GC100 Defense Against Microbes
The host defense against microbes encompasses the integrated system of innate and adaptive immune mechanisms—including physical barriers, phagocytes, complement, and lymphocyte-mediated responses—that collectively recognize, contain, and eliminate pathogenic microorganisms.
Defense Against Microbes
This lecture, delivered by Dr. Siddharth Sridhar (Microbiology, HKU), is the conceptual backbone for understanding why infections happen and how the body fights them. It sits at the intersection of immunology and infectious disease — the "holy grail" triad of Microbe ↔ Host ↔ Intervention [1]. Every other microbiology lecture in the General Clerkship (antimicrobial resistance, diagnosis of infections, fever after chemotherapy, medically important microbes, practical antibiotic use) builds on the framework laid here.
Core thesis of this lecture: Infections do not happen without reason. If you understand which arm of immunity is broken, you can predict which organisms will cause disease, how to investigate, and how to intervene — including manipulating the immune system itself as a therapeutic tool [1].
Learning Objectives (from Slide 53)
"Infections do not happen without reason — recognizing and reversing common predisposing factors can save your patients a lot of trouble. Vaccination: prevention is better than cure. Try to recognize infection patterns suggestive of rarer immunodeficiency syndromes. Antimicrobials are good, but immunomodulation may be a very necessary adjunct to ensure good patient outcomes." [1]
The outcome of any infection is determined by three interacting factors: the Microbe, the Host, and the Intervention. [1]
The slide presents this as a pyramid rather than three isolated boxes: the clinical outcome emerges from the interaction between the microbe and host, while intervention modifies that interaction. You cannot think about treating infection without simultaneously considering:
- Microbe factors: virulence, resistance, inoculum size
- Host factors: immune status, barriers, comorbidities
- Intervention: antimicrobials, surgery, immunomodulation, vaccination
The immune system provides: defense against microbes, defense against cancers. BUT it also mediates: allergic reactions, aberrant responses to infections, autoimmune disease, and malignancy. [1]
This is why immunology is not just about "killing bugs." The same machinery that protects you can harm you. Understanding this duality is crucial for appreciating why steroids are used in some infections (to dampen harmful inflammation) and why immunosuppression predisposes to specific infection patterns.
| Feature | Innate Immunity | Adaptive Immunity |
|---|---|---|
| Timing | Immediate; pre-existing before infection | Needs time; stimulated by antigen exposure |
| Specificity | Non-specific | Highly specific |
| Diversity | Limited | Very diverse |
| Memory | No antigen-specific clonal memory (although trained innate states can occur) | Antigen-specific memory (basis of vaccination) |
| Role | First line; stimulates adaptive response | Elimination of specific antigens |
| Components | Physical/chemical barriers, phagocytes (neutrophils, macrophages), NK cells, complement, cytokines, platelets | B lymphocytes (antibodies), T lymphocytes (CD4+, CD8+) |
Why does this matter clinically?
Innate immunity acts within minutes-hours. If it fails (e.g., neutropenia), infections are fulminant and often bacterial/fungal. Adaptive immunity takes days-weeks to mount but provides lasting protection. If it fails (e.g., HIV), you get opportunistic infections that immunocompetent people handle easily.
4. Innate Immune System — Detailed Breakdown
Skin, gastrointestinal, genitourinary, and respiratory tract epithelium form the first line of defense. [1]
Why this matters: Any break in these barriers (burns, wounds, IV lines, urinary catheters, intubation, mucositis from chemotherapy) immediately predisposes to infection. This is the single most common reason hospitalized patients get infected. The vaginal canal's acidic pH (maintained by Lactobacillus) is another example — conditions that raise vaginal pH (menstruation, pregnancy, antibiotics) increase infection risk [8].
e.g., cathelicidins, defensins [1]
These are small peptides produced by epithelial cells and phagocytes that directly kill microbes by disrupting their membranes. Think of them as the body's own antibiotics at mucosal surfaces.
Pathogen-associated molecular patterns (PAMPs) on microbes are recognized by Pattern Recognition Receptors (PRRs) on host cell surfaces. Examples: Toll-like receptors (TLR), Nod-like receptors (NLR), RIG-I like receptors (RLR). [1]
Why from first principles: Microbes have conserved molecular structures (lipopolysaccharide in gram-negatives, peptidoglycan in gram-positives, flagellin, viral dsRNA) that human cells do not have. PRRs evolved to detect these foreign patterns without needing prior exposure. This is how the innate immune system "knows" something is foreign immediately.
Innate-to-Adaptive Bridge (Slide 6): PRR engagement triggers innate host-defence modules within hours, while the same signals induce module-specific adaptive effector responses over days. Critically, the adaptive response (T cells and antibodies) feeds back to indirectly activate innate modules in an antigen-specific manner — creating a positive-feedback loop that amplifies pathogen clearance [1].
| PRR Type | Location | Recognizes |
|---|---|---|
| TLRs | Cell surface + endosomal membranes | LPS (TLR4), flagellin (TLR5), dsRNA (TLR3), ssRNA (TLR7/8), CpG DNA (TLR9) |
| NLRs | Cytoplasm | Bacterial peptidoglycan fragments, danger signals → inflammasome activation |
| RLRs | Cytoplasm | Viral RNA (especially dsRNA) |
Neutrophils, Macrophages, Natural Killer cells [1]
- Neutrophils: First responders; recruited to sites of infection within hours. Kill by phagocytosis + respiratory burst (superoxide → hydrogen peroxide → hypochlorous acid). When neutrophils are deficient (quantitative = neutropenia; qualitative = CGD), bacterial and fungal infections dominate.
