Acute inflammation
Acute inflammation: vascular and cellular events, mediators, exudates and abscesses
Vascular changes, leucocyte rolling, adhesion and chemotaxis, mediators of pain and fever, exudates and abscesses for FCPS Part 1. Each step is explained by the molecule that drives it, so mediator questions become logical.
What acute inflammation does
- A rapid, short-lived response (minutes to days) that delivers fluid, plasma proteins and neutrophils to injured tissue. The cardinal signs are rubor, calor, tumor, dolor (Celsus) and functio laesa (Virchow).
Vascular events
- Transient arteriolar vasoconstriction (seconds), then vasodilatation from histamine, nitric oxide and prostaglandins: more flow gives heat and redness.
- Increased permeability lets protein-rich fluid out, causing swelling, concentrating red cells and slowing flow (stasis).
- Main site of leakage: post-capillary venules, where endothelial cells contract in response to histamine, bradykinin and leukotrienes (immediate, transient). Burns and toxins injure endothelium directly (immediate, sustained).
Exudate versus transudate
| Feature | Exudate | Transudate |
|---|---|---|
| Cause | Inflammation: leaky vessels | Raised hydrostatic pressure (heart failure) or low oncotic pressure (nephrotic syndrome, cirrhosis) |
| Protein | Over 30 g/L | Under 30 g/L |
| Specific gravity | Over 1.020 | Under 1.012 |
| Cells | Many | Few |
| Light criteria (pleura) | Fluid/serum protein over 0.5 or LDH over 0.6 | Below these |
- So pleural fluid with specific gravity 1.010 and protein 20 g/L is a transudate, typically from congestive cardiac failure.
- Exudate types: serous (blister), fibrinous (pericarditis, lobar pneumonia), purulent (pus), haemorrhagic, catarrhal, pseudomembranous (*C. difficile*, diphtheria).
Leucocyte events
| Step | Molecules |
|---|---|
| Margination | Stasis pushes leucocytes to the vessel wall |
| Rolling | Selectins: E- and P-selectin on endothelium, L-selectin on leucocytes, binding sialyl-Lewis X |
| Firm adhesion | Leucocyte integrins (LFA-1, Mac-1, with the CD18 beta-2 chain) bind endothelial ICAM-1 and VCAM-1, which TNF and IL-1 up-regulate |
| Transmigration | PECAM-1 (CD31) between endothelial cells of post-capillary venules |
| Chemotaxis | C5a, LTB4, IL-8 (CXCL8), bacterial N-formyl peptides |
| Phagocytosis | Opsonins IgG (Fc) and C3b; killing by NADPH oxidase respiratory burst and myeloperoxidase (hydrogen peroxide to hypochlorous acid), plus lysozyme, defensins, lactoferrin |
- Neutrophils dominate for the first 6–24 hours, being most numerous and quickest to respond; monocytes and macrophages replace them by 24–48 hours. Exceptions: *Pseudomonas* (neutrophils persist), viruses (lymphocytes), allergy and parasites (eosinophils).
| Defect | Missing | Clue |
|---|---|---|
| Leucocyte adhesion deficiency 1 | CD18 integrin | Delayed umbilical cord separation, infections without pus, neutrophilia |
| Chediak–Higashi | LYST, phagosome–lysosome fusion | Giant granules, partial albinism |
| Chronic granulomatous disease | NADPH oxidase | Catalase-positive infections, abnormal NBT or DHR test |
| Terminal complement (C5–C9) | Membrane attack complex | Recurrent Neisseria (meningococcal, gonococcal) infection |
Chemical mediators
| Mediator | Source | Key actions |
|---|---|---|
| Histamine | Mast cells, basophils, platelets | First, immediate vasodilatation and permeability; main mediator of IgE allergy (nut and fruit allergy) and urticaria |
| Bradykinin | Kinin system (factor XIIa activates kallikrein) | Permeability, vasodilatation and pain; the initial pain mediator after a cut; broken down by ACE in the lung (ACE inhibitor cough and angioedema) |
| PGE2 | COX on arachidonic acid | Pain (sensitises nerve endings to bradykinin) and fever |
| PGI2 / TXA2 | Endothelium / platelets | Vasodilator, anti-aggregant / vasoconstrictor, pro-aggregant |
| LTB4 | 5-lipoxygenase | Neutrophil chemotaxis |
| LTC4, LTD4, LTE4 | 5-lipoxygenase | Bronchoconstriction, permeability |
| Complement | Liver | C3a and C5a anaphylatoxins (release histamine); C5a chemotaxis; C3b opsonin; C5b–9 lysis |
| TNF, IL-1 | Macrophages | Endothelial activation, fever, acute phase response; TNF drives septic shock |
| IL-6 | Macrophages | Acute phase proteins (CRP) |
| IL-8 | Macrophages, endothelium | First chemokine for neutrophils |
| Nitric oxide | Endothelium, macrophages | Vasodilatation, killing |
- Drugs: corticosteroids block phospholipase A2 (via annexin) and cytokine genes; NSAIDs block COX; montelukast blocks leukotriene receptors.
