease [use IgG-based serology!], ITP, AIHA, SLE, T1DM)
Transfusion anaphylaxis (anti-IgA antibodies vs donor IgA → must use washed products)
Risk of progression to CVID

Key exam traps:

Cannot diagnose before age 4 (IgA matures slowly).
IgA-based coeliac serology (IgA anti-tTG) is falsely negative in SIgAD → use IgG anti-tTG.
Transfusion anaphylaxis: check IgA levels and anti-IgA antibodies.
SPUR infections framework for PID suspicion.
Low ESR may indicate low globulin — not necessarily reassuring.

Active Recall - Selective IgA Deficiency

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.410 — Primary Immunodeficiency, Selective IgA Deficiency) ^[2] Senior notes: Jerry's immunodeficiencies.pdf (CFB Pathology / Block A / Block C combined notes) ^[3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p.638 — Primary Immunodeficiency, warning signs) ^[4] Lecture slides: Investigations of Imm Disorders 2025.pdf (p.21 — Predominantly Antibody Deficiencies) ^[5] GC lecture slides: GC 096. Why do I always get sick.pdf (p.21 — Initial evaluation, SPUR infections, first-line investigations) ^[6] Senior notes: Ryan Ho GI.pdf (p.126 — Coeliac disease and IgA deficiency) ^[7] Senior notes: Ryan Ho Haemtology.pdf (p.117 — ITP secondary to selective IgA deficiency) ^[8] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (p.18 — IgA-deficient patients and transfusion anaphylaxis)

When a child's immunoglobulin profile returns showing a very low or undetectable IgA, the reflex reaction should not be "it's selective IgA deficiency, done." You need to think systematically — is this truly isolated IgA deficiency, or is it part of a broader immunodeficiency? And is it primary (genetic) or secondary (acquired)? The differential diagnosis therefore spans two axes:

Other causes of low/absent serum IgA (primary and secondary).
Clinical mimics — conditions that present similarly to SIgAD (recurrent sinopulmonary infections, chronic diarrhoea, atopy, autoimmune cytopenias) but have a different underlying cause.

1. Structured Approach: Why Is the IgA Low?

Axis 1 — Other Primary Immunodeficiencies That Feature Low IgA

SIgAD is a diagnosis of exclusion within the predominantly antibody deficiency group. Before labelling a child with SIgAD, you must exclude conditions where low IgA is accompanied by other immunoglobulin or cellular deficits.

The single most important differential — SIgAD and CVID sit on the same spectrum ^[1]^[2]^[9].

Feature	SIgAD	CVID
IgA	< 0.07 g/L	↓ (part of pan-hypogammaglobulinaemia)
IgG	Normal	↓↓↓ (hallmark — must be markedly decreased) ^[9]
IgM	Normal	↓ or normal
B cells (CD19+)	Normal	Normal or ↓ (B cells present but differentiation impaired) ^[4]
Switched memory B cells	Normal	Often low (< 70% of age-related normal) — correlates with risk of bronchiectasis and autoimmunity ^[9]^[10]
Vaccine responses	Usually preserved	Poor — absent protective titres despite vaccination ^[9]
Severity	Mostly asymptomatic	Moderate-to-severe: recurrent sinopulmonary infections, autoimmune cytopenias, granulomatous disease, polyclonal lymphoproliferation, malignancy risk ^[1]^[9]
Genetics	TACI, HLA-DQ2 overlap	TACI (TNFRSF13B) in 10–15%, BAFF-R, ICOS, PIK3CD, others ^[2]^[4]^[10]
Diagnosis after age	≥ 4 years	≥ 4 years (symptoms may predate) ^[9]

Why this matters: ~5–10% of children initially labelled SIgAD will have their IgG fall progressively and reclassify as CVID. The ESID diagnostic criteria for CVID require marked decrease of IgG AND marked decrease of IgA (with or without low IgM), measured at least twice, with poor vaccine responses or low switched memory B cells, secondary causes excluded, diagnosis after age 4, and no profound T-cell deficiency ^[9].

GC/Medicine Lecture High Yield — ESID CVID Criteria

From Investigations of Imm Disorders 2025 lecture ^[9]: CVID diagnosis requires all of: (1) at least one clinical criterion (infections, autoimmunity, granulomatous disease, polyclonal lymphoproliferation, or affected family member); (2) marked ↓IgG AND ↓IgA ± low IgM measured at least twice below 2 SD for age; (3) poor vaccine responses or low switched memory B cells; (4) exclusion of secondary causes; (5) diagnosis after age 4; (6) no profound T-cell deficiency. The key differentiating point from SIgAD is that IgG is normal in SIgAD but markedly low in CVID.

Feature	XLA	SIgAD
Inheritance	XLR — boys only	Polygenic/sporadic
Pathophysiology	Abnormal BTK gene → failure of B-cell maturation from pre-B to mature B stage ^[1]^[4]	Failed IgA class switch only
B cells (CD19+)	Absent or severely ↓ (< 1%) ^[4]	Normal
All Ig isotypes	Pan-hypogammaglobulinaemia (↓↓↓ IgG, IgA, IgM, IgE) ^[1]	Only IgA ↓
Tonsils/adenoids	Absent (no lymphoid follicles because no B cells) ^[1]	Present
Typical presentation	Recurrent severe sinopulmonary and GI infections after age 4–6 months (when maternal IgG wanes) ^[1]	Mostly asymptomatic

Key distinguishing point: In XLA, all immunoglobulins are undetectable and B cells are absent — this is dramatically different from SIgAD where only IgA is low and B cells are present. A male infant presenting at 6–9 months with severe bacterial infections, absent tonsils, and no B cells on flow cytometry should raise suspicion for XLA, not SIgAD ^[1]^[4].

Feature	Hyper-IgM	SIgAD
Pathophysiology	Failure of class-switch recombination from IgM to IgG/IgA (defects in CD40L [type 1, XLR], AID, UNG, or CD40) ^[1]^[2]	Failure of class switch specifically to IgA only
IgM	↑↑↑ (markedly elevated) ^[1]	Normal
IgG	↓↓	Normal
IgA	↓	↓↓↓
Susceptibility	Severe: encapsulated bacteria + opportunistic infections (PJP, Cryptosporidium) because CD40L defect also impairs T-cell–macrophage activation ^[1]	Mild or none
Associated features	Sclerosing cholangitis (Cryptosporidium), neutropaenia, liver disease	Atopy, autoimmunity

Why include it: Both HIGM and SIgAD show low IgA, but HIGM has the pathognomonic elevated IgM with low IgG — the class-switch block is global (IgM cannot switch to any downstream isotype), not selective.

IgG subclass deficiency (particularly IgG2 deficiency) can co-exist with SIgAD and is the main driver of symptomatic disease in otherwise "SIgAD" patients.
IgG2 is responsible for the antibody response to polysaccharide antigens (the capsule of encapsulated bacteria). Its deficiency explains why some SIgAD children have disproportionately severe sinopulmonary infections.
Key point: Total IgG may be normal even when IgG2 is low — you need subclass quantification.
When SIgAD + IgG2 deficiency co-exist, the picture can shade towards CVID functionally.

Feature	THI	SIgAD
Age	Typically presents at 3–6 months (when maternal IgG wanes)	Diagnosed ≥ 4 years
IgG	↓ (transiently)	Normal
IgA	May be low (physiologically immature)	< 0.07 g/L (persistent)
Course	Self-resolving by age 2–4 years as the immune system matures	Persistent (though some "partial" IgA deficiency may normalise)
Vaccine responses	Usually preserved	Usually preserved

Why include it: In a toddler with low immunoglobulins including IgA, THI must be considered — this is why SIgAD cannot be definitively diagnosed before age 4 ^[1].

All immunoglobulin levels (including IgA) are normal, but the child fails to mount a protective antibody response to specific antigens (particularly polysaccharide antigens such as pneumococcal serotypes).
Clinically mimics mild antibody deficiency (recurrent sinopulmonary infections) but IgA is normal — distinguishes it from SIgAD.
Diagnosed by measuring pre- and post-vaccination antibody titres to pneumococcal polysaccharide vaccine (should demonstrate ≥ 4-fold rise or protective levels in ≥ 70% of serotypes tested).

SCID presents in early infancy (< 6 months) with FTT, recurrent severe infections, absent thymus on CXR, low ALC (< 2500/µL in young children) ^[1]^[3].
IgA may be low, but all immunoglobulins are low and T cells are absent or severely deficient — this is categorically different from SIgAD.
Mentioned for completeness: in a young infant with low IgA, you must not jump to "SIgAD" — the T-cell compartment must be assessed to exclude combined deficiency ^[2]^[3].

Condition	Key Features Beyond Low IgA
22q11.2 deletion (DiGeorge) syndrome ^[3]	Conotruncal cardiac anomalies, hypoplastic thymus (T-cell deficiency), hypocalcaemia (hypoplastic parathyroids), palatal abnormalities, developmental delay — IgA can be low but is not the defining feature
Ataxia-telangiectasia	Progressive cerebellar ataxia, oculocutaneous telangiectasias, ↑AFP, IgA and IgG2 deficiency, radiosensitivity, lymphoid malignancy risk
Wiskott-Aldrich syndrome	Micro-thrombocytopenia, eczema, immunodeficiency, bloody diarrhoea — IgM low, IgA may be low or normal ^[2]

These must be excluded before diagnosing primary SIgAD ^[5]^[9].

From GC 096 "Why do I always get sick" ^[5]: Always exclude secondary immunodeficiency first — Diabetes, HIV, protein-losing states, CKD, malignancy, immunosuppression, drugs, structural defects.

Secondary Cause	Mechanism of Low IgA	How to Distinguish from Primary SIgAD
Drugs (phenytoin, carbamazepine, valproic acid, sulfasalazine, penicillamine, gold)	Direct suppression of IgA synthesis; may impair lymphocyte function	Drug history; IgA may recover after drug withdrawal
Protein-losing enteropathy	Loss of all immunoglobulins (including IgA) through damaged gut mucosa	Pan-hypoglobulinaemia, hypoalbuminaemia, oedema; faecal α1-antitrypsin elevated
Nephrotic syndrome	Urinary loss of smaller Ig (IgG, IgA); IgM preserved (too large to be filtered)	Proteinuria, hypoalbuminaemia, oedema, lipiduria
HIV infection	Immune dysregulation; paradoxically IgA may be elevated in HIV but can be low in advanced disease	HIV antigen or PCR testing ^[5]
Malignancy (lymphoma, leukaemia)	Bone marrow infiltration or immune dysregulation	Cytopaenias, blast cells, lymphadenopathy, organomegaly
Immunosuppressive therapy (corticosteroids, rituximab, mycophenolate, cyclophosphamide)	Direct suppression of B-cell function and Ig production	Medication history
Intestinal lymphangiectasia	Protein and lymphocyte loss via dilated intestinal lymphatics	Lymphopaenia, hypoalbuminaemia, oedema
Burns / extensive skin loss	Ig loss through damaged skin barrier	Clinical context

2. Clinical Mimics: Conditions Presenting Similarly to Symptomatic SIgAD

Since most SIgAD patients present with recurrent infections, atopy, or autoimmune disease, the differential must also include common paediatric conditions that cause these presentations without any immunoglobulin abnormality.

Condition	Distinguishing Features
Normal childhood infections	6–8 URTIs/year is normal in daycare-attending toddlers; infections are mild, self-limiting, with normal intervals of wellness
Allergic rhinitis / adenoidal hypertrophy	Nasal obstruction → impaired sinus drainage → secondary bacterial sinusitis; no immunoglobulin abnormality
Cystic fibrosis	Chronic wet cough, steatorrhoea, FTT, nasal polyps, recurrent Pseudomonas — sweat chloride test diagnostic; AR CFTR mutation
Primary ciliary dyskinesia (PCD)	Chronic wet cough from birth, recurrent otitis media, sinusitis, bronchiectasis, situs inversus (Kartagener syndrome in 50%) — nasal NO low, ciliary ultrastructure abnormal
Asthma	Episodic wheeze/cough with triggers; may co-exist with SIgAD; responds to bronchodilators and inhaled corticosteroids
Foreign body aspiration	Unilateral wheeze, sudden onset, history of choking episode; localised air trapping on CXR
Gastro-oesophageal reflux	Recurrent aspiration causing recurrent pneumonia — usually in young infants with neurological impairment
Congenital structural anomalies	Tracheomalacia, vascular ring, tracheo-oesophageal fistula, pulmonary sequestration

GC 096 emphasises: "Differentials — exclude anatomical and functional disorders" before attributing recurrent infections to immunodeficiency ^[5].

