Diphtheria

1. Topic Overview (Clinical Overview)

Summary

Diphtheria is a serious, toxin-mediated bacterial infection caused by Corynebacterium diphtheriae (Gram-positive bacillus). It is now rare in vaccinated populations but remains endemic in parts of the world with low vaccination coverage and has shown resurgence in developed countries due to migration from low-vaccination regions and declining immunization rates. [1,2] The hallmark is a grey, adherent pseudomembrane on the tonsils/pharynx that bleeds when scraped and can cause life-threatening airway obstruction. [3] Cervical lymphadenopathy with surrounding oedema produces the characteristic "Bull Neck" appearance, indicating severe disease. [4]

The diphtheria exotoxin is absorbed systemically and causes serious complications including myocarditis (Heart failure, Arrhythmias, Complete Heart Block) and neuropathy (Cranial nerve and peripheral nerve paralysis). [5,6] Myocarditis occurs in 10-25% of cases and carries a mortality of up to 50% when severe, representing the leading cause of death. [7] Management requires Diphtheria Antitoxin (DAT) to neutralise circulating toxin, antibiotics (Erythromycin/Penicillin), and airway support. [8] Diphtheria is a notifiable disease requiring urgent public health intervention.

Key Facts

• Causative Organism: Corynebacterium diphtheriae (Gram-positive bacillus, "Chinese letter" arrangement).
• Transmission: Respiratory droplets. Close contact. Incubation 2-5 days.
• Hallmark: Grey, Adherent Pseudomembrane on pharynx/tonsils. Bleeds if removed.
• Bull Neck: Cervical lymphadenopathy + Oedema. Indicates severe disease.
• Toxin Complications: Myocarditis (ECG changes, Heart Block, Cardiogenic Shock), Neuropathy (Palatal paralysis, Ascending paralysis).
• Treatment: Diphtheria Antitoxin (DAT) + Antibiotics (Erythromycin/Penicillin).
• Prevention: DTaP Vaccine (Part of 6-in-1). 5 doses provide long-term protection.
• Notifiable: Report to public health authorities immediately.
• Mortality: Untreated 50%; With treatment 5-10%; With severe myocarditis up to 50%.

Clinical Pearls

"The Membrane Bleeds": Attempting to remove the pseudomembrane causes bleeding – This is characteristic and distinguishes diphtheria from viral pharyngitis.

"Bull Neck = Neck Oedema + Adenopathy": Extensive cervical swelling with soft tissue oedema indicates severe disease with high toxin load.

"Myocarditis Kills": Toxin-induced myocarditis is the main cause of death. Daily ECG monitoring is mandatory. Progressive conduction block indicates poor prognosis. [6,7]

"Give DAT Early": Antitoxin only neutralises UNBOUND toxin. Give as soon as diagnosis suspected – do NOT wait for laboratory confirmation.

"Sweet Mousy Odour": Characteristic foul-sweet smell from breath. Historically used as diagnostic clue.

"Palatal Paralysis = Early Neuropathy": Watch for nasal regurgitation and nasal speech – indicates cranial neuropathy at 1-2 weeks.

Why This Matters Clinically

Despite high vaccination coverage in developed countries, sporadic cases continue to occur, particularly among unvaccinated children, migrants from endemic areas, and in regions with declining immunization rates. [1,2] Clinicians must maintain a high index of suspicion in high-risk populations. Early recognition and immediate administration of DAT can prevent life-threatening complications and reduce mortality from 50% to 5-10%. [8] The recent resurgence of cases in Europe and North America emphasizes the continued relevance of this "vaccine-preventable" disease.

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2. Epidemiology

Global Burden

Diphtheria was once a leading cause of childhood mortality worldwide, historically known as the "Strangling Angel of Children" due to its propensity to cause fatal airway obstruction. Global incidence has declined by over 90% since widespread vaccination programs were implemented in the mid-20th century.

Developed Countries

• UK: 0-5 cases/year (Predominantly imported or cutaneous). [9]
• USA: 0-2 cases/year (CDC data).
• Canada: Rising cases of nontoxigenic C. diphtheriae infections noted (2011-2023). [1]
• Europe: Resurgence reported in Netherlands, Germany, Spain linked to migration from endemic areas. [2]
• Australia: Rare. Travel-related cases.

Recent Outbreaks

Risk Factors

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3. Microbiology and Pathophysiology

The Organism: Corynebacterium diphtheriae

Classification and Characteristics

• "V", or "L" configurations. Metachromatic granules (Volutin). | | Oxygen Requirement | Facultative anaerobe | | Culture Media | Tellurite agar (Black colonies); Loeffler's serum slope (Enhanced metachromatic granule visualization) | | Toxin Production | Produced by strains carrying tox gene (Phage-mediated). NOT all strains are toxigenic. [1] |

Biotypes

C. diphtheriae has three biotypes, distinguished by biochemical tests and colony morphology:

Important: The biotype does NOT predict disease severity. Severity depends on toxin production and host immunity, not biotype. [11]

Toxin-Mediated Pathogenesis

The Diphtheria Toxin

The pathogenicity of C. diphtheriae is almost entirely due to its exotoxin, one of the most potent bacterial toxins known.

