Immunodeficiency and autoimmunity
Infection, immunodeficiency, hypersensitivity and autoimmunity: host response
Infection and host response for FCPS Part 1: sepsis, immunodeficiency, key organisms, hepatitis B serology, hypersensitivity and vasculitis. Each classic picture is linked to its mechanism.
Sepsis and septic shock
- Sepsis is life-threatening organ dysfunction caused by a dysregulated response to infection.
- Gram-negative LPS (lipid A) binds TLR4 on macrophages, releasing TNF, IL-1 and IL-6. Inducible nitric oxide synthase causes refractory vasodilatation: septic shock is distributive, with low systemic vascular resistance, warm peripheries, tachycardia and initially high cardiac output. Endothelial glycocalyx damage causes capillary leak; tissue factor triggers DIC.
- C3a and C5a are anaphylatoxins: mast cell degranulation and increased permeability; C5a is also chemotactic.
- Blood shows a left shift and toxic granulation; procalcitonin rises in bacterial infection. Sputum is neutrophil-rich in the first days, then macrophages take over.
- Infection is the commonest local cause of delayed wound healing: persistent inflammation and bacterial and neutrophil enzymes break down collagen and granulation tissue.
Host defects and the infections they predict
| Defect | Typical infection and clue |
|---|---|
| X-linked agammaglobulinaemia (BTK) | Boys with pneumonia and otitis from about 6 months (when maternal IgG wanes); no B cells or plasma cells (normal lymphocyte count overall), so no adenoids or tonsils (no follicles to form) |
| Selective IgA deficiency | Commonest primary immunodeficiency; sinopulmonary infections, Giardia diarrhoea, anaphylaxis to blood (anti-IgA antibodies) |
| DiGeorge (22q11) | Failed 3rd/4th pouches: no thymus (deficient T-cell maturation), hypocalcaemic tetany, interrupted arch or truncus |
| Chronic granulomatous disease | NADPH oxidase deficiency: catalase-positive organisms (S. aureus, Aspergillus); abnormal NBT or DHR test |
| Terminal complement (C5–C9) | Neisseria |
| Hyposplenism (splenectomy, sickle cell, coeliac disease) | Encapsulated organisms, especially Streptococcus pneumoniae; Howell–Jolly bodies; vaccinate |
| Hypogammaglobulinaemia (CLL, nephrotic urinary IgG loss) | Encapsulated bacteria |
| CD4 below 200 (HIV) | Pneumocystis; below 100, cryptococcus, toxoplasma; Cryptosporidium (small acid-fast oocysts on modified ZN) causing profuse watery diarrhoea |
| High-dose steroids | Strongyloides hyperinfection: Gram-negative septicaemia (larvae carry gut bacteria), pulmonary infiltrates, serpiginous rash; eosinophilia often absent |
| Burns on long antibiotics | Pseudomonas (classic bacterium); Candida albicans (classic fungus) |
- IgM does not cross the placenta; raised cord IgM means fetal infection.
Classic organisms and settings
| Setting | Organism |
|---|---|
| Clean surgery wound infection | Staphylococcus aureus |
| Rapidly fatal puerperal sepsis | Streptococcus pyogenes (group A) |
| IV drug user | S. aureus: tricuspid endocarditis, septic lung emboli |
| Fournier gangrene (diabetic, scrotum and perineum, crepitus, gas along fascial planes sparing testes) | Mixed aerobes and anaerobes (polymicrobial necrotising fasciitis) |
| Colitis after clindamycin, yellow plaques, accordion sign | Clostridioides difficile: toxins A and B damage colonocytes; treat with oral vancomycin (or fidaxomicin) |
| Pelvic actinomycosis with a long-standing IUCD | Actinomyces israelii (sulphur granules) |
| No cell wall, so penicillins fail | Mycoplasma pneumoniae |
| Malignant tertian malaria | Plasmodium falciparum |
| Shepherd with liver cyst containing daughter cysts | Echinococcus granulosus; avoid spillage (anaphylaxis, seeding) |
| Neurocysticercosis in a vegetarian | Swallowing Taenia solium eggs (faecal–oral); eating cysticerci in pork gives only intestinal tapeworm |
| Löffler syndrome (cough, eosinophilia), then long roundworm | Ascaris lumbricoides |
| Rectal prolapse, bloody diarrhoea in malnourished child | Trichuris trichiura |
| Night-time perianal itch in children | Enterobius: morning adhesive tape test |
| Painless cheek ulcer after an insect bite | Cutaneous leishmaniasis, sandfly (Phlebotomus) |
| Frothy yellow-green discharge, strawberry cervix | Trichomonas: metronidazole for both partners |
| H. pylori, non-invasive | Urea breath test or stool antigen |
Viral hepatitis serology
| Pattern | Meaning |
|---|---|
| HBsAg positive, anti-HBc IgM | Acute hepatitis B |
| HBsAg positive over 6 months, anti-HBc IgG | Chronic infection (HBeAg means high replication) |
| Anti-HBs alone | Vaccinated |
| Anti-HBs and anti-HBc IgG | Past infection, immune |
| Anti-HBc IgG only | Past infection with waned anti-HBs (or occult infection) |
- Hepatitis D needs HBsAg to make its coat. Superinfection of an HBV carrier (anti-HDV IgM in a known carrier) causes severe acute hepatitis and often chronic HDV; coinfection with acute HBV usually clears.