Condition	Key Features
Coeliac disease	May co-exist with SIgAD (shared HLA-DQ2); if IgA is low, IgA-based serology will be falsely negative → use IgG anti-tTG ^[6]
Cow's milk protein allergy	Common in infants; bloody stools, eczema, vomiting; resolves with elimination diet
Giardiasis	Giardia lamblia — chronic watery/fatty diarrhoea, bloating; can occur in immunocompetent children but is more severe/persistent in SIgAD
Inflammatory bowel disease	Crohn's or UC — bloody diarrhoea, weight loss, raised inflammatory markers; endoscopy/biopsy diagnostic ^[11]
Toddler's diarrhoea (functional)	Watery stools with undigested food; child is well and growing normally

Condition	How to Differentiate
Primary ITP	No underlying immunodeficiency found; isolated thrombocytopaenia with otherwise normal Ig levels ^[7]
SLE-associated cytopaenias	Multi-system features (malar rash, arthritis, nephritis, serositis); +ANA, +anti-dsDNA, low C3/C4
Evans syndrome	Concurrent AIHA + ITP; may be idiopathic or secondary to CVID, SLE, ALPS
Autoimmune lymphoproliferative syndrome (ALPS)	Chronic lymphadenopathy, splenomegaly, autoimmune cytopaenias; elevated double-negative T cells (CD3+CD4−CD8−); defective FAS-mediated apoptosis
Bone marrow failure (aplastic anaemia, leukaemia)	Pancytopaenia, abnormal blood film (blasts in leukaemia), bone marrow biopsy diagnostic ^[12]

Cause	Mechanism
IgA deficiency with anti-IgA antibodies	Anti-IgA IgG binds donor IgA → anaphylaxis ^[8]
Haptoglobin deficiency	Common in Chinese (~1:1000) — anti-haptoglobin antibodies react with donor haptoglobin ^[8]
Donor allergen transfer	Donor ingested allergen (e.g. penicillin, peanut) which is passively transferred in plasma → IgE-mediated reaction in sensitised recipient
ABO incompatibility (acute haemolytic)	More severe; fever, rigors, flank pain, dark urine, DIC — distinct from anaphylaxis

Condition	IgG	IgA	IgM	B Cells	T Cells	Key Distinguishing Feature
Selective IgA Deficiency	N	↓↓↓	N	N	N	Most common PID; mostly asymptomatic; IgA < 0.07 g/L with normal IgG/IgM
CVID	↓↓↓	↓	↓/N	N/↓	N	Marked ↓IgG + ↓IgA; poor vaccine responses; low switched memory B cells
XLA	↓↓↓	↓↓↓	↓↓↓	Absent	N	Pan-hypogammaglobulinaemia; absent B cells; absent tonsils; boys only (XLR)
Hyper-IgM	↓	↓	↑↑↑	N	N/↓	Elevated IgM; class-switch failure; opportunistic infections (PJP, Cryptosporidium)
THI	↓ (transient)	May be ↓	N	N	N	Self-resolves by age 2–4; cannot diagnose SIgAD before age 4 for this reason
IgG subclass deficiency	N (total)	N	N	N	N	Isolated IgG2/4 ↓; recurrent sinopulmonary infections; total IgG normal
SCID	↓↓↓ all	↓↓↓	↓↓↓	Variable	Absent/↓↓↓	Presents < 6 months; FTT; absent thymus; ALC < 2500
Drug-induced	N or ↓	↓	N	N	N	Temporal association with offending drug; may recover on withdrawal

GC 096: PID "may also present with non-infectious symptoms" ^[5]. This is a high-yield exam point.

Features of immune dysregulation that should trigger immunoglobulin measurement in a child:

Autoimmune cytopaenias (ITP, AIHA, Evans syndrome) ^[7]
Coeliac disease (especially if IgA-based serology is unexpectedly negative) ^[6]
Unexplained chronic diarrhoea ^[11]
Recurrent anaphylaxis to blood products ^[8]
Unexplained bronchiectasis in a child
Multiple autoimmune conditions in a single child

Exam Trap — Negative IgA Anti-tTG Does Not Exclude Coeliac in SIgAD

A child presents with chronic diarrhoea, FTT, and the gastroenterology team sends an IgA anti-tTG which returns negative. Before concluding "not coeliac," check the total serum IgA. If IgA is undetectable, the negative result is meaningless — it is a false negative. You must request IgG anti-tTG or IgG anti-deamidated gliadin peptide (DGP) antibodies instead ^[6]. This is repeatedly examined.

High Yield Summary — Differential Diagnosis of SIgAD

Must-exclude primary immunodeficiencies:

CVID (IgG also low; poor vaccine responses; low switched memory B cells — on the same spectrum as SIgAD; ~5–10% progress)
XLA (all Ig ↓↓↓; B cells absent; boys; BTK mutation)
Hyper-IgM syndrome (IgM ↑↑↑; IgG and IgA ↓; class-switch failure)
Ataxia-telangiectasia (ataxia, telangiectasias, ↑AFP, IgA/IgG2 ↓)
22q11.2 deletion (cardiac, thymic, parathyroid anomalies)
THI (transient; cannot diagnose SIgAD before age 4)

Must-exclude secondary causes: Drugs (phenytoin, carbamazepine), protein-losing states, nephrotic syndrome, HIV, malignancy, immunosuppressive therapy.

Clinical mimics of symptomatic SIgAD: Normal childhood infections, allergic rhinitis/adenoidal hypertrophy, cystic fibrosis, primary ciliary dyskinesia, coeliac disease, functional GI disorders, primary ITP.

Key differentiating investigations: Immunoglobulin profile (IgG, IgA, IgM, IgE), B-cell enumeration (CD19+), IgG subclasses, vaccine response titres, switched memory B cells, HIV testing, drug history.

Active Recall - Differential Diagnosis of Selective IgA Deficiency

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.410 — Primary Immunodeficiency, examples of humoral deficiency) ^[2] Senior notes: Jerry's immunodeficiencies.pdf (Block A and Block C — PID classification, antibody deficiencies) ^[3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p.638–640 — PID warning signs, history, physical examination; DiGeorge, SCID) ^[4] Lecture slides: Investigations of Imm Disorders 2025.pdf (p.21 — Predominantly Antibody Deficiencies diagnostic algorithm, B-cell enumeration) ^[5] GC lecture slides: GC 096. Why do I always get sick.pdf (p.19, p.21 — General principles, SPUR infections, initial evaluation, secondary immunodeficiency exclusion, first-line investigations) ^[6] Senior notes: Ryan Ho GI.pdf (p.126 — Coeliac disease and IgA deficiency, IgG-based serology) ^[7] Senior notes: Ryan Ho Haemtology.pdf (p.117 — ITP secondary to selective IgA deficiency and CVID) ^[8] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (p.18–19 — IgA-deficient patients, haptoglobin deficiency, transfusion anaphylaxis) ^[9] Lecture slides: Investigations of Imm Disorders 2025.pdf (p.14, p.16 — ESID CVID diagnostic criteria, CVID case with lab results) ^[10] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p.1748 — Differential diagnosis principles) ^[11] Senior notes: Block A - Chronic diarrhoea_ irritable bowel syndrome and inflammatory bowel disease.pdf (p.41 — IBD workup, infection exclusion) ^[12] AOS material: AOS - Paeds.pdf (p.1 — Paediatric PID AOS questions, CGD, ALL differentials)

1. Diagnostic Criteria

Selective IgA deficiency does not have elaborate multi-criterion diagnostic criteria like CVID. Instead, it is defined by a simple laboratory-based definition, but every element of that definition has a specific rationale:

Criterion	Requirement	Rationale
Serum IgA	< 0.07 g/L (i.e. < 7 mg/dL), measured on at least 2 separate occasions	This threshold represents "undetectable" by standard nephelometry. A single measurement could be a lab error or transient dip — repeating confirms persistence.
Serum IgG	Normal for age	If IgG is also low → consider CVID, XLA, or other broader antibody deficiency
Serum IgM	Normal for age	If IgM is elevated → consider Hyper-IgM syndrome; if low → broader deficiency
Age	≥ 4 years at the time of diagnosis	IgA is the slowest immunoglobulin to mature. Physiologically low IgA before age 4 may simply reflect normal immune development, not true deficiency.
Exclusion of secondary causes	Drugs, protein-losing states, nephrotic syndrome, HIV, malignancy, immunosuppression excluded ^[5]^[9]	Primary SIgAD is a diagnosis of exclusion. Secondary low IgA is treated by addressing the underlying cause.
Exclusion of T-cell deficiency	No evidence of combined immunodeficiency	If T cells are also deficient → reclassify as CID/SCID, not SIgAD

Partial IgA Deficiency — Not the Same Thing

If serum IgA is detectable but below 2 SD of the age-matched reference range (i.e. between 0.07 g/L and the lower limit of normal), this is termed "partial IgA deficiency." It does NOT meet the formal ESID definition of selective IgA deficiency. Partial IgA deficiency is far more common and even less clinically significant. Some of these children will normalise over time; a small fraction will progress to complete SIgAD or even CVID.

From Investigations of Imm Disorders 2025 lecture ^[9] — ESID CVID diagnostic criteria (directly examinable):

CVID requires ALL of:

At least one clinical criterion: increased susceptibility to infection, autoimmune manifestations, granulomatous disease, unexplained polyclonal lymphoproliferation, or affected family member with antibody deficiency
Marked decrease of IgG AND marked decrease of IgA with or without low IgM (measured at least twice; < 2 SD of normal for age)
At least one of: poor antibody response to vaccines (and/or absent isohemagglutinins) OR low switched memory B cells (< 70% of age-related normal value)
Secondary causes of hypogammaglobulinaemia excluded
Diagnosis established after the 4th year of life (symptoms may be present before)
No evidence of profound T-cell deficiency (defined as 2 out of: low CD4 numbers [2–6y < 300/µL, 6–12y < 250/µL, > 12y < 200/µL], low % naive CD4 [2–6y < 25%, 6–16y < 20%, > 16y < 10%], absent T-cell proliferation) ^[9]

The critical distinction: in SIgAD, IgG is NORMAL; in CVID, IgG is MARKEDLY DECREASED. If a child has low IgA AND low IgG → they do NOT have SIgAD, they have CVID (or another broader antibody deficiency).

Understanding why age matters requires knowing normal IgA development:

Age	Approximate Serum IgA Reference Range	Key Points
Cord blood / neonate	0–0.05 g/L (essentially absent)	IgA does NOT cross the placenta (unlike IgG). Neonatal IgA is negligible.
1–3 months	0.01–0.34 g/L	Very low; beginning endogenous production
4–6 months	0.04–0.60 g/L	Gradually rising; wide range
7–12 months	0.10–0.80 g/L	Still well below adult levels
1–3 years	0.15–1.10 g/L	Progressive rise; still variable
4–6 years	0.25–1.50 g/L	Earliest age for definitive SIgAD diagnosis
7–12 years	0.40–2.30 g/L	Approaching adult levels
13–18 years / Adults	0.70–4.00 g/L	Adult range

Why this matters practically: A 2-year-old with an IgA of 0.05 g/L is probably within physiological range or has transient hypogammaglobulinaemia of infancy — you cannot call this SIgAD. The same value in a 6-year-old is clearly below the < 0.07 g/L threshold and warrants the diagnosis (after confirmation and exclusion of secondary causes).

3. Diagnostic Algorithm

The diagnostic workup of SIgAD sits within the broader framework of evaluating a child with suspected primary immunodeficiency. The GC lectures provide the backbone:

From GC 096 ^[5]: Initial evaluation → (1) Exclude secondary immunodeficiency → (2) Identify "SPUR" infections → (3) Salient history → (4) First-line investigations

From GC 144 ^[13]: "Many IEIs require tailored investigations, and cannot be picked up by initial screening tests. Always consult immunology when clinically suspicious."

Step 1: Clinical Suspicion

Child presents with recurrent sinopulmonary/GI infections, atopy, autoimmune disease, or incidental low IgA found during workup for another condition (e.g. coeliac disease screening, pre-transfusion).