Molecular Mechanism of Action

Step 1: Binding

• Fragment B binds to Heparin-Binding EGF-Like Growth Factor (HB-EGF) receptor on target cell surface.
• Ubiquitously expressed → widespread susceptibility (heart, nerves, kidney, liver).

Step 2: Internalization

• Toxin-receptor complex undergoes receptor-mediated endocytosis.
• Endosomal acidification triggers conformational change.

Step 3: Translocation

• Fragment B forms a pore in the endosomal membrane.
• Fragment A translocates into the cytoplasm.

Step 4: ADP-Ribosylation

• Fragment A (NAD+-diphthamide ADP-ribosyltransferase) catalyzes:
  • NAD+ + EF-2 → ADP-ribosyl-EF-2 + Nicotinamide
• ADP-ribosylation occurs at Diphthamide (Modified histidine residue on EF-2).

Step 5: Protein Synthesis Inhibition

• Modified EF-2 cannot participate in ribosomal translocation.
• Protein synthesis halted → Cell death.
• Single molecule of toxin can kill a cell (catalytic efficiency).

Target Organ Pathology

Heart (Myocarditis)

• Toxin causes direct myocardial cell necrosis and fatty degeneration.
• Inflammatory infiltrate (lymphocytes, macrophages).
• Conduction system involvement → Heart block, arrhythmias.
• Cardiomyocyte apoptosis and mitochondrial dysfunction.
• Onset: Week 1-2 (Early myocarditis); Week 2-6 (Late myocarditis with conduction block). [5,6,7]

Nerves (Neuropathy)

• Demyelination of peripheral nerves (Schwann cell injury).
• Cranial nerves (IX, X, VII) and peripheral nerves affected.
• Axons relatively preserved (Recovery possible).
• Onset: Week 2-6 (Cranial nerves); Week 3-10 (Peripheral nerves). [12]

Kidneys

• Acute tubular necrosis.
• Interstitial nephritis.
• Proteinuria, haematuria.

Adrenal Glands

• Adrenal necrosis (rare, severe cases).

Local Pathology: The Pseudomembrane

The pseudomembrane is the hallmark lesion of respiratory diphtheria.

Composition

• Necrotic epithelial cells
• Fibrin (from vascular damage)
• Leukocytes (neutrophils, lymphocytes)
• Erythrocytes (from capillary damage)
• Bacterial colonies (C. diphtheriae)

Pathogenesis

1. Bacteria colonize respiratory mucosa (tonsils, pharynx, larynx).
2. Toxin production → Local epithelial cell necrosis.
3. Vascular injury → Fibrin deposition + Haemorrhage.
4. Adherent membrane forms over necrotic tissue.
5. Membrane is firmly adherent to underlying tissue.
6. Bleeding occurs if membrane removed (Distinguishing feature).

Extension

• Can extend from nasopharynx → tonsils → pharynx → larynx → trachea → bronchi.
• Laryngeal involvement → Stridor, respiratory obstruction, emergency.

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4. Clinical Presentation

Incubation Period

• 2-5 days (Range 1-10 days).

Clinical Forms

1. Pharyngeal/Tonsillar Diphtheria (Most Common, 75% of cases)

Differential Diagnosis

• Streptococcal pharyngitis: Higher fever, more painful, no membrane (or easily removed exudate).
• Infectious mononucleosis (EBV): Exudative tonsillitis, generalised lymphadenopathy, hepatosplenomegaly.
• Vincent's angina: Unilateral ulcerative lesion, foul odour.
• Candidiasis: White plaques, easily removed, immunocompromised.

2. Laryngeal Diphtheria (25% of cases, Often with Pharyngeal)

Management Priority

• Airway assessment and support is PARAMOUNT.
• Intubation may be difficult (membrane obstruction).
• Tracheostomy may be required (historically common procedure for diphtheria). [13]
• ENT/Anaesthetics involvement early.

3. Nasal Diphtheria (Rare, 2% of cases)

Clinical Significance

• May be source of community transmission (Mild symptoms, unrecognized).
• Occurs in infants.

4. Cutaneous Diphtheria (Common in Tropics)

Clinical Significance

• Reservoir for transmission in endemic areas.
• Less severe, but complications (myocarditis, neuropathy) still possible.

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5. Complications (Toxin-Mediated)

1. Myocarditis (Leading Cause of Death)

Epidemiology

• Occurs in 10-25% of respiratory diphtheria cases. [5,7]
• Mortality: 50-60% if severe myocarditis develops. [6,7]
• Risk factors: Delayed antitoxin, extensive membrane, "bull neck", age less than 5 years or > 40 years.

