A Child With Recurrent Infections Primary Immunodeficiencies
Primary immunodeficiencies are a group of inherited disorders characterized by defects in one or more components of the immune system, leading to increased susceptibility to recurrent, severe, or unusual infections in childhood.
Clinical Approach to Inborn Errors of Immunity (IEI) and Juvenile Idiopathic Arthritis (JIA)
Big idea: This lecture teaches you how to recognise a child with recurrent infections who may have a primary immunodeficiency (now termed Inborn Errors of Immunity, IEI), how to systematically investigate them, and how to distinguish JIA from other causes of joint disease in children. The lecture spans two major topics under one roof: IEI and JIA—both are paediatric immunology themes that examiners love because they test your understanding of immune mechanisms, pattern recognition, and clinical approach.
Learning Objectives (directly from the lecture): [1]
- Understand that patients with IEI may present with recurrent infections, autoimmune, inflammatory, atopic, and neoplastic diseases
- Understand that defects in different immune pathways cause susceptibility to different pathogens
- Understand the general principles of investigations (and treatments) in IEI
- Distinguish JIA from infectious and other noninfectious causes of arthralgia in children
Clinical relevance: IEI are individually rare (~1 in 10,000) but collectively significant. Missing the diagnosis means the child develops end-organ damage (bronchiectasis, failure to thrive, death). JIA is the most common chronic rheumatic disease in childhood—early recognition prevents joint destruction and blindness (from uveitis).
High Yield — Normal Infections in Childhood
8 to 10 URTIs per year in young children can be normal, provided there is no end organ damage — especially if the child is just starting nursery or has many siblings at home. Normal childhood infections are of short duration, self-limited, uncomplicated, and the child is healthy in between episodes. [1]
Why this matters: The most common exam trap is over-diagnosing immunodeficiency. 50% of children with recurrent infections are actually normal. [3] The key discriminator is the quality of the infections, not just the quantity.
Red flags that suggest pathological cause (the SPUR mnemonic): [2]
- Serious — need for IV antibiotics, hospitalisation
- Persistent — prolonged course, fail to clear with standard therapy
- Unusual — opportunistic organisms, vaccine-strain infections
- Recurrent — same site or different sites, with end-organ damage
| Category | Examples | Key Clues |
|---|---|---|
| Non-immunologic defects | Anatomical obstruction (eustachian tube → recurrent OM; bronchial obstruction → recurrent same-lobe pneumonia; urinary obstruction → recurrent UTI), foreign body (VP shunt, central line), barrier defects (burns, sinus tracts), ciliary dyskinesia, CF, aspiration | Recurrent infection of same site suggests local structural cause |
| Secondary immunodeficiency | HIV, measles, chemotherapy, malignancy, malnutrition, steroids, nephrotic syndrome (Ig loss) | Always exclude secondary causes before labelling primary |
| Primary immunodeficiency (IEI) | >500 genetic diseases of the immune system | Usually present in first few years of life |
Exam Trap
"Recurrent pneumonia" may merely reflect frequent URTI or asthma — always verify the diagnosis with imaging and microbiology before jumping to IEI. [1]
IEI are >500 different genetic diseases of the immune system. [1]
IUIS Classification of IEI (10 Categories) [1][2]
| # | Category | Prototype Example | Key Feature |
|---|---|---|---|
| 1 | Combined immunodeficiency (CID) | SCID | T+B cell defect → susceptible to everything |
| 2 | CID with syndromic features | Hyper-IgE syndrome (HIES), Wiskott-Aldrich | Immune defect + recognisable syndrome |
| 3 | Predominantly antibody deficiency | XLA, CVID | Most common group (~56.7% of all IEI) |
| 4 | Diseases of immune dysregulation | IL-10R deficiency | Autoimmunity/inflammation > infection |
| 5 | Phagocyte defects | CGD, severe congenital neutropenia, LAD | Bacterial/fungal abscesses, poor wound healing |
| 6 | Innate/intrinsic immunity defects | MSMD (STAT1 LOF) | Selective susceptibility (e.g. only mycobacteria) |
| 7 | Autoinflammatory disorders | CAPS (NLRP3 GOF) | Recurrent fever, urticaria, no infection |
| 8 | Complement deficiency | C3 deficiency, C5-C9 deficiency | Neisseria, pneumococcal infections |
| 9 | Bone marrow failure | Various | Pancytopenia |
| 10 | Phenocopies of IEI | Anti-IFN-I autoAb | Acquired autoantibodies mimicking genetic IEI |
| ? | Primary atopic disorder (newly described) | STAT6 GOF | Severe eczema, asthma, eosinophilic GI disease |
High Yield — Jeffrey Modell Foundation 10 Warning Signs
- ≥8 new ear infections within 1 year
- ≥2 serious sinus infections within 1 year
- ≥2 months on antibiotics with little effect
- ≥2 pneumonias within 1 year
- Failure of an infant to gain weight or grow normally
- Recurrent, deep skin or organ abscesses
- Persistent thrush in mouth or elsewhere on skin, after age 1
- Need for intravenous antibiotics to clear infections
- ≥2 deep-seated infections
- A family history of IEI [1]
Important Caveat
This is not a comprehensive list — do not exclude patients based on the 10 warning signs alone. Patients could present with noninfectious phenotypes (autoimmunity, atopy, malignancy, autoinflammation). Refer to paediatric or adult immunology when suspicious. [1]
This is the highest-yield concept for MCQs. If you know which immune pathway is defective, you can predict the organisms, and vice versa.
