The slides deliberately place immune deficiency and immune dysregulation on overlapping circles. An IEI may therefore cause both inadequate host defence and misdirected immunity: recurrent infection can coexist with autoimmunity, autoinflammation, severe atopy, lymphoproliferation, or malignancy. The second diagram maps the system by both adaptive versus innate and cellular versus humoral arms:

This is a reasoning map rather than four sealed boxes. A single pathway defect can disturb more than one arm, and a pathogen pattern is a clue—not a diagnosis by itself.

Category 1: Combined immunodeficiency without associated syndromic features ^[1]

Do not turn the slide's ALC cutoff into a rule: the slide prints “< 2500/mL,” but the intended unit is cells/µL, and normal lymphocyte counts change substantially with age and laboratory. A low infant ALC is an urgent clue, not a stand-alone definition of SCID; some leaky SCID phenotypes can have near-normal counts. Typical SCID is established with immunophenotyping and functional testing—current PIDTC criteria include fewer than 300 autologous T cells/µL, absent naïve T cells, and severely impaired mitogen proliferation. ^[10]

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]

What the serial images add: the chest radiographs show progression to severe bilateral lung disease during RSV-associated ARDS and subsequent improvement after ECMO/transplant care. The vesicular skin eruption from vaccine-strain VZV is the decisive visual clue that an apparently routine live vaccine has replicated in a child with impaired cellular immunity. Leaky RAG1 disease can therefore present later than classic neonatal SCID.

Additional case from lecture: A 4-month-old girl presented with failure to thrive, chronic diarrhoea, refractory oral candidiasis, and respiratory distress. CXR showed interstitial pneumonia; bronchoalveolar lavage revealed Pneumocystis jirovecii. Clinical photographs demonstrated erythroderma. She was diagnosed with SCID and received a bone marrow transplant, during which she developed Acremonium infection of the upper GI tract causing haematemesis. ^[1]

ADA-SCID image: the film shows an absent thymic shadow together with anterior rib/costochondral skeletal abnormalities. These can support ADA deficiency in the right phenotype, but neither finding is specific enough to diagnose SCID. ^[1]

Category 2: Combined immunodeficiency with associated syndromic features ^[1]

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 — persistent thin-walled cystic spaces after bacterial pneumonia. They are an important clue in the right syndromic context, but not pathognomonic. Once bronchiectasis or pneumatoceles exist, secondary infection with Gram-negative bacteria or molds such as Aspergillus becomes a major source of morbidity. ^[1][12]

Additional radiographic and skeletal features (from lecture): ^[1]

• Scoliosis — pronounced thoracic scoliosis visible on spinal radiograph
• Failure of primary-tooth exfoliation — the panoramic image shows retained primary teeth obstructing otherwise normally developing permanent teeth
• Pneumatoceles on CT — cystic/cavitary spaces, including an air-fluid level suggesting secondary infection, evolving over serial imaging (2010–2012)

The image montage is a useful three-system pattern: cavitary/pneumatocele lung disease, scoliosis, and retained primary teeth. A cold abscess with little surrounding erythema plus this skeletal/dental pattern strongly supports STAT3-HIES over uncomplicated atopic dermatitis. ^[12]

Category 3: Predominantly antibody deficiency ^[1]

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. The third photograph shows urticaria during the first IVIG infusion: recognise it as an infusion reaction requiring assessment and protocol-based management, not as evidence that future immunoglobulin replacement must be abandoned. ^[1]

Long-term complication: The adult radiographs and CT demonstrate established lower-lobe bronchiectasis in a 30-year-old with XLA. Immunoglobulin replacement reduces serious infection risk but cannot reverse existing structural lung damage; early diagnosis, individualised dosing, microbiology-guided treatment, and airway care remain important. ^[1]

Not a dedicated slide in this lecture but heavily tested and mentioned in supporting materials. ^[5][6]

Category 5: Defects in phagocyte number or function ^[1]

Why the organism pattern? CGD phagocytes cannot generate a normal NADPH-oxidase respiratory burst. “Catalase-positive organisms” is a useful exam shortcut, but catalase status alone does not predict every CGD pathogen; remember the characteristic clinical list and obtain microbiological diagnosis whenever possible. ^[13]

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

What the montage adds: CGD is not merely “recurrent abscesses.” The same child can show infection (cervical/perianal abscess, BCG disease, invasive aspergillosis with rib erosion) and dysregulated inflammation (granulomatous lung disease, IBD-like disease, arthritis/enthesitis, or iritis). A destructive fungal lesion crossing tissue planes or eroding bone is an especially important imaging clue.