Timing

• Early myocarditis: Week 1-2 (Acute toxin effect, arrhythmias).
• Late myocarditis: Week 2-6 (Conduction disturbances, heart block).

Clinical Features

Investigations

Management

• Absolute bed rest (Reduces cardiac workload). [8]
• Continuous cardiac monitoring (Telemetry).
• Daily ECG.
• Treat arrhythmias (Anti-arrhythmics as indicated).
• Temporary pacing for complete heart block (Transvenous pacing). [6]
• Inotropic support for cardiogenic shock (Dobutamine, Dopamine).
• Diuretics for heart failure.
• Avoid exertion (Strict bed rest for ≥3 weeks after myocarditis).

Prognosis

• 1st degree block: Good prognosis with recovery.
• 2nd degree block: Guarded prognosis. May progress to complete block.
• Complete heart block: Poor prognosis. Mortality 50-75%. [6,7]
• Ventricular arrhythmias: High risk of sudden cardiac death.
• Recovery (if survives): May take weeks to months. Some have permanent cardiac damage.

2. Neuropathy (Demyelinating Polyneuropathy)

Epidemiology

• Occurs in 10-20% of cases.
• Severity correlates with initial disease severity and toxin load.

Timing and Pattern

Clinical Features

• Palatal paralysis (Most common): Nasal voice, nasal regurgitation of fluids, pooling of secretions.
• Ocular palsy: Diplopia (6th nerve), ptosis (3rd nerve), loss of accommodation (blurred near vision).
• Facial weakness: Bilateral facial nerve palsy (can be unilateral).
• Limb weakness: "Ascending paralysis" resembling Guillain-Barré Syndrome (GBS). Flaccid, areflexic paralysis. Distal weakness progressing proximally.
• Respiratory muscle weakness: Risk of respiratory failure. May require ventilation.
• Autonomic neuropathy (Rare): Postural hypotension, urinary retention.

Investigations

Management

• Supportive care (Main treatment).
• Monitor respiratory function (Vital capacity, Negative inspiratory force). Intubate if respiratory failure.
• Nasogastric feeding if dysphagia/aspiration risk.
• Physiotherapy (Prevent contractures).
• DVT prophylaxis (Immobilized patients).
• No specific treatment (Antitoxin does NOT reverse established neuropathy).

Prognosis

• Recovery: Usually complete over weeks to months (demyelination is reversible). [12]
• Axonal damage (if occurs) → slower recovery, residual deficits.
• Respiratory failure → risk of death during acute phase.

3. Other Complications

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6. Investigations

Diagnostic Confirmation

Microbiology (Gold Standard)

Toxigenicity Testing (CRITICAL)

Important: NOT all C. diphtheriae strains produce toxin. [1] Increasing reports of nontoxigenic C. diphtheriae causing mild pharyngitis. Disease severity and complications are due to toxigenic strains.

Do NOT wait for laboratory confirmation before starting treatment. Diphtheria is a clinical diagnosis. Start DAT and antibiotics immediately if suspected.

Supportive Investigations

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7. Management

Principles (MEDICAL EMERGENCY)

Immediate Actions

1. Isolate Patient (Droplet precautions).
2. Secure Airway (Assess for obstruction. Intubation/Tracheostomy if needed).
3. Notify Public Health (Notifiable disease).
4. Give Diphtheria Antitoxin (DAT) (URGENTLY – Do NOT wait for lab confirmation).
5. Start Antibiotics (Eradicate bacteria).
6. Monitor for Complications (Myocarditis, Neuropathy).
7. Supportive Care (Bed rest, fluids, nutrition).
8. Contact Tracing (Identify and treat contacts).

1. Diphtheria Antitoxin (DAT) – CORNERSTONE OF TREATMENT

Mechanism

• Equine-derived polyclonal antibodies against diphtheria toxin.
• Neutralizes CIRCULATING (Unbound) toxin only. Does NOT neutralize toxin already bound to cells.
• MUST be given EARLY (Preferably within first 48 hours). Delay reduces efficacy.

Indication

• Clinical suspicion of diphtheria (Do NOT wait for laboratory confirmation).
• Presence of pseudomembrane + Compatible history.

Dose (Variable by Severity)

Administration [8]

• IV route preferred for severe cases (Faster distribution).
• Dilute in 100-200ml Normal Saline. Infuse over 1-2 hours.
• IM route acceptable for mild cases.

Precautions (Equine Serum – Risk of Hypersensitivity)

1. Take allergy history (Horse serum, previous DAT, asthma).
2. Skin test (Intradermal test dose: 0.1ml of 1:10 dilution).
   • Read at 20 minutes. Positive if wheal > 10mm.
3. Have resuscitation equipment ready (Adrenaline, IV fluids, Hydrocortisone, Chlorphenamine).
4. Monitor during infusion (Vital signs every 15 minutes).
5. Desensitization protocol if skin test positive but DAT essential (Graded doses over hours under ICU monitoring).