| Immune Defect | Susceptible Pathogens | Why |
|---|---|---|
| T cell / Combined | All organisms — viruses (CMV, VZV, EBV), fungi (PJP, Candida), intracellular bacteria, live vaccines (BCG dissemination) | T cells coordinate entire adaptive response; without them, nothing works |
| B cell / Antibody | Encapsulated bacteria (S. pneumoniae, H. influenzae, N. meningitidis), Giardia, enteroviruses | Antibodies are needed to opsonise encapsulated bacteria; IgA protects mucosal surfaces |
| Phagocyte | Catalase-positive bacteria (S. aureus, Serratia, Burkholderia, Nocardia, Aspergillus), mycobacteria (BCG) | Catalase-positive organisms destroy their own H₂O₂, so they rely entirely on the phagocyte oxidative burst which is defective in CGD |
| Complement (C3) | Encapsulated bacteria (pneumococcus, Neisseria) | C3 is the convergence point for all complement pathways → opsonisation |
| Complement (C5-C9, terminal) | Neisseria (meningitidis, gonorrhoeae) | MAC is needed to lyse Neisseria's thin outer membrane |
| IFN-gamma pathway | Mycobacteria and Salmonella only | IFN-gamma activates macrophages to kill intracellular organisms |
| Type I IFN pathway | Viruses (including severe COVID-19) | Type I IFN is the first line of antiviral defence |
Why Antibody Deficiency Presents After 4-6 Months
Detailed IEI Prototypes (Slide-by-Slide)
Category 1: Combined immunodeficiency without associated syndromic features [1]
| Feature | Detail |
|---|---|
| Immune pathway | T and B cell defect |
| Gene | IL2RG (X-linked, loss of function) — most common form; also RAG1/2 (AR), ADA (AR) |
| Pathogens | Any — fungus (PJP), BCG dissemination, Candida, viruses (RSV, CMV, VZV) |
| Tests | Low TREC on newborn screening; low ALC ( < 2500/mL in infant); low/zero T cell count; low naive T cells |
| Treatment | HSCT (curative); gene therapy for ADA-SCID |
| CXR | Absent thymus shadow |
| Clinical | FTT, chronic diarrhoea, oral thrush, BCG scar not healing, disseminated BCG |
Why ALC < 2500 in infants = lymphopenia: Normal infants have higher lymphocyte counts than adults. An ALC of 2500 in an adult would be normal, but in an infant it's the lower limit of normal. If an infant has ALC < 2500, think SCID. [1]
David Vetter ("Bubble Boy"): Born with X-linked SCID, lived 12 years in a sterile bubble (1972-1984). This is the historical teaching case. [1]
Case from lecture: A 13-month-old girl with severe RSV pneumonia requiring ECMO, cutaneous VZV vaccine-strain reactivation, FTT, persistent lymphopenia → compound heterozygous RAG1 mutations → hypomorphic (leaky) SCID → cured by BMT at 20 months. [1]
ADA-SCID: CXR shows absent thymus and may show rib notching (a specific feature). [1]
SCID and Newborn Screening
TREC (T-cell Receptor Excision Circle) is a byproduct of T-cell receptor rearrangement in the thymus. Low TREC on newborn dried blood spot = low T-cell production = possible SCID. This is the basis for newborn screening. Similarly, KREC (Kappa-deleting Recombination Excision Circle) screens for agammaglobulinaemia. [1]
Category 2: Combined immunodeficiency with associated syndromic features [1]
| Feature | Detail |
|---|---|
| Immune pathway | Th17 cell defect |
| Gene | STAT3 (AD, loss of function) |
| Pathogens | Bacteria (massive "cold" staphylococcal abscesses), fungi |
| Tests | High IgE, high AEC (absolute eosinophil count) |
| Treatment | Trimethoprim-sulfamethoxazole (TMP-SMX) and IVIG |
| Clinical features | Cold abscesses (no warmth/erythema because Th17 deficiency impairs neutrophil recruitment), coarse facial features, poor dentition (retained primary teeth), pneumatoceles, skeletal abnormalities, eczema |
