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]
The Case That Anchors the Lecture
M/22, previously healthy salesperson. Presented with THREE episodes of meningitis over ~1 year, including two culture-proven episodes of Neisseria meningitidis serogroup Y disease. CT/MRI brain, sinuses and skull base were unremarkable; ENT and Neurology found no structural cause. Immunology work-up ultimately demonstrated complete C6 deficiency. [1][7]
| Episode | Key findings | Teaching point |
|---|---|---|
| September 2017 | Serum WBC 19.9 × 10⁹/L (neutrophils 16.6); CSF WBC 715 × 10⁶/L with 77% polymorphs and protein 0.76 g/L. Culture was negative after empirical antibiotics; he improved with ceftriaxone. | Prior antibiotics can sterilise CSF; the inflammatory CSF pattern and response still supported bacterial meningitis. |
| January 2018 | Septic shock; Gram-negative diplococci were seen and blood/CSF grew N. meningitidis serogroup Y. A left-sided hearing deficit followed. | A severe invasive infection plus a neurological complication is a strong SPUR signal. |
| June 2018 | Blood and CSF again grew N. meningitidis serogroup Y. | Recurrence with the same uncommon serogroup makes an immune or anatomical predisposition much more likely than chance. |
The lecture also noted that this patient accounted for 3 of the 10 notified invasive meningococcal episodes in Hong Kong in 2018. This is historical lecture context, not current epidemiology. [1]
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 initially undetectable. Because both assays depend on the shared C3-to-terminal pathway, this pattern localises the problem to a shared component or complement consumption; it does not identify C5-C9 by itself. Repeat functional testing plus component assays and genetics established complete C6 deficiency in this family. [6][7]
- 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 recurrent meningococcal disease, especially in a young adult, think of terminal complement deficiency early. CH50 and AH50 are screening/localisation tests: if both are persistently absent, measure the shared components (C3 and C5-C9), exclude consumption or pre-analytical error, and confirm the specific defect with component and genetic testing. [6]
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 is jumping straight to a rare IEI without looking for HIV, diabetes, malignancy, medications or protein-losing states. The lecture explicitly states: "Exclude secondary immunodeficiency" before pursuing PID workup [1]. Current HIV laboratory screening starts with a fourth-generation HIV-1/2 antigen/antibody assay; a reactive result is followed by an HIV-1/2 differentiation assay, with nucleic-acid testing used to resolve discordant/indeterminate results or suspected acute infection. [10]
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) | An isolated infection can occur in an immunocompetent host; repeated episodes of the same invasive infection demand evaluation for an anatomical or immune predisposition |
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
The numbers above are the lecture-era classification. Current terminology favours inborn errors of immunity (IEIs). The 2024 IUIS phenotypic update lists 559 IEIs, including 67 newly described monogenic defects and two new phenocopies; the companion genotypic classification covers 508 genes and 17 phenocopies. The lesson is not to memorise a fixed count, but to recognise that the classification continues to expand. [8][9]
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]
- Pregnancy losses and early infant deaths in the family (asked in the case; a non-specific clue that may help reveal an inherited lethal disorder, but not proof of X-linked inheritance)
- STI history including Neisseria gonorrhoeae (another Neisseria; if recurrent, think complement deficiency)
Core Concept 6: Investigations
The laboratory screenshots matter because they show how a normal-looking routine screen does not end the work-up when the phenotype is compelling. His CBC and lymphocyte count, liver/renal function and chest radiograph were unremarkable; HIV Ag/Ab was negative; serum electrophoresis showed no monoclonal immunoglobulin. IgA 2.06 g/L, IgG 12.30 g/L and IgM 2.07 g/L were within the reported reference ranges, and lymphocyte subsets were broadly preserved. Anti-HBs and isohaemagglutinins were present. [1]
Together, these findings made a profound quantitative B-cell/antibody-production defect unlikely, but did not exclude every specific antibody defect. The unusually narrow pathogen pattern therefore justified testing complement function.
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
The list above reproduces the slide. For current practice, use the HIV diagnostic sequence and phenotype-driven respiratory imaging described below rather than treating PCR or CT thorax as universal first-line tests.