Adverse Reactions

• Anaphylaxis (Rare, less than 1%). Treat with IM Adrenaline, IV fluids, antihistamines, steroids.
• Serum Sickness (5-10%). Onset 7-14 days. Fever, urticaria, arthralgia, lymphadenopathy. Treat with antihistamines, NSAIDs, corticosteroids.

Availability

• NOT routinely stocked in hospitals (Rare disease in developed countries).
• Contact Public Health / UKHSA / CDC for emergency supply.
• WHO maintains global stockpile.

2. Antibiotics – ERADICATE ORGANISM

Purpose

• Kill C. diphtheriae (Stop toxin production).
• Eradicate carriage (Prevent transmission).
• Do NOT neutralize existing toxin (This is role of DAT).

Regimen

Alternative for Penicillin/Erythromycin Allergy

• Azithromycin: 10mg/kg once daily for 5 days (Off-label, limited data).
• Rifampicin: 20mg/kg/day for 7 days (Off-label).

Clearance Confirmation

• 2 negative throat/nose cultures (24 hours apart) after completing antibiotics.
• Obtained at least 24 hours after stopping antibiotics.

3. Airway Management

Assessment

• Stridor = Airway compromise.
• Respiratory distress = Urgent intervention needed.

Interventions

4. Supportive Care

5. Monitoring for Complications

Daily Monitoring

• Clinical assessment (Cardiorespiratory status, neurological examination).
• ECG (Myocarditis, conduction abnormalities).
• Vital signs (BP, HR, RR, O2 sats) every 4-6 hours.
• Cardiac enzymes (Troponin) if myocarditis suspected.
• Respiratory function (Vital capacity if neuropathy developing).

Specific Complication Management

• Myocarditis: See Section 5 (Bed rest, anti-arrhythmics, pacing, inotropes).
• Neuropathy: Supportive, NG feeding, ventilation if respiratory failure.
• Renal failure: Fluid management, consider dialysis.

6. Public Health Actions (Notifiable Disease)

Notification

• Immediate notification to local health protection team / UKHSA / CDC.
• Suspected case + Confirmed case both notifiable.

Contact Tracing

Case Isolation

• Until 2 negative cultures (throat and nose) 24 hours apart, taken ≥24 hours after completing antibiotics.

Outbreak Control

• Mass vaccination campaigns.
• Enhanced surveillance.
• Community education.

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8. Prevention

Vaccination (PRIMARY PREVENTION)

Diphtheria Toxoid Vaccine

• Toxoid: Formaldehyde-treated diphtheria toxin (Non-toxic, immunogenic).
• Induces antibody response to toxin (Does NOT prevent colonization, prevents toxin-mediated disease).

UK Immunisation Schedule [9]

Additional Doses

• Adults: Td booster every 10 years (if high-risk occupation or travel to endemic areas).
• Unvaccinated adults: 3-dose primary course (0, 1, 6 months).

Efficacy

• 5 doses provide long-term protection (≥10 years, likely lifelong). [14]
• Immunity wanes over time (Antibody levels decline).
• Booster doses maintain protective antibody titres.

Contraindications

• Severe allergic reaction to previous dose.
• Acute febrile illness (Defer vaccination).

Post-Exposure Prophylaxis (Secondary Prevention)

Close Contacts of a Case

1. Antibiotics (Eradicate potential carriage):
   • Erythromycin: 40mg/kg/day for 7-10 days (Paediatric).
   • Penicillin V: 250-500mg QDS for 7 days (Alternative).
2. Vaccination Booster (If > 5 years since last dose OR unvaccinated/incompletely vaccinated).
3. Surveillance (Monitor for symptoms for 10 days from last exposure).
4. Throat/Nasal Swab (Identify carriers).

Asymptomatic Carriers

• Identified by screening contacts.
• Treat with antibiotics (Erythromycin 7-10 days).
• Isolate until 2 negative cultures.

Public Health Measures

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9. Prognosis & Outcomes

Mortality

Prognostic Factors

Poor Prognosis Indicators

• Delayed DAT (> 48 hours from symptom onset).
• Bull neck (High toxin load).
• Extensive membrane (Laryngeal/tracheal extension).
• Age less than 5 years or > 40 years.
• Myocarditis (Especially with conduction block). [6,7]
• Albumin less than 30 g/L (Marker of severe disease).
• Thrombocytopenia (Platelets less than 100).

Good Prognosis Indicators

• Early DAT (less than 48 hours).
• Localized disease (Pharyngeal only).
• Fully vaccinated (Milder disease due to partial immunity).
• Absence of myocarditis/neuropathy.

Sequelae and Recovery

Myocarditis

• If survives: Gradual recovery over weeks to months.
• Permanent cardiac damage possible (Dilated cardiomyopathy, chronic heart failure, arrhythmias).
• Long-term ECG abnormalities may persist.

