Hypersensitivity Reactions: Types I–IV, Mechanisms and Emergency Care

Hypersensitivity Reactions: Gell–Coombs Types I–IV, Mechanisms, Diagnosis and Emergency Care

Study level: Clinical medicine, emergency medicine and pathology | Topic: Immunopathology

Learning objectives

• Define hypersensitivity and differentiate allergy, autoimmunity, drug intolerance and ordinary toxicity.
• Compare the immune effector, timing, tissue injury and examples of types I–IV.
• Explain sensitisation, elicitation, mast-cell mediators, complement, immune complexes and T-cell injury.
• Recognise anaphylaxis, severe cutaneous drug reactions, serum sickness, haemolysis and other emergencies.
• Use a history-led diagnostic approach and select appropriate tests without over-interpreting positive results.
• Outline acute treatment, prevention, documentation and referral principles.

1. Definition and terminology

Hypersensitivity is an immune response that is excessive, misdirected or damaging to the host. The inciting antigen may be a harmless environmental allergen, a drug, a microbial antigen, an alloantigen or a self-antigen. Allergy usually refers to clinically important hypersensitivity to an otherwise harmless external substance. Atopy is an inherited tendency to make IgE against common environmental allergens; not every atopic person has severe allergy.

Condition	Immune status	Example
Expected protective immunity	Proportionate response that controls a pathogen with acceptable tissue injury.	Antibody response after vaccination.
Hypersensitivity	Immune response causes clinically important host damage.	Anaphylaxis after peanut or penicillin.
Autoimmunity	Response is directed at self-antigens.	Anti-acetylcholine-receptor antibody in myasthenia.
Drug intolerance/toxicity	Nonimmune pharmacologic or toxic effect.	Gastric irritation from an NSAID without an allergic mechanism.
Idiosyncratic reaction	Unusual response not explained by predictable pharmacology; mechanism may be immune or nonimmune.	Some severe drug eruptions.

2. The four-type framework at a glance

Type	Main effector	Typical onset	Principal injury	Classic examples
I: immediate	Allergen-specific IgE, mast cells, basophils; late eosinophilic inflammation.	Seconds to minutes; late phase 4–24 hours.	Vasodilation, oedema, bronchospasm, mucus, smooth-muscle contraction.	Anaphylaxis, allergic rhinitis, urticaria, atopic asthma, food allergy.
II: antibody-mediated	IgG/IgM against cell-surface or extracellular-matrix antigen.	Hours to days; depends on antibody and target.	Complement/phagocyte destruction, receptor stimulation or blockade, structural disruption.	Autoimmune haemolysis, ITP, Goodpasture syndrome, Graves disease, myasthenia.
III: immune-complex	Soluble antigen–IgG/IgM complexes, complement and neutrophils.	Hours to weeks depending on exposure and clearance.	Vasculitis, glomerulonephritis, arthritis and tissue necrosis.	Serum sickness, Arthus reaction, SLE, some post-infectious syndromes.
IV: delayed/cell-mediated	Antigen-specific CD4 T cells, macrophages and/or CD8 cytotoxic T cells.	Usually 24–72 hours; chronic forms evolve over weeks.	Cytokine inflammation, granulomas or direct cytotoxic cell death.	Contact dermatitis, tuberculin reaction, granulomatous disease, coeliac disease, type 1 diabetes.

3. Type I hypersensitivity: IgE-mediated immediate reaction

3.1 Sensitisation

1. An allergen crosses an epithelial barrier and is taken up by dendritic cells.
2. Antigen is presented to naïve CD4 T cells, which polarise toward a Th2 response under IL-4 and related signals.
3. Th2 cells provide CD40L and cytokines, especially IL-4 and IL-13, to B cells.
4. B cells class-switch to allergen-specific IgE, which binds high-affinity Fc-epsilon-RI receptors on mast cells and basophils.
5. The person is now sensitised; symptoms usually appear on re-exposure, not necessarily the first encounter.

3.2 Elicitation and mediator release

On re-exposure, allergen cross-links adjacent IgE molecules on mast cells. Rapid degranulation releases preformed histamine, tryptase and proteases. Newly synthesised leukotrienes, prostaglandin D2, platelet-activating factor and cytokines follow. Histamine causes vasodilation, increased vascular permeability, itching, bronchoconstriction and glandular secretion; leukotrienes produce potent prolonged bronchospasm and mucus. A late phase, driven by eosinophils, Th2 cells and cytokines, causes persistent airway or tissue inflammation.