Step 2: First-Line Screening Investigations ^[5]^[13]

CBC and differentials — looking for lymphopaenia (if present → think combined deficiency, not SIgAD), neutropaenia, thrombocytopaenia
Immunoglobulin profile: IgG, IgA, IgM, IgE — the single most important test
Serum protein and globulin level — low total globulin may be first clue
Acute phase reactants (ESR/CRP) — ↓ ESR may indicate low globulin/fibrinogen ^[5]

Step 3: Confirm Low IgA, Verify IgG and IgM Are Normal

If IgA < 0.07 g/L with normal IgG and IgM → proceed to confirm
If IgG also low → redirect workup toward CVID, XLA, or Hyper-IgM

Step 4: Repeat Immunoglobulins

Must be measured at least twice to confirm persistence (not a transient dip or lab error)
In children < 4 years: label as "probable IgA deficiency" and recheck after age 4

Step 5: Exclude Secondary Causes

Drug history (phenytoin, carbamazepine, valproic acid, sulfasalazine)
HIV testing (antigen or PCR) ^[5]
Protein-losing state workup if clinically suspected (urine protein, faecal α1-antitrypsin)
Renal function, liver function ^[5]

Step 6: Assess for Associated Conditions and Complications

IgG subclass levels (especially IgG2) — co-deficiency drives symptomatic disease
Coeliac screen using IgG-based serology (IgG anti-tTG or IgG anti-DGP) ^[6]
Anti-IgA antibodies — relevant if transfusion history or planned
Autoimmune screen (ANA, CBC for cytopaenias)

Step 7: Assess Immune Function More Broadly (If Symptomatic)

Lymphocyte subsets by flow cytometry (CD3+ T cells, CD19+ B cells, CD16+/56+ NK cells) ^[13]
Vaccine response titres (tetanus, diphtheria IgG; pneumococcal serotype-specific IgG pre- and post-vaccination)
Switched memory B cells (CD27+IgD−IgM−) — if low, raises concern for evolution toward CVID ^[9]

Step 8: Genetic Testing (If Indicated)

Not routine for isolated SIgAD
Consider if: family history of PID, evolving toward CVID, or atypical features
Test: TACI (TNFRSF13B), BAFF-R (TNFRSF13C) ^[4]
Broader next-generation sequencing (NGS) panel for inborn errors of immunity if diagnostic uncertainty

Step 9: Longitudinal Monitoring

Repeat immunoglobulins annually (especially IgG) — 5–10% of SIgAD patients progress to CVID
Monitor for development of autoimmune disease, bronchiectasis

4. Investigation Modalities — Key Findings and Interpretations

4.1 First-Line Investigations

From GC 144 ^[13]: CBC findings and their associations in PID:

ALC low < 3000 (< 1 year) or < 1000 (> 1 year) → severe combined immunodeficiencies

AEC high → primary atopic disorders

ANC < 1 → severe congenital neutropaenia

ANC high → leukocyte adhesion deficiency

PLT low → Wiskott-Aldrich syndrome

Parameter	Expected in SIgAD	Interpretation If Abnormal
Absolute lymphocyte count (ALC)	Normal	If low (< 2500/µL in young children, < 1500/µL in > 5 years) → think combined deficiency, NOT SIgAD ^[3]
Haemoglobin	Usually normal	If low → anaemia of associated autoimmune disease (AIHA), coeliac malabsorption, or iron deficiency from chronic GI disease
WBC / neutrophils	Normal	Neutropaenia → different PID category
Platelets	Usually normal	If low → consider associated ITP ^[7] or Wiskott-Aldrich if also low IgM and small platelets ^[2]^[13]
Eosinophils	May be mildly elevated	Reflects associated atopy
Blood film	Normal	Blasts → leukaemia; Howell-Jolly bodies → functional asplenia (seen in coeliac-associated hyposplenism) ^[6]

This is the cornerstone investigation.

From GC 144 ^[13] — IgGAME findings:

Low IgGAM → agammaglobulinaemia (e.g. XLA)

High IgE → Hyper-IgE syndrome, primary atopic disorder

High IgM → Hyper-IgM syndrome

High IgGAM → chronic granulomatous disease

Low IgM → DOCK8 deficiency, Wiskott-Aldrich, ataxia-telangiectasia

Immunoglobulin	Expected in SIgAD	Interpretation of Deviations
IgA	< 0.07 g/L (undetectable)	This IS the diagnostic finding. Must be age-appropriate reference range.
IgG	Normal for age	If ↓ → NOT SIgAD → CVID workup. CVID requires marked ↓IgG AND ↓IgA ^[9]
IgM	Normal for age	If ↑ → Hyper-IgM syndrome. If ↓ → broader deficiency (WAS, AT, DOCK8)
IgE	Normal or elevated	Elevated IgE in SIgAD reflects increased mucosal allergen penetration → atopic sensitisation. Markedly elevated → consider Hyper-IgE syndrome (but IgA is not typically low in HIES)

GC 144 High Yield — Interpreting the Immunoglobulin Profile

The immunoglobulin profile pattern is the single most important first-line investigation for classifying antibody deficiencies ^[13]:

Pan-low (all Ig down) + absent B cells = XLA
Pan-low + B cells present = CVID
Low IgA only + normal IgG/IgM = SIgAD
Low IgG/IgA + high IgM = Hyper-IgM syndrome
All Ig elevated = chronic granulomatous disease (reactive polyclonal expansion)

Technical notes on IgA measurement:

Measured by nephelometry (quantitative) — most labs can detect down to ~0.05–0.07 g/L
Values below the limit of detection are reported as "< 0.07 g/L" or "undetectable"
Always interpret against age-specific reference ranges — a lab reporting "low" IgA in a 2-year-old may simply be reflecting physiological immaturity

Parameter	Expected in SIgAD	Interpretation
Total protein	Usually normal	Low → protein-losing state or broader hypogammaglobulinaemia
Albumin	Normal	Low → nephrotic syndrome, protein-losing enteropathy, liver disease
Globulin	Normal or slightly low	Low globulin is a non-specific clue to hypogammaglobulinaemia — the globulin fraction on electrophoresis includes immunoglobulins; loss of one Ig class (IgA alone) may not significantly reduce total globulin

From GC 096 ^[5]: "↓ ESR if low globulin/fibrinogen"

Parameter	Expected in SIgAD	Interpretation
ESR	Normal (isolated IgA loss may not significantly ↓ ESR)	If unexpectedly low in a child with recurrent infections → consider broader hypogammaglobulinaemia (CVID, XLA) because ESR depends on rouleaux formation which requires adequate globulins ^[5]
CRP	Normal (unless active infection or autoimmune flare)	Elevated during acute infections; useful for monitoring but not diagnostic

From GC 096 ^[5]: Include "HIV status (Antigen or PCR)" in first-line investigations

Rationale: HIV causes secondary immunodeficiency that can mimic or co-exist with primary antibody deficiency. Must be excluded before diagnosing any primary immunodeficiency.
In paediatrics, infants born to HIV-positive mothers require HIV DNA PCR (not antibody testing, which reflects maternal antibodies up to ~18 months).

4.2 Second-Line Investigations (Characterisation and Associated Conditions)

These are ordered once the diagnosis of SIgAD is confirmed (or strongly suspected) to characterise severity, identify co-existing deficiencies, and screen for associated conditions.

Subclass	Clinical Relevance in SIgAD
IgG1	Rarely deficient in SIgAD alone
IgG2	Most commonly co-deficient with IgA deficiency — IgG2 is the principal antibody against polysaccharide antigens (capsules of S. pneumoniae, H. influenzae). Its deficiency explains disproportionate sinopulmonary infections in some SIgAD patients.
IgG3	May be low; contributes to antiviral defence
IgG4	Often low but least clinically significant

Key point: Total IgG can be normal even when IgG2 is significantly low (because IgG1 accounts for ~65% of total IgG and compensates). You must request IgG subclass quantification specifically.

This is the most clinically meaningful test of humoral immune function beyond quantitative Ig levels.

Test	Method	Expected in SIgAD	Interpretation
Anti-tetanus IgG	Post-vaccination serology	Normal (protective)	Tests protein antigen response (T-cell dependent) — usually preserved in SIgAD
Anti-diphtheria IgG	Post-vaccination serology	Normal (protective)	Same as above
Anti-pneumococcal serotype-specific IgG	Pre- and 4–6 weeks post- Pneumovax 23 (PPSV23)	Usually normal — but may be impaired if co-existing IgG2 deficiency	Tests polysaccharide antigen response (T-cell independent) — this is the more sensitive test. Protective response = ≥ 4-fold rise or ≥ 1.3 µg/mL in ≥ 70% of serotypes tested.
Isohemagglutinins (anti-A, anti-B)	Naturally occurring IgM antibodies against ABO blood group antigens	Usually present (normal)	Absent isohemagglutinins → raises concern for broader humoral defect (CVID) ^[9]. Note: absent in blood group AB patients (no foreign ABO antigens to react against).

Why this matters in SIgAD: If vaccine responses are normal, the child has SIgAD with intact functional humoral immunity and the prognosis is excellent. If vaccine responses are impaired (especially to polysaccharide antigens), this suggests a more significant defect approaching CVID territory, and the child may need immunoglobulin replacement.

From Investigations of Imm Disorders 2025 ^[9]: CVID criteria include "poor antibody response to vaccines (and/or absent isohemagglutinins)" — testing these differentiates SIgAD from early CVID.

Practical Note on Pneumococcal Vaccine Response Testing in Children

In children < 2 years, use conjugated pneumococcal vaccine (PCV13/15/20) because young children cannot respond to pure polysaccharide antigens (T-cell independent response matures slowly).
In children ≥ 2 years, PPSV23 (unconjugated polysaccharide) can be used for diagnostic purposes — it tests the T-cell independent IgG2 response specifically.
A child who has received only PCV and not PPSV23 can still have serotype-specific IgG measured, but the response reflects T-cell dependent (conjugate) immunity, which is less discriminating for subtle antibody deficiency.

From GC 144 ^[13]: Lymphocyte subset findings:

Low T cells (with or without low B and/or NK) → combined immunodeficiencies

Low B cells only → agammaglobulinaemia

"In some forms of CID, T cell may be normal in count but not in function, or they may be maternally grafted memory T cells in Omenn syndrome, a form of SCID"

Marker	Expected in SIgAD	If Abnormal
CD19+ (B cells)	Normal	If absent → XLA; if low → broader antibody deficiency
CD3+ (T cells)	Normal	If low → combined immunodeficiency
CD4+ (T helper)	Normal	Low CD4 → consider HIV, DiGeorge, CID
CD8+ (T cytotoxic)	Normal	—
CD16+/56+ (NK cells)	Normal	Low NK → certain rare combined deficiencies
CD27+IgD−IgM− (switched memory B cells)	Usually normal	If < 70% of age-related normal → more consistent with CVID phenotype; associated with risk of bronchiectasis and autoimmune cytopaenias ^[9]

From Investigations of Imm Disorders 2025 ^[4]: The diagnostic algorithm for predominantly antibody deficiencies starts with B-lymphocyte (CD19+) enumeration by flow cytometry:

B cells absent → XLA (BTK) or AR agammaglobulinaemia

B cells > 1% → CVID phenotype or other antibody deficiency (including SIgAD)

In SIgAD, all lymphocyte subsets are expected to be normal. The purpose of checking them is to exclude combined deficiency and to characterise the B-cell compartment for prognostic purposes (switched memory B cells).

Test	Method	Key Point in SIgAD
IgA anti-tTG	Standard coeliac screen	FALSELY NEGATIVE in SIgAD — the patient cannot produce IgA, so any IgA-based test is meaningless ^[6]
IgG anti-tTG	Alternative for IgA-deficient patients	Must be specifically requested — not part of routine coeliac panels unless flagged
IgG anti-deamidated gliadin peptide (DGP)	Additional IgG-based test	High sensitivity and specificity for coeliac disease in IgA-deficient patients
Total serum IgA	Always co-requested with coeliac serology	ESPGHAN guidelines (2020) recommend measuring total IgA alongside IgA anti-tTG to detect IgA deficiency that would invalidate the result
Small bowel biopsy	OGD with duodenal biopsies	Gold standard confirmation — villous atrophy, crypt hyperplasia, intraepithelial lymphocytosis

Must-Know Exam Point — ESPGHAN Coeliac Screening and IgA Deficiency

Every paediatric coeliac screening panel should include measurement of total serum IgA alongside IgA anti-tTG. If total IgA is low/undetectable, the IgA anti-tTG result cannot be interpreted, and IgG-based serology must be performed ^[6]. Failure to do this is a common clinical and exam error.