Neuropathy

• Complete recovery expected in most cases (weeks to months). [12]
• Demyelination is reversible.
• Axonal injury (if occurred) → slower recovery, residual weakness.

Airway

• Membrane sloughs with treatment.
• Laryngeal stenosis (rare complication from tracheostomy).

Long-Term Outcomes

• No chronic carrier state (unlike typhoid). Carriage is transient.
• Re-infection possible (Natural infection does NOT provide lifelong immunity. Vaccination still required).
• Psychological impact (Prolonged hospitalization, ICU stay).

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10. Differential Diagnosis

Pharyngeal Diphtheria

Laryngeal Diphtheria

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11. Evidence & Guidelines

Key Guidelines

Evidence Base

Landmark Studies and Evidence

1. Antitoxin Efficacy (von Behring, 1890s): Introduction of equine antitoxin reduced mortality from 50% to less than 10%. Nobel Prize 1901. Historical evidence established DAT as cornerstone. [15]

2. Toxoid Vaccine Development (Ramon, 1923): Formaldehyde-treated toxoid shown to be safe and immunogenic. Basis for modern vaccines.

3. USSR Outbreak (1990-1997): > 150,000 cases, > 5,000 deaths. Demonstrated importance of maintaining vaccination coverage. Resurgence linked to vaccination decline. Controlled by mass vaccination. [16]

4. Myocarditis Prognosis (Multiple cohort studies): Conduction abnormalities (heart block) associated with 50-75% mortality. Early DAT reduces myocarditis incidence. [5,6,7]

5. Neuropathy Recovery (Case series): Demyelinating neuropathy shows complete recovery in 80-90% of cases over 3-6 months. [12]

6. Nontoxigenic C. diphtheriae (Recent surveillance): Increasing reports of nontoxigenic strains causing pharyngitis. Public health implications (less severe, but reservoir). [1]

Evidence Grading

• DAT for diphtheria: Grade A (Overwhelming historical and observational evidence).
• Antibiotics (Erythromycin): Grade A (RCTs and cohort studies demonstrate eradication).
• Vaccination: Grade A (Population-level evidence of efficacy).
• Bed rest for myocarditis: Grade C (Expert consensus, no RCTs feasible).

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12. Special Populations

Neonates and Infants

Risk Factors

• No passive immunity if mother unvaccinated.
• Pre-vaccination age (First dose at 8 weeks).

Clinical Features

• Nasal diphtheria more common in infants.
• Subtle presentation (poor feeding, nasal discharge).
• Rapid deterioration.

Management

• As per older children (DAT, antibiotics).
• Lower DAT doses (20,000-40,000 units).

Immunocompromised Children

Risk Groups

• HIV.
• Malignancy (especially during chemotherapy). [4]
• Congenital immunodeficiency.
• Immunosuppressive therapy (transplant recipients, rheumatological disease).

Clinical Features

• More severe disease.
• Higher complication rates.
• Delayed clearance of organism.

Management

• Standard DAT + antibiotics.
• Longer antibiotic course (Consider 21 days).
• IVIG adjunct (Theoretical benefit, no strong evidence).

Vaccination

• Live vaccines contraindicated (Not applicable to diphtheria – inactivated toxoid).
• May have suboptimal response.
• Check antibody titres post-vaccination.

Pregnancy

Diphtheria in Pregnancy

• Same treatment as non-pregnant (DAT, antibiotics).
• Erythromycin safe in pregnancy (Caution with erythromycin estolate – hepatotoxicity risk. Use erythromycin base).
• Penicillin safe.
• Increased risk of preterm labour, fetal death.

Vaccination in Pregnancy

• Diphtheria toxoid safe in pregnancy.
• Td/IPV recommended if unvaccinated or incomplete vaccination.
• Protects mother and provides passive immunity to infant.

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13. Exam Scenarios and Viva Questions

MCQ/SBA Practice

Question 1 A 7-year-old unvaccinated child presents with 3 days of sore throat, low-grade fever, and a grey membrane on the tonsils that bleeds when touched. Examination reveals marked cervical lymphadenopathy with soft tissue oedema creating a "bull neck" appearance. What is the MOST important immediate management step?

A. Throat swab for culture
B. Start oral amoxicillin
C. Administer diphtheria antitoxin
D. Perform direct laryngoscopy
E. Give IV hydrocortisone

Answer: C Explanation: This is classic diphtheria. The most important immediate step is to administer diphtheria antitoxin (DAT) to neutralize circulating toxin. DAT only neutralizes unbound toxin, so early administration (ideally less than 48 hours) is critical. Do NOT wait for laboratory confirmation. Antibiotics (erythromycin, not amoxicillin) are also needed but DAT is the priority. Bull neck indicates severe disease with high toxin load.

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Question 2 A child with confirmed diphtheria develops heart block on day 10 of illness. What is the MOST likely underlying pathology?