- Macrophages: Tissue-resident phagocytes; also serve as antigen-presenting cells bridging innate and adaptive immunity. Activated by IFN-γ from Th1 cells to kill intracellular organisms.
- NK cells: Kill virus-infected cells and tumor cells without prior sensitization. Also produce IFN-γ.
Plasma proteins activated by microbes. Promotes destruction and inflammation. [1]
Three activation pathways:
| Pathway | Trigger | Clinical Relevance |
|---|---|---|
| Classical | Antigen-antibody complex binds C1 | Deficiency → encapsulated bacterial infections; also associated with SLE |
| Lectin (MBL) | Mannose on microbial surfaces binds Mannose-Binding Lectin | Deficiency → sinopulmonary infections, Neisseria meningitidis |
| Alternative | Spontaneous C3b binding to microbial surfaces | Less common deficiency; also → Neisseria meningitidis |
Terminal components (C5-C9) — the Membrane Attack Complex (MAC):
Terminal component deficiency (C5-C9) → Neisseria meningitidis [1]
Why? The MAC inserts into Gram-negative outer membranes, and Neisseria depends particularly heavily on terminal-complement killing. Without an effective terminal pathway, recurrent invasive meningococcal (and sometimes gonococcal) infection can occur. This association is much stronger than a simplistic “thin versus thick cell wall” explanation.
How to read the slide diagram: all three entry pathways converge on C3 cleavage. C3b coats the organism for phagocytosis, C3a and C5a recruit/amplify inflammation, and C5b–C9 forms the MAC. Thus, a defect before C3 can impair opsonization as well as inflammation, whereas a terminal-pathway defect produces the particularly strong recurrent-Neisseria phenotype.
Current diagnostic nuance
The lecture's organism associations are pattern-recognition aids, not one-to-one rules. Recurrent invasive Neisseria should prompt assessment of the terminal pathway (and properdin), while recurrent encapsulated bacterial infection may reflect an early classical-pathway or C3 defect. Screening commonly starts with CH50 plus AH50; if both are normal but suspicion remains, lectin-pathway/MBL testing can be considered. Isolated low MBL is common and its clinical significance is variable [13].
The innate immune system communicates using cytokines (e.g., IL-1, IL-6, TNF-α, IFN-γ, IFN-α/β). These recruit more immune cells, activate adaptive immunity, cause fever, and trigger the acute phase response.
5. Adaptive Immune System — Detailed Breakdown
B cells differentiate into plasma cells, which produce antibodies. [1]
Antibody Structure (Slide 9): Y-shaped molecule composed of two heavy chains and two light chains. The Fab region (arms of the Y) contains the antigen-binding sites (one per arm). The Fc region (stem of the Y) determines the antibody class and binds Fc receptors on phagocytes/NK cells and C1q to activate complement [1].
Antibody Effector Functions (Slide 10):
| Effector Function | Mechanism |
|---|---|
| Neutralization | Antibodies bind microbes/toxins and block their ability to infect cells or cause damage |
| Opsonization & phagocytosis | Antibody-coated microbes are recognized via Fc receptors on phagocytes → enhanced uptake and killing |
| Antibody-dependent cellular cytotoxicity (ADCC) | NK cells recognize antibody-coated target cells via Fc receptors → target cell lysis |
| Complement activation | Antibody–antigen complexes activate the classical pathway → C3b opsonization, C5a inflammation, MAC lysis |
Antibody Key Features IgM First antibody produced; appears before IgG; pentameric → excellent at activating complement IgG Appears later; most abundant in serum; crosses placenta; provides neonatal passive immunity IgA Secreted at mucosal surfaces; key defense in GI and respiratory tracts IgE Bound to mast cells → allergic reactions; also important in helminth defense IgD Cell signaling in B cells; minor clinical role
IgM vs IgG — Exam Classic
The usual teaching sequence is IgM first, then IgG. Treat that as a timing framework, not a universal diagnostic rule: persistent or false-positive IgM, early absent IgM, vaccination, reinfection and assay-specific behaviour can all mislead. Interpret the organism-specific assay, sampling interval, avidity/paired titres where relevant, and the clinical context rather than equating any positive IgM with acute infection.
T cells are divided into:
- Cytotoxic T cells (CD8+): Kill cells harboring intracellular microbes (viruses, intracellular bacteria)
- T helper cells (CD4+):
- Th1: Activate macrophages to kill intracellular microbes via IFN-γ. Key for Mycobacterium tuberculosis.
- Th2: Promote IgE production and eosinophil/mast cell responses via IL-4. Key for helminth infections.
- Th17: Protect against extracellular bacteria and fungi.
- Regulatory T cells: Suppress immune responses; prevent autoimmunity.