Abscesses and imaging
- Brain abscess: ring-enhancing lesion whose centre is very bright on DWI with low ADC, because thick viscous pus restricts water motion; necrotic tumour usually has a high ADC.
- Brodie abscess: subacute S. aureus osteomyelitis, lucent metaphyseal lesion with sclerotic rim. Childhood osteomyelitis starts in the metaphysis (sluggish flow in looped vessels). A sequestrum stays dense.
- Pelvic abscess after perforated appendicitis: swinging fever, mucus diarrhoea, tenesmus, boggy anterior rectal wall.
- Cold abscess (tuberculous psoas): granulomatous, so no heat or redness.
- Mycotic aneurysms from septic emboli in endocarditis lie in distal MCA branches, at branch points near the cortex; most are bacterial.
Tuberculosis
- Bacilli survive in macrophages by blocking phagosome–lysosome fusion. Th1 interferon-γ forms granulomas; TNF-α maintains them.
- Primary: Ghon focus with hilar nodes. Post-primary: apical cavitation. Miliary: 1–2 mm nodules; Mantoux may be negative (anergy).
| Site | Features |
|---|---|
| Spine | Disc destroyed with adjacent vertebrae, paravertebral abscess, gibbus |
| Urinary tract | Sterile pyuria, calcified putty kidney, thimble bladder |
| Female genital tract | Tubes almost always; beaded on HSG |
| Abdomen | Ileocaecal transverse ulcers; lymphocytic ascites |
| Meninges | Basal enhancement, infarcts |
Hypersensitivity (Gell and Coombs)
| Type | Mechanism | Examples |
|---|---|---|
| I | IgE on mast cells, immediate | Anaphylaxis, asthma, hay fever |
| II | IgG or IgM against a cell or receptor | Haemolytic disease of the newborn (Rh), transfusion reactions, anti-GBM (Goodpasture), myasthenia gravis, Graves disease, AIHA, ITP |
| III | Immune complexes (IgG) | SLE, post-streptococcal glomerulonephritis, serum sickness, Arthus reaction, HSP |
| IV | T cells, delayed 48–72 hours | Mantoux, granulomas, contact dermatitis, Hashimoto, SJS/TEN |
- IgG takes part in types II and III. An Rh-negative mother carrying an Rh-positive baby becomes sensitised at delivery; in later pregnancies her IgG anti-D crosses the placenta: type II. Anti-D given within 72 hours prevents sensitisation.
- Hypersensitivity pneumonitis (farmer's or bird fancier's lung): symptoms ease away from exposure (on holiday) and return on coming back; diffuse small nodules; type III plus IV.
Autoimmunity and autoantibodies
- Mechanisms: molecular mimicry (rheumatic fever), loss of tolerance, HLA associations (HLA-B27 ankylosing spondylitis: inflammatory back pain better with exercise; earliest X-ray change at the sacroiliac joints).
| Antibody | Meaning |
|---|---|
| ANA | Most sensitive SLE screen |
| Anti-dsDNA | Highly specific; tracks lupus nephritis activity |
| Anti-Smith | Most specific; does not track activity |
| Anti-histone | Drug-induced lupus |
| Anti-Ro | Neonatal lupus, congenital heart block |
| Anti-Jo-1 | Polymyositis, dermatomyositis |
| c-ANCA (PR3) | Granulomatosis with polyangiitis: epistaxis, saddle nose, haemoptysis, haematuria, necrotising granulomas |
| p-ANCA (MPO) | Microscopic polyangiitis, EGPA |
- Dermatomyositis (heliotrope rash, Gottron papules, proximal weakness) in an adult: screen for underlying malignancy.