Test	When to Order	Expected Finding	Clinical Significance
Anti-IgA antibodies (usually IgG class)	Before any blood product transfusion, or after unexplained transfusion anaphylaxis	Present in ~30–40% of SIgAD patients	Identifies patients at risk for anaphylaxis to blood products containing IgA. If positive → future transfusions must use washed cellular products (to remove donor plasma IgA) or products from IgA-deficient donors ^[8]

Test	Rationale
ANA	Screen for SLE and other autoimmune conditions (associated with SIgAD)
Anti-dsDNA, complement C3/C4	If ANA positive, to characterise SLE
Direct Coombs test (DAT)	If anaemia present → screen for AIHA
Thyroid function + anti-thyroid antibodies	Screen for autoimmune thyroiditis
CBC with reticulocyte count	Assess for autoimmune cytopaenias (ITP, AIHA)

4.3 Third-Line / Specialist Investigations

These are typically ordered by a paediatric immunologist and are not routine.

Test	Indication	Genes Tested
Targeted sequencing	Family history of PID, features suggesting evolution to CVID, atypical presentation	TACI (TNFRSF13B), BAFF-R (TNFRSF13C), ICOS ^[4]
NGS panel for inborn errors of immunity	Diagnostic uncertainty, syndromic features, severe phenotype	Broad panel covering > 400 PID-associated genes
Whole exome/genome sequencing	Research or when targeted panels are non-diagnostic	—

From Investigations of Imm Disorders 2025 ^[4]: TACI deficiency (TNFRSF13B) — AD or AR, variable clinical expression and penetrance for monoallelic variants. Found in both SIgAD and CVID, confirming the shared genetic basis.

Modality	Indication	Key Findings
CXR	Baseline assessment; recurrent LRTI	May show signs of bronchiectasis (tram-track lines, ring shadows) in severe/long-standing cases; useful to confirm thymus shadow is present (absent → SCID, not SIgAD) ^[5]
HRCT thorax	If bronchiectasis suspected (chronic productive cough despite treatment)	Bronchial wall thickening, dilated bronchi, mucus plugging — establishes end-organ damage from recurrent infection

In children ≥ 6 years with recurrent LRTI
May show obstructive pattern (co-existing asthma, which is more common in SIgAD) or mixed pattern if bronchiectasis has developed

From Block A Haematological Investigations ^[14]: Pan-immunoparesis on SPE → think inherited or acquired immunodeficiencies.

Pattern	Interpretation in SIgAD Context
Normal	Expected in SIgAD (loss of one Ig class may not be visible on SPE)
Pan-immunoparesis	Broader antibody deficiency (CVID, XLA) → NOT SIgAD
Monoclonal band (M-protein)	Plasma cell dyscrasia → secondary cause of hypogammaglobulinaemia → NOT primary SIgAD

SPE is primarily used to exclude secondary causes (myeloma, lymphoma producing paraprotein) rather than to diagnose SIgAD itself ^[4]^[14].

Tier	Tests	Purpose
1st Line (Screening)	CBC with diff, IgG/IgA/IgM/IgE, total protein/albumin/globulin, ESR/CRP, HIV test ^[5]^[13]	Detect IgA deficiency; exclude secondary causes; screen for combined deficiency
2nd Line (Characterisation)	IgG subclasses, vaccine response titres, lymphocyte subsets (CD3/4/8/19/16+56, switched memory B cells), coeliac screen (IgG-based), anti-IgA antibodies, autoimmune screen (ANA, DAT, TFTs)	Define severity; identify co-existing IgG2 deficiency; detect associated conditions; assess CVID risk
3rd Line (Specialist)	Genetic testing (TACI, BAFF-R, NGS panel), HRCT thorax, spirometry, SPE	Identify genetic cause; assess end-organ damage; exclude secondary causes

Pitfall	Explanation	How to Avoid
Diagnosing SIgAD before age 4	IgA matures slowly; low values before age 4 may be physiological	Label as "probable IgA deficiency"; recheck after age 4
Accepting negative IgA anti-tTG as excluding coeliac	False negative if IgA is undetectable	Always co-measure total IgA with coeliac serology; use IgG-based tests if IgA low ^[6]
Missing IgG decline	SIgAD can evolve to CVID (5–10%)	Monitor IgG annually in symptomatic SIgAD patients
Ignoring IgG subclass deficiency	Total IgG normal but IgG2 low → explains symptomatic infections	Request IgG subclasses if recurrent infections despite normal total IgG
Low ESR misinterpreted as reassuring	Low ESR in a child with recurrent infections may reflect low globulin ^[5]	Correlate with Ig levels
Not repeating IgA measurement	Single measurement could be transient or lab error	Must confirm on at least 2 occasions
Attributing all infections to SIgAD	Most SIgAD patients are asymptomatic; normal children have 6–8 URTI/year	Assess whether infections are truly excessive in frequency, severity, or duration (SPUR)

High Yield Summary — Diagnosis and Investigations

Diagnostic definition: Serum IgA < 0.07 g/L measured on ≥ 2 occasions, with normal IgG and IgM, in a child ≥ 4 years, with secondary causes excluded and no T-cell deficiency.

Key differentiating investigation from CVID: IgG level — normal in SIgAD, markedly low in CVID. Also check vaccine responses and switched memory B cells.

First-line panel: CBC + diff, IgG/IgA/IgM/IgE, total protein/globulin, ESR/CRP, HIV test.

Must-do additional tests: IgG subclasses (especially IgG2), coeliac screen with IgG-based serology (NOT IgA-tTG alone), anti-IgA antibodies (for transfusion safety), autoimmune screen.

GC high-yield points:

CBC interpretation: low ALC → SCID not SIgAD; low platelets → WAS; high IgE → HIES
Ig profile pattern: low IgA only + normal IgG/IgM = SIgAD
CVID requires ↓IgG + ↓IgA + poor vaccine responses + diagnosis after age 4
B-cell enumeration by flow cytometry → absent = XLA, present = CVID or SIgAD
Low ESR may paradoxically indicate low globulin in PID

Active Recall - Diagnosis and Investigations of Selective IgA Deficiency

^[2] Senior notes: Jerry's immunodeficiencies.pdf (Block A and Block C — PID classification table, tests for each category) ^[3] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p.640 — History taking, physical examination, lymphopaenia thresholds) ^[4] Lecture slides: Investigations of Imm Disorders 2025.pdf (p.21 — Predominantly antibody deficiencies diagnostic algorithm, B-cell enumeration, TACI/BAFF-R) ^[5] GC lecture slides: GC 096. Why do I always get sick.pdf (p.19, p.21 — General principles, SPUR infections, first-line investigations, ESR and low globulin) ^[6] Senior notes: Ryan Ho GI.pdf (p.126 — Coeliac disease, IgA deficiency, IgG-based serology) ^[7] Senior notes: Ryan Ho Haemtology.pdf (p.117 — ITP secondary to SIgAD) ^[8] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (p.18–19 — Anti-IgA antibodies, transfusion anaphylaxis, washed products) ^[9] Lecture slides: Investigations of Imm Disorders 2025.pdf (p.14, p.16 — ESID CVID diagnostic criteria, vaccine responses, switched memory B cells, isohemagglutinins) ^[13] GC lecture slides: GC 144. A child with recurrent infections Primary immunodeficiencies.pdf (p.50 — CBC interpretation, IgGAME findings, lymphocyte subsets, 2024 update) ^[14] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf (p.27 — SPE interpretation, pan-immunoparesis)

Before diving into specifics, understand three fundamental truths about managing SIgAD in children:

Most patients require no treatment at all. The majority (~70–85%) are asymptomatic because compensatory secretory IgM at mucosal surfaces is sufficient. Management in these children is education, monitoring, and anticipatory guidance — not therapy.
There is no way to "replace" IgA. Unlike IgG (which can be replaced via IVIG/SCIG), IgA replacement is not feasible because: (a) commercial immunoglobulin preparations contain predominantly IgG with negligible IgA; (b) intravenous IgA would not reach mucosal surfaces where it is needed (sIgA must be actively transcytosed across epithelium via the polymeric Ig receptor); (c) even if you infused IgA, patients with anti-IgA antibodies could develop anaphylaxis.
Management is directed at complications and associated conditions, not at "fixing" the IgA deficiency itself. The approach is therefore stratified by clinical severity.

Category	Definition	Approximate Proportion	Management Intensity
Asymptomatic SIgAD	Confirmed SIgAD, no recurrent infections, no autoimmune disease, no atopy beyond normal	~70–85%	Education + monitoring only
Mildly symptomatic SIgAD	Recurrent mild mucosal infections (URTI, otitis media, sinusitis) responding to standard antibiotics; mild atopy	~10–20%	Treat infections aggressively + manage atopy + monitor
Significantly symptomatic SIgAD	Recurrent severe/lower respiratory infections, bronchiectasis, co-existing IgG2 deficiency with poor vaccine responses, significant autoimmune disease	~5–10%	Consider immunoglobulin replacement (for co-existing IgG subclass deficiency); treat autoimmune disease; specialist follow-up
SIgAD evolving to CVID	Progressive decline in IgG levels over time	~5–10% (of all SIgAD)	Reclassify as CVID; immunoglobulin replacement therapy

4. Treatment Modalities — Detailed

4.1 Education, Counselling and Anticipatory Guidance (ALL Patients)

This is the most important intervention for the majority of SIgAD patients and must not be underestimated.

Use age-appropriate, family-centred communication:
- "IgA is one type of antibody that normally protects the lining of the nose, throat, and gut. Your child's body doesn't make enough of it. The good news is that most children with this condition are perfectly healthy because the body has backup systems."
Reassure that most children with SIgAD live completely normal lives.
Explain the need for long-term monitoring (annual blood tests) because a small proportion may develop other immune problems over time.

All patients with confirmed SIgAD should carry medical identification documenting their IgA deficiency — primarily for transfusion safety.

Rationale: In an emergency situation (e.g. trauma requiring urgent blood transfusion), the treating team needs to know the child is IgA-deficient to avoid anaphylaxis from standard blood products.

Vaccine Type	Safety in SIgAD	Notes
All routine childhood vaccines	Safe and recommended	SIgAD is a B-cell class-switch defect for one isotype only; T-cell function is normal, and IgG responses to vaccines are intact
Live vaccines (MMR, VZV, rotavirus, BCG, OPV, LAIV)	Safe — NOT contraindicated in isolated SIgAD	Live vaccines are contraindicated in T-cell deficiencies and combined immunodeficiencies, NOT in isolated antibody deficiencies where T-cell function is normal. SIgAD patients handle live vaccines without complication.
Pneumococcal vaccines (PCV, PPSV23)	Particularly important	Encapsulated bacteria are the main pathogens; maximising pneumococcal protection is a priority. Follow the national immunisation schedule (HK: PCV13 at 2, 4, 12 months; consider supplementary PPSV23 at ≥ 2 years if recurrent infections).
Influenza vaccine (annual)	Recommended	Reduces respiratory infection burden

Live Vaccines Are Safe in SIgAD — Do Not Withhold Them

A common exam mistake is to state that live vaccines are contraindicated in SIgAD. They are NOT. Live vaccine contraindications apply to T-cell deficiencies (SCID, DiGeorge with significant T-cell depletion) and combined deficiencies, not to isolated antibody deficiencies with intact T-cell function ^[2]. SIgAD patients should receive all routine vaccines on schedule.