T-Cell Activation & Th Polarization (Slide 13)
Naïve CD4⁺ T cells are activated when an APC presents antigen via MHC II → TCR/CD4 interaction, with co-stimulation via CD80/CD86 → CD28. The cytokine milieu then polarizes differentiation:
| Th Subset | Polarizing Cytokines | Produced Cytokines | Key Function |
|---|---|---|---|
| Th1 | IFN-γ, IL-12 | IFN-γ, TNF-α | Macrophage activation; intracellular pathogen killing |
| Th2 | IL-2, IL-4 | IL-4, IL-5, IL-9, IL-13 | IgE production; eosinophil/mast cell responses; helminth defense |
| Th17 | IL-6, IL-23, TGF-β | IL-17, IL-22 | Extracellular bacteria and fungi defense |
| Treg | IL-10, TGF-β | IL-10, TGF-β | Immune suppression; prevent autoimmunity |
Why Th1/Th2 distinction matters: If Th1 responses are impaired (e.g., HIV destroying CD4+ cells, anti-IFN-γ antibodies), intracellular pathogens like TB, non-tuberculous mycobacteria (NTM), and fungi flourish. If Th2 responses dominate inappropriately, you get allergic disease.
6. Clinical Syndromes of Impaired INNATE Immunity
Pathway Deficiency Associated Infections Classical pathway Encapsulated bacteria (S. pneumoniae, H. influenzae, N. meningitidis) MBL pathway Variable association with recurrent infection; clinical penetrance is incomplete Alternative pathway Defects including properdin/factor D can predispose to invasive Neisseria Terminal components (C5-C9) Neisseria meningitidis
High Yield
The take-home: Neisseria meningitidis is the hallmark organism of complement deficiency — especially terminal component deficiency. Early classical pathway deficiency also predisposes to SLE (immune complex clearance failure) [7].
6.2 Neutrophil Defects
Most common causes: hematological malignancy, drugs (chemotherapy, antibiotics) [1]
Problems in neutropenia:
- Bacterial infection:
- Gram-positive: Staphylococcus, Streptococcus, Enterococcus
- Gram-negative: E. coli, Pseudomonas aeruginosa
- Fungal infection:
- Candida
- Aspergillus, Fusarium, Zygomycetes
Why Pseudomonas can be so severe: It has intrinsic resistance to many antibiotics, forms biofilms, produces toxins (exotoxin A, elastase), and exploits the absence of neutrophils to cause rapidly progressive sepsis. The slide's “> 50% mortality” is a lecture-era headline, not a universal contemporary estimate: outcome varies greatly with syndrome, resistance, illness severity and speed of active treatment.
Clinical images from the lecture:
- Slide 17 — disseminated candidiasis: the erythematous-to-dusky nodules have central necrosis/crust. In a neutropenic patient, new papules or nodules are not automatically benign dermatitis; they can be a cutaneous clue to invasive fungal infection and should trigger urgent systemic evaluation, with tissue sampling/culture when feasible.
- Slide 18 — post-liver-transplant aspergillosis: the axial scan is paired with a culture plate to emphasize that imaging raises suspicion but is not organism-specific; microbiology and/or histopathology establishes the diagnosis. Blood culture is often unrevealing for Aspergillus, unlike candidemia [14].
Exam Intelligence
Past paper 2021 Q12(a): "A 40-year-old man had bone marrow transplant for CML. He developed high fever on day 10 after conditioning with high dose chemotherapy. ANC < 0.1. List common microbes found in blood culture." The expected categories were Gram-positive bacteria (Staphylococcus, Streptococcus, Enterococcus), Gram-negative bacteria (E. coli, Pseudomonas, Klebsiella) and fungi [9]. Clinically, Candida may cause fungemia, but routine blood cultures are insensitive for invasive aspergillosis; when aspergillosis is suspected, do not delay appropriate diagnostic or empiric management while waiting for an Aspergillus blood culture [14].
Usually X-linked (66% gp91phox mutation). Defect in intracellular killing due to abnormal respiratory burst oxidase (NADPH oxidase) activity. Susceptible to catalase-positive organisms:
- Staphylococcus aureus
- Serratia marcescens
- Burkholderia cepacia
- Chromobacterium violaceum
- Nocardia
- Aspergillus
Respiratory-burst pathway shown on Slide 20:
- Normal neutrophils kill bacteria using the respiratory burst: the NADPH oxidase complex (subunits gp91, p22, p47, p40, p67) transfers electrons from cytoplasmic NADPH across the phagosomal membrane → generates superoxide → SOD converts superoxide to H₂O₂ (hydrogen peroxide) → MPO converts H₂O₂ to HOCl (hypochlorous acid), the actual killing agent [1]
- In CGD, this pathway is broken — neutrophils cannot generate reactive oxygen species (ROS)
- The familiar idea that CGD neutrophils can “borrow” microbial H₂O₂ from catalase-negative organisms is a useful mnemonic, but it is not a complete or absolute mechanism. Susceptibility reflects the interaction of microbial peroxide handling, phagocyte-independent killing and other virulence factors; learn the characteristic organism pattern without treating catalase status as a perfect diagnostic classifier.