- C1q deficiency predisposes to SLE; falling C3 and C4 point to active lupus nephritis.
Vasculitis by vessel size
| Size | Disease | Key points |
|---|---|---|
| Large | Giant cell arteritis | Elderly; blindness; steroids at once |
| Large | Takayasu arteritis | Young Asian women; absent radial pulses |
| Medium | Polyarteritis nodosa | HBV; renal and mesenteric microaneurysms; spares lungs |
| Small | GPA; EGPA (Churg–Strauss); HSP | EGPA: adult-onset asthma, nasal polyps, eosinophilia, mononeuritis multiplex, fleeting infiltrates; HSP: IgA purpura, intussusception |
- All vasculitides can show fibrinoid necrosis of the vessel wall.
Remember TB destroys the disc; most metastases spare it.
Exam trap Myasthenia gravis, Graves disease and Rh disease are type II; SLE and post-streptococcal glomerulonephritis are type III.
Exam trap A negative Mantoux does not exclude TB: miliary disease and HIV cause anergy.
How FCPS asks about this
- Rh haemolytic disease of the newborn: type II hypersensitivity; post-streptococcal GN and SLE are type III.
- Anti-HBc IgG alone: past infection with waned anti-HBs.
- No adenoids, infections from 6 months in a boy: X-linked agammaglobulinaemia, no B cells.
- Commonest organism in clean surgical wound infection: Staphylococcus aureus; fatal puerperal sepsis: Streptococcus pyogenes.
- Ring lesion with bright DWI and low ADC: pyogenic abscess (viscous pus).
- Asthma, eosinophilia and mononeuritis multiplex: eosinophilic GPA.
- Septic shock mechanism: NO-mediated vasodilatation with low SVR and high cardiac output.
Test yourself on this topic
5 of the 168 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A 30-year-old man had induction chemotherapy for acute myeloid leukaemia. Now that his neutrophil count has recovered he has persistent fever and a rising ALP, and liver biopsy shows small abscesses and granulomas around yeasts. Why has this infection become evident only after count recovery?
Answer: Returning neutrophils form inflammatory foci
This is hepatosplenic (chronic disseminated) candidiasis. Candida seeds the liver and spleen through the portal blood from damaged gut mucosa during neutropenia, but without neutrophils there is little inflammatory reaction around the yeasts, so there are few signs and imaging looks normal. When the neutrophil count recovers, neutrophils and later macrophages gather around the organisms, forming small abscesses and granulomas that produce fever, a raised ALP and visible target lesions. The clinical disease is therefore largely the host response.
Hepatosplenic candidiasis
- Seeding during neutropenia
- Few cells: silent at first
- Neutrophils return: abscesses
- Fever + raised ALP in recovery
Remember Lesions appear when neutrophils come back.
Exam trap Blood cultures are often negative in hepatosplenic candidiasis.
Why the other options are wrong
- The fungus only invades after recovery Invasion happens during neutropenia; recovery only makes it evident.
- Chemotherapy has scarred the liver Chemotherapy does not cause abscesses and granulomas.
- Transfusions have caused iron deposits Iron overload does not form abscesses.
- Leukaemic deposits grow as counts recover Biopsy shows yeasts and inflammation, not leukaemic cells.
A 34-year-old man with infective endocarditis of the mitral valve has a sudden headache and becomes drowsy. He has a lobar haemorrhage near the cortex of the right parietal lobe from a ruptured infective (mycotic) aneurysm. Where are such aneurysms typically found?
Answer: Distal middle cerebral branches
Infective (mycotic) aneurysms form when septic emboli from a heart valve lodge in a cerebral artery. Bacteria spread through the vasa vasorum and adventitia and weaken the wall, so a fragile aneurysm develops at the site of impaction. Emboli follow the main flow into the middle cerebral artery and lodge in its small, distal cortical branches. Berry aneurysms, in contrast, arise at the proximal branch points of the circle of Willis.
Mycotic aneurysm
- Septic emboli from valve
- Wall weakened from the adventitia
- Site: distal MCA branches
- Lobar haematoma near the cortex
Remember Endocarditis + peripheral bleed: distal MCA mycotic aneurysm.
Exam trap Despite the name, most mycotic aneurysms are bacterial, often Streptococcus or Staphylococcus.
Why the other options are wrong
- Anterior communicating artery Common site of berry aneurysms, not mycotic ones.
