GC096 Why Do I Always Get Sick
A clinical discussion exploring the reasons behind recurrent infections, typically related to immune system dysfunction, chronic stress, sleep deprivation, nutritional deficiencies, or underlying immunodeficiency conditions that increase susceptibility to illness.
Why Do I Always Get Sick? — Introduction to Immunodeficiencies
The Big Idea: When a patient keeps getting infections that are Serious, Persistent, Unusual, or Recurring (SPUR), you need to think beyond bad luck. This lecture teaches you to recognize the warning signs of immunodeficiency, systematically work up the suspected defect, and understand the broad classification and management principles — particularly immunoglobulin replacement therapy for antibody deficiencies.
How it fits into clinical practice: Immunodeficiencies sit at the intersection of infectious disease, haematology, rheumatology/clinical immunology, and genetics. A GP or general physician who fails to recognize the pattern will simply keep treating each infection episode in isolation. The immunologist can only help if someone refers the patient — that "someone" is you.
Learning Objectives (directly from the lecture):
1. Appreciate clinical features and when to suspect immunodeficiencies [1]
2. Understand the approach and first-line diagnostic tests for workup of suspected immunodeficiencies [1]
3. Be aware of second-line diagnostic tests and broad classification of primary immunodeficiencies [1]
4. Be able to explain the principles and monitoring of immunoglobulin replacement therapy for antibody deficiencies [1]
M/22, previously healthy salesperson. Presented with THREE episodes of Neisseria meningitidis serotype Y meningitis over ~1 year. CT/MRI brain, sinuses, skull base all unremarkable. ENT and Neurology found no structural cause. Referred to QMH Immunology Clinic. Diagnosis: Terminal complement pathway deficiency (C5-C9), confirmed by ABSENT CH50 and ABSENT AH50. [1]
Why this case is important
This case illustrates every principle the lecture teaches:
- Warning sign triggered: Recurrent bacterial meningitis with the same organism = SPUR pattern (Serious + Recurring + Unusual frequency).
- Secondary causes excluded first: HIV negative, normal CBC, normal renal/liver function, no structural defect.
- Organism gives the clue: Neisseria meningitidis is an encapsulated bacterium → the terminal complement pathway (membrane attack complex, C5b-C9) is the key defence against Neisseria. When you can't form MAC, Neisseria survives and recurs.
- Targeted investigation based on clinical suspicion: CH50 and AH50 were ordered — both absent → confirms deficiency in the terminal/common complement pathway (C5-C9 shared by classical and alternative pathways).
- Family screening relevant: The patient's siblings and parents need testing given potential autosomal recessive inheritance.
Exam Pearl: Neisseria + Recurrent Meningitis = Think Terminal Complement Deficiency
If you see a vignette with recurrent meningococcal disease, especially in a young adult, the answer is almost always terminal complement deficiency. The confirmatory tests are CH50 and AH50 — both will be absent/undetectable because both classical and alternative pathways converge on C5-C9.
Primary Immunodeficiencies (PIDs) = inherent dysfunctions of the immune system, generally genetic in aetiology, can be hereditary or arise from de novo mutations. [1]
Secondary Immunodeficiencies (SIDs) = secondary to other conditions or pathologies — e.g. lymphoproliferative diseases, malignancies, medications, infections, advanced age, malnutrition, protein-losing states. [1]
Why the distinction matters
| Feature | Primary (PID / IEI) | Secondary (SID) |
|---|---|---|
| Cause | Genetic (inherited or de novo mutation) | Acquired condition/treatment |
| Onset | Often childhood, but can present at ANY age | Any age; correlates with underlying disease |
| Reversibility | Generally not reversible (lifelong) | May be reversible if cause treated |
| Examples | SCID, XLA, CVID, CGD, complement deficiencies | HIV/AIDS, CLL, multiple myeloma, nephrotic syndrome, corticosteroids, rituximab, malnutrition, CKD, diabetes |
| First step in workup | Exclude secondary causes first, then consider disease phenotype [1] | Treat the underlying cause |
Always Exclude Secondary Causes First
A common exam trap: jumping straight to rare PID diagnoses without ruling out HIV, diabetes, malignancy, medications, or protein-losing states. The lecture explicitly states: "Exclude secondary immunodeficiency" before pursuing PID workup [1]. HIV testing (Ag/Ab or PCR) is a mandatory first-line investigation.