Educate families to seek review if the child develops:

Infections that are unusually frequent, severe, or prolonged
Persistent diarrhoea or poor weight gain (→ coeliac disease, Giardia)
Unexplained bruising or pallor (→ autoimmune cytopaenias)
Any reaction during blood transfusion

4.2 Infection Management

Principle	Detail	Rationale
Low threshold for antibiotics	Initiate empirical antibiotics early for bacterial sinopulmonary infections; do not adopt a "watch and wait" approach that might be appropriate for immunocompetent children	Impaired mucosal defence means infections may escalate faster; delayed treatment risks complications (empyema, mastoiditis, bronchiectasis)
Appropriate empirical cover	Target encapsulated organisms: amoxicillin (first-line for otitis media, sinusitis, community-acquired pneumonia in children)	Common pathogens: S. pneumoniae, H. influenzae (non-typeable), M. catarrhalis ^[1] — standard paediatric antibiotic choices apply
Obtain cultures when possible	Especially for recurrent or treatment-resistant infections	Identifies resistant organisms; guides targeted therapy
Complete full course	Do not abbreviate antibiotic courses	Incomplete treatment → chronic colonisation → further mucosal damage

Paediatric antibiotic specifics:

Infection	First-Line Antibiotic	Paediatric Dose	Notes
Acute otitis media	Amoxicillin	80–90 mg/kg/day in 2 divided doses (high-dose for resistant pneumococcus)	10 days if < 2 years; 5–7 days if ≥ 2 years
Acute sinusitis	Amoxicillin or amoxicillin-clavulanate	Amox-clav: 90 mg/kg/day (amoxicillin component) in 2 divided doses	Consider amox-clav if β-lactamase-producing H. influenzae suspected
Community-acquired pneumonia	Amoxicillin (oral, mild); IV ampicillin or co-amoxiclav (moderate-severe)	80–90 mg/kg/day oral; 150 mg/kg/day IV	Add macrolide if atypical coverage needed
Giardiasis	Metronidazole	15 mg/kg/day in 3 divided doses × 5–7 days	May recur in SIgAD; consider repeat course or tinidazole

Indication	Regimen	Rationale
Recurrent sinopulmonary infections (≥ 4 significant episodes/year) failing standard treatment	Low-dose prophylactic antibiotic — e.g. co-trimoxazole (trimethoprim 2 mg/kg/day) or azithromycin (10 mg/kg once weekly)	Reduces bacterial colonisation at mucosal surfaces; decreases frequency of acute infections; prevents progressive lung damage
Pre-operative prophylaxis for ENT/dental procedures	Standard surgical prophylaxis (amoxicillin)	Not different from immunocompetent patients unless co-existing IgG subclass deficiency

Important: Prophylactic antibiotics should be a time-limited trial (e.g. 3–6 months over winter) and reassessed, not indefinite, to minimise antibiotic resistance.

For children with established or developing bronchiectasis (a complication of recurrent LRTI):
- Chest physiotherapy and airway clearance techniques (e.g. active cycle of breathing, positive expiratory pressure devices)
- Regular sputum surveillance cultures
- Consider long-term low-dose azithromycin (anti-inflammatory + antimicrobial properties, as used in non-CF bronchiectasis)

4.3 Immunoglobulin Replacement Therapy

Commercial immunoglobulin preparations (IVIG and SCIG) contain predominantly IgG (> 95%) with only trace amounts of IgA and IgM. They are used to replace IgG, not IgA.

Therefore, IVIG/SCIG is NOT indicated for isolated SIgAD with normal IgG and normal vaccine responses.

Indication	Rationale
SIgAD with co-existing IgG subclass deficiency (especially IgG2) AND impaired vaccine responses AND recurrent significant infections	The IgG subclass deficiency, not the IgA deficiency, is the therapeutic target. Replacing IgG restores opsonisation of encapsulated bacteria.
SIgAD evolving to CVID (progressive IgG decline)	Now meets CVID criteria → standard CVID management with regular IVIG/SCIG ^[2]
Specific clinical scenarios: recurrent severe pneumonia, bronchiectasis, failure to thrive from chronic infections despite aggressive antibiotic management	Even if IgG subclasses are borderline, a trial of Ig replacement may be warranted in selected cases after immunology consultation

Parameter	IVIG (Intravenous Ig)	SCIG (Subcutaneous Ig)
Route	Intravenous infusion	Subcutaneous infusion (via pump or manual push)
Frequency	Every 3–4 weeks	Weekly or biweekly
Setting	Hospital/day centre (requires IV access, nursing supervision)	Home-based (after training)
Dose	400–600 mg/kg/dose every 3–4 weeks	100–200 mg/kg/dose weekly (equivalent monthly dose split)
IgA content	Varies by product — some products have higher IgA content than others	Also varies by product
Steady-state IgG levels	Peaks and troughs (fluctuating)	More stable serum IgG levels (smaller, more frequent doses)
Side effects	Headache, fever, chills, nausea during infusion; rare: aseptic meningitis, renal impairment, thromboembolic events	Local site reactions (swelling, redness); systemic reactions rare
Advantage in SIgAD	—	Home-based → less school disruption; avoids IV access in children; lower IgA content in some SCIG products → may reduce anaphylaxis risk

IgA Content in Ig Products — Anaphylaxis Risk

If a child with SIgAD and anti-IgA antibodies requires immunoglobulin replacement for co-existing IgG deficiency, the product must be selected carefully:

Use a preparation with the LOWEST possible IgA content (some SCIG products have very low IgA, e.g. Hizentra has < 50 µg/mL).
First infusion must be given under close monitoring in a hospital setting with anaphylaxis management available.
Pre-medicate with antihistamines ± corticosteroids if anti-IgA antibodies are present.
IVIG products vary widely in IgA content — always check the product datasheet.

Parameter	Frequency	Target
Trough IgG level	Every 3–6 months (pre-infusion)	Trough IgG > 5–8 g/L (aim for clinical wellbeing — reduction in infection frequency is the primary endpoint, not a specific number)
Clinical infection frequency	Every visit	Should decrease significantly; if not → reassess dose, compliance, other causes
Liver and renal function	Every 6–12 months	IVIG can rarely cause renal impairment (osmotic nephropathy) or transaminitis
Growth and development	Every visit	Expected to improve if infections and malabsorption were limiting growth

4.4 Management of Associated Conditions

Aspect	Management
Screening	Use IgG-based serology (IgG anti-tTG or IgG anti-DGP) — NOT IgA anti-tTG ^[6]
Confirmation	Duodenal biopsy (OGD) — villous atrophy, crypt hyperplasia, intraepithelial lymphocytes
Treatment	Strict lifelong gluten-free diet
Monitoring	Adherence assessment, repeat IgG anti-tTG, nutritional status, bone density
Dietitian referral	Essential in paediatric coeliac — growth and nutrition must be carefully monitored

Condition	First-Line Treatment	Second-Line	Special Considerations in SIgAD
ITP	Observation if mild (platelet > 20 × 10⁹/L and no significant bleeding); corticosteroids (prednisolone 1–2 mg/kg/day × 1–2 weeks) if treatment indicated; IVIG (0.8–1 g/kg single dose) for rapid platelet rise	Rituximab, TPO-receptor agonists (eltrombopag, romiplostim), splenectomy (last resort, especially delayed in children)	IVIG used for ITP in SIgAD patients carries the same anti-IgA anaphylaxis risk — use low-IgA product; splenectomy further increases infection risk in an already immunodeficient child → delay as long as possible and ensure full vaccination + post-splenectomy antibiotic prophylaxis ^[15]
AIHA	Corticosteroids (prednisolone 1–2 mg/kg/day)	Rituximab, mycophenolate, splenectomy	Monitor for Evans syndrome (concurrent ITP + AIHA) → may indicate evolution toward CVID or ALPS

Splenectomy in SIgAD — Heightened Risk

Post-splenectomy patients are vulnerable to overwhelming sepsis from encapsulated bacteria (S. pneumoniae, N. meningitidis, H. influenzae) ^[15]^[16]. In a child who already has SIgAD (impaired mucosal defence against these same organisms), losing the spleen compounds the risk. Therefore:

Splenectomy should be a last resort in SIgAD children with refractory cytopaenias.
Pre-splenectomy vaccination: Pneumococcal (PCV + PPSV23), meningococcal (MenACWY + MenB), H. influenzae type b.
Post-splenectomy lifelong antibiotic prophylaxis: Oral penicillin V (phenoxymethylpenicillin) or amoxicillin daily ^[16].

Standard paediatric management — no modification needed specifically for SIgAD:

Condition	Management
Asthma	Stepwise approach: SABA PRN → low-dose ICS → escalate per GINA guidelines. Environmental trigger avoidance.
Eczema	Emollients (mainstay), topical corticosteroids for flares, calcineurin inhibitors (tacrolimus/pimecrolimus) for sensitive areas, manage secondary infection
Allergic rhinitis	Intranasal corticosteroids, oral antihistamines, allergen avoidance
Food allergy	Allergen avoidance, emergency action plan with adrenaline auto-injector if history of anaphylaxis

Aspect	Detail
Treatment	Metronidazole 15 mg/kg/day in 3 divided doses × 5–7 days (or tinidazole 50 mg/kg single dose, max 2 g)
Relapse	Common in SIgAD because absent luminal sIgA cannot prevent re-attachment of trophozoites. May need repeat or prolonged courses.
Prevention	Good hand hygiene, safe water; no specific chemoprophylaxis

This is a critical and highly examined management point.

From Block A Transfusion lecture ^[8]: After anaphylaxis post-transfusion, check for IgA-deficient patients and haptoglobin-deficient patients.

Management of Transfusion Risk in SIgAD

Scenario	Action	Rationale
Elective transfusion planned	Check anti-IgA antibodies before first transfusion. If positive → order special products.	Identifies patients at risk of anaphylaxis before it occurs
Anti-IgA antibodies positive	Use washed cellular blood products (RBC, platelets) — washing removes > 99% of donor plasma proteins including IgA ^[8]	Removes the trigger for the anaphylactic reaction
Alternative if washed products unavailable	IgA-deficient donor blood products (rare — requires special donor registry)	Donor blood naturally lacks IgA → no antigen to trigger anti-IgA reaction
Emergency transfusion, no washed products available	Use the oldest available blood bag — lymphocytes and plasma proteins degrade over storage ^[8]; have anaphylaxis kit ready (IM adrenaline, IV fluids, antihistamines, corticosteroids)	Pragmatic approach in emergencies; cannot delay life-saving transfusion
Anti-IgA antibodies negative	Standard blood products can be used, but still monitor for reactions	Most SIgAD patients without anti-IgA antibodies tolerate transfusions without issue

From Block A Transfusion lecture ^[8]: For immunocompromised patients requiring transfusion, use irradiated blood products to prevent transfusion-associated GVHD. However, isolated SIgAD does NOT require irradiated products — irradiation is for T-cell deficiencies and combined immunodeficiencies where donor lymphocytes could engraft. SIgAD patients have intact T-cell function and can reject donor lymphocytes normally ^[8]^[15].

Irradiated Products Are NOT Needed for SIgAD

Irradiated blood products prevent transfusion-associated GVHD by inactivating donor T lymphocytes. They are indicated for patients with T-cell deficiency (SCID, DiGeorge, post-HSCT, Hodgkin lymphoma, intrauterine transfusion) ^[8]^[15]. SIgAD is a pure B-cell/IgA defect with normal T-cell function → donor T cells will be rejected normally → irradiation is unnecessary. The key special product for SIgAD is washed (not irradiated) cellular products.

Component	Frequency	Purpose
Quantitative immunoglobulins (IgG, IgA, IgM)	Annually	Detect IgG decline signalling progression to CVID (5–10% of SIgAD patients)
Growth and nutritional assessment	Every visit	Detect FTT from chronic infections, malabsorption, or coeliac disease
Respiratory assessment	Annual (or more if symptomatic)	Detect developing bronchiectasis early; consider HRCT if chronic wet cough develops
Autoimmune screening	If new symptoms arise	Low threshold for checking CBC, DAT, TFTs, coeliac screen
Developmental assessment	Per standard schedule	SIgAD itself does not cause developmental delay, but chronic illness and recurrent hospitalisations can affect school performance and psychosocial wellbeing
Anti-IgA antibody status	Before any planned transfusion or procedure with potential blood loss	Ensures safe transfusion planning
Family support and psychosocial	Ongoing	Address parental anxiety; connect with PID support groups if needed

Trigger	Action
Recurrent severe infections despite appropriate antibiotic management	Referral for comprehensive immune function assessment
Co-existing IgG subclass deficiency with poor vaccine responses	Referral for consideration of Ig replacement therapy
Declining IgG levels on serial monitoring (evolving toward CVID)	Referral for reclassification and initiation of IVIG/SCIG
Significant autoimmune disease (especially if multi-system)	Co-management with immunology and relevant subspecialty
Diagnostic uncertainty	Referral for advanced testing (genetic panels, functional assays)

From GC 144 ^[13]: "Many IEIs require tailored investigations, and cannot be picked up by initial screening tests. Always consult immunology when clinically suspicious."