Why "cold" abscesses? STAT3 is essential for Th17 differentiation. Th17 cells produce IL-17, which recruits neutrophils to sites of infection. Without adequate Th17 function, neutrophil chemotaxis is poor → abscesses form but lack the typical inflammatory signs (warmth, redness). [1][2]
Radiographic hallmark: Pneumatoceles — thin-walled cystic spaces in the lung parenchyma that persist after staphylococcal pneumonia. These are nearly pathognomonic in the right clinical context. [1]
Category 3: Predominantly antibody deficiency [1]
| Feature | Detail |
|---|---|
| Immune pathway | B cell defect |
| Gene | BTK (Bruton Tyrosine Kinase) (X-linked, loss of function) |
| Pathogens | Bacteria (encapsulated), enteroviruses, protozoa (Giardia) |
| Tests | Low KREC on newborn screening; low IgG, IgA, IgM (panhypogammaglobulinaemia); low/zero B cell count |
| Treatment | IVIG/SCIG replacement (lifelong) |
| Clinical | Recurrent sinopulmonary infections (sinusitis, otitis media, pneumonia), chronic diarrhoea, bronchiectasis if late diagnosis; absent/hypoplastic tonsils/lymph nodes (because these are B-cell organs); can develop chronic enteroviral meningoencephalitis |
Why enteroviruses but not influenza? Enterovirus clearance depends heavily on antibody-mediated neutralisation. Influenza can be handled partly by T-cell immunity and innate responses. This is a common viva question. [2]
Case from lecture: 3-year-old boy with recurrent sinopulmonary infections since 6 months → CT showing sinusitis and HRCT showing bronchiectasis → panhypogammaglobulinaemia and absent B cells → diagnosed XLA → started on regular IVIG with growth improvement. [1]
Long-term complication: Even with IVIG replacement, bronchiectasis develops in many patients (30-year-old XLA male with bronchiectasis shown in lecture). This emphasises the importance of early diagnosis and adequate Ig trough levels. [1]
Immunoglobulin Levels in Neonates
Maternal IgG is the only immunoglobulin that crosses the placenta (via FcRn receptor). It peaks at birth and gradually declines over 4-6 months. The infant begins producing its own IgM first (detectable at birth), then IgG (reaches adult levels by ~5-7 years). There is a physiological nadir at 3-6 months ("transient hypogammaglobulinaemia of infancy"). XLA becomes apparent when maternal IgG wanes. [1]
Not a dedicated slide in this lecture but heavily tested and mentioned in supporting materials. [5][6]
| Feature | Detail |
|---|---|
| Epidemiology | Most common form of severe antibody deficiency |
| Pathophysiology | Impaired B cell differentiation → defective Ig production |
| Ix | Low IgG (always), low IgA/IgM (variable), normal or low B cells |
| Clinical | Recurrent sinopulmonary infections, bronchiectasis, chronic diarrhoea, autoimmune cytopenias (ITP, AIHA in ~25%), granulomatous disease (8-22%), lymphoproliferation, increased risk of GI and lymphoid malignancy |
| Treatment | IVIG replacement, prophylactic antibiotics |
| Genes | ICOS, CD19, BAFF-R, TACI — together only account for 10-15% of cases |
Category 5: Defects in phagocyte number or function [1]
| Feature | Detail |
|---|---|
| Immune pathway | Respiratory burst in phagocytes (NADPH oxidase defect) |
| Gene | CYBB (X-linked, loss of function) — also AR forms (CYBA, NCF1, NCF2) |
| Pathogens | Bacteria (catalase-positive: S. aureus, Serratia, Burkholderia, Nocardia), mycobacteria (BCG dissemination), fungi (Aspergillus) |
| Tests | Low dihydrorhodamine reduction (DHR) — previously nitroblue tetrazolium (NBT) test |
| Treatment | TMP-SMX, itraconazole, and HSCT |