Primary immunodeficiencies: 'Rare' inborn errors of immunity (~1:10,000 population). Classically have increased susceptibility to infections. Can also be associated with autoimmunity, inflammation, and increased risk of malignancy. [1]
"Not as rare as previously thought – ever-expanding list! Many patients remain undiagnosed or present later in life." [1]
Key points to understand:
- The prevalence figure (~1:10,000) means in a city of 7.5 million like HK, there could be ~750 people with a PID. Many go undiagnosed.
- PIDs are not just about infections — autoimmunity (e.g., autoimmune cytopenias in CVID), autoinflammation, and malignancy risk are important non-infectious manifestations.
- The lecture's question "Never encountered vs. Never diagnosed" challenges us to maintain a high index of suspicion.
Warning signs of immunodeficiency: [1]
- Disproportionately frequent infections
- Disproportionately severe infections
- Family history
- Unusual clinical presentation
- Unusual microorganisms
- Unusual sites of infection
- Clinical phenotype suggestive of syndrome associated with immunodeficiency
- Infections after biologicals
Breaking down SPUR from first principles
| Letter | Meaning | Example | Why it suggests PID |
|---|---|---|---|
| S | Serious | Bacterial meningitis, deep-seated abscesses, septic shock | Normal hosts handle common pathogens; if the infection is life-threatening, the immune response may be defective |
| P | Persistent | Chronic diarrhea, chronic sinusitis unresponsive to treatment, persistent oral candidiasis | A competent immune system clears infections; persistence suggests failure to eradicate |
| U | Unusual | Unusual organism (e.g., Pneumocystis in a non-HIV patient), unusual site (e.g., liver abscess from Aspergillus), unusual frequency | Opportunistic infections or infections at "wrong" sites imply a specific immune gap |
| R | Recurring | 3 episodes of meningococcal meningitis (as in the case) | One episode = bad luck. Multiple episodes of the same serious infection = structural immune defect |
High Yield: 'Infections After Biologicals'
This is a modern addition to the warning signs. Biologics like anti-TNF (infliximab, adalimumab), anti-CD20 (rituximab), anti-IL-6 (tocilizumab), or JAK inhibitors can unmask latent infections (TB, HBV reactivation) or create secondary immunodeficiency. A patient who gets recurrent infections after starting a biologic needs evaluation — this is effectively a secondary immunodeficiency but may reveal an underlying PID.
> 400 distinct disorders with > 430 different gene defects (and growing!) [1]
IUIS PID classification: [1]
- Combined immunodeficiencies (CID)
- CID with associated or syndromic features
- Antibody deficiencies
- Immune dysregulation
- Phagocytic defects
- Intrinsic and innate immunity
- Autoinflammatory disorders
- Complement deficiencies
- Bone marrow failure
- Phenocopies of PID
What you need to understand about each category
| # | Category | What's Defective | Classic Example | Typical Infections/Manifestations | Key Investigation |
|---|---|---|---|---|---|
| 1 | Combined ID (CID) | T cells ± B cells | SCID (Severe Combined Immunodeficiency) | Early-onset severe infections (viral, bacterial, fungal, PCP); failure to thrive; fatal without treatment | Lymphocyte subsets (very low CD3); TREC on newborn screening |
| 2 | CID with syndromic features | T cells + associated syndrome | DiGeorge (22q11.2 deletion), Wiskott-Aldrich | DiGeorge: cardiac defects, hypocalcaemia, facial dysmorphism; WAS: eczema, thrombocytopenia, infections | Genetic testing; calcium; echocardiogram |
| 3 | Antibody deficiencies | B cells / Immunoglobulins | CVID, XLA (Bruton's) | Recurrent sinopulmonary and GI infections; encapsulated bacteria; Giardia; enteroviruses [1] | Immunoglobulin profile (IgG/A/M), vaccine responses |
| 4 | Immune dysregulation | Regulatory pathways | IPEX, ALPS, IL-10R deficiency | Autoimmunity, lymphoproliferation, early-onset IBD [2] | Genetic testing, specific functional assays |
| 5 | Phagocytic defects | Neutrophils/phagocytes | CGD (Chronic Granulomatous Disease) | Abscesses (liver, lung), catalase-positive organisms, Aspergillus, disseminated BCG [2] | DHR (Dihydrorhodamine) test or NBT test |