Error	Why It Is Wrong	Correct Approach
Starting IVIG for isolated SIgAD with normal IgG	IVIG replaces IgG, not IgA. No benefit if IgG is normal and vaccine responses are intact. Exposes child to unnecessary IV infusions, side effects, and anaphylaxis risk (anti-IgA antibodies).	Observe and monitor; treat infections promptly
Withholding live vaccines	SIgAD has intact T-cell function → live vaccines are safe	Give all routine vaccines on schedule
Ordering irradiated blood products	Irradiation prevents TA-GVHD (a T-cell mediated problem). SIgAD has normal T cells.	Order washed products if anti-IgA antibodies present
Using IgA anti-tTG for coeliac screening	False negative in SIgAD	Use IgG-based serology ^[6]
Labelling the child as "immunocompromised" broadly	SIgAD is a mild, selective defect. Over-labelling leads to unnecessary restrictions (school, sports, social activities) and parental anxiety.	Reassure that the child can lead a normal life; specify the precise nature and implications of the deficiency
Not monitoring IgG longitudinally	Misses progression to CVID	Annual Ig levels in all confirmed SIgAD patients

Outcome	Detail
Most patients (70–85%)	Excellent prognosis — remain asymptomatic throughout life
Symptomatic minority	Good prognosis with appropriate infection management and treatment of associated conditions
Progression to CVID	~5–10%; prognosis then depends on CVID severity and management
Spontaneous resolution	Rare but documented — some children with partial IgA deficiency normalise IgA levels by adolescence. True complete SIgAD (IgA < 0.07 g/L) very rarely resolves.
Life expectancy	Normal in uncomplicated SIgAD

High Yield Summary — Management of SIgAD

Core principles:

No IgA replacement exists — IVIG/SCIG replaces IgG only
Most patients need education and monitoring only — NOT treatment
IVIG/SCIG is indicated only when co-existing IgG subclass deficiency with poor vaccine responses, or progression to CVID

Infection management: Low threshold for antibiotics; target encapsulated bacteria; prophylactic antibiotics if ≥ 4 significant infections/year; vaccinate fully including live vaccines (safe in SIgAD)

Blood product safety: Check anti-IgA antibodies; use washed cellular products if positive; irradiation is NOT needed (T cells are normal)

Associated conditions: Coeliac → gluten-free diet, screen with IgG serology; ITP/AIHA → standard treatment, low-IgA IVIG products, delay splenectomy; Giardia → metronidazole, may need repeat courses

Monitoring: Annual immunoglobulins (watch for IgG decline → CVID); growth; respiratory status; autoimmune screening

Common exam errors: Starting IVIG for isolated SIgAD; withholding live vaccines; ordering irradiated (not washed) blood products; using IgA-based coeliac serology

Active Recall - Management of Selective IgA Deficiency

^[2] Senior notes: Jerry's immunodeficiencies.pdf (Block A and Block C — PID classification, treatment column for antibody deficiencies: IVIG/SCIG) ^[6] Senior notes: Ryan Ho GI.pdf (p.126 — Coeliac disease screening with IgG-based serology in IgA deficiency) ^[8] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (p.18–22 — IgA-deficient patients, anti-IgA antibodies, washed products, irradiated products, transfusion anaphylaxis, oldest blood bag in emergency) ^[13] GC lecture slides: GC 144. A child with recurrent infections Primary immunodeficiencies.pdf (p.50 — "Always consult immunology when clinically suspicious") ^[15] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf (p.19 — Splenectomy indications, post-splenectomy infection risk, overwhelming post-splenectomy infection from encapsulated bacteria) ^[16] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (p.14 — Post-splenectomy encapsulated organisms: pneumococcus, N. meningitidis, H. influenzae)

Complications of SIgAD flow logically from three mechanistic pillars established in the pathophysiology section:

Loss of mucosal immune exclusion (absent sIgA) → recurrent mucosal infections → structural end-organ damage.
Increased mucosal permeability (absent sIgA barrier) → enhanced antigen/allergen penetration → immune dysregulation → autoimmunity and atopy.
Shared genetic susceptibility (HLA-DR3/DQ2, TACI variants) → co-existing autoimmune diseases that develop independently of (but are potentiated by) the IgA deficiency itself.

A fourth axis — progression to a more severe immunodeficiency (CVID) — represents the natural history of the underlying immune defect worsening over time.

Not every SIgAD patient develops complications. Remember: most patients are asymptomatic ^[1]. Complications arise in the symptomatic minority (~15–30%) and are more likely when compensatory mechanisms (secretory IgM, IgG subclasses) are inadequate.

2. Infectious Complications

Complication	Pathophysiology	Clinical Features in Children
Recurrent acute otitis media	Absent sIgA in middle ear and Eustachian tube mucosa → failure of immune exclusion → encapsulated bacteria (S. pneumoniae, H. influenzae, M. catarrhalis) adhere and invade repeatedly	Ear pain, fever, purulent ear discharge; ≥ 4 episodes/year raises PID concern ^[3]
Chronic/recurrent sinusitis	Same mechanism in sinus mucosa; anatomically, the paediatric sinuses are small and drain poorly → trapped bacteria proliferate	Nasal congestion, purulent postnasal drip, facial pain, cough (especially nocturnal from drip)
Recurrent pneumonia	Lower airway mucosal sIgA absent → increased bacterial adherence → recurrent lower respiratory tract infections	Cough, fever, tachypnoea, focal crackles; must distinguish from asthma exacerbations

Why encapsulated bacteria specifically? The polysaccharide capsule is anti-phagocytic — bacteria surrounded by a capsule resist engulfment by neutrophils and macrophages unless they are first coated (opsonised) by antibodies. At mucosal surfaces, sIgA is the first line of opsonisation and exclusion. Without it, and especially when IgG2 (the key anti-polysaccharide IgG subclass) is also low, encapsulated organisms gain a survival advantage ^[1].

Bronchiectasis is listed as a complication of selective IgA deficiency in the Ryan Ho Respiratory notes ^[17]: "Immunodeficiency syndromes, e.g. primary agammaglobulinaemia, CVID, selective IgA deficiency" are causes of bronchiectasis.

Aspect	Detail
Pathophysiology	Recurrent lower respiratory tract infections → chronic bronchial inflammation → destruction of bronchial wall elastic and muscular components → permanent irreversible dilation of bronchi = bronchiectasis. This follows the "vicious cycle" model: infection → inflammation → structural damage → impaired mucociliary clearance → more infection ^[17].
Typical pattern	Lower lobe predominance — consistent with immunodeficiency-related bronchiectasis (gravity-dependent areas receive the most inhaled pathogens) ^[17]
Clinical features	Chronic productive cough with copious purulent sputum, recurrent exacerbations, haemoptysis (from hypertrophied bronchial arteries), clubbing (late sign), coarse inspiratory crackles that may partially clear with coughing
Colonising organisms	H. influenzae (most common), S. pneumoniae, Moraxella catarrhalis; Pseudomonas aeruginosa colonisation indicates advanced/severe bronchiectasis
Investigation	HRCT thorax — gold standard for diagnosis: shows bronchial dilation (signet-ring sign), bronchial wall thickening, mucus plugging
Significance	Once established, bronchiectasis is irreversible — this is why early detection and aggressive infection management in symptomatic SIgAD children is crucial to prevent progression to this point

Bronchiectasis — The Dreaded End-Organ Consequence

Bronchiectasis is the single most important structural complication of recurrent sinopulmonary infections in antibody deficiencies. It is irreversible and progressive once established. Preventing bronchiectasis is the primary justification for aggressive infection management and, where indicated, immunoglobulin replacement therapy in symptomatic SIgAD patients ^[2]^[17]. In CVID, absent switched memory B cells correlate with bronchiectasis risk — the same likely applies to SIgAD patients evolving toward CVID ^[9].

Complication	Pathophysiology	Clinical Features
Chronic/recurrent Giardia lamblia infection	sIgA in the gut lumen normally prevents trophozoite adherence to small bowel epithelium via immune exclusion. Without sIgA, Giardia trophozoites attach to the brush border → villous damage → malabsorption	Chronic watery/fatty diarrhoea, bloating, abdominal cramps, FTT in children; stool O&P or Giardia antigen test diagnostic
Bacterial gastroenteritis	Increased susceptibility to enteric pathogens (Salmonella, Campylobacter) due to loss of luminal sIgA	Acute diarrhoea, fever; may be prolonged compared to immunocompetent children
Small intestinal bacterial overgrowth (SIBO)	Absent sIgA → failure to control commensal bacterial populations in small bowel → overgrowth	Bloating, flatulence, diarrhoea, malabsorption; diagnosed by glucose hydrogen breath test

3. Autoimmune Complications

From Jerry's immunodeficiencies ^[2]: "Remember that immunodeficiency not just infection susceptible, also increased risk for autoimmune diseases, malignancy etc."

This is a crucial conceptual point — immunodeficiency and autoimmunity are not opposites. They coexist because the same genetic and immune regulatory defects that impair targeted immune responses can also disrupt self-tolerance.

3.1 Autoimmune Cytopaenias

From Ryan Ho Haematology ^[7]: Secondary ITP is associated with "Immunodeficiency: CVID, HIV, selective IgA deficiency."

Aspect	Detail
Pathophysiology	Loss of immune tolerance → autoantibodies (IgG) against platelet surface glycoproteins (GPIIb/IIIa, GPIb/IX) → premature platelet destruction in the reticuloendothelial system (spleen, liver) → thrombocytopaenia ^[7]
Why in SIgAD?	(1) Shared HLA susceptibility (DR3/DQ2 autoimmune haplotype); (2) Immune dysregulation from defective B-cell class switching may extend beyond IgA → aberrant antibody production including autoantibodies; (3) Increased mucosal antigen exposure → molecular mimicry
Clinical features in children	Petechiae, purpura, bruising, mucosal bleeding (epistaxis, gum bleeding), rarely severe haemorrhage; often presents acutely after a viral illness
Management concern	IVIG used for ITP may trigger anaphylaxis if the SIgAD child has anti-IgA antibodies → use low-IgA IVIG products under close monitoring

Aspect	Detail
Pathophysiology	Autoantibodies (usually IgG warm-type) against red cell surface antigens → extravascular haemolysis in spleen
Clinical features	Pallor, jaundice (unconjugated hyperbilirubinaemia), splenomegaly, dark urine (if severe intravascular component), reticulocytosis
Diagnosis	Positive direct antiglobulin test (DAT/Coombs), raised reticulocytes, raised LDH, low haptoglobin

Aspect	Detail
Definition	Concurrent or sequential AIHA + ITP (± autoimmune neutropaenia)
Significance in SIgAD	Evans syndrome in a child should trigger investigation for underlying immunodeficiency — it may be the presenting feature of SIgAD or CVID
Prognosis	More refractory than isolated ITP or AIHA; may herald progression to CVID

From Adrian Lui Paediatrics Notes ^[18]: Coeliac disease is associated with "other HLA-linked diseases, e.g. IDDM, thyroid disorders, PBC, Sjogren syndrome, IgA deficiency."

Also ^[18]: "serology: IgA anti-tTG antibody, IgA EMA +ve (may be –ve in co-existent IgA deficiency → test IgG instead)"

Aspect	Detail
Prevalence in SIgAD	Up to 2–3% of SIgAD patients (10–20× the general population prevalence)
Shared genetic basis	Both conditions are linked to HLA-DQ2 (and to a lesser extent HLA-DQ8)
Pathophysiology	Gluten peptides → deamidated by tissue transglutaminase (tTG) in endomysium → bind HLA-DQ2/DQ8+ APCs → T-cell activation → immune-mediated small bowel damage (villous atrophy, crypt hyperplasia, intraepithelial lymphocytosis) ^[18]
Paediatric presentation	FTT after weaning onto cereals (peak 8–24 months) ^[18], chronic diarrhoea (steatorrhoea), abdominal distension, irritability, iron deficiency anaemia, short stature, delayed puberty
Diagnostic pitfall	IgA anti-tTG will be falsely negative in SIgAD → must use IgG anti-tTG or IgG anti-deamidated gliadin peptide (DGP) ^[6]^[18]
Complications of coeliac itself	2× risk of malignancy (especially T-cell lymphoma, small bowel carcinoma) ^[18]; ulcerative jejuno-ileitis; bone loss (osteoporosis, osteomalacia from vitamin D/calcium malabsorption)

Coeliac Screening in SIgAD — Must-Know Exam Point

In any child with confirmed SIgAD, actively screen for coeliac disease using IgG-based serology (IgG anti-tTG or IgG anti-DGP), NOT standard IgA-based tests ^[6]^[18]. Failure to screen — or using the wrong test — means missed coeliac disease → ongoing mucosal damage → FTT, iron deficiency, osteopaenia, and ultimately malignancy risk. This is examined repeatedly.