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 may indicate hypogammaglobulinaemia (e.g. CVID or XLA). Raised IgE is non-specific and must be interpreted with phenotype; it does not diagnose a hyper-IgE syndrome by itself. |
| Serum + urine electrophoresis | Monoclonal gammopathy, myeloma | Myeloma causes secondary immunodeficiency (immunoparesis); also rules out paraprotein |
| C3/C4 | Complement deficiency or consumption | Concentrations can support a consumption pattern but do not replace functional testing. Normal C3/C4 does not exclude a terminal complement defect; use CH50/AH50 when the phenotype warrants it. |
| ANA ± autoimmune serologies | Autoimmune causes / immune dysregulation | PIDs can present with autoimmunity; SLE itself causes secondary immunodeficiency |
| HIV status | HIV/AIDS | An important, treatable secondary cause; start with a laboratory fourth-generation HIV-1/2 Ag/Ab assay and follow the current diagnostic algorithm. [10] |
| Respiratory assessment | Bronchiectasis or chronic lung damage | A chest radiograph may be an initial test; lung function and CT are phenotype-driven, not universal screening tests. "Idiopathic" bronchiectasis should prompt assessment for antibody deficiency. [1] |
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 |
| Isohaemagglutinins (anti-A, anti-B) | Naturally occurring antibodies that provide one window on humoral function | In the case, anti-HBs and isohaemagglutinins were present [1] → a profound antibody-production defect was less likely, but not every functional antibody defect was excluded. |
| 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 low/absent suggests a shared-component defect (C3 or C5-C9) or complement consumption; repeat and measure individual components. [6] |
| 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]. DHR flow cytometry is the preferred modern assay; NBT is an older semiquantitative test. |
| 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 |
How to interpret the pattern:
- Low/absent CH50 with normal AH50 points toward an early classical-pathway defect (C1, C2 or C4).
- Normal CH50 with low/absent AH50 points toward an alternative-pathway defect (for example factor B, factor D or properdin).
- Low/absent both CH50 and AH50 points toward a shared component (C3 or C5-C9) or active complement consumption. The lecture laboratory report appropriately advised repeating the assays; persistent abnormality then requires component-level testing. [1][6]
The pathway diagram shows that CH50 and AH50 begin through different recognition systems but converge at C3 and the terminal C5b-C9 membrane-attack complex. The accompanying family study resolved the ambiguity: the index patient and two siblings were compound heterozygotes for C6 p.Arg596Ter and p.Arg606Ter. They had near-absent C6 with absent CH50/AH50. Relatives carrying one variant had intermediate C6 concentrations but preserved functional assays, while the wild-type sibling was normal. Thus, the functional tests localised the defect and C6 measurement plus genetics made the diagnosis. [7]
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]
A B cell recognises antigen through its B-cell receptor, then proliferates and—usually with T-helper-cell signals—differentiates into antibody-secreting plasma cells and memory B cells. The antibodies then neutralise pathogens/toxins, opsonise microbes for phagocytosis and activate complement. A humoral phenotype can therefore arise from absent B cells, failed maturation or class switching, inadequate T-cell help, or acquired B-cell depletion. Preserved T cells, NK cells and phagocytes cannot fully compensate for loss of antibody-mediated defence against encapsulated organisms. [1]
The medication slide groups causes of hypogammaglobulinaemia into antiepileptic drugs (for example carbamazepine, phenytoin or valproate), conventional immunosuppressants (such as azathioprine, cyclophosphamide, mycophenolate or systemic corticosteroids) and targeted/B-cell-directed therapies (including rituximab, ofatumumab and belimumab). The practical point is to record baseline IgG, IgA and IgM before planned B-cell depletion when feasible, then repeat testing according to the drug, infection history, baseline result and local protocol. The slide's fixed 3–6-month treatment and 6–12-month post-treatment schedule is useful lecture-era practice, not a universal interval for every immunosuppressant. Monitoring immunoglobulins before and after rituximab helps identify patients at higher risk of persistent hypogammaglobulinaemia and infection. [14]
| 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; a monogenic cause is identifiable in only a subset | Childhood to adulthood | A common symptomatic IEI; low IgG plus low IgA and/or IgM, impaired vaccine responses, bronchiectasis/chronic diarrhoea, autoimmune cytopenias, granulomatous disease and increased lymphoid/GI malignancy risk [2] | Ig replacement; treat complications; prophylactic antibiotics only when individually indicated |
| Selective IgA deficiency | Low/absent IgA | Any | Often asymptomatic; prevalence varies markedly by population; may cause recurrent mucosal infection and is associated with coeliac disease. Only a small subgroup develops clinically important anti-IgA-associated transfusion reactions. | Usually no Ig replacement. Do not impose a blanket ban on blood products: if there is a previous anaphylactic transfusion reaction and anti-IgA, involve transfusion medicine and use washed cellular components or IgA-deficient components as appropriate. [12] |