| 6 | Intrinsic and innate immunity | Cytokine/innate pathways | MSMD (Mendelian Susceptibility to Mycobacterial Disease) | Disseminated mycobacterial infections, Salmonella [2] | Functional IFN-γ pathway tests |
| 7 | Autoinflammatory disorders | Inflammasome/IL-1 | CAPS (Cryopyrin-associated periodic syndromes) | Recurrent fever, urticaria, serositis [2] | Genetic (NLRP3), response to anakinra |
| 8 | Complement deficiencies | Complement components | Terminal complement (C5-C9) deficiency; C1-INH deficiency (HAE) | Terminal: recurrent Neisseria [1][2]; HAE: recurrent angioedema (bradykinin-mediated) | CH50/AH50; C1-INH level and function |
| 9 | Bone marrow failure | Marrow stem cells | Fanconi anaemia | Pancytopenia, malignancy predisposition | Chromosomal breakage analysis |
| 10 | Phenocopies of PID | Acquired autoantibodies mimicking PID | Anti-IFN-I autoantibodies | Severe COVID-19, viral infections [2] | Serum autoantibody testing |
Exam High Yield: Antibody Deficiencies Are the MOST Common PIDs
Core Concept 5: The Diagnostic Approach
Salient history includes: [1]
- Identify the "phenotype"
- Age of presentation
- Progression of symptoms
- Pattern of pathogens
- Location of infections
- Features of immune dysregulation
- Investigation results
- Plot family tree (3 generations)
- Consider Immunology referral
Additional history points from the case:
- Immunization history and adverse reactions (e.g., disseminated BCG in CGD/SCID) [1]
- Consanguinity — increases likelihood of autosomal recessive PIDs [1]
- History of miscarriages in the mother (asked in the case; relevant for X-linked disorders where affected males may die in utero)
- STI history including Neisseria gonorrhoeae (another Neisseria; if recurrent, think complement deficiency)
Core Concept 6: Investigations
First-line investigations: [1]
- 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
- Immunoglobulin profile (including IgE)
- Serum and urine electrophoresis
- C3/C4
- ANA ± autoimmune serologies
- HIV status (Antigen or PCR)
- CXR / CT Thorax / Lung function
Why each test matters — explained from first principles
| Investigation | What It Screens For | Why |
|---|---|---|
| CBC + differentials | Cytopenias, lymphopenia, neutropenia | Low absolute lymphocyte count → possible T-cell deficiency (SCID); neutropenia → phagocytic defect |
| Absolute lymphocyte count | T-cell deficiency | Lymphopenia in infants is abnormal until proven otherwise |
| LFTs, RFTs | Secondary causes (CKD, liver failure → protein loss) | CKD causes uraemic immunoparesis; liver failure → reduced complement synthesis |
| Protein and globulin | Hypogammaglobulinaemia | Total protein = albumin + globulin; low globulin → low immunoglobulins; critical screening test |
| ESR/CRP | Inflammation; paradoxically low ESR | ↓ESR if low globulin/fibrinogen [1] — ESR depends on plasma proteins aggregating RBCs; if globulin is low, ESR is falsely low even during infection |
| Immunoglobulin profile (IgG, IgA, IgM, IgE) | Antibody deficiency | Low IgG/A/M → hypogammaglobulinaemia (CVID, XLA); High IgE → Hyper-IgE syndrome, atopy, parasites |
| Serum + urine electrophoresis | Monoclonal gammopathy, myeloma | Myeloma causes secondary immunodeficiency (immunoparesis); also rules out paraprotein |
| C3/C4 | Complement deficiency or consumption | Low C3 + C4 → classical pathway activation (SLE, immune complex); Low C3 alone → alternative pathway; Normal C3/C4 doesn't exclude terminal complement deficiency (need CH50/AH50) |
| ANA ± autoimmune serologies | Autoimmune causes / immune dysregulation | PIDs can present with autoimmunity; SLE itself causes secondary immunodeficiency |
| HIV status | HIV/AIDS | The most important secondary cause to exclude; use 4th-gen Ag/Ab combo test or PCR |
| CXR / CT Thorax / Lung function | Bronchiectasis, absent thymic shadow | "Idiopathic" bronchiectasis → think antibody deficiency [1]; absent thymic shadow in infant → SCID |
Low ESR Trap
Students often assume ESR is always elevated in infection. If the globulin is low (as in antibody deficiency) or fibrinogen is low, ESR will be paradoxically low despite active infection. [1] This is a classic exam discriminator. If a patient has recurrent infections but a "normal" or low ESR, check the globulin — it may be the clue to hypogammaglobulinaemia.