Mediator	Major effects	Clinical correlate
Histamine H1	Itch, flushing, wheal, bronchoconstriction, vasodilation and capillary leak.	Urticaria, rhinitis, wheeze and hypotension.
Histamine H2	Gastric secretion and some vasodilation/tachycardia.	GI symptoms and cardiovascular effects.
Leukotrienes C4/D4/E4	Powerful bronchoconstriction, increased vascular permeability and mucus.	Asthma and severe anaphylactic bronchospasm.
Prostaglandin D2	Bronchoconstriction and vasodilation.	Airway symptoms and flushing.
Tryptase	Protease marker of mast-cell activation.	Supports recent anaphylaxis if sampled appropriately; a normal result does not exclude it.
PAF and cytokines	Platelet activation, vascular leak, leukocyte recruitment and late inflammation.	Persistent shock and late-phase disease.

3.3 Clinical forms

• Anaphylaxis: rapidly developing systemic reaction with airway, breathing, circulation and/or severe gastrointestinal involvement.
• Urticaria and angioedema: superficial wheals and deeper dermal/submucosal swelling. Bradykinin-mediated angioedema is not IgE-driven and responds poorly to antihistamines.
• Allergic rhinitis and conjunctivitis: sneezing, nasal itch, watery discharge and conjunctival symptoms.
• Atopic asthma: reversible bronchoconstriction plus chronic eosinophilic airway inflammation; not every asthma exacerbation is allergic.
• Food allergy: oral itching, urticaria, vomiting, wheeze or anaphylaxis; reactions can be dose-dependent and exercise/cofactor-amplified.
• Insect-venom and latex allergy: local reactions may be mild, but systemic reactions can progress rapidly.

4. Anaphylaxis: emergency recognition and management

4.1 Red flags

• Airway: tongue/throat swelling, hoarseness, stridor, inability to swallow secretions.
• Breathing: wheeze, severe bronchospasm, cyanosis, hypoxia or exhaustion.
• Circulation: collapse, hypotension, weak pulse, syncope or cardiac arrest.
• Skin/mucosa: generalised urticaria, flushing, pruritus or angioedema (may be absent).
• Gastrointestinal: repetitive vomiting, cramping or severe diarrhoea, especially with another system involved.
• Neurologic: anxiety, confusion, dizziness or loss of consciousness from hypoperfusion.

4.2 Immediate treatment sequence

1. Call for help, remove the trigger if possible, position supine with legs raised; allow a patient with severe breathing difficulty to sit with legs extended. Do not let a shocked patient stand or walk.
2. Give IM adrenaline (epinephrine) into the anterolateral thigh immediately. Common emergency guidance uses adrenaline 1 mg/mL (1:1000): adult 0.5 mg (0.5 mL); child 0.01 mg/kg up to 0.5 mg. Repeat after about 5 minutes if airway, breathing or circulation problems persist, following local protocol and available concentration.
3. Assess airway, breathing, circulation and disability; give high-flow oxygen, attach ECG/BP/SpO2 monitoring and obtain IV access.
4. For persistent hypotension, give rapid isotonic crystalloid boluses and repeat adrenaline under senior/critical-care supervision. Refractory shock may require an IV adrenaline infusion in a monitored setting.
5. For bronchospasm, add inhaled short-acting beta-2 agonist; for upper-airway oedema prepare early expert airway management.
6. Antihistamines can relieve itch and urticaria after adrenaline, but they do not reverse shock or airway obstruction. Corticosteroids are not a substitute for adrenaline and do not act immediately.
7. Observe for recurrence or biphasic reactions according to severity, comorbidity, treatment response and local policy; provide an action plan and specialist referral before discharge.

Important: IV bolus adrenaline is hazardous outside specialist resuscitation practice. Always check concentration, route and local emergency protocol.

5. Type II hypersensitivity: antibody against a fixed target

IgG or IgM binds antigen on a cell surface, basement membrane or receptor. Injury can be destructive, inflammatory, stimulatory, blocking or structural.

Mechanism	How injury occurs	Examples
Complement and opsonisation	Antibody activates complement or coats cells for splenic/hepatic phagocytosis.	Autoimmune haemolytic anaemia, immune thrombocytopenia, haemolytic transfusion reaction.
Antibody-dependent cellular cytotoxicity	NK cells or macrophages recognise Fc portions and kill the antibody-coated target.	Some drug-induced cytopenias and autoimmune tissue injury.
Basement-membrane injury	Antibody and complement damage a structural matrix antigen.	Anti-GBM disease (Goodpasture syndrome): pulmonary haemorrhage and rapidly progressive glomerulonephritis.
Receptor stimulation	Antibody behaves as an agonist.	TSH-receptor antibody in Graves disease.
Receptor blockade	Antibody prevents physiologic ligand or neurotransmitter action.	Acetylcholine-receptor/MuSK antibodies in myasthenia gravis.
Adhesion disruption	Antibody interferes with intercellular adhesion.	Pemphigus vulgaris against desmosomal proteins.