Condition	Mechanism	Key Points for Paediatrics
Type 1 diabetes mellitus	Shared HLA-DR3/DQ2 susceptibility; T-cell mediated destruction of pancreatic β-cells	Screen with anti-GAD, anti-IA2, anti-insulin antibodies if polyuria/polydipsia develop; note that IgA anti-tTG screening for coeliac in T1DM patients must account for co-existing SIgAD ^[19]
Autoimmune thyroiditis (Hashimoto's)	Anti-TPO and anti-thyroglobulin antibodies; lymphocytic infiltration of thyroid	Hypothyroidism: fatigue, weight gain, constipation, goitre; screen TFTs
Juvenile idiopathic arthritis (JIA)	Immune dysregulation → joint inflammation; some overlap with HLA-DR susceptibility	Joint swelling, morning stiffness, limp
Systemic lupus erythematosus (SLE)	Multi-system autoimmune disease; SIgAD more prevalent in SLE cohorts	Malar rash, arthritis, nephritis, cytopaenias, serositis
Inflammatory bowel disease (IBD)	Impaired mucosal immune regulation without sIgA → chronic gut inflammation	Bloody diarrhoea, abdominal pain, weight loss, perianal disease (Crohn's)
Pernicious anaemia	Anti-intrinsic factor antibodies → B12 malabsorption	Rare in children; megaloblastic anaemia, neurological symptoms

Complication	Pathophysiology	Clinical Features
Asthma	Absent sIgA → increased aeroallergen penetration across respiratory mucosa → enhanced IgE sensitisation → allergic airway inflammation, bronchial hyper-reactivity	Wheeze, cough (especially nocturnal/exercise-induced), chest tightness, dyspnoea
Allergic rhinitis	Same mechanism at nasal mucosa → mast cell degranulation, chronic nasal inflammation	Sneezing, rhinorrhoea, nasal congestion, itchy nose/eyes
Atopic dermatitis (eczema)	Increased percutaneous and mucosal allergen exposure → systemic IgE sensitisation; impaired mucosal tolerance	Pruritic, erythematous, lichenified plaques in flexural areas
Food allergy	Absent gut sIgA → increased food antigen absorption → IgE sensitisation to food proteins	Urticaria, angioedema, vomiting, anaphylaxis after specific food exposure
Drug allergy	Increased mucosal permeability may facilitate drug-antigen complex formation	Variable presentations; document and manage per standard allergy protocols

The atopic march in SIgAD: Children with SIgAD may be more susceptible to the "atopic march" progression (eczema → food allergy → allergic rhinitis → asthma) because the absence of mucosal sIgA facilitates allergen sensitisation at every mucosal interface from infancy onward.

From Block A Transfusion lecture ^[8]: "Your patient has developed anaphylaxis after transfusion. After treatment, check for: IgA-deficient patients, haptoglobin-deficient patients."

Complication	Mechanism	Frequency	Prevention
Anaphylaxis to blood products	Anti-IgA antibodies (IgG class) in the SIgAD patient react with donor IgA present in plasma of standard blood products → immune complex formation → complement activation → mast cell degranulation → anaphylaxis ^[8]	Anti-IgA antibodies present in ~30–40% of SIgAD patients; clinically significant anaphylaxis is rare but potentially fatal	Pre-transfusion: check anti-IgA antibodies; use washed cellular products if positive; have anaphylaxis kit ready ^[8]
Urticarial transfusion reaction	Milder allergic reaction to donor plasma proteins (not necessarily IgA-specific) — IgE-mediated type 1 reaction ^[8]	More common (~3% of all transfusions)	Antihistamine pre-medication; slow infusion rate

Haptoglobin Deficiency — A Parallel Consideration in Hong Kong

Haptoglobin deficiency is common in Chinese populations (~1:1000) ^[8] and can also cause transfusion anaphylaxis via anti-haptoglobin antibodies. In a Hong Kong paediatric setting, when investigating post-transfusion anaphylaxis, check both IgA levels and haptoglobin levels to identify the cause.

This is not merely a "complication" but represents the natural history of the underlying immune defect worsening in a subset of patients.

CVID clinical phenotypes include: recurrent infections, polyclonal lymphoproliferation, autoimmune cytopaenias, granulomatous disease, and increased risk for GI and lymphoid malignancies ^[2]^[4].

Aspect	Detail
Frequency	~5–10% of SIgAD patients progress to CVID over months to years
Mechanism	The same B-cell class-switch/differentiation defect that prevents IgA production progressively impairs IgG production. Shared genetic basis (TACI mutations) predisposes to both conditions.
How it manifests	Serial annual immunoglobulin monitoring shows progressive decline in IgG levels falling below 2 SD of age-matched normal range
Clinical significance	CVID is a much more serious condition than SIgAD — carries risks of severe infections, bronchiectasis, granulomatous-lymphocytic interstitial lung disease (GLILD), autoimmune disease, and malignancy (especially non-Hodgkin lymphoma and GI malignancies) ^[2]
Implications	Once reclassified as CVID, the child requires regular IVIG/SCIG replacement therapy and more intensive monitoring

Why Annual Ig Monitoring Is Non-Negotiable

The 5–10% progression rate from SIgAD to CVID means that approximately 1 in 10–20 SIgAD children will develop a significantly more serious immunodeficiency. The only way to detect this early is serial immunoglobulin quantification — ideally annually. A falling IgG is the critical red flag. Early initiation of Ig replacement in evolving CVID prevents cumulative end-organ damage (especially bronchiectasis).

Complication	Pathophysiology	Clinical Features
Nodular lymphoid hyperplasia (NLH) of small bowel	Absent sIgA → chronic luminal antigen exposure → compensatory lymphoid tissue proliferation in gut mucosa	Usually asymptomatic (incidental endoscopic finding); may cause mild abdominal pain, diarrhoea
Chronic non-specific diarrhoea	Multifactorial: impaired mucosal barrier, subclinical infection, altered microbiome	Intermittent loose stools without specific pathogen; diagnosis of exclusion after ruling out coeliac, Giardia, IBD
Malabsorption	Secondary to coeliac disease, Giardia, SIBO, or chronic mucosal inflammation	FTT, nutritional deficiencies (iron, folate, fat-soluble vitamins), steatorrhoea
Inflammatory bowel disease (IBD)	Immune dysregulation; absent mucosal IgA may disrupt tolerance to commensal flora → chronic intestinal inflammation	Bloody diarrhoea (UC), abdominal pain, weight loss, perianal disease (Crohn's)

Malignancy	Mechanism	Risk Magnitude
Gastrointestinal malignancies (gastric carcinoma, small bowel adenocarcinoma)	Chronic mucosal inflammation without sIgA protection → increased cellular turnover → accumulation of mutations. Additionally, associated coeliac disease independently increases GI malignancy risk.	Slightly increased compared to general population (less than the risk in CVID)
Lymphoid malignancies (non-Hodgkin lymphoma)	Chronic immune stimulation → lymphoid hyperplasia → potential malignant transformation; shared genetic susceptibility	Low but above population baseline; higher risk if progresses to CVID
T-cell lymphoma (enteropathy-associated)	Specifically associated with refractory coeliac disease in SIgAD patients ^[18]	Rare; mitigated by strict gluten-free diet compliance in those with co-existing coeliac

Important paediatric perspective: Malignancy as a complication of SIgAD is overwhelmingly an adult concern. In children, the risk is very low and routine cancer screening is not recommended. However, the foundation for malignancy risk is laid in childhood (cumulative mucosal damage, chronic inflammation), which reinforces the importance of managing associated conditions early.

When SIgAD co-exists with IgG2 deficiency (the most common IgG subclass co-deficiency), complications are amplified:

Complication	Why Worse With IgG2 Co-Deficiency
Recurrent sinopulmonary infections	IgG2 is the primary IgG subclass responding to polysaccharide antigens (bacterial capsules). Losing both sIgA (mucosal defence) and IgG2 (systemic opsonisation of encapsulated bacteria) creates a "double hit."
Bronchiectasis	Higher infection frequency and severity → faster progression to irreversible airway damage
Sepsis from encapsulated bacteria	Without either mucosal or systemic protection, invasive disease (bacteraemia, meningitis) becomes more likely, though still uncommon

These are often overlooked but are important in family-centred care:

Issue	Explanation
Parental anxiety	A diagnosis of "immunodeficiency" — even a mild one — can cause significant parental distress. Parents may become overly protective, restricting the child's activities unnecessarily.
School absenteeism	Recurrent infections → frequent medical visits and hospital admissions → missed school days → academic underperformance
Over-medicalisation	Frequent blood tests and medical reviews can be distressing for children; balance monitoring with minimising invasive procedures
Social isolation	Parents may isolate the child from peers due to infection fears
Antibiotic resistance concerns	Frequent antibiotic courses → selection of resistant organisms → harder-to-treat future infections

Management: Proactive counselling, emphasising the benign nature of SIgAD in the majority, encouraging normal activities, involving school nurses, and connecting families with PID support groups.

Complication Category	Specific Complications	Frequency in SIgAD	Mechanism	Reversible?
Infectious	Recurrent otitis media, sinusitis, pneumonia	Common (symptomatic minority)	Lost mucosal sIgA → encapsulated bacteria	Treatable but recurrent
Structural	Bronchiectasis	Uncommon but serious	Cumulative damage from recurrent LRTI	Irreversible
Autoimmune	ITP, AIHA, Evans syndrome	~10–25% of SIgAD	Immune dysregulation, shared HLA	Treatable; may be chronic
Autoimmune — GI	Coeliac disease	2–3%	Shared HLA-DQ2; increased mucosal Ag exposure	Controlled with gluten-free diet
Autoimmune — Endocrine	T1DM, autoimmune thyroiditis	Increased over baseline	Shared HLA susceptibility	Irreversible (T1DM); treatable (thyroiditis)
Autoimmune — Rheumatic	JIA, SLE	Increased over baseline	Immune dysregulation	Treatable; may be chronic
Atopic	Asthma, eczema, allergic rhinitis, food allergy	~30–40% of SIgAD	Increased allergen penetration	Manageable; often chronic
Transfusion	Anaphylaxis	Rare (in those with anti-IgA Ab)	Anti-IgA Ab vs donor IgA	Preventable with washed products
GI (non-infectious)	NLH, chronic diarrhoea, malabsorption, IBD	Variable	Impaired mucosal barrier, chronic Ag stimulation	Variable
Malignancy	GI carcinoma, lymphoma	Slightly increased	Chronic inflammation, immune dysregulation	—
Immune progression	Progression to CVID	5–10%	Progressive B-cell differentiation failure	Irreversible; manageable with Ig replacement
Psychosocial	Anxiety, school disruption, over-medicalisation	Common in families	Diagnosis impact	Addressable with counselling

High Yield Summary — Complications of SIgAD

Infectious: Recurrent sinopulmonary infections (encapsulated bacteria) and GI infections (Giardia). Key structural consequence: bronchiectasis (irreversible, preventable with early aggressive management).

Autoimmune (most examined):

Coeliac disease (2–3%): screen with IgG-based serology, NOT IgA anti-tTG
ITP, AIHA, Evans syndrome: may be presenting feature; IVIG for ITP carries anti-IgA anaphylaxis risk
T1DM, autoimmune thyroiditis, JIA, SLE, IBD

Atopic: Asthma, eczema, allergic rhinitis, food allergy (~30–40%) — due to increased allergen penetration across deficient mucosal barrier.

Transfusion anaphylaxis: Anti-IgA antibodies react with donor IgA → use washed products. Also check haptoglobin (Chinese population).

Progression to CVID (~5–10%): The most consequential long-term complication. Detected by annual IgG monitoring. CVID carries much higher risks (bronchiectasis, GLILD, malignancy, severe infections).