Case from lecture (X-CGD): A 17-year-old boy with X-CGD (history of left buttock abscess, pulmonary aspergillosis, and TB since early infancy; two prior BMTs at 2½ and 4 years) developed left hip pain, abdominal skin nodules, and headache. MRI brain showed multiple brain abscesses in the left parietal and occipital lobes with vasogenic oedema. Whole-body PET-CT revealed disseminated aspergillosis with hypermetabolic lesions in the left iliopsoas, left gluteus maximus, right external oblique muscle, right lateral abdominal wall, and both lungs. He required a third HSCT at 18 years old. ^[1]

Case from lecture (AR-CGD): A 3-month-old girl with AR-CGD (NCF-1 deficiency) presented with granulomatous lung inflammation. Histology showed granuloma with central necrosis surrounded by epithelioid cells, with loss of alveolar air space. FDG PET-CT demonstrated a focal hypermetabolic pulmonary lesion (SUV max 5.7). ^[1]

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]

Why mycobacteria and Salmonella? IFN-gamma is a key cytokine for macrophage activation against intracellular pathogens. Mycobacteria and Salmonella are archetypal organisms that survive inside macrophage phagosomes. The exact susceptibility and severity depend on where and how completely the IL-12/IFN-γ circuit is disrupted. ^[1][2]

Case from lecture: Two siblings heterozygous for STAT1 c.2129C>T → disseminated BCG infection. The radiographs, bone scan, and serial long-bone films show multifocal BCG osteitis/osteomyelitis with gradual remodelling over months and after completion of treatment. A persistent or multifocal bony lesion after BCG is therefore a pathway clue, not simply routine pyogenic osteomyelitis. ^[1]

Reading the pathway diagram: an infected macrophage/dendritic cell produces IL-12/IL-23; lymphocytes respond and produce IFN-γ; IFN-γ then signals back to activate macrophage killing. Defects can occur on either side of this two-cell conversation (for example IL12RB1, IFNGR1/2, STAT1), which is why specialist functional assays and genetics are needed.

Category 8: Complement deficiency ^[1]

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 → greatly increased risk of Neisseria meningitidis infection. MenACWY and MenB vaccination are indicated, but breakthrough disease can still occur despite vaccination and prophylaxis; patients need urgent assessment for compatible symptoms. ^[7][11]

C1 inhibitor is a different clinical pattern: although the prototype slide places C1 esterase inhibitor deficiency beside complement defects, its hallmark is bradykinin-mediated hereditary angioedema—recurrent non-urticarial swelling, abdominal attacks, or potentially fatal laryngeal oedema—rather than recurrent infection. Screen with C4 plus C1-inhibitor antigen and function; a suspected airway attack is an emergency, and standard allergy treatment may be ineffective. ^[19]

Category 4: Diseases of immune dysregulation ^[1]

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]

What the photographs/endoscopy add: neonatal-onset diarrhoea plus severe perianal fistulising disease, pustular/pyodermatous skin lesions, and florid Crohn-like ulcerating mucosa is a monogenic-IBD red flag. The slide lists steroids and several biologics, but these are not interchangeable routine options; IL-10/IL-10-receptor defects are often refractory to conventional IBD therapy, and HSCT is the definitive pathway-directed treatment.

Category 7: Autoinflammatory diseases ^[1]

The CAPS spectrum includes:

• Familial Cold Autoinflammatory Syndrome (FCAS) — mildest
• Muckle-Wells Syndrome
• CINCA (Chronic Infantile Neurological Cutaneous and Articular Syndrome) — most severe

CINCA/NOMID clinical features (from lecture): ^[1]

• Urticaria since birth
• Papilloedema and headache with cerebral vasculitis
• Joint and skeletal deformities (hands, feet) in long-standing disease
• A 48-year-old man with CINCA showed dramatic improvement after 3 years of canakinumab (IL-1 blockade)

Somatic vs germline mutations: the slide's mosaic case was milder than classic germline disease, because the pathogenic variant was present in only a fraction of cells. Do not make this an absolute rule: phenotype depends on the variant and mosaic fraction/distribution. ^[1]

Visual recognition: the severe CINCA/NOMID end of CAPS combines an urticaria-like rash beginning in infancy with chronic aseptic CNS inflammation (headache/papilloedema and MRI abnormalities) and destructive or overgrowth arthropathy. The serial rash images also teach that low-level somatic mosaicism may be missed by routine Sanger sequencing; a convincing phenotype should prompt expert review and sufficiently sensitive testing rather than dismissal after one negative assay.

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.

