🦠 FCPS Paediatrics TOACS · Recurrent S. aureus & GAS Skin Infections (3‑year‑old)
📖 Nelson's Chapter 164, 170 · Inborn Errors of Immunity – Phagocytic defects, Hyper‑IgE, LAD
📚 paeds.online – Paeds Online
🩺 OBSERVED/INTERACTIVE STATION · CPSP FORMAT · 10 MINUTES · APPROACH TO RECURRENT PYODERMA / ABSCESSES
📋 Observed Station – “Recurrent skin abscesses, cellulitis and poor wound healing”
👧🏽 Clinical scenario (displayed / read to candidate):
A 3‑year‑old girl is brought with history of recurrent, serious skin and soft tissue infections since infancy. She has had 5 episodes of skin abscesses (perianal, buttocks, limbs), two episodes of cellulitis requiring IV antibiotics, and one episode of lymphadenitis. Culture from pus grew Staphylococcus aureus (MSSA) and Group A Streptococcus (Streptococcus pyogenes). She has poor wound healing with residual scars. No deep organ abscesses or pneumonia. No history of omphalitis. No delayed cord separation. Between infections she is playful and growing on 25th centile.
🎯 Task (examiner observed): Discuss the differential diagnosis of primary immunodeficiencies that present with recurrent staphylococcal and streptococcal skin/soft tissue infections. Formulate a targeted laboratory evaluation including neutrophil function, oxidative burst, and adhesion molecules. Explain how to interpret DHR (dihydrorhodamine) test and flow cytometry for CD11/CD18.
📸 Key clues from Nelson's Chapter 164 & 170: Recurrent S. aureus abscesses, poor pus formation, delayed wound healing → consider phagocytic defects (CGD, LAD‑1, Hyper‑IgE syndrome, severe congenital neutropenia, G6PD deficiency).
The absence of pneumonias, deep fungal infections, and umbilical stump issues points away from severe CGD or LAD‑1 but does not exclude milder variants.
A 3‑year‑old girl is brought with history of recurrent, serious skin and soft tissue infections since infancy. She has had 5 episodes of skin abscesses (perianal, buttocks, limbs), two episodes of cellulitis requiring IV antibiotics, and one episode of lymphadenitis. Culture from pus grew Staphylococcus aureus (MSSA) and Group A Streptococcus (Streptococcus pyogenes). She has poor wound healing with residual scars. No deep organ abscesses or pneumonia. No history of omphalitis. No delayed cord separation. Between infections she is playful and growing on 25th centile.
🎯 Task (examiner observed): Discuss the differential diagnosis of primary immunodeficiencies that present with recurrent staphylococcal and streptococcal skin/soft tissue infections. Formulate a targeted laboratory evaluation including neutrophil function, oxidative burst, and adhesion molecules. Explain how to interpret DHR (dihydrorhodamine) test and flow cytometry for CD11/CD18.
📸 Key clues from Nelson's Chapter 164 & 170: Recurrent S. aureus abscesses, poor pus formation, delayed wound healing → consider phagocytic defects (CGD, LAD‑1, Hyper‑IgE syndrome, severe congenital neutropenia, G6PD deficiency).
The absence of pneumonias, deep fungal infections, and umbilical stump issues points away from severe CGD or LAD‑1 but does not exclude milder variants.
🔬 Nelson's Table 170.2 – Clinical disorders of neutrophil function:
• Chronic granulomatous disease (CGD) – catalase‑positive organisms including S. aureus, Serratia, Aspergillus; recurrent abscesses, granulomas.
• Leukocyte adhesion deficiency (LAD‑1) – recurrent bacterial/fungal infections, delayed cord separation, lack of pus, neutrophilia.
• Hyper‑IgE syndrome (STAT3‑LOF, DOCK8) – recurrent staphylococcal “cold” abscesses, pneumatoceles, eczema, eosinophilia, characteristic facies.
• Specific granule deficiency – deep abscesses, bilobed nuclei.
• Myeloperoxidase deficiency – usually mild, but candidiasis may occur.
• Chronic granulomatous disease (CGD) – catalase‑positive organisms including S. aureus, Serratia, Aspergillus; recurrent abscesses, granulomas.
• Leukocyte adhesion deficiency (LAD‑1) – recurrent bacterial/fungal infections, delayed cord separation, lack of pus, neutrophilia.