Malignancy: Slightly increased GI and lymphoid malignancy risk; higher if co-existing coeliac disease (T-cell lymphoma).

Active Recall - Complications of Selective IgA Deficiency

^[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.410 — Primary Immunodeficiency, SIgAD: "most common PID, usually asymptomatic") ^[2] Senior notes: Jerry's immunodeficiencies.pdf (p.1–4 — CVID complications: lymphoproliferation, autoimmune cytopaenias, GI and lymphoid malignancies; PID classification: "immunodeficiency not just infection susceptible, also increased risk for autoimmune diseases, malignancy etc.") ^[4] Lecture slides: Investigations of Imm Disorders 2025.pdf (p.21 — CVID phenotype: recurrent infections, polyclonal lymphoproliferation, autoimmune cytopaenias, granulomatous disease; TACI deficiency) ^[6] Senior notes: Ryan Ho GI.pdf (p.126 — Coeliac disease and IgA deficiency: IgG-based serology required) ^[7] Senior notes: Ryan Ho Haemtology.pdf (p.117 — ITP secondary to selective IgA deficiency; anti-platelet antibody mechanism) ^[8] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (p.18–19 — IgA-deficient patients, anti-IgA antibodies, haptoglobin deficiency in Chinese, transfusion anaphylaxis) ^[9] Lecture slides: Investigations of Imm Disorders 2025.pdf (p.16 — ESID CVID criteria, switched memory B cells and bronchiectasis risk) ^[17] Senior notes: Ryan Ho Respiratory.pdf (p.128–129 — Bronchiectasis causes including selective IgA deficiency, lower lobe predominance in immunodeficiency, vicious cycle pathogenesis) ^[18] Senior notes: Adrian Lui Pediatrics Notes.pdf (p.260 — Coeliac disease: HLA-DQ2 link, IgA deficiency association, IgA anti-tTG false negative, complications including T-cell lymphoma and SB carcinoma, FTT in paediatrics) ^[19] Senior notes: Ryan Ho Endocrine.pdf (p.94 — T1DM complication screening: anti-tTG IgA at diagnosis for concomitant autoimmune diseases)

High Yield Summary

Definition: Serum IgA < 0.07 g/L in patient ≥ 4 years, with normal IgG and IgM, other causes excluded.

Epidemiology: Most common PID (~1:500 in Caucasians, rarer in Chinese). Most patients asymptomatic.

Compensatory mechanism: Secretory IgM partially substitutes at mucosal surfaces — explains why most are asymptomatic.

Clinical features (symptomatic minority):

Recurrent sinopulmonary + GI infections (encapsulated bacteria, Giardia)
Atopy (asthma, eczema, allergic rhinitis, food allergy)
Autoimmune disease (coeliac disease [use IgG-based serology!], ITP, AIHA, SLE, T1DM)
Transfusion anaphylaxis (anti-IgA antibodies vs donor IgA → must use washed products)
Risk of progression to CVID

Key exam traps:

Cannot diagnose before age 4 (IgA matures slowly).
IgA-based coeliac serology (IgA anti-tTG) is falsely negative in SIgAD → use IgG anti-tTG.
Transfusion anaphylaxis: check IgA levels and anti-IgA antibodies.
SPUR infections framework for PID suspicion.
Low ESR may indicate low globulin — not necessarily reassuring.

High Yield Summary — Differential Diagnosis of SIgAD

Must-exclude primary immunodeficiencies:

CVID (IgG also low; poor vaccine responses; low switched memory B cells — on the same spectrum as SIgAD; ~5–10% progress)
XLA (all Ig ↓↓↓; B cells absent; boys; BTK mutation)
Hyper-IgM syndrome (IgM ↑↑↑; IgG and IgA ↓; class-switch failure)
Ataxia-telangiectasia (ataxia, telangiectasias, ↑AFP, IgA/IgG2 ↓)
22q11.2 deletion (cardiac, thymic, parathyroid anomalies)
THI (transient; cannot diagnose SIgAD before age 4)

Must-exclude secondary causes: Drugs (phenytoin, carbamazepine), protein-losing states, nephrotic syndrome, HIV, malignancy, immunosuppressive therapy.

High Yield Summary — Diagnosis and Investigations

Diagnostic definition: Serum IgA < 0.07 g/L measured on ≥ 2 occasions, with normal IgG and IgM, in a child ≥ 4 years, with secondary causes excluded and no T-cell deficiency.

Key differentiating investigation from CVID: IgG level — normal in SIgAD, markedly low in CVID. Also check vaccine responses and switched memory B cells.

First-line panel: CBC + diff, IgG/IgA/IgM/IgE, total protein/globulin, ESR/CRP, HIV test.

Must-do additional tests: IgG subclasses (especially IgG2), coeliac screen with IgG-based serology (NOT IgA-tTG alone), anti-IgA antibodies (for transfusion safety), autoimmune screen.

GC high-yield points:

CBC interpretation: low ALC → SCID not SIgAD; low platelets → WAS; high IgE → HIES
Ig profile pattern: low IgA only + normal IgG/IgM = SIgAD
CVID requires ↓IgG + ↓IgA + poor vaccine responses + diagnosis after age 4
B-cell enumeration by flow cytometry → absent = XLA, present = CVID or SIgAD
Low ESR may paradoxically indicate low globulin in PID

High Yield Summary — Management of SIgAD

Core principles:

No IgA replacement exists — IVIG/SCIG replaces IgG only
Most patients need education and monitoring only — NOT treatment
IVIG/SCIG is indicated only when co-existing IgG subclass deficiency with poor vaccine responses, or progression to CVID

Blood product safety: Check anti-IgA antibodies; use washed cellular products if positive; irradiation is NOT needed (T cells are normal)

Monitoring: Annual immunoglobulins (watch for IgG decline → CVID); growth; respiratory status; autoimmune screening

Common exam errors: Starting IVIG for isolated SIgAD; withholding live vaccines; ordering irradiated (not washed) blood products; using IgA-based coeliac serology

High Yield Summary — Complications of SIgAD

Autoimmune (most examined):

Coeliac disease (2–3%): screen with IgG-based serology, NOT IgA anti-tTG
ITP, AIHA, Evans syndrome: may be presenting feature; IVIG for ITP carries anti-IgA anaphylaxis risk
T1DM, autoimmune thyroiditis, JIA, SLE, IBD

Atopic: Asthma, eczema, allergic rhinitis, food allergy (~30–40%) — due to increased allergen penetration across deficient mucosal barrier.

Transfusion anaphylaxis: Anti-IgA antibodies react with donor IgA → use washed products. Also check haptoglobin (Chinese population).

Malignancy: Slightly increased GI and lymphoid malignancy risk; higher if co-existing coeliac disease (T-cell lymphoma).

Selective Iga Deficiency

Selective IgA Deficiency — Paediatrics

2. Epidemiology

3. Anatomy & Function of IgA — Understanding What Is Lost

4. Aetiology & Pathophysiology

5. Classification

6. Clinical Features

6.2 Symptoms

Active Recall - Selective IgA Deficiency

1. Structured Approach: Why Is the IgA Low?

Axis 1 — Other Primary Immunodeficiencies That Feature Low IgA

2. Clinical Mimics: Conditions Presenting Similarly to Symptomatic SIgAD

Active Recall - Differential Diagnosis of Selective IgA Deficiency

1. Diagnostic Criteria

3. Diagnostic Algorithm

4. Investigation Modalities — Key Findings and Interpretations

4.1 First-Line Investigations

4.2 Second-Line Investigations (Characterisation and Associated Conditions)

4.3 Third-Line / Specialist Investigations

Active Recall - Diagnosis and Investigations of Selective IgA Deficiency

4. Treatment Modalities — Detailed

4.1 Education, Counselling and Anticipatory Guidance (ALL Patients)

4.2 Infection Management

4.3 Immunoglobulin Replacement Therapy

4.4 Management of Associated Conditions

Management of Transfusion Risk in SIgAD

Active Recall - Management of Selective IgA Deficiency

2. Infectious Complications

3. Autoimmune Complications

3.1 Autoimmune Cytopaenias

Active Recall - Complications of Selective IgA Deficiency

On this page

Selective Iga Deficiency

Selective IgA Deficiency — Paediatrics

1. Definition

2. Epidemiology

2.1 Prevalence

2.2 Age at Diagnosis

2.3 Risk Factors

3. Anatomy & Function of IgA — Understanding What Is Lost

3.1 IgA Basics

3.2 Two Subclasses

3.3 Secretory IgA (sIgA) System

3.4 Distribution of IgA-Producing Plasma Cells

4. Aetiology & Pathophysiology

4.1 The Core Defect: Failure of Terminal B-Cell Differentiation to IgA-Secreting Plasma Cells

4.2 Genetic Basis

4.3 The SIgAD → CVID Continuum

4.4 Compensatory Mechanisms — Why Most Patients Are Asymptomatic

4.5 Secondary/Drug-Induced IgA Deficiency

5. Classification

5.1 Within the IUIS Classification of PIDs

5.2 Subclassification of SIgAD (Clinically Practical)

6. Clinical Features

6.1 Overview

6.2 Symptoms

A. Recurrent Infections (Mucosal — Sinopulmonary and GI)

B. Allergic / Atopic Disease

C. Autoimmune Disease

D. GI Manifestations (Beyond Infection)

E. Anaphylaxis to Blood Products

F. Malignancy Risk

6.3 Signs

6.4 When to Suspect SIgAD in a Child (Red Flags in Paediatric Practice)

7. Key Associations — Summary Table (High Yield)

8. Comparison with Other Predominantly Antibody Deficiencies (For Exam Clarity)

9. Initial Evaluation Framework for Suspected PID (from GC Lectures) [5]

10. Warning Signs of PID in Children (from Felix PY Lai Senior Notes) [3]

Active Recall - Selective IgA Deficiency

References

Differential Diagnosis of Selective IgA Deficiency in Paediatrics

1. Structured Approach: Why Is the IgA Low?

Axis 1 — Other Primary Immunodeficiencies That Feature Low IgA

A. Common Variable Immunodeficiency (CVID)

B. X-Linked Agammaglobulinaemia (XLA / Bruton Disease)

C. Hyper-IgM Syndrome (HIGM)

D. IgG Subclass Deficiency (Especially IgG2)

E. Transient Hypogammaglobulinaemia of Infancy (THI)

F. Specific Antibody Deficiency with Normal Immunoglobulins (SAD)

G. Combined Immunodeficiencies (CID) Including SCID

H. Other Syndromic PIDs with Low IgA

Axis 2 — Secondary (Acquired) Causes of Low IgA

2. Clinical Mimics: Conditions Presenting Similarly to Symptomatic SIgAD

A. Recurrent Sinopulmonary Infections — DDx Beyond SIgAD

B. Chronic Diarrhoea — DDx Beyond SIgAD

C. Autoimmune Cytopaenias — DDx Beyond SIgAD-Associated ITP/AIHA

D. Transfusion Anaphylaxis — DDx Beyond IgA Deficiency

3. Diagnostic Differentiation Algorithm

4. High-Yield Summary Table: Key Distinguishing Features

5. Non-Infectious Presentations That Should Prompt IgA Measurement

Active Recall - Differential Diagnosis of Selective IgA Deficiency

References

Diagnostic Criteria, Diagnostic Algorithm & Investigations for Selective IgA Deficiency in Paediatrics

1. Diagnostic Criteria

1.1 ESID / IUIS Consensus Definition (Current Standard)

1.2 Contrasting with CVID Criteria (To Know What You Are Excluding)

2. Paediatric Age-Specific Reference Ranges for IgA

3. Diagnostic Algorithm

3.1 Step-by-Step Approach

3.2 Mermaid Diagnostic Algorithm

4. Investigation Modalities — Key Findings and Interpretations

4.1 First-Line Investigations

A. Complete Blood Count with Differential

B. Quantitative Serum Immunoglobulins (IgG, IgA, IgM, IgE)

C. Total Serum Protein and Albumin/Globulin

D. Acute Phase Reactants (ESR, CRP)

E. HIV Testing

4.2 Second-Line Investigations (Characterisation and Associated Conditions)

A. IgG Subclass Quantification

B. Specific Antibody Responses to Vaccination (Functional Antibody Assessment)

C. Lymphocyte Subset Analysis (Flow Cytometry)

D. Coeliac Disease Screening