The slide marks this 2024 update with a question mark. “Primary atopic disorders” are an emerging phenotype group within the IUIS framework, not an eleventh numbered category. ^[1][9]

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 improved with dupilumab (anti-IL-4Rα antibody). The photographs show marked lichenification of the hands before therapy and much less inflammation two years later; eosinophils and SCORAD/EASI scores fell while IgE remained high. This is a targeted-treatment example, not a claim that every child with severe eczema has STAT6 GOF. ^[1][16]

Clinical features of STAT6 GOF primary atopic disorder (n=16 patients, JEM 2023): ^[1]

Growth chart from lecture: The Hong Kong patient's height and weight tracked far below expected centiles. Growth hormone began at 16 years and dupilumab at 19 years, followed by catch-up. Because both treatment and maturation changed over time, read this as evidence that serial growth exposes systemic disease burden—not proof that dupilumab alone caused the growth response. ^[1]

Category 10: Phenocopies of IEI ^[1]

Phenocopies are conditions that mimic genetic IEI but are caused by acquired autoantibodies or somatic mutations: ^[1]

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.

Management is mechanism- and infection-specific. The slide's shorthand “vaccination, antivirals, replacement” is not a universal regimen: treat the active pathogen, prevent predictable infection where evidence supports it, and involve immunology/infectious diseases for strategies directed at the pathogenic autoantibody or clone.

• Complete review of systems
• IEIs can affect many different organs → don't just look for infections
• Five phenotypes to document: ^[1]
  1. Infections (recurrent, opportunistic, or live vaccine)
  2. Autoinflammation, autoimmunity (IBD, AIHA, arthritis)
  3. Non-malignant lymphoproliferation
  4. Atopy
  5. 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 and, where included in the regional programme, 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

In the lecture's ILAR classification, JIA is arthritis of unknown cause beginning before age 16, persisting for at least 6 weeks, after exclusion of other causes. ILAR remains useful for reading the slides, but current treatment guidelines increasingly act on the child's clinical phenotype (oligoarthritis, polyarthritis, sacroiliitis/enthesitis, or systemic disease) rather than forcing every decision through a classification label. ^[1][17][18]

Clinical examination and imaging for enthesitis: palpation and functional assessment remain essential, while targeted ultrasound or MRI can confirm inflammation or identify axial disease. The slide's claim that examination is “more sensitive than MRI” comes from an adult axial-spondyloarthritis comparison in which more tender sites were found clinically; tenderness can also reflect mechanical pain, so this should not be generalised into a universal paediatric accuracy rule. ^[1]

Psoriatic visual clue: the hand photograph shows marked nail dystrophy with pitting/onycholysis and periungual scale. Inspect every nail and hidden psoriasis sites (scalp, umbilicus, natal cleft); fungal nail disease and trauma remain differentials.

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]

The formal ILAR definition requires arthritis, but arthritis can appear weeks or months after systemic inflammation. In a highly compatible presentation, paediatric rheumatology may treat before arthritis appears—especially with serositis or macrophage activation syndrome (MAS)—only after actively excluding infection and malignancy.

Current treatment frame (not the slide's undifferentiated drug list): ^[17]

• sJIA without MAS: a short NSAID trial is reasonable only in selected mild cases; if response is not rapid and complete, escalate promptly. Oral glucocorticoid monotherapy is not preferred, and prolonged steroids should be avoided. IL-1 or IL-6 inhibition is favoured for active systemic disease; csDMARDs do not adequately control the systemic phenotype.
• sJIA with MAS: glucocorticoids are part of initial therapy, with IL-1/IL-6-directed therapy and/or a calcineurin inhibitor chosen by the specialist team. Infection must be assessed and treated in parallel.
• TNF inhibitors, JAK inhibitors, emapalumab, IL-18-binding protein, and HSCT are not interchangeable steps. They belong to selected residual-articular, MAS/HLH, investigational, or highly refractory scenarios in expert centres.

The lecture's fixed “NSAID for 6 weeks → wait 2–3 months → methotrexate → biologic” sequence is too slow and ignores phenotype. Current principles are: ^[17][18]

1. Exclude urgent mimics and define phenotype/severity (joint count, TMJ/hip/cervical involvement, sacroiliitis/enthesitis, systemic features, uveitis, damage risk, function and quality of life).
2. Oligoarthritis: a brief scheduled NSAID trial may help symptoms, but intra-articular glucocorticoid is strongly recommended as initial therapy for active joints. Move to a csDMARD (usually methotrexate) if response is inadequate; use a biologic after inadequate response/intolerance to appropriate conventional therapy.
3. Polyarthritis: start a DMARD rather than relying on NSAID monotherapy; methotrexate is generally preferred, with earlier biologic escalation for inadequate response or high-risk disease.
4. Active enthesitis/sacroiliitis: NSAIDs are initial therapy; persistent active disease favours a TNF inhibitor over methotrexate or sulfasalazine, particularly for axial disease.
5. All phenotypes: use treat-to-target reassessment rather than automatic waiting periods; add PT/OT, exercise, pain and school support, vaccination planning, and toxicity monitoring.

• 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

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.