Why catalase-positive organisms? Normal phagocytes use NADPH oxidase to generate reactive oxygen species (superoxide → H₂O₂). When this pathway is defective (CGD), the phagocyte relies on H₂O₂ produced by the bacteria themselves. Catalase-negative organisms (e.g. Streptococcus) produce H₂O₂ but don't destroy it → the phagocyte can still use that bacterial H₂O₂ for killing. Catalase-positive organisms (e.g. Staphylococcus) produce AND destroy their own H₂O₂ → so the phagocyte has no oxidative killing mechanism at all. [2][3]
Clinical features from the lecture: [1]
- Cervical abscesses, perianal abscesses/scars
- BCG-osis (disseminated BCG infection after vaccination)
- Pulmonary aspergillosis with rib erosion
- Granulomatous inflammation (histology)
- Can present with IBD-like colitis, enthesitis-related JIA, iritis
The "granulomatous" in CGD: Frustrated phagocytes cannot kill the organisms, so the immune system walls them off with granulomas — hence "chronic granulomatous disease."
Not a full dedicated slide but mentioned in lecture context: [1][3]
- Delayed separation of umbilical cord ( > 30 days) suggests leukocyte adhesion defect — this is because neutrophils are needed for the inflammatory process that causes cord separation
- Absent pus formation (hallmark) — neutrophils cannot leave the vasculature → persistent neutrophilia in blood but no neutrophils at infection site
- Poor wound healing
Category 6: Innate or intrinsic immunity defects [1]
| Feature | Detail |
|---|---|
| Immune pathway | IFN-gamma pathway |
| Gene | STAT1 (AD or AR, loss of function) — also IFNGR1, IFNGR2, IL12B, IL12RB1 |
| Pathogens | Mycobacteria and Salmonella only |
| Tests | Advanced functional tests |
| Treatment | Antimycobacterials |
Why only mycobacteria and Salmonella? IFN-gamma is the master cytokine for macrophage activation against intracellular pathogens. Mycobacteria and Salmonella are archetypal intracellular organisms that survive inside macrophage phagosomes. Without IFN-gamma signalling, macrophages cannot upregulate their killing machinery. [1][2]
Case from lecture: Two siblings heterozygous for STAT1 c.2129C>T → disseminated BCG infection. [1]
Monogenic Infections
Some IEI patients are susceptible to only one group of pathogens — these are called "Mendelian infections" or "monogenic infections." Examples: viral infections in type I IFN deficiency; mycobacterial/Salmonella infections in IFN-gamma deficiency. This concept is important because it explains why some IEI patients don't have broadly recurrent infections. [1]
Category 8: Complement deficiency [1]
| Component | Gene/Inheritance | Pathogens | Tests | Treatment |
|---|---|---|---|---|
| C3 deficiency | C3 (AR, LOF) | Neisseria, pneumococcus | Low CH50 and C3 | Antibiotic prophylaxis |
| C5-C9 (terminal) | Various | Neisseria (especially) | Low CH50, low AH50 | Vaccination + antibiotic prophylaxis |
| C1, C2, C4 (early classical) | Various | Predispose to autoimmune disorders (SLE) | Low CH50 | Varies |
Why Neisseria? The membrane attack complex (MAC, C5b-C9) inserts pores into the bacterial outer membrane. Neisseria species have a thin outer membrane and are particularly dependent on MAC for killing. Without terminal complement, Neisseria infections become recurrent and severe. [1][4]
Past paper connection: Eculizumab (anti-C5 monoclonal antibody) blocks MAC formation → increased risk of Neisseria meningitidis infection. Patients must be vaccinated against meningococcus before starting eculizumab. [7]
Category 4: Diseases of immune dysregulation [1]
| Feature | Detail |
|---|---|
| Immune pathway | IL-10 pathway |
| Gene | IL10R1 (AR, loss of function) |
| Features | Early-onset IBD (presenting 1st month of life with diarrhoea, perianal sepsis, pyoderma gangrenosum) |
| Tests | Genetics |
| Treatment | Biologics (anti-TNFα, anti-IL-6, anti-IL-23), HSCT, steroids |