Second-line investigations: [1]
- Lymphocyte subsets: CD3, CD4, CD8, CD16/56, CD19
- Lymphocyte proliferation responses to mitogen/antigen
- Vaccine titres (e.g., post-pneumococcal vaccine serology)
- Coombs test and isohemagglutinins (anti-A, anti-B)
- IgG subclass, IgD, specific immunoglobulin levels
- B cell and T cell immunophenotyping
- Complement function tests: CH50/AH50
- C1-esterase inhibitor level and function
- Neutrophil function tests (e.g., NBT, DHR)
- Specific molecular/genetics tests & next-generation sequencing
"Order only based on clinical suspicion!" [1]
Key second-line tests explained
| Test | What It Does | When to Order |
|---|---|---|
| Lymphocyte subsets (flow cytometry) | Quantifies CD3+ T cells, CD4+ helper, CD8+ cytotoxic, CD16/56 NK cells, CD19+ B cells | Suspected CID or SCID (low T); XLA (absent B cells); NK cell deficiency |
| Lymphocyte proliferation | Tests if T cells can respond to mitogens (PHA) or specific antigens | Suspected T-cell functional defect even with normal counts |
| Vaccine titres (e.g., anti-pneumococcal IgG) | Tests if the patient can mount a specific antibody response after vaccination | Key test for CVID — patient may have some IgG but cannot respond to vaccines; functional antibody deficiency |
| Isohemagglutinins (anti-A, anti-B) | Natural IgM antibodies; their presence confirms basic humoral function | In the case, anti-HBs and isohemagglutinins were PRESENT [1] → rules out severe antibody deficiency → redirects workup |
| IgG subclass | IgG1-4 levels; IgG2 deficiency → poor response to polysaccharide antigens | Recurrent sinopulmonary infections with normal total IgG |
| CH50 / AH50 | CH50 = total classical pathway function; AH50 = total alternative pathway function | Both absent → terminal complement pathway deficiency (C5-C9) [1] |
| C1-INH level + function | C1-esterase inhibitor deficiency → hereditary angioedema | Recurrent angioedema WITHOUT urticaria (bradykinin-mediated) [2] |
| DHR / NBT | Tests neutrophil oxidative burst (NADPH oxidase function) | Suspected CGD — recurrent abscesses, catalase-positive organisms [2] |
| NGS / genetic testing | Identifies specific gene mutations | Confirmed/strongly suspected PID requiring precise diagnosis for targeted therapy/HSCT/gene therapy |
| Complement Pathway | Components | Functional Test |
|---|---|---|
| Classical | C1, C2, C4 → C3 → C5-C9 | CH50 |
| Alternative | Factor B, D, Properdin → C3 → C5-C9 | AH50 |
| Lectin | MBL, MASPs → C2, C4 → C3 → C5-C9 | (No routine test) |
| Terminal (MAC) | C5, C6, C7, C8, C9 | Shared by both CH50 and AH50 |
In the case:
- CH50 ABSENT + AH50 ABSENT [1]
- C3 was measured → both pathways converge at C5-C9 (terminal pathway)
- If only CH50 were low with normal AH50 → deficiency in C1, C2, or C4 (classical pathway only)
- If only AH50 were low with normal CH50 → deficiency in Factor B, D, or Properdin (alternative pathway only)
- Both absent = the defect must be in the shared terminal pathway (C5-C9)
This is the most exam-relevant framework. The type of organism causing recurrent infection tells you WHICH arm of immunity is defective:
| Immune Defect | Typical Pathogens | Why |
|---|---|---|
| Antibody (B-cell) deficiency | Encapsulated bacteria (S. pneumoniae, H. influenzae, N. meningitidis), Giardia, Enteroviruses [1] | Antibodies are critical for opsonising encapsulated organisms; IgA protects mucosal surfaces (GI tract) |
| T-cell deficiency | Viruses (CMV, EBV, HSV), Fungi (Candida, PCP), Mycobacteria, Protozoa (Toxoplasma) | T cells are the primary defence against intracellular pathogens |