Lecture-era breakdown: 66% X-linked (gp91phox), 30% autosomal recessive (p47phox), 5% other mutations [1]
Current classification recognises pathogenic variants in six genes, so the slide percentages should not be used as an exhaustive modern genetic scheme. The preferred screening test is flow-cytometric dihydrorhodamine (DHR) oxidation, interpreted with appropriate controls; some variants, including NCF4-related disease, can be missed by routine DHR patterns [15].
Clinical presentation (Slide 21): the 2.5-year-old has a striking left cervical swelling, while the coronal CT shows multiloculated/rim-enhancing cervical-retropharyngeal collections with airway displacement/narrowing. This teaches two points: recurrent deep abscess/lymphadenitis can be the first clue to CGD, and a deep-neck collection is also an airway emergency, independent of the immune diagnosis. Other presentations include hepatosplenomegaly, skin/perianal abscess and TB/BCG dissemination [5].
Impaired adhesion of inflammatory cells within vasculature → inability to migrate into tissues. Recurrent infections with Staphylococcus and Pseudomonas aeruginosa. [1]
Why from first principles: Neutrophils need to adhere to vessel walls (using integrins like CD18) and then squeeze through (diapedesis) to reach infection sites. In LAD, neutrophils are trapped in the bloodstream → paradoxically, the blood neutrophil count is HIGH, but tissues are defenseless.
Clinical hallmarks (from Pediatric notes): Poor wound healing, absent pus formation, omphalitis with delayed umbilical cord separation [5].
Clinical image (Slide 23): the infant has a small black necrotic eschar with marked surrounding erythema—ecthyma gangrenosum due to Pseudomonas aeruginosa [1]. The image is a useful paradox: profound tissue destruction can occur despite impaired neutrophil migration and scant pus.
Adult-onset; Asians. IFN-γ activates macrophages to kill intracellular microbes. Anti-IFN-γ autoantibodies → susceptibility to:
- NTM (called MOTT on the slide; including M. chelonae, M. abscessus)
- Non-typhoidal Salmonella
- Burkholderia pseudomallei
- Talaromyces marneffei (formerly Penicillium marneffei)
- VZV
- (Cryptococcosis, histoplasmosis)
Why this condition is important: It is an acquired phenocopy of primary immunodeficiency. It predominantly affects Asian adults with previously good health, who present with disseminated infections by organisms that are normally controlled by cell-mediated immunity. On Slide 25, the 55-year-old woman has an erythematous plaque/nodules on the forearm; biopsy and mycobacterial culture identified M. chelonae. The visual lesson is to sample atypical skin lesions, rather than trying to identify an NTM from appearance alone [1].
Anti-IFN-γ Autoantibodies vs. HIV
Both cause susceptibility to intracellular organisms. Key difference: Anti-IFN-γ autoantibody disease is adult-onset, typically in Asians, and the CD4 count is normal. HIV patients have low CD4 counts. Both get NTM, but the organism spectrum differs slightly (anti-IFN-γ patients get more M. abscessus-type organisms).
The slide reproduces the early-pandemic Bastard et al. cohort: neutralising autoantibodies were found in 0/663 people with asymptomatic or mild infection versus 101/987 (10.2%) with life-threatening COVID-19. The diagram shows the proposed block upstream of IFNAR signalling—preventing pSTAT activation and interferon-stimulated gene expression. This remains important mechanistic evidence that a pre-existing innate immune defect can determine severity, but the 2020 cohort statistic is historical evidence and not a recommendation for routine clinical screening [16].
7. Clinical Syndromes of Impaired ADAPTIVE Immunity
7.1 Impaired Humoral Immunity (Antibody Deficiency)
Key organisms: Streptococcus pneumoniae, Haemophilus influenzae [1]
Presents with:
- Sinusitis, otitis media, pneumonia (S. pneumoniae, H. influenzae, Meningococci, Mycoplasma)
- Intestinal infections (Salmonella, Shigella, Campylobacter, Giardia, Rotavirus)
Why these organisms? Antibodies opsonize encapsulated bacteria for phagocytosis and activate complement via the classical pathway. Without antibodies, encapsulated organisms (which resist phagocytosis due to their polysaccharide capsule) thrive. At mucosal surfaces (sinopulmonary, GI), secretory IgA normally neutralizes pathogens — without it, mucosal infections predominate.
Lecture statement: recurrent sinopulmonary infection; “anaphylactic reaction if given IVIG” [1]
Selective IgA deficiency is often asymptomatic, but some patients have recurrent respiratory/GI infection, allergy or autoimmunity. A minority develop anti-IgA antibodies. Severe allergic reactions to blood products are rare, even when IgA and anti-IgA are present; IgA deficiency is therefore not a blanket contraindication to all immunoglobulin or transfusion therapy. Investigate anti-IgA mainly after a previous anaphylactic or repeated severe allergic transfusion reaction and involve transfusion medicine/immunology in product selection [17].
Safety correction — IgA deficiency and IVIG
For an exam, recognise the possible association between profound IgA deficiency, anti-IgA and anaphylaxis. In practice, do not deny indicated therapy solely because IgA is low: assess previous reaction history and use specialist/product-specific precautions [17].