Why does IL-10 deficiency cause IBD? IL-10 is the master anti-inflammatory cytokine. It suppresses excessive inflammatory responses in the gut. Without it, there is unchecked inflammation in the intestinal mucosa → very early-onset, severe, medically refractory IBD. [1]
Category 7: Autoinflammatory diseases [1]
| Feature | Detail |
|---|---|
| Immune pathway | Inflammasome and IL-1 |
| Gene | NLRP3 (AD, gain of function) |
| Features | Recurrent fever and urticaria |
| Tests | Genetics |
| Treatment | Biologics — IL-1 blockade (anakinra, canakinumab) |
The CAPS spectrum includes:
- Familial Cold Autoinflammatory Syndrome (FCAS) — mildest
- Muckle-Wells Syndrome
- CINCA (Chronic Infantile Neurological Cutaneous and Articular Syndrome) — most severe
Somatic vs germline mutations: Somatic mutations in NLRP3 cause milder disease than germline mutations. [1] This is because somatic mutations are present in only a fraction of cells (mosaicism).
Why gain-of-function? NLRP3 encodes cryopyrin, a component of the inflammasome. Gain-of-function mutations cause constitutive activation → excessive IL-1β production → chronic systemic inflammation without infection.
Not yet assigned an IUIS category number [1]
| Feature | Detail |
|---|---|
| Immune pathway | Various, e.g. IL4R/JAK/STAT6 pathway |
| Gene | STAT6 (AD, gain of function) |
| Features | Early-onset, recalcitrant eczema, asthma, eosinophilic gastroenteritis |
| Tests | High IgE, high AEC |
| Treatment | Biologics (dupilumab) — monitor response using SCORAD/EASI |
Why this is a new concept: Previously, severe eczema/atopy was considered multifactorial. Now it's recognised that some cases have a single-gene cause (monogenic atopy). STAT6 gain-of-function drives excessive Th2 responses → IgE overproduction, eosinophilia, and allergic inflammation. [1]
Case from lecture: A child with severe eczema dramatically improved with dupilumab (anti-IL-4Rα antibody). Peripheral blood eosinophilia reduced, SCORAD/EASI scores improved, and growth improved after treatment. [1]
Category 10: Phenocopies of IEI [1]
Phenocopies are conditions that mimic genetic IEI but are caused by acquired autoantibodies or somatic mutations: [1]
| Autoantibody Target | Clinical Phenotype |
|---|---|
| Anti-IFN-gamma | Mycobacterial infections (adult-onset) |
| Anti-IL-17/IL-22 | Chronic mucocutaneous candidiasis |
| Anti-IFN-I (type I interferon) | Severe COVID-19, severe viral infections |
Why this matters clinically: These patients look like they have a genetic IEI but don't. Testing for autoantibodies against cytokines is important, especially in adults with unexplained severe infections.
Clinical Approach: History Taking
Systematically documented in the lecture [1]:
- Complete review of systems
- IEIs can affect many different organs → don't just look for infections
- Five phenotypes to document: [1]
- Infections (recurrent, opportunistic, or live vaccine)
- Autoinflammation, autoimmunity (IBD, AIHA, arthritis)
- Non-malignant lymphoproliferation
- Atopy
- Cancer (e.g. lymphoma)
- Age of onset — usually first few years of life; SCID mostly in first year
- Pathogen — pathogen-immunophenotype-genotype correlations
- Look for opportunistic pathogens, vaccine strains
- May be sensitive to one group of pathogens only (Mendelian infections)
- Severity and resolution/recurrence
- Steroids, immunosuppressants (exclude secondary causes)
- History of blood product transfusions
- Maternal illnesses (HIV, CMV)
- Detachment of umbilical cord — > 30 days suggests leukocyte adhesion defect
- Neonatal hypocalcaemia (think DiGeorge)
- Newborn screening — TREC for SCID, KREC for agammaglobulinaemia
- Weight and height curves — failure to thrive
- Development — especially in ataxia-telangiectasia and DiGeorge syndrome
- Up to date on vaccines?