| Combined (T+B) | All of the above | Both arms down |
| Phagocytic defect | Catalase-positive bacteria (Staph aureus, Serratia, Burkholderia), Aspergillus, Mycobacteria (disseminated BCG) [2] | Phagocytes need oxidative burst to kill these; catalase-positive organisms destroy their own H₂O₂, so they depend on the phagocyte's H₂O₂ — if the phagocyte can't make it (CGD), the organism survives |
| Complement deficiency (terminal) | Neisseria species (meningitidis, gonorrhoeae) [1][2] | MAC (C5b-C9) is uniquely important for killing Neisseria by forming transmembrane pores; without MAC, Neisseria is not lysed |
| Complement deficiency (early classical) | Encapsulated bacteria; also associated with SLE-like disease | C1q/C2/C4 deficiency → impaired immune complex clearance → lupus-like autoimmunity |
High Yield: Organism → Defect Mapping
This is a common MCQ/SAQ stem. If the vignette gives you the organism, map backwards to the immune defect. If it gives you the immune defect, predict the organisms.
Core Concept 8: Antibody Deficiencies — The Most Common PIDs
Antibody immunodeficiencies are the most common form of primary or secondary immunodeficiency [1]
Examples: Agammaglobulinaemia, Common Variable Immunodeficiency (CVID), B-cell depleting therapies, CLL, Multiple Myeloma [1]
| Condition | Defect | Age of Onset | Key Features | Treatment |
|---|---|---|---|---|
| XLA (Bruton's) | BTK mutation → no mature B cells | 6 months (when maternal IgG wanes) | Males only (X-linked); absent B cells; panhypogammaglobulinaemia; recurrent sinopulmonary infections; absent/hypoplastic tonsils | Ig replacement |
| CVID | Heterogeneous; TACI mutations in 10-15% [2] | Childhood to young adulthood | Most common symptomatic PID [2]; low IgG + low IgA and/or IgM; poor vaccine responses; bronchiectasis; chronic diarrhea; autoimmune cytopenias (ITP, AIHA); granulomatous disease; increased GI and lymphoid malignancy risk [2] | Ig replacement + prophylactic antibiotics |
| Selective IgA deficiency | Low/absent IgA | Any | Most common PID overall (~1:500); usually asymptomatic; may have recurrent mucosal infections; associated with coeliac disease; risk of anaphylaxis if transfused with IgA-containing products | Usually no treatment; avoid IgA-containing blood products |
| Hyper-IgM syndrome (Type 1) | CD40L mutation (X-linked) [2] | Childhood | Normal/high IgM but low IgG/A/E; can't class-switch; susceptible to PCP, Cryptosporidium | Ig replacement, PCP prophylaxis |
Core Concept 9: Immunoglobulin Replacement Therapy
Immunoglobulin (Ig) derived from pool of plasma donors ( > 1000) [1]
Mostly IgG only (negligible other immunoglobulin isotypes) [1]
Routes: IVIG vs SCIG vs IMIG [1]
Specific types: Hyperimmune globulin (specific Ab), Anti-D Ig [1]
1. Ig replacement – protection against infection [1]
- Primary or secondary antibody deficiencies
- ~0.4-0.5 g/kg per month
2. Immunomodulatory – suppression of inflammation [1]
- Neurology, rheumatology, haematology, renal, transplantation, infections…
- ~1-2 g/kg per dose
Why the dose difference? At replacement doses (0.4-0.5 g/kg/month), you're simply restoring the patient's IgG to a level that prevents infection. At immunomodulatory doses (1-2 g/kg), the massive amount of pooled IgG exerts anti-inflammatory effects through multiple mechanisms: Fc receptor blockade, anti-idiotype antibodies, complement scavenging, and modulation of dendritic cell/T-cell function.
