Diphtheria is an infectious disease caused by Corynebacterium diphtheriae, which is usually transmitted via respiratory droplets. The clinical features of diphtheria are caused by a toxin produced by C. diphtheriae after it colonizes the upper respiratory tract. Patients initially present with fever, malaise, and sore throat. Within a few days, a grayish-white pseudomembrane develops over the tonsils, posterior pharyngeal wall, and/or larynx. Other manifestations include cervical lymphadenopathy, soft tissue swelling of the neck, stridor, and/or difficulty breathing as a result of partial airway obstruction. Systemic absorption of the toxin can result in myocarditis, acute tubular necrosis, and/or polyneuropathy. Even before culture reports come back positive, patients should be promptly treated with penicillin and antitoxins, as untreated diphtheria is associated with a high mortality rate. In tropical countries, there is also a cutaneous form of diphtheria without systemic manifestations. Cutaneous diphtheria manifests as a scaly erythematous rash and/or a deep punched-out ulcer following direct entry of C. diphtheriae into the skin. Since the introduction of routine immunization against diphtheria in the 1920s, the incidence of the disease has decreased dramatically in the US.
- Incidence: 0–2 cases/year 
- Most cases occur in patients 20 years of age or older.
Epidemiological data refers to the US, unless otherwise specified.
Pathogen: Corynebacterium diphtheriae
- A gram-positive, nonsporulating, club-shaped bacillus
- Contains metachromatic granules; (volutin granules; stain red with a blue dye)
Route of infection
- Droplet transmission
- Less commonly through direct or indirect contact with open lesions
- Infectious period: variable
- C. diphtheriae colonizes the mucous membrane of the respiratory tract (respiratory diphtheria) and, less commonly, preexisting skin lesions (cutaneous diphtheria) .
C. diphtheriae has both toxigenic and nontoxigenic strains; toxigenic strains contain a beta-prophage gene (tox), which encodes for the exotoxin diphtheria toxin
- General characteristics: a heat-labile protein with a molecular weight of 62,000 kDa made of A and B fragments
- Mechanism of action: : the A fragment enters cells and catalyzes the transfer of ADP-ribosylation of the elongation factor-2 (EF-2) → inhibition of EF-2 → arrested protein translation and synthesis → cell death and necrosis
- Local effects of the toxin: destruction of the respiratory epithelium with a subsequent inflammatory response
- Systemic effects of the toxin
ABCDEFG of C. diphtheria: ADP-ribosylation, Beta-prophage, Club-shaped, Diphtheria, Elongation Factor 2, metachromatic Granules.
Patients initially present with prodromal symptoms: fever, malaise, and sore throat. Four to five days after the onset of prodromal symptoms, symptoms due to the local and systemic effects of the toxin occur.
- Incubation period: 2–5 days
- Anterior nasal diphtheria: bloody rhinorrhea
Tonsillar and pharyngeal diphtheria
- Grayish-white pseudomembrane over the posterior pharyngeal wall, and/or tonsils
- Any attempt to scrape off the pseudomembrane exposes the underlying capillaries and results in heavy bleeding.
- Bull neck due to cervical lymphadenopathy and swelling of the soft tissue of the neck → airway obstruction
- Foul mouth odor
- Laryngeal diphtheria: difficulty breathing, inspiratory stridor
- Systemic features (due to dissemination of toxin)
- Cutaneous diphtheria is the result of direct inoculation of C. diphtheriae into the skin (e.g., skin abrasions) or preexisting skin lesions.
- Usually seen in tropical regions, where it is more common than respiratory diphtheria
- Patients present with scaly erythematous rash, impetigo, or deep, punched-out ulcers
- Cutaneous diphtheria does not result in systemic effects.
Cultures: Obtain from all suspected patients (before initiating antibiotic therapy) to confirm the diagnosis.
- Respiratory diphtheria: Obtain nasal and pharyngeal cultures.
- Cutaneous diphtheria: Obtain cultures from skin lesions
- Microscopic examination: multiple Gram-positive club-shaped bacilli clustered in angular arrangements
- Culture media of choice
- Tests to identify toxigenic strains (if the culture reveals C. diphtheriae)
Therapy (including antitoxin administration) should be started immediately upon clinical suspicion, even before diagnostic confirmation of diphtheria. 
- The patient should be isolated as soon as diphtheria is suspected. 
- Antibiotic therapy; : penicillin G (IM injection) OR erythromycin (oral/IV) for 14 days 
- Immediate administration of diphtheria antitoxin: The antitoxin can only neutralize the unbound toxin and should therefore be administered early in the course of the disease.
- Airway support
- Monitor for myocarditis; : Conduct multiple ECGs; and serial measurement of cardiac markers.
- The diphtheria vaccine is a .
- Four diphtheria vaccines are available in the US:
- See “” for details.
Exposure control 
Close contacts 
- Those with frequent direct contact with the patient
- Anybody exposed to secretions from the infected source .
- For healthcare workers, exposure includes:
Management of exposed contacts
In addition to isolating and treating infected patients, the following measures should be performed in exposed close contacts regardless of their diphtheria immunity status. 
- All exposed contacts
- If cultures are negative: Discontinue quarantine and complete chemoprophylaxis. 
- If cultures are positive: 
- Asymptomatic individuals (carriers): Isolate until completion of chemoprophylaxis and two cultures are negative.
- Symptomatic patients: See “Treatment.”
Postexposure prophylaxis for diphtheria 
- Antibiotic chemoprophylaxis: erythromycin OR a single IM dose of benzathine penicillin G 
Active immunization with a diptheria vaccine 
- Unknown or incomplete diphtheria vaccine status (see “ACIP immunization schedule”): Administer an immediate dose of a diphtheria vaccine.
- Up-to-date diphtheria vaccine status (see “ACIP immunization schedule”):
- Last dose ≥ 5 years prior: Immediately administer a booster dose of a diphtheria vaccine.
- Last dose < 5 years prior: No dose is required at this time.