Systemic effects
- Fever and pain after surgery: IL-1, TNF and IL-6 induce PGE2 in the hypothalamus, resetting the set point; PGE2 and bradykinin cause the pain.
- Acute phase proteins (liver, IL-6): CRP, fibrinogen (raises ESR), serum amyloid A, ferritin, hepcidin. Albumin and transferrin fall.
- Leucocytosis: neutrophils (bacteria), lymphocytes (viruses), eosinophils (parasites, allergy). Overwhelming response causes sepsis, DIC and shock.
Outcomes
- Resolution when damage is limited and tissue regenerates (lobar pneumonia).
- Fibrosis when tissue cannot regenerate or fibrin is not cleared.
- Progression to chronic inflammation when the agent persists.
- Abscess: a walled-off collection of pus (neutrophils, necrotic debris, organisms) surrounded by granulation tissue and later fibrous tissue. Antibiotics penetrate poorly, so drainage is the treatment.
| Abscess | Cause and clue |
|---|---|
| Pyogenic liver abscess | E. coli commonest (biliary source), also *Klebsiella*; often multiple |
| Amoebic liver abscess | *Entamoeba histolytica*; single right lobe abscess with "anchovy sauce" pus; stool often negative, so serology confirms it |
| Actinomycosis | *Actinomyces israelii*: jaw abscesses with sinuses draining yellow sulphur granules of branching Gram-positive filaments |
| Pelvic abscess | After perforated appendicitis; swinging fever, mucus diarrhoea, tenesmus, tender boggy anterior rectal wall |
| Brodie abscess | Subacute osteomyelitis: night pain in a teenager's tibial metaphysis, lucent area with a sclerotic rim; pain not relieved by aspirin (unlike osteoid osteoma) |
Remember Selectins roll, integrins stick, PECAM squeezes through, C5a, LTB4 and IL-8 lead the way.
Exam trap The main site of leakage is the post-capillary venule, not the capillary.
Exam trap Delayed cord separation with no pus means leucocyte adhesion deficiency (CD18).
How FCPS asks about this
- Pleural fluid with specific gravity 1.010 and protein 20 g/L: transudate from congestive cardiac failure.
- Initial pain mediator after a cut: bradykinin, with PGE2 sensitising nerve endings; histamine is the first vascular mediator.
- Key neutrophil chemoattractants: C5a, LTB4 and IL-8; opsonins IgG and C3b.
- Terminal complement deficiency: recurrent Neisseria infection.
- Anchovy sauce liver abscess with negative stools: amoebic; confirm with Entamoeba serology. Pyogenic liver abscess is usually E. coli.
- Jaw abscesses with sulphur granules: Actinomyces israelii, branching Gram-positive filaments.
- Boggy anterior rectal wall after appendicectomy: pelvic abscess; night pain with sclerotic-rimmed metaphyseal lucency is a Brodie abscess.
Test yourself on this topic
5 of the 96 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A boy has recurrent abscesses with catalase-positive organisms such as Staphylococcus aureus. His neutrophils fail the nitroblue tetrazolium test. Which enzyme is deficient?
Answer: NADPH oxidase
Neutrophils kill by the respiratory (oxidative) burst: NADPH oxidase converts O₂ to superoxide, which becomes hydrogen peroxide; myeloperoxidase then converts H₂O₂ and chloride to hypochlorous acid (bleach). In chronic granulomatous disease, NADPH oxidase is defective (usually X-linked). Catalase-positive organisms (Staph aureus, Aspergillus, Serratia, Nocardia) destroy their own H₂O₂, so the neutrophil has none to use. Diagnosis: abnormal NBT test or dihydrorhodamine flow cytometry. Myeloperoxidase deficiency is usually mild, with Candida infections.