7.2 HIV/AIDS — The Prototype of Adaptive Immune Deficiency
AIDS caused by HIV. Main problem: reduced CD4+ T cells. Also affects other parts of immune system. [1]
Slide 31 charts surveillance through 2020 (10,785 cumulative HIV reports and 2,230 AIDS reports; annual HIV reports peaked at 725 in 2015 and were 505 in 2020). Keep those figures as historical context. The Hong Kong Department of Health reports 331 new HIV cases and 86 AIDS cases in 2025, with cumulative totals of 12,734 HIV reports and 2,643 AIDS reports by December 2025 [18]. Surveillance reports are not the same as the number of people currently living with HIV.
This is an extremely comprehensive list from the lecture. The examiners expect you to know the categories and the most important examples:
| Category | Organisms |
|---|---|
| Bacteria | Disseminated NTM (e.g., MAC, M. kansasii), tuberculosis, recurrent Salmonella septicaemia |
| Virus | CMV (retinitis, other organs), HSV (chronic ulcers, esophagitis), PML (JC virus) |
| Fungal | Candida (esophageal, bronchial), Cryptococcosis (meningitis), PCP (Pneumocystis jirovecii pneumonia), Histoplasmosis, Coccidioidomycosis |
| Parasite | Cryptosporidium (chronic diarrhoea), Toxoplasma (brain abscess), Cystoisospora belli (formerly Isospora) |
| Cancer | Kaposi sarcoma (HHV-8), Burkitt's lymphoma, Primary CNS lymphoma, Invasive cervical cancer |
| HIV-related | Encephalopathy, Wasting syndrome |
Hong Kong-specific additions:
- Lecture-era AIDS surveillance wording for MTB
- Penicilliosis (now talaromycosis; Talaromyces marneffei) — disseminated
Do not turn the slide's surveillance definition into a diagnostic rule: tuberculosis can occur across the CD4 spectrum, and pulmonary disease does not require CD4 < 200 cells/µL.
Talaromyces marneffei (formerly Penicillium marneffei) is a thermally dimorphic fungus endemic in Hong Kong, southern China and parts of Southeast Asia. Slide 33 links three clues: a centrally umbilicated/necrotic facial papule, intracellular yeast-like organisms within macrophages, and culture morphology—mould at 25°C with a diffusible red pigment, yeast at 37°C. In advanced HIV, skin lesions occur in roughly 40–80% of talaromycosis cases, but diagnosis requires microscopy/culture or another validated test; the papule is not pathognomonic [19].
Systemic diseases/conditions that affect immune functions:
- Breaks in physical barriers (skin, mucosa)
- Diabetes mellitus
- Cirrhosis
- Autoimmune disease (e.g., SLE)
- Malignancy
- Transplantation
- Iron overload
- Splenectomy
- Drugs (e.g., steroids)
- Malnutrition
- Pregnancy
- Extremes of age
Clinical images from the lecture:
- Slide 36 — eczema plus a pacemaker: diffuse lichenification/excoriation represents barrier failure; the implanted device provides a surface for biofilm. The S. aureus bacteraemia/pacemaker infection therefore reflects both host-barrier and device-related risk [1].
- Slide 37 — crusted scabies after renal transplant: thick hyperkeratotic plaques/crusts are paired with microscopy showing mite/eggs. Crusted scabies may itch little or not at all, carries an enormous mite burden and is extremely contagious—treat promptly and institute contact/outbreak precautions rather than waiting for classic nocturnal itch [20].
- Slide 38 — Aeromonas necrotising fasciitis in diabetes/cirrhosis: the preoperative photograph shows dusky purpura, bullae and necrosis; the postoperative image shows the extent of debridement. Suspected necrotising infection is a surgical emergency: obtain prompt surgical review and start broad empiric antibiotics; do not wait for a perfect organism label [21].
- Slide 40 — severe sepsis image: an intubated critically ill patient is shown alongside grouped vesiculobullous/purpuric lesions. The photograph reinforces rapid deterioration and the value of a full skin examination, but a pathogen cannot be assigned from the image alone.
8.1 Post-Splenectomy Sepsis — HIGH YIELD
Splenectomy or functional hyposplenism
Major functions of spleen in immunity:
- Production of antibody (especially against polysaccharide antigens)
- Clearance of encapsulated bacteria
Organisms (mainly bacteria with polysaccharide capsule):
- Streptococcus pneumoniae
- Haemophilus influenzae type B
- N. meningitidis
- Capnocytophaga canimorsus
Rapid progression → need urgent antibiotic treatment
Vaccination:
- Streptococcus pneumoniae
- Influenza
- (Haemophilus influenzae type B)
- (Neisseria meningitidis)
Why the spleen is so critical: The spleen is the primary site where blood-borne pathogens are filtered and presented to B cells in the marginal zone. It is especially important for generating IgM antibodies against polysaccharide antigens (the capsules of encapsulated bacteria). Without a spleen, the initial antibody response to these organisms is severely impaired → overwhelming sepsis can develop within hours.