| 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? The lecture's replacement starting range (about 0.4–0.5 g/kg/month) aims to provide protective antibody, but subsequent dosing is individualised to infection burden, trough/steady-state IgG, bronchiectasis, protein loss and adverse effects. Immunomodulatory regimens use much larger short-course doses (often 1–2 g/kg per course) to exert anti-inflammatory effects through mechanisms including Fc-receptor blockade and immune-cell/complement modulation. [13]
Before Starting Ig Replacement: Save the Diagnostic Evidence
Pooled donor IgG transfers many passive antibodies. After Ig replacement starts, infection serology, vaccine titres/functional antibody responses and other IgG-based assays may reflect the product rather than the patient. Obtain pretreatment immunoglobulins, vaccine responses and stored serum before IgRT when clinically safe. Afterwards, favour direct pathogen tests (antigen, PCR or culture when appropriate) and seek specialist laboratory advice when interpreting serology. [15][16]
IVIG: Once per month (IV) [1]
SCIG: Once per week, daily push, or facilitated SCIg (SC) [1]
| Feature | IVIG | SCIG |
|---|---|---|
| Route | Intravenous | Subcutaneous |
| Frequency | Commonly every 3–4 weeks | Product- and patient-specific: weekly, more frequent small doses, or facilitated regimens |
| 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 | Infusion reactions (headache, fever, chills) are more common; severe anaphylaxis is rare | Fewer systemic adverse reactions [1] |
| Local reactions | Rare | More common (local swelling at injection site) |
| Infection protection | Effective when adequately dosed | Broadly comparable to IVIG when adequately dosed [13] |
| Ig level achieved | Lower troughs | Higher steady-state level [1] |
| Quality of life | May suit patients who prefer supervised intermittent infusion | Home autonomy may improve quality of life for some patients |
| Cost/resources | Requires infusion resources | May reduce facility use, but total cost is health-system and product dependent |
The concentration–time graph explains the pharmacokinetic difference: IVIG produces a high post-infusion peak followed by a trough, whereas smaller, frequent SCIG doses produce a steadier level after the initial wash-in period. The patient photographs show pump and manual-push administration into the abdomen and the expected transient local erythema/swelling; the abdomen, thigh, upper arm and hip are potential sites depending on product guidance. Safe home treatment requires training, aseptic technique, site rotation and a product-specific schedule. [1]
Exam Note: SCIG Advantages
SCIG usually gives steadier IgG levels, avoids venous access, permits home treatment and causes fewer systemic reactions, at the cost of more frequent administration and local-site reactions. IVIG and SCIG provide broadly equivalent infection protection overall; route selection should be individualised to clinical risk, venous access, treatment burden and patient preference. [13]
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] | Antibiotic prophylaxis is considered for selected patients with ongoing infections despite optimised IgRT and airway care | XLA generally requires lifelong replacement; CVID management is individualised |
| CGD | Septrin + Itraconazole [2] | Antimicrobial prophylaxis | HSCT |
| Terminal complement deficiency | MenACWY and MenB vaccination, plus boosters while risk remains; vaccination does not eliminate risk [11] | Antibiotic prophylaxis is individualised with immunology/infectious-disease input; give an urgent-care plan for fever or meningitis symptoms | None |
| HAE (C1-INH deficiency) | On-demand: C1-INH concentrate or icatibant. First-line long-term prophylaxis: plasma-derived C1-INH, lanadelumab or berotralstat. [17] | Avoid ACE inhibitors; attenuated androgens such as danazol are now second-line, not preferred first-line prophylaxis. [17] | 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 serogroup Y | Encapsulated → complement or antibody deficiency |
| Recurrence | 3 episodes in 1 year | SPUR: Recurring + Serious |
| HIV | Negative | Secondary cause excluded |
| CBC, LFT, RFT | Normal | Made major cytopenia and renal/hepatic dysfunction less likely; did not by itself exclude malignancy |
| Anti-HBs, isohaemagglutinins | Present | Makes a profound antibody-production defect unlikely, without excluding every specific antibody defect |
| CXR | Normal | No obvious radiographic lung abnormality; a normal chest radiograph does not exclude bronchiectasis |
| CT/MRI brain, sinuses | Normal | Structural causes excluded |
| CH50 | ABSENT [1] | Classical-pathway functional assay was non-functional; repeat testing was needed |
| AH50 | ABSENT [1] | Alternative-pathway functional assay was non-functional; the combined pattern localised a shared-pathway problem |
| Specific diagnosis | Complete C6 deficiency [7] | C6 concentration and compound-heterozygous C6 variants explained the recurrent meningococcal disease and absent functional assays |
Management principles for this patient:
- Give both MenACWY and MenB vaccination and keep boosters up to date while the risk remains, using the local schedule. For reference, current US ACIP guidance uses MenACWY boosters every 5 years and MenB boosters 1 year after the primary series then every 2–3 years while risk persists; local Hong Kong recommendations may differ. [11]
- Explain that vaccination does not abolish meningococcal risk. Provide a written plan to seek urgent assessment for fever, petechiae/purpura, severe headache, neck stiffness or rapidly progressive illness.