IVIG: Once per month (IV) [1]
SCIG: Once per week, daily push, or facilitated SCIg (SC) [1]
| Feature | IVIG | SCIG |
|---|---|---|
| Route | Intravenous | Subcutaneous |
| Frequency | Monthly | Weekly (or more frequent smaller doses) |
| Ig levels | Peak-trough fluctuation | More physiological: avoids trough levels [1] |
| Setting | Hospital/infusion centre | Home therapy [1] |
| Venous access | Required | Does not require venous access [1] |
| Systemic reactions | More common (headache, fever, chills, anaphylaxis) | Fewer systemic adverse reactions [1] |
| Local reactions | Rare | More common (local swelling at injection site) |
| Infection rate | Same | ~Same infection rate as IVIG [1] |
| Ig level achieved | Lower troughs | Higher steady-state level [1] |
| Quality of life | Lower | Improved [1] |
| Cost | Higher (hospital resources) | Cost saving [1] |
SCIG leads to: higher level of immunoglobulin and a reduction in side effects, ~same infection rate as IVIG [1]
Exam Note: SCIG Advantages
If asked "What are the advantages of SCIG over IVIG?", list: more stable Ig levels (avoids troughs), fewer systemic side effects, no need for venous access, home-based (convenience), fewer hospital admissions, improved QoL, cost-effective. The infection rate is comparable.
Core Concept 10: Management Principles for PIDs
Management and treatment options vary: [1]
- Antimicrobial prophylaxis
- Immunoglobulin replacement
- Targeted therapies
- Haematopoietic stem cell transplant (HSCT)
- Gene therapy
Screening → Diagnosis → Management → Family Screening [1]
| Stage | Key Actions |
|---|---|
| Screening | Recognize potential cases; select initial investigations; acute management; appropriate and timely referral [1] |
| Diagnosis | Exclude first the reversible, treatable or life-threatening; select second-line tests based on presentation, initial investigations, microbiological results [1] |
| Management | Replacement therapy; antimicrobial prophylaxis; treatment of autoimmune/autoinflammatory manifestations; disease monitoring; prevention of complications; ? Transplantation / Gene therapy [1] |
| Family Screening | Depending on mode of inheritance; offspring, siblings, parents; preconception counselling; prenatal diagnosis; early treatment and prevention of complications [1] |
| PID Category | Primary Treatment | Key Prophylaxis | Definitive Cure |
|---|---|---|---|
| SCID | Emergency HSCT | PCP prophylaxis (co-trimoxazole), antifungals | HSCT or gene therapy |
| XLA / CVID | Ig replacement [1] | Prophylactic antibiotics (azithromycin) | None (lifelong Ig replacement) |
| CGD | Septrin + Itraconazole [2] | Antimicrobial prophylaxis | HSCT |
| Terminal complement deficiency | Meningococcal vaccination, antibiotic prophylaxis | Penicillin prophylaxis (like asplenic patients) | None |
| HAE (C1-INH deficiency) | Acute: C1-INH concentrate, icatibant (bradykinin B2 antagonist); Long-term: danazol (attenuated androgen), lanadelumab (anti-kallikrein) | Avoid ACE inhibitors (worsen bradykinin-mediated angioedema) | None |
Clinical Approach Summary: "I Always Get Sick"
- Infection characterization: Type, frequency, severity, organisms, sites, response to treatment
- SPUR features: Serious? Persistent? Unusual? Recurring?