- Basilar artery tip Berry aneurysm site in the posterior circulation.
- Posterior communicating artery origin A typical berry aneurysm site.
- Cavernous internal carotid artery Usually a berry or traumatic aneurysm site.
A 28-year-old woman with tuberculosis of the L2 vertebra develops a painless swelling in the right groin. The swelling is fluctuant but not warm or red. Why is this abscess 'cold'?
Answer: Granulomas, not neutrophil inflammation
Tuberculous abscesses are formed of caseous material from granulomatous inflammation, driven by T cells and macrophages rather than by an acute neutrophil response. Acute inflammation produces heat and redness through vasodilatation by mediators such as histamine and prostaglandins; this is minimal in tuberculosis. Pus from the vertebra tracks down the psoas sheath to the groin below the inguinal ligament. Calcification in such a collection also points to TB rather than a pyogenic abscess.
Cold abscess
- Caseous material
- Granulomatous, T cell and macrophage driven
- Little vasodilatation, no heat or redness
- Calcification suggests TB
Remember No heat, no redness, calcified wall: tuberculous abscess.
Exam trap A cold abscess should not be incised and left open, because a chronic sinus forms.
Why the other options are wrong
- Mycobacteria cannot reach the skin Cold abscesses can reach and discharge through the skin.
- Psoas fascia is insensitive to heat The fascia is not why it is cold.
- The pus contains no organisms Acid-fast bacilli are often present, though scanty.
- Calcium in the wall blocks inflammation Calcification does not block inflammation.
A 32-year-old woman has a dry cough, painful ankles and tender red nodules on both shins. She has bilateral hilar lymphadenopathy. Which bronchoalveolar lavage finding best supports the likely diagnosis?
Answer: Lymphocytosis with a high CD4:CD8 ratio
Erythema nodosum, ankle arthritis and bilateral hilar lymphadenopathy form Löfgren syndrome, an acute form of sarcoidosis. The non-caseating granulomas are driven by activated CD4 Th1 cells, which gather in the alveoli, so lavage shows a lymphocytosis with a CD4:CD8 ratio above about 3.5. Hypersensitivity pneumonitis also gives a lymphocytosis but typically with a low ratio (CD8 predominant). Biopsy showing non-caseating granulomas remains the confirmation.
Sarcoidosis lavage
- Bilateral hilar nodes
- Löfgren: erythema nodosum, arthritis
- BAL: CD4:CD8 high
- Non-caseating granulomas
Remember Sarcoid is a CD4 disease: ratio high.
Exam trap Tuberculosis and lymphoma also enlarge hilar nodes, but they are usually asymmetrical.
Why the other options are wrong
- Lymphocytosis with a low CD4:CD8 ratio Typical of hypersensitivity pneumonitis.
- Many neutrophils with Gram-positive cocci Suggests bacterial pneumonia.
- Many eosinophils over 25% Suggests eosinophilic pneumonia.
- Haemosiderin-laden macrophages Suggests alveolar haemorrhage.
A newborn has bilateral cataracts, a continuous murmur and fails the hearing screen. His mother had a rash with tender nodes behind her ears in the 8th week of pregnancy. Which organism is responsible?
Answer: Rubella virus
Rubella in the first trimester causes the congenital rubella syndrome: cataract, sensorineural deafness and heart defects such as patent ductus arteriosus or pulmonary artery stenosis. The virus slows cell division and damages small vessels during organogenesis, so the risk is highest in the first 12 weeks. In bone it disturbs metaphyseal ossification ('celery stalk' metaphyses). Congenital syphilis causes periostitis and metaphyseal erosions instead.
Congenital rubella
- First trimester infection
- Cataract, deafness, PDA
- Bones: celery stalk metaphyses
- Prevent with MMR before pregnancy
Remember Cataract + PDA + streaky metaphyses = rubella.
Exam trap Celery stalk metaphyses are also seen in congenital CMV, but cataract with PDA points to rubella.
Why the other options are wrong
- Cytomegalovirus Causes periventricular calcification and deafness, rarely cataract with PDA.
- Toxoplasma gondii Causes hydrocephalus, chorioretinitis and scattered calcification.
- Treponema pallidum Causes periostitis and erosions of the metaphyses (Wimberger sign).
- Herpes simplex virus Causes vesicles and encephalitis, usually from birth-canal exposure.
Where this sits in the CPSP syllabus
- Diagnostic Radiology, Paper 2: General pathology and genetics, Infection and the body's response; hypersensitivity and autoimmunity
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