Common clinical examples

• Autoimmune haemolytic anaemia: warm IgG or cold IgM antibodies produce anaemia, jaundice, raised LDH and a positive direct antiglobulin test.
• Immune thrombocytopenia: platelet antibody-mediated clearance causes isolated thrombocytopenia and mucocutaneous bleeding.
• Incompatible blood transfusion: preformed antibodies activate complement; fever, back pain, hypotension, haemoglobinuria and DIC require immediate transfusion-stop and emergency protocol.
• Goodpasture syndrome: anti-GBM antibodies cause pulmonary–renal syndrome; haemoptysis plus haematuria is an emergency.
• Graves disease and myasthenia gravis: receptor stimulation versus blockade demonstrates that type II disease is not always cell destruction.

6. Type III hypersensitivity: immune-complex disease

6.1 Formation and deposition

Soluble antigen combines with IgG or IgM in the circulation. Small or intermediate complexes are cleared less efficiently and deposit in vessel walls, glomeruli, joints, skin and serosal surfaces. Fc-receptor engagement and complement activation generate C3a/C5a, recruit neutrophils and trigger proteases and reactive oxygen species.

6.2 Factors that increase injury

• Persistent antigen or chronic infection.
• High-complex load or an antigen excess that forms small soluble complexes.
• High vascular pressure and filtration in glomeruli.
• Defective complement or phagocyte-mediated clearance.

Pattern	Timing/site	Examples
Local Arthus reaction	Hours after antigen enters skin already containing antibody; painful oedema, haemorrhage and necrosis.	Local immune-complex reaction after repeated antigen exposure.
Serum sickness	Usually 1–2 weeks after foreign protein or some drugs; fever, urticaria, arthralgia, lymphadenopathy and renal involvement.	Antiserum, biologics, beta-lactams and other drugs.
Systemic immune-complex disease	Multisystem inflammation with low complement, vasculitis and glomerulonephritis.	SLE, some post-infectious diseases and cryoglobulinaemia.
Immune-complex organ injury	Antigen-specific deposition in a target tissue.	Post-streptococcal glomerulonephritis, hypersensitivity pneumonitis components.

7. Type IV hypersensitivity: delayed T-cell-mediated disease

Type IV reactions are antibody-independent. Sensitised T cells recognise antigen presented by MHC and recruit inflammatory cells or kill target cells. They usually peak at 48–72 hours, although chronic disease can persist for weeks or years.

Subtype	Dominant cells/cytokines	Examples
IVa	Th1 cells, IFN-gamma and activated macrophages.	Contact dermatitis, tuberculin reaction and granulomatous inflammation.
IVb	Th2 cells, IL-4/IL-5 and eosinophils.	Some drug rashes and eosinophilic airway disease.
IVc	CD8 cytotoxic cells and Fas/perforin pathways.	Viral-like drug eruptions, Stevens–Johnson syndrome/toxic epidermal necrolysis mechanisms.
IVd	Th17 cells and neutrophils.	Acute generalized exanthematous pustulosis and selected neutrophilic drug reactions.

Clinical examples

• Allergic contact dermatitis: small chemicals such as nickel, fragrances or topical drugs act as haptens, bind skin proteins and produce an itchy eczematous eruption after a delay.
• Tuberculin skin reaction: memory T cells produce induration, not an immediate wheal; measure at the correct time.
• Granulomatous inflammation: persistent intracellular organisms or foreign material drive macrophage activation and granuloma formation.
• Coeliac disease and type 1 diabetes: mucosal or endocrine tissue is damaged by antigen-specific T-cell responses with autoantibodies as useful markers.
• Drug hypersensitivity: delayed morbilliform eruption, DRESS, acute generalized exanthematous pustulosis and SJS/TEN require different urgency and specialist assessment.

8. Drug hypersensitivity and severe cutaneous reactions

8.1 History is the central test

Record the exact drug, dose, route, first and last exposure, latency, morphology, mucosal involvement, organ abnormalities, treatment and re-exposure. Distinguish predictable side effects (nausea, sedation), drug interactions, viral exanthems and immune hypersensitivity.