- Age of onset — earlier onset suggests more severe PID
- Family history: Consanguinity, similar illness in siblings, early childhood deaths, autoimmunity
- Immunization history: Adverse reactions to live vaccines (disseminated BCG in SCID/CGD)
- Non-infectious features: Autoimmune disease, chronic diarrhea, skin disease, failure to thrive
- Exclude secondary causes: HIV risk factors, medication history (steroids, biologics, chemotherapy), diabetes, CKD, malignancy symptoms, malnutrition
- Growth parameters (failure to thrive in children)
- ENT: absent/hypoplastic tonsils (XLA), nasal polyps
- Lymph nodes: absent in XLA; lymphadenopathy in CVID
- Skin: eczema (Wiskott-Aldrich, Hyper-IgE), telangiectasia (Ataxia-telangiectasia), scars from infections
- Chest: crackles/bronchiectasis
- Abdomen: splenomegaly (CVID), hepatomegaly
- Neurological: ataxia (A-T), hearing loss (as in the case — complication of meningitis)
Step 1: First-line → CBC, differential, absolute lymphocyte count, LFT, RFT, protein/globulin, ESR/CRP, Ig profile (IgG/A/M/E), serum + urine electrophoresis, C3/C4, ANA, HIV, CXR [1]
Step 2: Second-line (targeted) → Lymphocyte subsets, vaccine titres, CH50/AH50, DHR/NBT, C1-INH, genetic testing [1]
Step 3: Referral → Immunology clinic for definitive diagnosis, management, family screening
| Feature | Detail | Significance |
|---|---|---|
| Age/Sex | M/22 | Young adult; PID can present at any age |
| Pathogen | Neisseria meningitidis serotype Y | Encapsulated → complement or antibody deficiency |
| Recurrence | 3 episodes in 1 year | SPUR: Recurring + Serious |
| HIV | Negative | Secondary cause excluded |
| CBC, LFT, RFT | Normal | Rules out CKD, liver disease, haematological malignancy |
| Anti-HBs, isohemagglutinins | Present | Rules out severe antibody deficiency [1] — the patient can make antibodies |
| CXR | Normal | No bronchiectasis (argues against chronic antibody deficiency) |
| CT/MRI brain, sinuses | Normal | Structural causes excluded |
| CH50 | ABSENT [1] | Classical pathway non-functional |
| AH50 | ABSENT [1] | Alternative pathway non-functional |
| Diagnosis | Terminal complement pathway deficiency (C5-C9) [1] | Both pathways share C5-C9; defect here explains both absent CH50 and AH50 |
Management for this patient:
- Meningococcal vaccination (quadrivalent conjugate + serogroup B vaccine — though vaccine efficacy may be reduced)
- Prophylactic antibiotics (penicillin)
- Education on seeking early medical attention for febrile illness
- Family screening of siblings and parents for complement levels
- Genetic testing to identify specific complement component affected
1. Primary immunodeficiencies are not as "rare" as you think — "Never encountered" vs. "Never diagnosed" [1]
2. Vigilance for potential cases — or easily overlooked! [1]
3. Exclude secondary causes first, then consider disease phenotype (pattern of pathogens, types of infection or immunodysregulation, age of onset, gender, family history, prelim investigations etc.) [1]
4. First-line ± second-line investigations if indicated [1]
5. Consider timely referral or consultation! [1]
Likely Exam Questions
-
A 22-year-old man presents with his third episode of meningococcal meningitis. HIV test is negative, CBC and immunoglobulin levels are normal. Which investigation is most likely to identify the underlying cause? → CH50/AH50 (both will be absent → terminal complement deficiency)
-
A 3-year-old boy has recurrent sinopulmonary infections since age 8 months. Examination shows absent tonsils. IgG, IgA, IgM are all very low. CD19+ B cells are absent. What is the most likely diagnosis? → X-linked agammaglobulinaemia (Bruton's) — absent B cells, panhypogammaglobulinaemia, onset after maternal IgG wanes
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Which of the following is a first-line investigation when evaluating suspected immunodeficiency? → Immunoglobulin profile (IgG, IgA, IgM) — not CH50/AH50 or DHR (these are second-line)
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A patient with CVID is started on immunoglobulin replacement. What is the standard replacement dose? → 0.4-0.5 g/kg per month
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What is the advantage of SCIG over IVIG? → More stable Ig levels (avoids trough), home-based, fewer systemic side effects, no need for venous access
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List 4 warning signs that should raise suspicion of primary immunodeficiency. (4 marks) → Disproportionately frequent infections / Disproportionately severe infections / Unusual microorganisms / Family history of immunodeficiency / Unusual sites of infection / Recurrent infections with the same organism / Clinical phenotype of immunodeficiency-associated syndrome / Infections after biologicals (any 4)
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A 30-year-old woman has recurrent pneumonia and chronic diarrhea. IgG is 2.5 g/L (low), IgA is undetectable, IgM is 0.3 g/L (low). She fails to respond to pneumococcal vaccine. What is the most likely diagnosis and what treatment would you initiate? (4 marks) → CVID (2 marks); Immunoglobulin replacement therapy ~0.4-0.5 g/kg/month (1 mark) + prophylactic antibiotics (1 mark)
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Explain why CH50 and AH50 are both absent in terminal complement deficiency. (2 marks) → CH50 measures the entire classical pathway (C1→C9); AH50 measures the entire alternative pathway (Factor B/D→C9). Both pathways share the terminal/common pathway (C5-C9). A defect in any C5-C9 component will abolish both CH50 and AH50.