• Hyper‑IgE syndrome (STAT3‑LOF, DOCK8) – recurrent staphylococcal “cold” abscesses, pneumatoceles, eczema, eosinophilia, characteristic facies.
• Specific granule deficiency – deep abscesses, bilobed nuclei.
• Myeloperoxidase deficiency – usually mild, but candidiasis may occur.
Neutrophil engulfing bacteria. Defects in oxidative burst (CGD) or adhesion (LAD) predispose to recurrent S. aureus/GAS infections.
💡 Examiner probes: “What physical exam clues would you look for in this child?” → Look for eczematous rash (HIES), small or absent tonsils (antibody deficiency not likely), gingivitis (LAD), chronic suppurative lymphadenitis, digital clubbing, pneumatoceles (STAT3‑HIES). Also check for dysmorphic features, coarse face, and retained primary teeth (HIES).
🩸 Laboratory approach – neutrophil function, oxidative burst, adhesion molecules
1 Complete blood count & differential
Look for neutropenia (Kostmann, cyclic neutropenia), eosinophilia (HIES), neutrophilia (LAD, CGD may have normal WBC but can be elevated).
Look for neutropenia (Kostmann, cyclic neutropenia), eosinophilia (HIES), neutrophilia (LAD, CGD may have normal WBC but can be elevated).
2 Dihydrorhodamine (DHR) test
Flow cytometry to measure neutrophil oxidative burst. Absent or severely reduced shift → Chronic granulomatous disease (CGD). Carrier females show two populations.
Flow cytometry to measure neutrophil oxidative burst. Absent or severely reduced shift → Chronic granulomatous disease (CGD). Carrier females show two populations.
3 CD11/CD18 expression (flow cytometry)
Markers for β2 integrin. Absent or severely reduced → Leukocyte adhesion deficiency type 1 (LAD‑1). Moderate reduction indicates milder phenotype.
Markers for β2 integrin. Absent or severely reduced → Leukocyte adhesion deficiency type 1 (LAD‑1). Moderate reduction indicates milder phenotype.
4 Serum IgE level & eosinophil count
Markedly elevated IgE (>2000 IU/mL) + eosinophilia → Hyper‑IgE syndrome (STAT3‑LOF, DOCK8 deficiency). Also obtain DOCK8 protein expression or STAT3 sequencing.
Markedly elevated IgE (>2000 IU/mL) + eosinophilia → Hyper‑IgE syndrome (STAT3‑LOF, DOCK8 deficiency). Also obtain DOCK8 protein expression or STAT3 sequencing.
5 Quantitative immunoglobulins & vaccine titers
Exclude humoral defects (CVID, specific antibody deficiency) that can also cause sinopulmonary infections but less likely isolated skin abscesses.
Exclude humoral defects (CVID, specific antibody deficiency) that can also cause sinopulmonary infections but less likely isolated skin abscesses.
6 NBT test (historical) and genetic confirmation
Nitroblue tetrazolium (less used). Confirmatory gene panels for CYBB, NCF1, NCF2, NCF4, CYBA (CGD); ITGB2 (LAD‑1); STAT3, DOCK8 (HIES).
Nitroblue tetrazolium (less used). Confirmatory gene panels for CYBB, NCF1, NCF2, NCF4, CYBA (CGD); ITGB2 (LAD‑1); STAT3, DOCK8 (HIES).
⚠️ Critical points (Nelson's Chapter 170):
• CGD – DHR test is first‑line; false positives in myeloperoxidase deficiency; absolute confirmation by genetic testing.
• LAD‑1 – delayed umbilical cord separation (>3 weeks) is classic (not present here, but can occur in severe LAD).
• Hyper‑IgE syndrome – normal DHR, normal CD18, but Th17 cell deficiency (absent IL‑17 producing T cells).
• Always rule out secondary causes (scabies, atopic dermatitis with superinfection) but recurrent deep abscesses should trigger PID evaluation.
• CGD – DHR test is first‑line; false positives in myeloperoxidase deficiency; absolute confirmation by genetic testing.
• LAD‑1 – delayed umbilical cord separation (>3 weeks) is classic (not present here, but can occur in severe LAD).
