🛡️ Chapter 41: Recurrent Fever, Infections, & Immune Disorders

Nelson's Pediatric Symptom-Based Diagnosis | Primary Immunodeficiencies · SCID · Antibody deficiency · CVID · Hyper-IgM · Chronic granulomatous disease · Autoinflammatory syndromes (FMF, TRAPS, CAPS) · Immune dysregulation

🔍 Recurrent Fever, Infections & Immune Disorders: Key Concepts

🧠 Primary Immunodeficiency (PID) Red Flags
≥2 serious pneumonias, ≥2 systemic infections, unusual organisms, family history, failure to thrive, absence of tonsils/lymph nodes, persistent thrush after 6 months.
💉 Humoral (B cell) Defects
XLA (BTK mutation, absent B cells), CVID (low IgG/IgA, recurrent sinopulmonary), IgA deficiency, specific antibody deficiency. Encapsulated bacteria.
🧬 Combined Immunodeficiency (SCID/T cell)
SCID (absence of naive T cells, TREC screen). X-linked SCID (IL2RG), ADA deficiency, Omenn syndrome. Opportunistic infections, graft-versus-host from transfusions.
🦠 Phagocyte Disorders
CGD (NADPH oxidase, catalase-positive organisms, DHR test), LAD-1 (delayed cord separation, leukocytosis), congenital neutropenia (ELANE, HAX1).
🔄 Autoinflammatory (Periodic Fever) Syndromes
FMF (MEFV, serositis, colchicine-responsive), TRAPS (TNFRSF1A), CAPS (NLRP3, IL-1 mediated), HIDS (MVK). Recurrent fever + inflammation without autoantibodies.
🧪 Immune Dysregulation
IPEX (FOXP3, enteropathy, diabetes, eczema), ALPS (FAS, lymphoproliferation, autoimmune cytopenias), HLH (perforin, MUNC13-4, macrophage activation).

💡 Key takeaway: Most recurrent infections are NOT immunodeficiencies — consider atopy, anatomic defects, day care exposure. Red flags: invasive infections, opportunistic pathogens, failure to thrive, family history. Suspected PID → immunology referral.

🩺 Clinical Approach to Recurrent Infections: When to Suspect Immunodeficiency

🔹 Step 1: Identify red flags for primary immunodeficiency (Jeffrey Modell Foundation)
• ≥8 new ear infections in 1 year
• ≥2 serious sinus infections in 1 year
• ≥2 pneumonias in 1 year
• Recurrent deep skin or organ abscesses
• Persistent thrush after age 1 year
• Need for IV antibiotics to clear infections
• Family history of PID or unexplained early deaths
🔹 Step 2: Distinguish between atopy, anatomic defects, and true immunodeficiency
• Atopy: clear triggers, seasonal, family history, normal growth, eosinophilia.
• Anatomic: localized to organ (sinuses, lungs, urinary tract), imaging abnormal.
• Immunodeficiency: systemic, unusual organisms, failure to thrive, recurrent systemic infections.
🔹 Step 3: Initial screening labs for suspected PID
• CBC with differential (absolute neutrophil count, lymphocyte count)
• Quantitative immunoglobulins (IgG, IgA, IgM, IgE)
• Specific antibody titers to vaccines (tetanus, pneumococcal, Hib)
• CH50 (classical complement), AH50 (alternative complement)
• HIV testing
• Newborn SCID screening (TREC assay) if available
🔹 Step 4: Advanced testing based on pattern
• Humoral defect: B cell subsets (flow cytometry), vaccine response (tetanus, pneumococcal)
• T cell defect: lymphocyte subsets (CD3, CD4, CD8, CD19, NK), mitogen proliferation
• Phagocyte defect: DHR (dihydrorhodamine) for CGD, CD18 expression for LAD-1
• Autoinflammatory: CRP/ESR during episodes, genetic testing (MEFV, MVK, NLRP3, TNFRSF1A)
🔹 Step 5: Management principles
• Antibiotic prophylaxis for select defects (CGD, asplenia, antibody deficiency)
• IVIG replacement for antibody deficiencies (XLA, CVID, X-linked agammaglobulinemia)
• HSCT for SCID, CGD, WAS, certain combined deficiencies
• IL-1 inhibitors for CAPS, DIRA, FMF if colchicine fails
• Avoid live vaccines in suspected T cell defects until evaluated