Reaction	Usual timing	Key features	Urgency
Immediate IgE reaction	Minutes to approximately 1 hour.	Urticaria, angioedema, wheeze, hypotension, anaphylaxis.	Immediate adrenaline if anaphylaxis.
Morbilliform eruption	Several days after exposure; faster on re-exposure.	Symmetric maculopapular rash, often without organ injury.	Stop suspected nonessential culprit; evaluate red flags.
Serum-sickness-like reaction	Days to weeks.	Fever, rash, arthralgia; complement may be normal in serum-sickness-like illness.	Assess renal and systemic involvement.
DRESS	Usually 2–8 weeks.	Fever, facial oedema, diffuse rash, eosinophilia, lymphadenopathy and hepatitis/nephritis.	Stop culprit urgently; admit and monitor organs.
SJS/TEN	Usually 1–3 weeks.	Painful dusky rash, epidermal detachment, mucosal erosions and systemic illness.	Life-threatening dermatologic emergency; stop culprit and transfer to specialist care.
AGEP	Often rapid, frequently within 1–2 days.	Numerous non-follicular pustules, fever and neutrophilia.	Stop drug; assess systemic involvement.

9. Diagnostic approach

9.1 First classify the event

1. Was there a plausible trigger and reproducible relationship?
2. How fast did symptoms begin: minutes, hours, days or weeks?
3. Which systems were involved: skin, airway, lungs, circulation, gastrointestinal tract, kidneys, liver, blood or nervous system?
4. Could it be infection, vasovagal syncope, panic, asthma, sepsis, mast-cell disease, drug toxicity or an autoimmune flare instead?
5. Was the patient exposed to cofactors such as exercise, alcohol, NSAIDs, infection, pregnancy or beta-blockers?

9.2 Tests selected by mechanism

Test	Use	Caution
Serum tryptase	Supports mast-cell activation when sampled after suspected anaphylaxis and compared with a baseline.	Normal tryptase does not rule out anaphylaxis, especially food-triggered reactions; treatment must not wait.
Specific IgE/skin-prick testing	Identifies sensitisation to selected allergens in a compatible clinical history.	Positive sensitisation is not equal to clinical allergy; antihistamines affect skin testing.
Supervised challenge	May confirm or exclude food or drug allergy when risk is acceptable.	Never perform unsupervised challenge after severe anaphylaxis or SCAR.
Direct antiglobulin test	Identifies antibody/complement on red cells in type II haemolysis.	Interpret with haemolysis markers and transfusion history.
Complement, urinalysis, renal function	Assess immune-complex disease and organ injury.	Normal complement does not exclude every type III disease.
Biopsy and histology	Clarifies dermatitis, vasculitis, granuloma, blistering or organ injury.	Sample early active lesions and communicate the suspected mechanism.
CBC, liver profile and eosinophils	Detect cytopenia, eosinophilia and drug-organ injury.	Serial trends are often more informative than a single value.

10. Management by type

Type	Immediate measures	Long-term principles
I	Adrenaline for anaphylaxis; oxygen, airway support, fluids and bronchodilator as required.	Trigger avoidance, written action plan, allergist referral, appropriate antihistamine/inhaled therapy and selected immunotherapy.
II	Stop the offending exposure; support oxygen delivery, bleeding control, renal function or neuromuscular ventilation.	Disease-specific immunosuppression, IVIG/plasma exchange or replacement therapy when indicated.
III	Remove persistent antigen where possible; assess shock, renal injury and vasculitis.	Treat infection or underlying systemic disease; corticosteroid/immunomodulator therapy for organ-threatening disease.
IV	Stop culprit drug/contact exposure; evaluate skin, mucosa, airway and internal organs.	Topical/systemic anti-inflammatory therapy, specialist treatment of chronic disease and strict re-exposure avoidance.

11. Prevention and patient safety

• Document the suspected culprit, reaction phenotype, date and severity in the medical record; “allergy” without details is unsafe.
• Use generic and brand names, route and co-administered drugs when recording reactions.
• Do not label a predictable side effect as an allergy; inaccurate labels deny effective first-line treatment.
• For confirmed anaphylaxis, provide education, an emergency plan and appropriate adrenaline autoinjectors where available; teach technique and expiry checks.
• Check cross-reactivity rather than banning an entire drug class unnecessarily; involve allergy specialists for beta-lactam delabelling or desensitisation decisions.
• Patients taking beta-blockers or ACE inhibitors may have more difficult anaphylaxis; clinicians should anticipate refractory shock and seek expert support.
• For severe cutaneous reactions, permanently avoid the culprit and related cross-reactive agents according to specialist advice.