- Infection by live attenuated vaccines, e.g. BCG → disseminated BCG = think CGD or SCID
- Draw a pedigree
- Infections, rheumatic/atopic diseases, unexplained deaths, age of onset
- Inheritance patterns:
- Consanguinity → autosomal recessive (rare in HK Chinese)
- Maternal uncles → X-linked disease in a boy
- AD diseases often have incomplete penetrance
From the lecture slide [1]:
| Finding | What It Suggests |
|---|---|
| Growth — Failure to thrive | Chronic disease, SCID, any severe IEI |
| Mucocutaneous — Candidiasis | T-cell defect, CMC |
| Lymphatic tissue — Too much or too little | Too little → XLA (absent tonsils); Too much → CVID, lymphoproliferation |
| Lung — Bronchiectasis | Antibody deficiency, ciliary dyskinesia |
| Hepatosplenomegaly | Lymphoproliferation, CGD |
| Arthritis | JIA, CGD with enthesitis |
| Neurology — Ataxia | Ataxia-telangiectasia |
| Nails — Dysplastic or Candidiasis | CMC, dyskeratosis congenita |
| Skin — Poor wound healing or scar | Phagocyte defect, HIES |
High Yield — First-Line Investigations for IEI
Always consult paediatric or medical immunology when clinically suspicious. [1]
First-line: [1]
- CBC and differentials
- IgG, IgA, IgM, and IgE
- Lymphocyte subsets (T, B, NK cells by flow cytometry)
- Genetics:
- Targeted gene sequencing (e.g. IL2RG for X-SCID, BTK for XLA, CYBB for X-CGD, WAS)
- NGS panel (~400-500 known IEI genes)
- Whole exome sequencing (all coding regions)
Consider: [1]
- T/B cell subsets (naive vs memory)
- Functional antibodies (vaccine responses)
- DHR (dihydrorhodamine reduction test) for CGD
- Other functional assays (available at QMH, research setting, or overseas)
Interpreting First-Line Results
| Test | Findings | Diagnosis to Consider |
|---|---|---|
| ALC | Low < 3000 ( < 1y) or < 1000 ( > 1y) | SCID, combined immunodeficiency |
| AEC | High | Primary atopic disorder |
| ANC | *** < 1*** | Severe congenital neutropenia |
| ANC | High | Leukocyte adhesion deficiency |
| AMC | Low | GATA2 deficiency |
| PLT | Low | Wiskott-Aldrich syndrome |
| IgGAM | Low IgGAM | Agammaglobulinaemia (XLA) |
| IgE | High | Hyper-IgE syndrome, primary atopic disorder |
| IgM | High | Hyper-IgM syndrome |
| IgGAM | High | CGD (chronic stimulation) |
| IgM | Low | DOCK8, WAS, ataxia-telangiectasia |
| Lymphocyte subsets | Low T ± low B ± NK | Combined immunodeficiency |
| Lymphocyte subsets | Low B only | Agammaglobulinaemia |
Critical Point
Many IEIs require tailored investigations and cannot be picked up by initial screening tests. Always consult immunology when clinically suspicious. [1] In some forms of CID, T-cell count may be normal but function is impaired, or they may be maternally grafted memory T cells (as in Omenn syndrome, a form of SCID). [1]
Mentioned in the neonatal history context: [1][3]
| Feature | Detail |
|---|---|
| Genetics | 22q11.2 microdeletion |
| Triad | Conotruncal cardiac anomaly + hypoplastic thymus (T-cell deficiency) + hypoplastic parathyroids (hypocalcaemia) |
| Clinical | Palatal abnormalities, developmental delay, facial dysmorphism |
| Ix | Neonatal hypocalcaemia, low T cells |
| IEI Type | Treatment |
|---|---|
| SCID | HSCT (curative), gene therapy (for ADA-SCID) |
| XLA / CVID | Lifelong IVIG or SCIG replacement |
| CGD | TMP-SMX prophylaxis, itraconazole prophylaxis, HSCT |
| HIES | TMP-SMX prophylaxis, IVIG |
| MSMD | Antimycobacterials |
| Complement deficiency | Antibiotic prophylaxis, vaccination |
| IL-10R deficiency | Biologics, HSCT |
| CAPS | IL-1 blockade (anakinra, canakinumab) |
| Primary atopic disorder | Biologics (dupilumab) |
| Phenocopies | Vaccination, antivirals, replacement |
Juvenile Idiopathic Arthritis (JIA)
The second half of this lecture covers JIA. This is clinically important and frequently tested.