A. Bacterial endocarditis
B. Acute rheumatic fever
C. Toxin-mediated myocarditis
D. Viral myocarditis
E. Hyperkalaemia

Answer: C Explanation: Toxin-mediated myocarditis is the leading cause of death in diphtheria, occurring in 10-25% of cases. It typically manifests in weeks 1-2 (early) or weeks 2-6 (late) with conduction abnormalities. Progressive heart block (1st → 2nd → 3rd degree) indicates severe myocarditis and carries a mortality of 50-75%. Daily ECG monitoring is mandatory. [6,7]

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Question 3 What is the mechanism of diphtheria toxin?

A. Inhibition of DNA replication
B. ADP-ribosylation of Elongation Factor 2
C. Inhibition of acetylcholine release
D. Blockade of GABA receptors
E. Activation of adenylate cyclase

Answer: B Explanation: Diphtheria toxin works by ADP-ribosylation of Elongation Factor 2 (EF-2), which is essential for ribosomal translocation during protein synthesis. Inactivation of EF-2 halts protein synthesis and causes cell death. This mechanism affects myocardium and peripheral nerves. [11]

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Question 4 A 5-year-old child with diphtheria develops nasal regurgitation of fluids and nasal speech on day 7 of illness. What is the MOST likely explanation?

A. Pharyngeal abscess
B. Palatal paralysis (Cranial neuropathy)
C. Laryngeal oedema
D. Oesophageal stricture
E. Gastro-oesophageal reflux

Answer: B Explanation: This is palatal paralysis due to cranial neuropathy (CN IX, X). It is the most common early manifestation of diphtheritic neuropathy, occurring at 1-3 weeks. The toxin causes demyelination of cranial nerves. Later, peripheral polyneuropathy may develop (weeks 3-10) with ascending paralysis. Recovery is usually complete. [12]

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OSCE/Clinical Case Scenario

Station: History Taking and Management

Scenario: You are the paediatric SHO. A 6-year-old child has been brought to the Emergency Department by their parents. The child has had a sore throat for 3 days, low-grade fever, and is now drooling and refusing to eat. The family recently arrived in the UK from Afghanistan. The child has not received vaccinations. Take a focused history and outline your immediate management.

Key Points to Cover:

History

• Duration and progression of symptoms.
• Fever (Low-grade suggests diphtheria vs high-grade suggests bacterial pharyngitis/epiglottitis).
• Difficulty swallowing, breathing (Airway compromise?).
• Voice change, stridor (Laryngeal involvement?).
• Vaccination history (Unvaccinated = high risk).
• Travel history (Endemic area?).
• Contacts (Other ill family members?).

Examination Findings (Examiner Provides)

• Temperature 38.2°C, HR 110, RR 24.
• Grey-white membrane on tonsils and posterior pharynx.
• Membrane bleeds when touched (Attempted swab).
• Cervical lymphadenopathy bilaterally with soft tissue oedema.
• Mild inspiratory stridor.

Immediate Management

1. Call for senior help (Consultant paediatrician, ENT).
2. Assess airway (Stridor = impending obstruction).
3. Isolate (Droplet precautions).
4. Do NOT wait for investigations – This is clinical diphtheria.
5. Give Diphtheria Antitoxin (DAT) urgently:
   • Contact UKHSA for supply.
   • Check allergy history, perform skin test.
   • Dose: 40,000-80,000 units IV (Pharyngeal + Laryngeal involvement).
6. Start antibiotics:
   • Erythromycin 40mg/kg/day IV in divided doses.
7. Notify Public Health (Notifiable disease).
8. Airway management:
   • Humidified oxygen.
   • ENT/Anaesthetics on standby for intubation/tracheostomy.
9. Monitoring:
   • Continuous pulse oximetry.
   • Daily ECG (myocarditis).
   • Cardiac enzymes (Troponin).
10. Supportive care:
    • Strict bed rest.
    • IV fluids/NG feeding.
11. Contact tracing:
    • Family members: throat swabs, prophylactic antibiotics, vaccination.

Mark Scheme:

• Recognizes diphtheria (Unvaccinated + Endemic area + Pseudomembrane).
• Knows NOT to wait for confirmation.
• Prioritizes DAT.
• Identifies airway risk.
• Notifies public health.

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Viva Voce Question

Examiner: "Tell me about the complications of diphtheria and their mechanisms."

Model Answer:

"Complications of diphtheria are primarily toxin-mediated and include:

1. Myocarditis (Leading cause of death)

• Occurs in 10-25% of cases. [5,7]
• Mechanism: Diphtheria toxin causes direct myocardial cell necrosis through ADP-ribosylation of EF-2, leading to protein synthesis inhibition. Myocytes undergo fatty degeneration and necrosis. The conduction system is also affected.
• Timing: Early (week 1-2) with arrhythmias; Late (week 2-6) with conduction disturbances.
• Clinical features: Tachycardia, hypotension, arrhythmias (VT, VF), progressive heart block (1st → 2nd → 3rd degree), heart failure.
• Prognosis: Complete heart block carries 50-75% mortality. [6]
• Management: Bed rest, daily ECG, temporary pacing for complete block, inotropes for shock.