12. Clinical cases

Case 1: food-triggered anaphylaxis

A student develops widespread urticaria, hoarseness, wheeze and dizziness within minutes of eating a snack. This is Type I anaphylaxis. Give IM adrenaline immediately, call for resuscitation help, monitor continuously and treat airway/breathing/circulation problems. An oral antihistamine alone is unsafe because it cannot reverse laryngeal oedema or shock.

Case 2: pulmonary–renal syndrome

A patient taking no new medicine has haemoptysis, falling haemoglobin, haematuria and rapidly worsening creatinine. Anti-GBM disease is a Type II antibody-mediated emergency until proven otherwise. Stabilise oxygenation, involve renal/critical-care teams, obtain antibody tests and tissue diagnosis when safe, and do not delay urgent specialist treatment.

Case 3: delayed rash with organ involvement

Two months after starting an anticonvulsant, a patient develops fever, facial oedema, diffuse rash, eosinophilia and hepatitis. DRESS is likely (delayed T-cell drug hypersensitivity). Stop the culprit, admit, assess liver/kidney/heart involvement and seek dermatology/medical specialist care. Do not re-challenge.

Case 4: contact dermatitis

An itchy, sharply demarcated eczematous rash appears 48 hours after a new belt buckle. This is typical Type IV contact dermatitis. Remove the exposure, examine for infection and consider patch testing if recurrent; the delayed onset distinguishes it from immediate urticaria.

13. Exam comparison table

Feature	Type I	Type II	Type III	Type IV
Effector	IgE/mast cell.	IgG/IgM fixed antigen.	Soluble IgG/IgM complexes.	T cells.
Peak timing	Minutes; late phase hours.	Hours to days.	Hours to weeks.	48–72 hours or chronic.
Target	Allergen in tissues.	Cell, receptor or matrix.	Vessel/glomerulus/joint/serosa.	Cellular antigen or persistent pathogen.
Key pathology	Oedema, bronchospasm, mucus.	Cell destruction, receptor effect.	Complement/neutrophil vasculitis.	Macrophage inflammation or cytotoxicity.
Signature example	Anaphylaxis.	Graves or autoimmune haemolysis.	Serum sickness or SLE.	Contact dermatitis or TB skin test.

14. Quick self-test

1. What must happen before an IgE-mediated reaction occurs on re-exposure?
2. Why can a patient have anaphylaxis without urticaria?
3. Contrast Type II receptor stimulation with Type II cell destruction.
4. Why do immune complexes injure glomeruli and small vessels?
5. What makes a drug eruption a medical emergency?
6. List the first five priorities in anaphylaxis.

Answers

1. Sensitisation: allergen-specific IgE must be produced and bound to mast-cell Fc-epsilon-RI receptors.
2. Severe mediator-driven airway/circulatory disease can occur without visible skin signs; absence of rash never excludes anaphylaxis.
3. Stimulation is agonist antibody activation of a receptor, as in Graves; destruction involves complement, phagocytosis or ADCC, as in haemolysis.
4. They deposit where filtration, pressure and vascular geometry favour trapping; complement and neutrophils then cause tissue injury.
5. Airway/breathing/circulation compromise, mucosal involvement, epidermal detachment, shock, organ injury, eosinophilia or rapid progression.
6. Call for help, position safely, give IM adrenaline, assess ABCDE with oxygen/monitoring, and obtain IV access/fluids while preparing advanced airway support.

Key take-home points

• Classify by mechanism, but remember that one patient can have overlapping mechanisms.
• Type I is rapid IgE/mast-cell disease; anaphylaxis is a clinical emergency treated first with IM adrenaline.
• Type II antibodies may destroy cells, stimulate receptors, block receptors or damage basement membrane.
• Type III immune complexes activate complement and neutrophils in vessels, glomeruli and joints.
• Type IV is delayed T-cell disease; the IVa–IVd subtypes help explain contact dermatitis, drug eruptions and granulomatous injury.
• Timing, morphology, organ involvement and exposure history are often more useful than broad indiscriminate testing.
• Never let an allergy label, a negative tryptase or absent rash delay treatment of clinical anaphylaxis.

Selected references

• NCBI Bookshelf: Allergy and Hypersensitivity
• NCBI Bookshelf: Type I Hypersensitivity Reaction
• NCBI Bookshelf: Type II Hypersensitivity Reaction
• NCBI Bookshelf: Type III Hypersensitivity Reaction
• NCBI Bookshelf: Type IV Hypersensitivity Reaction
• MSD Manual Professional: Anaphylaxis
• Resuscitation Council UK: Anaphylaxis guidance