Onset under 16 years old, persistent manifestations > 6 weeks, no other cause [1]
| Subtype | Criteria | Key Features |
|---|---|---|
| Systemic JIA (sJIA) | Fever ≥2 weeks (quotidian ≥3 days) + arthritis + ≥1 of: evanescent rash, hepatosplenomegaly, serositis, lymphadenopathy | Autoinflammatory; can cause MAS (macrophage activation syndrome) |
| Polyarthritis, RF+ve or -ve | ≥5 joints; RF positive at 2 times, 3 months apart; anti-CCP | Exclude those with FHx of psoriasis or ERA features |
| Oligoarthritis | Persistent: 1-4 joints during first 6 months, never progresses to ≥5; Extended: < 5 joints in first 6 months, then > 4 joints | Most common subtype; risk of chronic anterior uveitis |
| Enthesitis-Related Arthritis (ERA) | Arthritis + enthesitis, OR either alone + ≥2 of: SI/LS joint tenderness, HLA-B27, FHx of AS/IBD, acute anterior uveitis, male onset > 6 years | Paediatric equivalent of ankylosing spondylitis |
| Psoriatic Arthritis | Psoriasis + arthritis, OR arthritis + ≥2 of: FHx psoriasis, dactylitis, nail pitting/onycholysis | Exclude if ERA, sJIA, or RF+ |
Fever for > 2 weeks; onset of arthritis may be delayed for weeks/months [1]
If with serositis or MAS manifestations, can manage as sJIA without arthritis [1]
Treatment escalation: [1]
- NSAID
- Steroids
- IL-1 inhibitors (anakinra, canakinumab)
- IL-6 inhibitors (tocilizumab)
- TNF-α inhibitors
- IL-18 binding protein
- Emapalumab (targets IFN-gamma) for HLH/MAS
- HSCT and JAK inhibitors
- NSAID (naproxen) — if not in remission in 6 weeks
- Consider methotrexate with folic acid — if not in remission in 2-3 months
- Consider biologics: TNF-α inhibitors (adalimumab, etanercept), IL-6 inhibitor (tocilizumab)
- PT/OT support
- Bacterial bone and joint infection
- Viral and postinfectious arthritis
- Other autoimmune/autoinflammatory: Kawasaki disease, IBD, SLE, MCTD, PAN, JDM, Behçet, CINCA
- Malignancy: leukaemia, lymphoma
- Malaria
JIA vs Septic Arthritis vs Malignancy
The most important differential to exclude in a child with joint swelling is septic arthritis (orthopaedic emergency) and leukaemia (bone pain can mimic arthritis, and blasts may not appear on initial CBC). Always check CBC with differential, CRP/ESR, blood culture, and consider joint aspiration before diagnosing JIA.
Integration with Related Material
Antibody immunodeficiencies are the most common form of primary or secondary immunodeficiency. [4] This adult-focused lecture reinforces the same pathogen-defect correlations. Management principles overlap: Ig replacement, prophylactic antibiotics.
Secondary immunodeficiency from chemotherapy follows the same principles: neutropenic patients are susceptible to bacteria and fungi; T-cell suppressed patients to viruses and PJP. PJP prophylaxis with TMP-SMX is indicated in primary immunodeficiencies (e.g. SCID, hyper-IgM syndrome). [6]
Eculizumab (anti-C5) → blocks MAC → increased susceptibility to Neisseria meningitidis. This was directly examined in the 2023 MCQ (Q84). [7]
The 2025 investigation lecture [5] provides detailed flowcharts for working up antibody deficiencies: absent B cells → XLA; B cells present but low Ig → CVID phenotype. CVID mutations (ICOS, CD19, BAFF-R, TACI) together account for only 10-15% of cases.
Stem: A 4-month-old Chinese girl with poor feeding, recurrent chest infections, chronic diarrhoea since 2 months, temperature 38°C, weight 2.5 kg, oral and perineal thrush, BCG scar not healed with serous discharge, RR 60, parents are first cousins.