Capnocytophaga canimorsus is transmitted by dog/cat bites and is especially dangerous in asplenic patients — a classic exam question stem.
Past Paper Link — 2021 SAQ Q12(c)
"He did not come back for routine vaccination after transplant for 1 year. Four years after transplant, sudden high fever, hypotension, purpuric rash, died within 24 hours. Peripheral blood smear showed Howell-Jolly bodies. List organisms found in blood cultures." Answer: S. pneumoniae, H. influenzae, N. meningitidis. Howell-Jolly bodies = functional asplenia (RBC inclusions normally removed by the spleen) [9].
Functional asplenia (e.g., sickle cell disease, post-radiation) carries the same risk as surgical splenectomy.
Current prevention principles for asplenia
Vaccination schedules evolve. In addition to annual influenza and indicated routine vaccines, ensure pneumococcal, Hib and both meningococcal ACWY and B protection according to age, vaccine history and the current local schedule. As one current US example, pneumococcal options include PCV20/21 alone or PCV15 followed by PPSV23; adults with asplenia receiving MenACWY need a two-dose primary series plus five-yearly boosters, while MenB requires a high-risk primary series and ongoing boosters if risk remains [22,23]. This replaces the older one-size-fits-all “PCV13 + PPSV23” answer. Vaccines reduce but do not abolish risk: fever in an asplenic patient requires urgent assessment and prompt antibiotics according to the patient's emergency plan/local protocol.
9. Immunization
Artificially induce immunity. Active vs Passive. [1]
| Type | Mechanism | Duration | Examples |
|---|---|---|---|
| Active (Vaccination) | Stimulate host's own immune response | Long-lasting; memory | All vaccines |
| Passive (Immunoglobulin) | Provide pre-formed antibodies | Temporary (weeks-months) | Pathogen-specific immunoglobulin for selected exposures; replacement immunoglobulin for antibody deficiency |
Vaccine Type Principle Examples Live attenuated Replication-competent attenuated organism; usually produces a strong response but can cause disease in susceptible hosts MMR, BCG, oral polio (selected settings), yellow fever, varicella Inactivated (killed) Whole killed organism; weaker immune response; needs boosters Rabies, some COVID-19 vaccines, Hepatitis A Toxoid Inactivated toxin; generates antitoxin antibodies Tetanus, Diphtheria Soluble capsular material Purified polysaccharide capsule Pneumococcal vaccine (PPSV23) Recombinant protein Genetically engineered protein subunit HBV, HPV Vector vaccines Harmless virus delivers antigen gene Some COVID-19 vaccines (AstraZeneca) mRNA vaccines mRNA encodes antigen; host cells produce it Pfizer/BioNTech, Moderna COVID-19 vaccines
Live vaccines require defect-specific assessment
Live vaccines are generally contraindicated during severe immunosuppression because replication of the vaccine organism can cause disease—not because every product routinely “reverts to virulence.” The decision is vaccine- and immune-defect-specific: asplenia alone is not a live-vaccine contraindication, and some people with HIV can receive selected live vaccines when immune criteria are met. BCG is contraindicated in important cellular/phagocyte defects such as CGD. Check the current product/local immunisation guideline rather than applying a blanket rule [24].
Lecture simplification: influenza/pneumococcal vaccines emphasise antibody responses; BCG emphasises cell-mediated immunity [1]
Most vaccines recruit both arms to differing degrees. Protein antigens and conjugate vaccines recruit T-cell help, germinal-centre maturation and memory B cells; conjugating a polysaccharide to a protein is precisely what converts a weak T-independent response into a stronger, memory-forming response. Use the humoral/cellular split as a teaching emphasis, not a rigid taxonomy.
10. Treatment of Infectious Disease by Manipulating the Immune System
Examples:
- Glucose control in DM
- Antiretroviral therapy (ART; “HAART” in the slide) for HIV
- G-CSF in patients with neutropenia
- IVIG in patients with CVID (Common Variable Immunodeficiency)
The slide calls these “reversal,” but restoration or replacement is more accurate:
- Glucose control in DM: Hyperglycemia impairs neutrophil chemotaxis, phagocytosis, and intracellular killing. Good glycemic control directly improves immune function.
- ART for HIV: Viral suppression permits immune recovery and reduces opportunistic infection risk. Rapid immune recovery can unmask or worsen inflammation as IRIS (immune reconstitution inflammatory syndrome) [3].
- G-CSF: Stimulates neutrophil production. Its use in cancer care is selective (especially prophylaxis based on febrile-neutropenia risk or particular clinical circumstances), not routine treatment for every low neutrophil count.
- Immunoglobulin replacement for CVID: Replaces missing humoral function and reduces bacterial infections; it does not cure the underlying immune defect.
10.2 Immunomodulators
Types: Naturally occurring cytokines, Immunoglobulins, Glucocorticoids, Biologics, Synthetic immunomodulatory compounds [1]
Rationale: Antiviral activity. Treatment of:
- HCV (pegylated interferon is obsolete for routine treatment; replaced by DAAs)
- HBV (pegylated interferon remains a finite-duration option for selected patients)
- (Kaposi sarcoma)
- (Condyloma acuminatum)
Do not merge the two hepatitis updates: modern pan-genotypic direct-acting antivirals cure more than 95% of chronic HCV infections, whereas chronic HBV is usually suppressed with high-barrier nucleos(t)ide analogues and pegylated interferon remains a specialist-selected finite-duration option rather than being universally obsolete [27,28].