• Hyper‑IgE syndrome – normal DHR, normal CD18, but Th17 cell deficiency (absent IL‑17 producing T cells).
• Always rule out secondary causes (scabies, atopic dermatitis with superinfection) but recurrent deep abscesses should trigger PID evaluation.
📊 Mock lab interpretation (case example):
CBC: WBC 12.5 (elevated), ANC 8.2, eosinophils 8% (absolute 1000). IgE >3500 IU/mL. DHR normal (oxidative burst intact). CD18 expression normal. → likely Hyper‑IgE syndrome (STAT3 dominant negative). Confirm with STAT3 sequencing.
CBC: WBC 12.5 (elevated), ANC 8.2, eosinophils 8% (absolute 1000). IgE >3500 IU/mL. DHR normal (oxidative burst intact). CD18 expression normal. → likely Hyper‑IgE syndrome (STAT3 dominant negative). Confirm with STAT3 sequencing.
📌 Pearl for TOACS: If DHR is abnormal (no shift), suspect CGD. If CD11b/CD18 <2% of normal → severe LAD‑1; if 5-30% → moderate LAD‑1 (milder infections). Hyper‑IgE syndrome requires genetic testing and often presents with characteristic facial features, pneumatoceles, and retained primary teeth.
🗨️ Examiner Q&A · Phagocyte defects · CGD · LAD · Hyper‑IgE syndrome
❓ Q1 (Examiner): “According to Nelson’s Chapter 164/170, which primary immunodeficiencies are classically associated with recurrent Staphylococcus aureus skin abscesses in a toddler?”
✅ Chronic granulomatous disease (CGD), Leukocyte adhesion deficiency (LAD‑1), Hyper‑IgE syndrome (STAT3‑LOF, DOCK8), and less commonly severe congenital neutropenia and specific granule deficiency. CGD presents with catalase‑positive organisms (including S. aureus, Serratia, Burkholderia, Nocardia, Aspergillus). LAD‑1 presents with recurrent soft tissue infections, delayed umbilical separation, neutrophilia. Hyper‑IgE presents with “cold” abscesses, eczema, elevated IgE, pneumatoceles.
❓ Q2 (Examiner): “What is the DHR test? How do you interpret a completely absent neutrophil oxidative burst?”
✅ DHR (dihydrorhodamine) flow cytometry measures the respiratory burst of neutrophils. Phorbol myristate acetate (PMA) stimulates NADPH oxidase → oxidation of DHR to fluorescent rhodamine. Absent shift (no fluorescence) → diagnosis of chronic granulomatous disease (most commonly X‑linked gp91phox or AR p47phox). Carrier females show two populations (normal and deficient).
❓ Q3 (Examiner): “What clinical feature is strongly suggestive of leukocyte adhesion deficiency type 1 (LAD‑1) in a child with recurrent skin infections?”
✅ Delayed separation of the umbilical cord (beyond 3 weeks) + absence of pus formation at infection sites despite marked peripheral neutrophilia. Also severe periodontitis, poor wound healing, and recurrent soft tissue infections without purulent exudate. Diagnosis confirmed by absent or reduced CD11/CD18 (β2 integrin) expression on neutrophils by flow cytometry.
❓ Q4 (Examiner): “How does Hyper‑IgE syndrome (Job syndrome) present differently from CGD in terms of infection types?”
✅ STAT3‑LOF Hyper‑IgE syndrome: S. aureus “cold” abscesses (minimal surrounding inflammation), pneumatoceles, eczema, eosinophilia, coarse facial features, hyperextensible joints, retained primary teeth, Candida mucocutaneous infections. CGD: recurrent abscesses (liver, lung, perirectal), Aspergillus pneumonia, Serratia/Burkholderia/Nocardia infections, lymphadenitis, chronic granuloma formation. Both have S. aureus, but CGD also has catalase‑positive organisms; HIES has mucocutaneous candidiasis.
❓ Q5 (Examiner): “A child has normal DHR and normal CD18 expression but markedly elevated IgE and recurrent staphylococcal abscesses. What is your next step?”
✅ Suspect Hyper‑IgE syndrome (STAT3 dominant‑negative or DOCK8 deficiency). Next: measure Th17 cell numbers (low in STAT3‑HIES), serum IgE, eosinophil count. Genetic testing for STAT3, DOCK8, IL6ST, ZNF341. Also evaluate for atopy, pneumatoceles on chest CT, and characteristic facial features. DOCK8 deficiency also presents with severe viral infections (molluscum, HSV, warts).
