Diphtheria

Definition and Organism

• Harrison's Principles of Internal Medicine, 22nd ed., p. 1265
• Rosen's Emergency Medicine, p. 2583

Pathogenesis and Toxin Mechanism

• Fragment B binds to host cell surface receptors and facilitates entry
• Fragment A is the active enzyme - it catalyzes the ADP-ribosylation of Elongation Factor-2 (EF-2), irreversibly inactivating it and halting cellular protein synthesis

• Rosen's Emergency Medicine, p. 2583
• Harrison's Principles of Internal Medicine, 22nd ed., p. 1265

Epidemiology

• Humans are the only reservoir
• Transmission: respiratory droplets, direct contact with secretions or skin lesions, rarely fomites
• R0: 1.7-4.3; untreated cases infectious for ~18.5 days
• Incubation: mean 1.4 days (range 1-10 days)
• In the pre-vaccine era, US incidence exceeded 100/100,000; 206,000 cases and 15,520 deaths in 1921 alone
• Vaccination has reduced this to near-zero in developed nations; only 2 cases in the US between 2004-2017
• Sporadic cases in inadequately immunized adolescents/adults; recent outbreaks in Yemen (2022-23) and Nigeria

Fig. Global annual reported diphtheria cases (bars) vs. DTP3 immunization coverage (lines), 1980-2016 - Rosen's Emergency Medicine

Types of Diphtheria

Clinical Features

• Low-grade fever, sore throat
• Malaise, weakness, dysphagia, headache
• Voice changes (hoarseness)

• The hallmark is the pseudomembrane - initially white, becoming gray, tough, and adherent; bleeds on removal
• Limited to tonsils = milder disease; extends across the entire pharynx = severe disease
• "Bull neck": marked cervical lymphadenopathy with neck tissue edema due to cellulitis - characteristic of malignant diphtheria
• Malignant form: high fever, severe muscle weakness, vomiting, diarrhea, restlessness, delirium

• Classic "barking" cough, inspiratory stridor, hoarseness
• Marked risk of acute airway obstruction and death

Complications

1. Myocarditis (Cardiac Toxicity)

• Appears 1-2 weeks after illness onset (earlier in severe cases)
• ECG changes (ST-T wave changes, AV block, dysrhythmias) in up to two-thirds of patients
• Clinical myocarditis in 10-25% of cases
• Dilated or hypertrophic cardiomyopathy on echo
• Serum troponin correlates with severity
• Can cause sudden death from arrhythmia or heart failure

2. Neuropathy (Neurologic Toxicity)

• Palatal paralysis - most common cranial nerve involvement; nasal voice, regurgitation, dysphagia
• Other cranial nerves: trigeminal, facial, vagus, hypoglossal

• Ciliary body paralysis - loss of accommodation, blurred vision, but pupillary light reaction preserved (opposite of Argyll Robertson pupil)
• Rarely, extraocular muscle weakness

• Sensorimotor polyneuropathy - may resemble Guillain-Barre syndrome (ascending paralysis, elevated CSF protein, acellular CSF)
• About 5% of respiratory cases develop polyneuritis; 75% of severe cases have some form of neuropathy
• Recovery is usually complete but may take months

• Adams and Victor's Principles of Neurology, 12th ed.
• Rosen's Emergency Medicine, p. 2583

Diagnosis

• Notify the laboratory specifically that C. diphtheriae is suspected (routine cultures will miss it)
• Throat/nasopharyngeal swab before antibiotics; plate on tellurite selective medium (Loeffler's or potassium tellurite)
• Toxin detection: Elek test (immunodiffusion), or PCR for the tox gene (more sensitive)
• Mass spectrometry detection methods are emerging
• Up to 30% of diphtheria patients also test positive for Group A streptococcus - this does NOT exclude diphtheria
• Leukocytosis, mild thrombocytopenia, proteinuria are common but nonspecific
• ECG, troponin, echocardiogram for cardiac monitoring

Management

1. Airway Management

• Respiratory isolation immediately
• Early intubation for laryngeal involvement
• Manage fluid resuscitation carefully - myocardial toxicity may limit fluid tolerance

2. Diphtheria Antitoxin (DAT)

• Most critical intervention - neutralizes only unbound circulating toxin; toxin already bound to tissues cannot be neutralized
• Must be given on clinical suspicion without waiting for culture confirmation - delay increases mortality
• Dose: 10,000-100,000 units depending on severity and membrane extent
• Test for equine hypersensitivity before administration (DAT is horse-derived)
• Administer IV for severe/late cases, IM for mild cases

3. Antibiotics

• Penicillin (benzylpenicillin) or erythromycin are first-line
• Purpose: halt toxin production, eliminate the organism, reduce transmission
• Antibiotics alone are insufficient - antitoxin is required
• Treatment continues until two consecutive negative cultures are obtained

4. Supportive Care

• Cardiac monitoring (continuous ECG)
• Respiratory support, including mechanical ventilation if needed
• Nasogastric feeding if palatal paralysis prevents swallowing

5. Contacts and Public Health

• All close contacts: nasopharyngeal cultures + prophylactic antibiotics (erythromycin or penicillin)
• Unimmunized contacts: diphtheria toxoid
• Report to public health authorities

Differential Diagnosis

Vaccination

• DTaP (diphtheria, tetanus, pertussis) for children: primary series at 2, 4, 6 months; boosters at 15-18 months and 4-6 years
• Tdap/Td boosters every 10 years in adults
• Vaccine prevents toxin-mediated disease but does not prevent carriage

• 95% efficacy with complete primary series

Key Points (High-Yield Summary)

1. Causative organism: C. diphtheriae; gram-positive club-shaped bacillus; toxin encoded by bacteriophage beta
2. Toxin mechanism: ADP-ribosylation of EF-2 → inhibits protein synthesis
3. Hallmark: Gray, adherent, bleeding pseudomembrane
4. Systemic complications: Myocarditis (1-2 weeks), palatal paralysis (5-12 days), ciliary paralysis with accommodation loss but intact pupillary light reflex (2-3 weeks), delayed polyneuropathy (5-8 weeks)
5. Treatment: Antitoxin (give immediately on clinical grounds) + penicillin/erythromycin
6. Critical point: Antitoxin neutralizes only free (unbound) toxin - early administration is essential