Rationale: Reduce detrimental effects of inflammation. Used in:
- Pneumocystis pneumonia (PCP) — for moderate-to-severe disease
- TB meningitis — reduces mortality and neurological sequelae by decreasing meningeal inflammation
- COVID-19 patients requiring supplemental oxygen — dexamethasone (RECOVERY trial)
- Bacterial meningitis — dexamethasone before/with first dose of antibiotics reduces hearing loss (especially in pneumococcal meningitis)
Current thresholds and limits: for HIV-associated PCP, start adjunctive corticosteroids as soon as possible (ideally within 72 hours) when room-air PaO₂ < 70 mmHg or A–a gradient ≥35 mmHg [25]. For COVID-19, systemic corticosteroids are recommended for severe/critical hypoxaemic disease, but not routinely when the patient does not require supplemental oxygen [26]. Dexamethasone timing and benefit in bacterial meningitis are pathogen- and setting-dependent, so follow the local meningitis protocol and give it before or with the first antibiotic dose when indicated.
Steroids in Infection — Paradox Explained
Why would you give an immunosuppressant during an infection? In these specific conditions, the host's inflammatory response causes MORE damage than the pathogen itself. Steroids dampen this excessive inflammation while antimicrobials handle the pathogen. This only works when effective antimicrobial therapy is given simultaneously.
Mechanism: Bind to pathogens/toxins + Immunomodulation
Treatment:
- Toxic shock syndrome due to Group A Streptococcus / Staphylococcus (controversial)
- Parvovirus B19 infection in immunocompromised patients
Prophylaxis:
- Post-exposure prophylaxis: VZV, measles, hepatitis A
- Prophylaxis in patients with humoral immunodeficiencies
Why immunoglobulin may be considered for toxic shock: toxic shock is driven by superantigens, which pooled immunoglobulin may neutralise. Evidence is uncertain; it is a specialist adjunct sometimes considered in severe streptococcal toxic shock after source control and antibiotics, not routine treatment for every staphylococcal or streptococcal toxic-shock presentation.
Why IVIG for Parvovirus B19: This virus causes pure red cell aplasia in immunocompromised patients who cannot mount an adequate antibody response. IVIG provides the anti-Parvovirus antibodies they cannot make.
Do not treat all immune globulin products as interchangeable
Post-exposure prophylaxis is pathogen- and exposure-specific: VZV immunoglobulin, measles immunoglobulin and hepatitis A immunoglobulin have distinct indications, doses and timing. Generic IVIG is not automatically a substitute. Use the current local public-health/product protocol.
Tocilizumab: IL-6 antagonist Sarilumab: IL-6 antagonist Baricitinib: JAK inhibitor Tofacitinib: JAK inhibitor
Current framing: severe COVID-19 may involve a dysregulated inflammatory response, but “cytokine storm” is an oversimplification. Current IDSA guidance supports adding either baricitinib or tocilizumab to systemic corticosteroids in selected patients with rapidly progressive severe or critical disease when an additional immunomodulator is indicated—not automatically in everyone receiving oxygen, and not as indiscriminate combinations. Sarilumab/tofacitinib are alternatives discussed in the evidence base rather than default equivalents [26].
The lecture highlights a single case report of disseminated coccidioidomycosis treated with IFN-γ and dupilumab (an IL-4 receptor antagonist, used here to redirect an unfavourable immune response). It is valuable proof-of-concept for mechanism-guided adjunctive therapy, not standard treatment and not evidence that this combination should be generalised beyond expert/research settings [1].
| Related GC Lecture | Connection to This Lecture |
|---|---|
| GC 096 — Why do I always get sick | Primary immunodeficiencies in detail; SPUR criteria (Serious, Persistent, Unusual, Recurring) |
| GC 099 — Antimicrobial resistance | The "host-microbe-antibiotic" triad directly parallels the "host-microbe-intervention" triad here |
| GC 101 — Diagnosis of infections | IgM vs IgG serology; using immune markers to diagnose infection |
| GC 102 — Fever after chemotherapy | Direct clinical application of neutropenia concepts; empirical antibiotics in febrile neutropenia |
| GC 104 — Infection outbreak/control | Barrier defenses (hand hygiene = protecting epithelial barriers at population level) |
| GC 105 — Medically important microbes | The organisms listed here (encapsulated bacteria, catalase-positive organisms, intracellular pathogens) are classified systematically in GC 105 |
| GC 106 — Practical antibiotic use | Why empirical coverage must be broad in neutropenic patients (Pseudomonas coverage mandatory) |
12. Exam Intelligence
- "List organisms causing infection in a patient with [specific immune defect]" — Must match defect to organism pattern (see tables above)
- "What is the mechanism of increased susceptibility in [condition]?" — Expect you to explain the immunology, not just name organisms
- "Name vaccines recommended for a splenectomised patient" — Pneumococcal, influenza, Hib, meningococcal
- "Why are steroids used in PCP / TB meningitis / bacterial meningitis?" — Reduce detrimental inflammatory response
- "What is CGD? Which organisms are characteristic?" — NADPH oxidase defect with impaired phagocyte respiratory burst; recognise the classic catalase-positive organism pattern, while remembering catalase status is not a perfect classifier
- Mini-case: Immunocompromised patient with specific organism — Reverse-engineer which immune defect allows that organism
| Trap | Correct Approach |
|---|---|
| Confusing neutropenia organisms with splenectomy organisms | Neutropenia → broad spectrum (GP + GN bacteria + fungi). Splenectomy → specifically encapsulated bacteria |
| Forgetting Capnocytophaga in post-splenectomy | It's in the lecture slide — always include it |
| Saying “IgA deficiency absolutely contraindicates IVIG” | Severe reactions are rare; assess prior reactions and use transfusion/immunology guidance |
| Listing only bacteria for neutropenic patients | Must include fungi (Candida, Aspergillus) |
| Treating “catalase-positive” as a perfect CGD rule | Use the characteristic organism pattern plus the NADPH-oxidase mechanism; confirm suspected CGD with appropriate testing |
High Yield Summary
- Infection outcome reflects the microbe–host interaction modified by intervention.