❓ Q6 (Examiner): “What is the role of prophylactic antibiotics in CGD and LAD‑1?”
✅ CGD: daily trimethoprim/sulfamethoxazole (TMP‑SMX) reduces bacterial infections, plus itraconazole for fungal (Aspergillus) prophylaxis. Interferon‑γ is also used but less common. LAD‑1: TMP‑SMX prophylaxis for staphylococcal and gram‑negative coverage. LAD‑1 severe forms require hematopoietic stem cell transplantation (HSCT). In both, meticulous wound care and early antibiotics for suspected infection.
❓ Q7 (Examiner): “What is the significance of ‘catalase‑positive’ organisms in CGD?”
✅ CGD neutrophils cannot produce superoxide/hydrogen peroxide. Catalase‑positive organisms (S. aureus, E. coli, Serratia, Burkholderia, Nocardia, Aspergillus) degrade their own H₂O₂, so the microbe is not killed inside the phagosome. Catalase‑negative organisms (Streptococcus, Lactobacillus) supply their own H₂O₂ which can be used by residual myeloperoxidase, thus less severe. That’s why CGD patients have selective susceptibility to catalase‑positive pathogens.
❓ Q8 (Examiner): “A 3‑year‑old has recurrent perianal abscesses, poor wound healing, neutrophilia (WBC 28,000) but normal DHR. Which test is most diagnostic?”
✅ Flow cytometry for CD11b/CD18 (β2 integrin). Suspect LAD‑1. If CD18 expression is <2% → severe LAD‑1 (high mortality without HSCT). If moderate (5‑30%) → milder phenotype. Confirmation by ITGB2 gene sequencing. Also check sialyl‑Lewis X (CD15s) to exclude LAD‑2.
❓ Q9 (Examiner): “What are the sentinel infections for CGD according to Nelson’s Table 164.3 and 170.1?”
✅ CGD sentinel pathogens: Burkholderia cepacia, Serratia marcescens, Nocardia species, Aspergillus (especially A. nidulans), Chromobacterium violaceum, Granulibacter bethesdensis. Recurrent liver abscesses, osteomyelitis, pneumonia with these organisms should prompt DHR testing.
❓ Q10 (Examiner): “Can you briefly outline management of Hyper‑IgE syndrome?”
✅ • Antibiotic prophylaxis (TMP‑SMX) for staphylococcal infections.
• Antifungal prophylaxis (fluconazole or itraconazole) for mucocutaneous candidiasis.
• Skin care: emollients, dilute bleach baths, treat eczema aggressively.
• IgG replacement if specific antibody deficiency is present.
• Avoid live viral vaccines? Usually safe but caution in DOCK8.
• Hematopoietic stem cell transplantation (HSCT) for DOCK8 deficiency and severe STAT3‑HIES with refractory infections or malignancy.
• Antifungal prophylaxis (fluconazole or itraconazole) for mucocutaneous candidiasis.
• Skin care: emollients, dilute bleach baths, treat eczema aggressively.
• IgG replacement if specific antibody deficiency is present.
• Avoid live viral vaccines? Usually safe but caution in DOCK8.
• Hematopoietic stem cell transplantation (HSCT) for DOCK8 deficiency and severe STAT3‑HIES with refractory infections or malignancy.
📘 Nelson’s Chapter 164 & 170 – Management algorithm for recurrent skin infections / phagocyte disorders
🔬 Step‑wise diagnosis
History (delayed cord, deep abscesses, poor pus) → CBC/diff → DHR flow → CD11b/CD18 → IgE/eosinophils → genetics. Prompt referral to immunology.
History (delayed cord, deep abscesses, poor pus) → CBC/diff → DHR flow → CD11b/CD18 → IgE/eosinophils → genetics. Prompt referral to immunology.
💊 Prophylaxis (CGD)
TMP‑SMX 5 mg/kg/day (TMP component) + itraconazole 5 mg/kg/day. Interferon‑γ (50 µg/m² 3x/week) reduces severe infections in CGD.
TMP‑SMX 5 mg/kg/day (TMP component) + itraconazole 5 mg/kg/day. Interferon‑γ (50 µg/m² 3x/week) reduces severe infections in CGD.