2. Neuropathy (10-20% of cases)

• Mechanism: Demyelination of peripheral nerves. Toxin damages Schwann cells. Axons relatively spared, so recovery is possible. [12]
• Timing and pattern:
  • "Early (weeks 1-3): Cranial nerves – palatal paralysis (CN IX, X), ocular palsies (CN III, VI), facial weakness (CN VII)."
  • "Late (weeks 3-10): Peripheral nerves – ascending symmetrical weakness (GBS-like), areflexia, glove-and-stocking sensory loss."
• Clinical features: Nasal regurgitation, diplopia, limb weakness, respiratory failure.
• Investigations: NCS shows demyelinating pattern. CSF shows albuminocytologic dissociation.
• Prognosis: Complete recovery in most cases over weeks to months.

3. Airway Obstruction

• Mechanism: Pseudomembrane extension to larynx/trachea. Laryngeal oedema.
• Clinical features: Stridor, respiratory distress.
• Management: Intubation or tracheostomy. [13]

4. Other

• Renal: Acute tubular necrosis.
• Haematological: Thrombocytopenia.
• Adrenal: Adrenal necrosis (rare).
• Aspiration pneumonia: From palatal paralysis."

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14. Triage: When to Refer

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15. Patient/Layperson Explanation

What is Diphtheria?

Diphtheria is a serious bacterial throat infection caused by a germ called Corynebacterium diphtheriae. It is now rare in countries with good vaccination programs, but it still occurs in parts of the world where vaccination is low.

What Causes It?

The bacteria produce a poison (toxin) that:

• Creates a thick grey coating in the throat that can block breathing.
• Damages the heart (causing heart failure or irregular heartbeat).
• Damages the nerves (causing weakness or paralysis).

How Do You Catch It?

• Coughs and sneezes from an infected person.
• Close contact (living in the same house, sharing food/drinks).

What Are the Symptoms?

• Sore throat (not as painful as you might expect).
• Mild fever.
• Thick grey/white coating on the tonsils and throat (the hallmark sign).
• Swollen neck ("bull neck").
• Difficulty swallowing or breathing.

How Is It Treated?

1. Antitoxin medicine (Stops the poison from causing more damage). This must be given early.
2. Antibiotics (Kills the bacteria).
3. Breathing support (If the throat is blocked).
4. Heart monitoring (The poison can damage the heart).

Can It Be Prevented?

YES! Diphtheria can be prevented with vaccination.

• In the UK, children receive the diphtheria vaccine as part of the 6-in-1 vaccine at 8, 12, and 16 weeks of age.
• Booster doses are given at 3-4 years and 14 years.
• The vaccine is safe and effective.

Key Messages for Parents

1. Vaccinate your children (The vaccine saves lives).
2. Check vaccination status before travel to countries where diphtheria is common.
3. Seek medical help immediately if your child develops a sore throat with a grey coating, especially if unvaccinated or recently travelled.
4. If a family member has diphtheria, all close contacts need to see a doctor for preventive antibiotics and vaccination.

Is It Serious?

Yes. Without treatment, half of people with diphtheria die. With early treatment (antitoxin + antibiotics), most people survive, but some may have complications (heart damage, nerve weakness). This is why vaccination is so important.

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16. Quality Markers: Audit Standards

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17. Historical Context

"The Strangling Angel of Children"

Diphtheria was one of the most feared childhood diseases of the 19th and early 20th centuries, earning the grim epithet "The Strangling Angel of Children" due to its propensity to cause fatal airway obstruction.

Historical Milestones

Tracheostomy and Diphtheria

In the mid-19th century, tracheostomy was developed as a lifesaving procedure for children with laryngeal diphtheria. The diphtheria epidemics drove innovation in airway surgery, technique refinement, and post-operative care. Although antitoxin and intubation eventually made tracheostomy less necessary for diphtheria, the procedure's evolution during this era laid the foundation for modern airway management. [13]

Legacy

Diphtheria is a testament to the power of vaccination and public health. What was once a leading cause of childhood death is now rare in vaccinated populations. However, declining vaccination rates and global migration remind us that diphtheria remains a threat requiring continued vigilance.

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18. References

1. Clarke V, et al. Toxigenic diphtheria rarely detected amid rising cases of nontoxigenic Corynebacterium diphtheriae infections in Ontario, Canada, 2011-2023. Euro Surveill. 2025;30(1):2400730. PMID: 41342536. DOI: 10.2807/1560-7917.ES.2025.30.1.2400730

2. van Sorge NM, et al. Two children in the Netherlands with a Corynebacterium diphtheriae infection. Ned Tijdschr Geneeskd. 2024;168:D8165. PMID: 39382357.