Respiratory burst
- O₂ → superoxide: NADPH oxidase
- H₂O₂ → HOCl: myeloperoxidase
- CGD: NADPH oxidase defect, catalase-positive infections
- Test: NBT / DHR
Remember No NADPH oxidase, no bleach.
Why the other options are wrong
- Myeloperoxidase Usually mild; Candida infections; NBT normal.
- Superoxide dismutase Detoxifies superoxide.
- Lysozyme Attacks bacterial cell walls; not the oxidative burst.
- Glucose-6-phosphatase Von Gierke disease.
What is the most common source of systemic (arterial) emboli that lodge in the brain, legs or gut?
Answer: Left heart mural thrombus
About 80% of systemic emboli arise from intracardiac mural thrombi, mostly in the left ventricle after myocardial infarction and in a dilated left atrium in atrial fibrillation. Others come from aortic aneurysms, ulcerated atherosclerotic plaques and valve vegetations. Venous thrombi from the legs travel to the lungs, unless they cross a patent foramen ovale (paradoxical embolism).
Systemic emboli
- Source: left heart mural thrombus (~80%)
- LV after MI; LA in AF
- Also: aneurysm, plaque, vegetation
- Venous clot: lungs unless PFO
Remember Left heart clots go to the body.
Exam trap Legs are the main target of systemic emboli; the brain, gut and kidneys follow.
Why the other options are wrong
- Deep veins of the calf Cause pulmonary emboli.
- Pelvic venous plexus Cause pulmonary emboli.
- Right atrial appendage Right heart clots go to the lungs.
- Pulmonary artery thrombus Already in the pulmonary circulation.
A baby's umbilical cord has not separated by 4 weeks. He has recurrent skin infections without pus formation and a very high neutrophil count. Which defect is present?
Answer: Leucocyte adhesion deficiency
Leucocyte adhesion deficiency type 1: defective CD18 (β2 integrin subunit of LFA-1 and Mac-1) prevents firm adhesion of neutrophils to endothelium and their migration into tissues. Neutrophils accumulate in blood (marked neutrophilia) but cannot reach infection sites, causing recurrent bacterial infections without pus, poor wound healing, periodontitis and delayed separation of the umbilical cord (normally within 2 weeks). Type 2 involves selectin ligand (fucosylation) defects. Stem cell transplantation is curative.
Leucocyte adhesion deficiency
- CD18 (β2 integrin) defect
- Delayed cord separation
- Infections without pus; neutrophilia
- Poor healing, periodontitis
Remember Neutrophils that cannot stick cannot make pus.
Why the other options are wrong
- Chédiak–Higashi syndrome Giant granules, albinism.
- Myeloperoxidase deficiency Usually mild; Candida infections.
- Bruton agammaglobulinaemia Antibody deficiency.
- Complement C5 deficiency Neisserial infections.
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 30-year-old woman has a slowly spreading reddish-brown plaque on her cheek for 3 years, with scarring in the centre. When a glass slide is pressed on it, small apple-jelly nodules are seen. Which of the following is the most likely diagnosis?
Answer: Lupus vulgaris
Lupus vulgaris is a chronic form of cutaneous tuberculosis in a person with moderate immunity, often on the face. It spreads slowly at the edge and scars in the centre. Pressing with a glass slide (diascopy) blanches the redness and shows yellow-brown 'apple-jelly' nodules made of granulomas. Long-standing lesions can develop squamous cell carcinoma, so a non-healing nodule in the scar needs biopsy.
Lupus vulgaris
- Chronic skin TB, often face
- Spreads at edge, scars centrally
- Diascopy: apple-jelly nodules
- Late risk: squamous cell carcinoma
Remember Glass slide shows apple jelly: lupus vulgaris.
Exam trap Apple-jelly nodules also occur in sarcoid skin lesions; culture or PCR may be needed to confirm TB.
Why the other options are wrong
- Discoid lupus erythematosus Scarring plaques with follicular plugging and scale; no apple-jelly nodules.
- Cutaneous leishmaniasis Usually an ulcer with a raised edge after a sandfly bite, over months.
- Basal cell carcinoma Pearly nodule with telangiectasia; not a spreading plaque.
- Lupus pernio of sarcoidosis Violaceous swelling of the nose and cheeks in sarcoidosis.
Where this sits in the CPSP syllabus
- Paper 1: General pathology, Acute inflammation: vascular events, leucocyte events, mediators, outcomes
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