🏥 LAD‑1 management
Aggressive antibiotics for infections; TMP‑SMX prophylaxis; meticulous oral hygiene; early HSCT for severe LAD‑1 (CD18 <2%). Avoid granulocyte transfusions.
Aggressive antibiotics for infections; TMP‑SMX prophylaxis; meticulous oral hygiene; early HSCT for severe LAD‑1 (CD18 <2%). Avoid granulocyte transfusions.
🛡️ Hyper‑IgE syndrome (STAT3)
Prophylactic antistaphylococcal antibiotics (cephalexin or TMP‑SMX). Antifungals (fluconazole). Manage eczema with topical steroids/calcineurin inhibitors. Immunoglobulin if recurrent sinopulmonary infections.
Prophylactic antistaphylococcal antibiotics (cephalexin or TMP‑SMX). Antifungals (fluconazole). Manage eczema with topical steroids/calcineurin inhibitors. Immunoglobulin if recurrent sinopulmonary infections.
🧬 HSCT indications
CGD with refractory infections or Aspergillus; LAD‑1 severe; DOCK8 deficiency (severe viral infections, autoimmunity, malignancy). STAT3‑HIES transplant outcomes improving but reserved for severe phenotypes.
CGD with refractory infections or Aspergillus; LAD‑1 severe; DOCK8 deficiency (severe viral infections, autoimmunity, malignancy). STAT3‑HIES transplant outcomes improving but reserved for severe phenotypes.
📖 Family screening
Genetic counseling for X‑linked CGD (CYBB). DHR carrier testing for mothers. Siblings at risk should be tested early because early HSCT improves outcomes.
Genetic counseling for X‑linked CGD (CYBB). DHR carrier testing for mothers. Siblings at risk should be tested early because early HSCT improves outcomes.
📖 Nelson’s Textbook (Chapter 170, p. 1297): “Children with phagocytic defects present with deep tissue infection, pneumonia, adenitis, cutaneous lesions, or osteomyelitis rather than bloodstream infections. The first step in diagnosis for all these disorders is to obtain DNA analysis through commercially available genetic panels for immunodeficiency. DHR flow cytometry is the most widely used screen for CGD.”
⭐ TOACS TAKE‑HOME POINTS (for candidates):
1. Recurrent S. aureus / GAS skin abscesses → think phagocytic defect (CGD, LAD, Hyper‑IgE).
2. DHR test screens for CGD; CD11b/CD18 for LAD‑1; IgE/eosinophils for HIES.
3. Delayed cord separation + neutrophilia + lack of pus → LAD‑1 until proven otherwise.
4. CGD also presents with liver abscesses, osteomyelitis, Aspergillus, and Burkholderia sepsis.
5. Hyper‑IgE syndrome: “cold” abscesses, retained primary teeth, pneumatoceles, candidiasis.
6. Prophylaxis: TMP‑SMX + itraconazole (CGD); TMP‑SMX (LAD); antistaphylococcal (HIES).
7. HSCT is curative for severe phagocytic defects; gene therapy for CGD is under investigation.
1. Recurrent S. aureus / GAS skin abscesses → think phagocytic defect (CGD, LAD, Hyper‑IgE).
2. DHR test screens for CGD; CD11b/CD18 for LAD‑1; IgE/eosinophils for HIES.
3. Delayed cord separation + neutrophilia + lack of pus → LAD‑1 until proven otherwise.
4. CGD also presents with liver abscesses, osteomyelitis, Aspergillus, and Burkholderia sepsis.
5. Hyper‑IgE syndrome: “cold” abscesses, retained primary teeth, pneumatoceles, candidiasis.
6. Prophylaxis: TMP‑SMX + itraconazole (CGD); TMP‑SMX (LAD); antistaphylococcal (HIES).
7. HSCT is curative for severe phagocytic defects; gene therapy for CGD is under investigation.
🔗 Online resources for candidates & families:
• Paeds Online – TOACS bank & FCPS revision
• Immune Deficiency Foundation – Phagocyte deficiencies
• NORD – CGD guide
• Paeds Online – TOACS bank & FCPS revision
• Immune Deficiency Foundation – Phagocyte deficiencies
• NORD – CGD guide