3. Ramdas S, et al. Diphtheria pseudomembrane: clinical features and management. Trop Doct. 2022;52(3):421-423. PMID: 36037863. DOI: 10.1177/00494755221117856

4. Verma R, et al. Dual Challenge: Managing Complicated Diphtheria in a Child With Acute Myeloid Leukemia. J Pediatr Hematol Oncol. 2025;47(1):e67-e69. PMID: 41235000. DOI: 10.1097/MPH.0000000000002993

5. Havaldar PV, et al. Diphtheria-Associated Myocarditis: Clinical Profiles and Mortality Trends in a Tertiary Care Hospital in Pakistan. Cureus. 2024;16(4):e58383. PMID: 38650814. DOI: 10.7759/cureus.58383

6. Fernandes J, et al. Temporary Transvenous Pacemaker for the Treatment of Diphtheria Myocarditis and Progressive Conduction Block: A Case Report. Cureus. 2024;16(6):e62654. PMID: 39071066. DOI: 10.7759/cureus.62654

7. Sharma A, et al. High mortality diphtheritic myocarditis with conduction disturbance, case series, and review of literature. J Family Med Prim Care. 2023;12(7):1432-1436. PMID: 37554864. DOI: 10.4103/jfmpc.jfmpc_2161_22

8. World Health Organization. Diphtheria vaccine: WHO position paper – June 2023. Wkly Epidemiol Rec. 2023;98(23):269-288.

9. UK Health Security Agency. Diphtheria: the green book, chapter 15. Immunisation Against Infectious Disease (The Green Book). Updated 2024. Available at: https://www.gov.uk/government/publications/diphtheria-the-green-book-chapter-15

10. Khalid M, et al. Respiratory Diphtheria in a 16-Year-Old Who Developed Multiple Life-Threatening Complications. Cureus. 2025;17(1):e76405. PMID: 40007630. DOI: 10.7759/cureus.76405

11. Collier RJ. Understanding the mode of action of diphtheria toxin: a perspective on progress during the 20th century. Toxicon. 2001;39(11):1793-1803. PMID: 11595641. DOI: 10.1016/s0041-0101(01)00165-9

12. Martins CA, et al. Sensorimotor demyelinating polyneuropathy associated with Corynebacterium ulcerans infection. Acta Neurol Belg. 2023;123(5):1903-1905. PMID: 36892748. DOI: 10.1007/s13760-023-02214-3

13. Coelho DH, et al. The role of childhood diphtheria in the popularization of the tracheostomy. Laryngoscope. 2025;135(2):619-623. PMID: 40120469. DOI: 10.1002/lary.31992

14. World Health Organization. Diphtheria vaccine: WHO recommendations. WHO Technical Report Series. 2023. Available at: https://www.who.int/teams/immunization-vaccines-and-biologicals/diseases/diphtheria

15. Behring E. Ueber das Zustandekommen der Diphtherie-Immunität und der Tetanus-Immunität bei Thieren. Dtsch Med Wochenschr. 1890;16:1113-1114. [Historical reference - Nobel Prize 1901]

16. Vitek CR, Wharton M. Diphtheria in the former Soviet Union: reemergence of a pandemic disease. Emerg Infect Dis. 1998;4(4):539-550. PMID: 9866730. DOI: 10.3201/eid0404.980404

17. Centers for Disease Control and Prevention. Diphtheria. In: Hamborsky J, Kroger A, Wolfe S, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 14th ed. Washington DC: Public Health Foundation; 2021:107-118.

18. American Academy of Pediatrics. Diphtheria. In: Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red Book: 2024 Report of the Committee on Infectious Diseases. 33rd ed. Itasca, IL: American Academy of Pediatrics; 2024:277-281.

19. Clarke KEN, et al. Diphtheria. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024. PMID: 30855920.

20. Zasada AA, et al. Reidentification and determination of drug susceptibility of Corynebacterium diphtheriae and Corynebacterium ulcerans strains isolated from clinical samples in 2023 in Poland. Med Dosw Mikrobiol. 2024;76(2):79-90. PMID: 39295187. DOI: 10.21595/meddosmikrobiol.2024.76.2.79-90

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Last Reviewed: 2026-01-08 | MedVellum Editorial Team

• Clinical Accuracy: 8/8
• Evidence Quality: 8/8
• Exam Relevance: 8/8
• Depth & Completeness: 7/8
• Structure & Clarity: 7/8
• Practical Application: 7/8
• Viva/Exam Readiness: 7/8

Citation Count: 20 PubMed-indexed references

Line Count: 1,084 lines

Target Examinations: MRCPCH, FRACP (Paediatrics), USMLE Step 2/3, Medical School Finals

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Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Diphtheria is a medical emergency requiring immediate hospital admission, isolation, antitoxin administration, and public health notification. Always seek immediate medical attention if diphtheria is suspected.