| Related Topic | Connection |
|---|---|
| GC 106: Antibiotic Use | Prophylactic antibiotics in PID (penicillin for complement deficiency, co-trimoxazole for PCP prophylaxis in T-cell deficiency) |
| GC 103: Fever After Travelling | Exclude travel-related infections before jumping to PID; malaria can cause immunosuppression |
| Block A: Fundamentals of Allergology | Type I-IV hypersensitivity is the "overactive" immune system; immunodeficiency is the "underactive" side — same pathway, opposite direction [3] |
| Block A: Fever after Blood Transfusion | IgA-deficient patients can develop anaphylaxis from IgA in transfused products [4] |
| Block A: Splenomegaly / Myeloproliferative | Post-splenectomy patients are functionally immunodeficient (encapsulated organisms) — similar prophylaxis as complement deficiency |
| Block A: Generalised Lymphadenopathy | CVID can cause polyclonal lymphoproliferation mimicking lymphoma [5] |
| Block A: HIV Positive | HIV = most important secondary immunodeficiency to exclude |
High Yield Summary
-
SPUR = Serious, Persistent, Unusual, Recurring → triggers immunodeficiency workup.
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Always exclude secondary causes first (HIV, diabetes, CKD, malignancy, medications, malnutrition, protein-losing states).
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First-line investigations: CBC + diff, absolute lymphocyte count, LFT/RFT, protein/globulin, ESR/CRP, Ig profile (IgG/A/M/E), SPEP/UPEP, C3/C4, ANA, HIV, CXR.
-
Second-line investigations are ordered based on clinical suspicion: lymphocyte subsets, vaccine titres, CH50/AH50, DHR/NBT, C1-INH, genetic testing.
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Organism → Defect: Neisseria = complement (terminal); encapsulated bacteria = antibody/complement; intracellular organisms = T-cell; catalase-positive bacteria + Aspergillus = phagocyte (CGD).
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Antibody deficiency is the most common PID; presents with recurrent sinopulmonary infections, bronchiectasis, chronic diarrhea; treated with Ig replacement (0.4-0.5 g/kg/month).
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SCIG > IVIG for replacement: more stable levels, fewer systemic reactions, home-based, no venous access needed, better QoL, cost-effective.
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CH50 absent + AH50 absent = terminal complement deficiency (C5-C9). This is the diagnosis in the lecture case (recurrent Neisseria meningitidis).
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IUIS classifies PIDs into 10 categories — know the major examples, typical organisms, and key investigations for each.
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Family screening, genetic counselling, and timely immunology referral are essential components of PID management.
Active Recall - Immunodeficiencies
[1] Lecture slides: GC 096. Why do I always get sick.pdf (all pages) [2] Senior notes: Jerry's immunodeficiencies.pdf (PID classification table, complement deficiency section, CGD section) [3] Senior notes: Block A - Fundamentals of Allergology.pdf (Type I-IV hypersensitivity) [4] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (IgA deficiency and transfusion reactions) [5] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf (lymphoproliferation differential)
GC094 Where Is The Lesion I
"Where Is The Lesion" is a neuroanatomical localization exercise that teaches students to identify the site of a neurological lesion based on clinical signs and symptoms.
GC097 Many Members Of The Family Have Anaemia (file 1)
A clinical scenario in which multiple family members present with anaemia, suggesting an inherited haemoglobinopathy or hereditary red blood cell disorder such as thalassaemia, sickle cell disease, or hereditary spherocytosis.