- Decide on long-term antibiotic prophylaxis with immunology/infectious-disease specialists rather than treating it as universal; account for recurrence, vaccination status, adherence, allergy and local resistance.
- Screen siblings and parents with appropriate functional/component assays, then offer genetic counselling and targeted testing using the established family variants. [7]
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]
| Related Topic | Connection |
|---|---|
| GC 106: Antibiotic Use | Antimicrobial prophylaxis in selected IEIs (for example co-trimoxazole for PCP prevention in profound T-cell deficiency); complement-deficiency prophylaxis is individualised |
| 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 | A small subgroup with IgA deficiency, previous anaphylactic transfusion reaction and anti-IgA needs a specialist component plan [4][12] |
| 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 is an important and treatable secondary immunodeficiency to exclude using the current laboratory algorithm [10] |
High Yield Summary
- SPUR = Serious, Persistent, Unusual, Recurring → consider immunodeficiency.
- Look for acquired causes first: HIV, diabetes, malignancy, medications, malnutrition and protein loss.
- Use the infection phenotype to target tests: Neisseria → terminal complement; encapsulated bacteria → antibody/complement; intracellular opportunists → T-cell; characteristic bacterial/fungal abscesses → phagocyte.
- First-line tests include CBC/differential and lymphocyte count, renal/liver function, protein/globulin, immunoglobulins, electrophoresis, C3/C4, HIV testing and phenotype-driven respiratory assessment.
- Second-line tests are targeted: lymphocyte subsets/function, vaccine responses, CH50/AH50, DHR, C1-INH, component assays and genetics.
- Both CH50 and AH50 absent is a localisation clue, not a component diagnosis: consider C3/C5-C9 defects or consumption, repeat the test, and measure components.
- The lecture patient had complete C6 deficiency, confirmed by C6 measurement and family genetics—not merely “unspecified C5-C9 deficiency.”
- Ig replacement route is individualised: SCIG gives steadier levels and fewer systemic reactions; IVIG gives less frequent supervised infusions. Overall infection protection is comparable when dosing is adequate.
- Collect diagnostic serum before IgRT when safe, because passive donor IgG confounds serology and vaccine-response testing.
- Family screening, genetic counselling, vaccination, an emergency infection plan and timely immunology referral are core management steps.
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) [6] ARUP Consult. Complement Deficiency Testing Algorithm (official laboratory interpretation; reviewed February 2023). [7] Li D, et al. Three patients with recurrent meningococcal meningitis and compound heterozygous mutations in the C6 gene. Clinical & Translational Immunology. 2020;9:e1148. [8] Tangye SG, et al. Human inborn errors of immunity: 2024 update on the classification from the IUIS Expert Committee (phenotypic classification). [9] Bousfiha A, et al. Human inborn errors of immunity: 2024 update on the classification from the IUIS Expert Committee (genotypic classification). [10] CDC. HIV Infection: Detection, Counseling, and Referral (current laboratory testing algorithm). [11] CDC/ACIP. Meningococcal Vaccination: Recommendations of the Advisory Committee on Immunization Practices, United States, 2020; CDC Yellow Book, Meningococcal Disease (persistent complement deficiency risk and booster principles). [12] Canadian Blood Services. Anaphylactic transfusion reactions and IgA deficiency (professional guidance). [13] UK Primary Immunodeficiency Network/British Society for Immunology. Consensus guideline for the management of immunoglobulin replacement therapy. Clinical & Experimental Immunology. 2022. [14] Barmettler S, et al. Association of immunoglobulin levels, infectious risk, and mortality with rituximab and hypogammaglobulinemia. JAMA Network Open. 2018;1:e184169. [15] Immune Deficiency Foundation. Laboratory tests (effect of Ig replacement on antibody testing). [16] Immune Deficiency Foundation. Immunoglobulin replacement therapy (pretreatment diagnostic testing). [17] Maurer M, et al. The international WAO/EAACI guideline for the management of hereditary angioedema—2021 revision and update. Allergy. 2022;77:1961–1990.
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