- Innate defence acts quickly through barriers, phagocytes, PRRs and complement; adaptive B/T-cell responses add antigen specificity and memory.
- Recurrent invasive Neisseria strongly suggests a terminal complement/properdin defect; screen thoughtfully with CH50/AH50.
- Neutropenia creates urgent bacterial and invasive-fungal risk. Skin nodules, necrosis or subtle imaging findings can be diagnostic clues.
- CGD is a NADPH-oxidase disorder with characteristic S. aureus, Serratia, Burkholderia, Nocardia and Aspergillus infection patterns.
- Adult-onset anti-IFN-γ autoantibodies should be considered in otherwise unexplained disseminated NTM or other intracellular infections, particularly in Asian adults.
- Antibody deficiency predisposes to encapsulated bacteria; isolated IgA deficiency does not automatically prohibit IVIG.
- Advanced HIV produces broad opportunistic-infection risk; in Hong Kong, remember talaromycosis and distinguish current terminology from the slide's older AIDS-surveillance wording.
- Asplenia creates lifelong risk of rapidly fatal encapsulated-bacterial sepsis: vaccinate to the current schedule and treat fever urgently.
- Immune-directed therapy is selective: ART and replacement immunoglobulin restore/replace host defence; corticosteroids, cytokine inhibitors or other adjuncts are syndrome- and severity-specific.
Active Recall - Defense Against Microbes
[1] Lecture slides: GC 100. Defense against microbes.pdf (all slides 1–54) [2] Lecture slides: GC 105. Medically important microbes what every doctor should know.pdf [3] Lecture slides: GC 102. Fever after chemotherapy infections in immunocompromised hosts [Handout].pdf (p4, p6) [4] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (p19) [5] Senior notes: Adrian Lui Pediatrics Notes.pdf (p411) [6] Senior notes: Jerry's immunodeficiencies.pdf (p1, p3, p4) [7] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p637) [8] Lecture slides: Block C - Vaginal discharge_ obstetric and gynaecological infections.pdf (p2–3) [9] Past papers: 2021 Fourth Summative SAQ.pdf (p14, Q12) [11] Senior notes: Maksim Surgery Notes.pdf (p153) [12] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1329) [13] ARUP Consult: Complement Deficiency Testing Algorithm [14] IDSA: Clinical Practice Guideline for the Diagnosis and Management of Aspergillosis [15] GeneReviews: Chronic Granulomatous Disease [16] Bastard et al., Science (2020): Autoantibodies against type I IFNs in life-threatening COVID-19 [17] Canadian Blood Services: Anaphylactic transfusion reactions and IgA deficiency [18] Hong Kong Department of Health: HIV/AIDS quarterly surveillance tables [19] NIH: Talaromycosis—Adult and Adolescent Opportunistic Infections Guidelines [20] CDC: Clinical Overview of Crusted Scabies [21] IDSA: Skin and Soft Tissue Infections Guideline [22] CDC: Pneumococcal Vaccine Recommendations [23] CDC: Adult Immunization Schedule Notes [24] CDC: Contraindications and Precautions—Vaccine Best Practices [25] NIH: Pneumocystis Pneumonia—Adult and Adolescent Opportunistic Infections Guidelines [26] IDSA: COVID-19 Treatment and Management Guideline [27] WHO: Hepatitis C fact sheet [28] WHO: 2024 Guidelines for the prevention, diagnosis, care and treatment of chronic hepatitis B infection
GC099 Antimicrobial Resistance
Antimicrobial resistance is the ability of microorganisms to survive and proliferate despite exposure to antimicrobial agents that would normally inhibit or kill them, rendering standard treatments ineffective.
GC101 Diagnosis Of Infections
Diagnosis of infections is the systematic process of identifying causative pathogens through clinical assessment, microbiological techniques (culture, microscopy, serology, molecular methods), and laboratory markers to guide appropriate antimicrobial therapy.