(a) List four investigations:
- CBC with differential (look for lymphopenia — ALC < 2500)
- Serum immunoglobulins (IgG, IgA, IgM, IgE)
- Lymphocyte subsets (T, B, NK cells by flow cytometry)
- Chest X-ray (absent thymus shadow, lung infiltrates)
- (Optional: TREC, HIV testing to exclude secondary cause, blood culture, stool studies)
(b) Two most likely differential diagnoses:
- Severe Combined Immunodeficiency (SCID) — most likely given consanguinity (AR inheritance), lymphopenia expected, FTT, oral thrush, disseminated BCG
- Chronic Granulomatous Disease (CGD) — BCG dissemination, but less likely because CGD doesn't typically cause severe lymphopenia or oral thrush; however, AR-CGD is possible with consanguinity
(c) List four treatments:
- Antimicrobial therapy (treat active infections — antibiotics, antifungals, anti-TB if BCG-osis)
- PJP prophylaxis (TMP-SMX)
- IVIG replacement
- HSCT (definitive curative treatment for SCID)
- (Isolation/protective environment, nutritional support, avoid live vaccines)
-
MCQ: A 6-month-old boy presents with recurrent pneumonia and oral thrush. CBC shows ALC 1500/µL. CXR shows absent thymus shadow. What is the most likely diagnosis? → SCID (low ALC in infant = < 2500 is lymphopenia; absent thymus; combined infection pattern)
-
MCQ: A patient on eculizumab develops meningitis. Which organism is most likely? → Neisseria meningitidis (eculizumab blocks C5 → no MAC formation)
-
SAQ: A 3-year-old boy with recurrent sinopulmonary infections since 6 months. Ig levels show panhypogammaglobulinaemia. B cells are absent on flow cytometry. Name the diagnosis, the defective gene, and the treatment. → XLA; BTK (Bruton Tyrosine Kinase); IVIG/SCIG replacement
-
SAQ: What is the characteristic investigation finding in CGD? → Low/absent DHR (dihydrorhodamine reduction test) — reflects failure of neutrophil respiratory burst
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OSCE/Viva: Why do antibody-deficient children typically present after 4-6 months of age? → Maternal IgG (transplacentally acquired) wanes by 4-6 months. Until then, the infant is protected by maternal antibodies. Once depleted, the child's own defective B-cell/antibody system cannot compensate.
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MCQ: Delayed umbilical cord separation ( > 30 days) in a neonate with recurrent infections and persistent neutrophilia suggests which diagnosis? → Leukocyte Adhesion Deficiency (LAD)
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SAQ: List the ILAR subtypes of JIA. → Systemic, polyarthritis (RF+/RF-), oligoarthritis (persistent/extended), enthesitis-related arthritis, psoriatic arthritis
High Yield Summary
IEI: > 500 genetic diseases; present with infections, autoimmunity, autoinflammation, atopy, or malignancy. Use the pathogen pattern to identify the defective immune pathway. First-line investigations: CBC (ALC critical in infants < 2500 = lymphopenia), IgGAME, lymphocyte subsets, genetics. Key prototypes: SCID (T+B, all pathogens, HSCT), XLA (B cell, encapsulated bacteria/enterovirus, IVIG), CGD (phagocyte, catalase+ organisms/fungi, DHR test), complement deficiency (Neisseria, CH50), HIES (Th17, cold Staph abscesses, high IgE), MSMD (IFN-gamma, mycobacteria only). Always consult immunology. JIA: onset < 16y, > 6 weeks, no other cause. Subtypes: systemic (quotidian fever + arthritis), polyarthritis, oligoarthritis, ERA, psoriatic. Treatment: NSAID → MTX → biologics. Always exclude septic arthritis and malignancy first.
Active Recall - Lecture Notes
[1] Lecture slides: GC 144. A child with recurrent infections Primary immunodeficiencies.pdf (all pages) [2] Senior notes: Jerry's immunodeficiencies.pdf (pp. 2-4) [3] Senior notes: Adrian Lui Pediatrics Notes.pdf (pp. 406-410) [4] Lecture slides: GC 096. Why do I always get sick.pdf (pp. 16, 23) [5] Lecture slides: Investigations of Imm Disorders 2025.pdf (pp. 4, 15, 21, 30) [6] Senior notes: Maksim Medicine Notes.pdf (p. 201) [7] Past papers: 2023 Fourth Summative MCQ.pdf (Q84) [8] Past papers: 2023 Fourth Summative SAQ.pdf (Q11)
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