Diphtheria is an infectious disease caused by Corynebacterium diphtheriae that most often results in respiratory disease with membranous inflammation of the pharynx, sore throat, fever, swollen glands, and weakness. The hallmark sign is a sheet of thick, gray material covering the back of the throat. Diphtheria can also manifest as cutaneous disease leading to nonspecific skin lesions. In advanced stages, diphtheria can damage the heart, kidneys, and nervous system. It is diagnosed via a culture of pharyngeal swabs and treated with antibiotic therapy and the diphtheria antitoxin.

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Etiology and Epidemiology

  • Pathogen: gram-positive bacillus Corynebacterium diphtheriae
    • Four biotypes: gravis, intermedius, mitis, and belfant
  • Transmission: close contact with infected respiratory secretion (direct or airborne droplets)
    • Can also transmit through skin lesions
  • Immunization has minimized toxigenic strain transmission in resource-rich countries.
  • Remains a widespread disease/endemic in resource-limited countries
  • Asymptomatic carriers are important in transmission.
    • 5% of populations in endemic areas have positive pharyngeal cultures.
  • Humans are the only known reservoir.
  • Peak incidence in colder months


Pathogenesis diphtheria

Pathogenesis of diseases associated with Corynebacterium: diphtheria exotoxin inactivates elongation factor (EF-2) via ADP-ribosylation.
This bacteriophage, a beta prophage, introduces itself into the cell and DNA of the host organism, resulting in the encoding of diphtheria exotoxin. The exotoxin has 3 domains: 1 is present in fragment A and is catalytic, while 2 are present in fragment B for receptor binding and membrane insertion and translocation. The exotoxin is the major cause of the disease in diphtheria because it ribosylates ADP present in the elongation factor. The elongation factor, specifically elongation factor 2 (EF-2), is critical for the elongation of protein chains. Diphtheria exotoxin inhibits EF-2 so that protein is not synthesized, resulting in cellular death and secondary clinical manifestations.

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Clinical Presentation

  • Respiratory diphtheria:
    • Symptoms begin 2–5 days after infection.
    • Onset is gradual: sore throat, malaise, cervical lymphadenopathy, low-grade fever, mild erythematous pharynx
    • Pseudomembranous pharyngitis: a grayish-white membrane covering the posterior pharyngeal wall and/or tonsils which bleeds heavily during attempts at removal due to its highly vascular nature, present in at least one-third of cases
      • Should never be scraped
    • Severe lymphadenopathy with “bull neck” appearance (pathognomonic)
    • Foul breath or mouth odor
  • Laryngeal diphtheria:
    • Characteristic swollen neck and throat or “bull neck”
    • Often accompanied by:
      • “Barking” cough
      • Stridor
      • Hoarseness
      • Difficulty breathing
      • Diphtheritic croup
  • Cutaneous (wound) diphtheria:
    • Initial papule → chronic non-healing ulcer with a dirty-gray membrane
    • Local trauma is a frequent precedent (e.g., IV drug use)
    • Most often seen in homeless patients or those with a history of drug abuse
  • Systemic toxemia:
    • Damage to distant organs: myocarditis, arrhythmia, heart block, central and peripheral neurologic toxicity, renal failure, hypotension
    • Demyelination and nerve deficits begin in the posterior oral pharynx.
  • Nasal diphtheria:
    • Mild irritation of external nares and upper lip
    • Serosanguineous or purulent nasal discharge
  • Tracheobronchial diphtheria:
    • Develops secondary to membrane spread
    • Can result in respiratory compromise, especially in children with smaller airways


  • Consider a diagnosis with relevant clinical manifestations listed above along with epidemiologic risk factors.
  • Definitive diagnosis requires culture + toxin assay.
  • Cultures of pharyngeal swabs show C. diphtheriae (gram-positive rods with blue and red metachromatic granules, club-shaped, V and Y formation).
  • Elek test is performed to determine if the strain is toxigenic:
    • C. diphtheriae grows on an agar culture that is embedded with an antitoxin-impregnated filter paper. The production of diphtheria toxin is shown by bands of precipitation.
    • Culture agar: Tellurite → shows black colonies with halos
    • Culture medium: Loeffler’s → shows metachromatic granules
  • PCR testing can identify the gene via subunit A.
    • Culture must be run to confirm the presence of the toxin.

Key points to remember about diphtheria:

ABCDEFG: ADP-ribosylation, Beta-prophage, Corynebacterium diphtheriae, Elongation factor 2, Granules

Management and Prevention

  • Treatment for respiratory diphtheria is antibiotic therapy + diphtheria antitoxin.
    • Antibiotics: erythromycin > penicillin G/V for 14 days
    • Antitoxin immunoglobulin to neutralize toxin (passive immunization)
  • Treatment for cutaneous diphtheria is antibiotic therapy only (same as above) unless systemic symptoms are also present.
  • Careful airway management is needed to prevent airway obstruction.
  • Serial electrocardiograms and cardiac enzymes can monitor potential myocarditis.
  • Respiratory droplet isolation should be performed to limit transmission until 2 consecutive negative cultures occur 24 hours apart.
  • Close contacts need to be monitored, cultured, and potentially prophylactically treated with antibiotics.
  • Prevention: toxoid vaccine (DPT vaccine)–booster every 10 years (active immunization)


Possible complications associated with diphtheria include:

  • Myocarditis: inflammatory disease of the heart muscle, which mostly arises due to infections with cardiotropic viruses, especially infections with the coxsackievirus
  • Arrhythmias: heart rate or rhythm disturbance in which the heart can beat too fast, too slowly, or with an irregular rhythm
    • Bradyarrhythmias, tachyarrhythmias, atrial fibrillation, supraventricular tachycardia, ventricular fibrillation, ventricular tachycardia, atrioventricular block, long QT syndrome, sick sinus syndrome
  • Epiglottitis: caused by streptococcal or staphylococcal infections. Can cause airway obstruction leading to difficulty in breathing, stridor, and cyanosis, ultimately leading to death
  • Infective endocarditis: the group of streptococci bacteria is the most common pathogen to cause bacterial or infectious endocarditis. Infective endocarditis is an inflammatory disease of the interior heart lining and most commonly affects the cardiac valves.
  • Pharyngitis: inflammation of the back of the throat that is usually caused by an upper respiratory tract infection. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness.
  • Retropharyngeal abscess: a collection of pus in the back of the throat caused by a bacterial infection. Clinical manifestations include difficulty and pain when swallowing, fever, stiff neck, and noisy breathing.
  • Tonsillitis: infection of the tonsils, which are lumps of lymphatic tissue found on bilateral sides of the back of the throat. Inflamed tonsils become red and swollen and result in sore throats.
  • Foreign body aspiration: aspirated food may lodge in the larynx or trachea, which can lead to choking and potentially death. Geographic differences in the material aspirated affect the relative frequency with which various objects are aspirated.
  • Oropharyngeal candidiasis: condition in which Candida albicans fungus accumulates on the lining of the mouth, resulting in white lesions that usually manifest on the tongue or inner cheeks

Differential Diagnosis

The differential diagnosis of respiratory diphtheria includes:

  • Infectious mononucleosis: a highly contagious viral infection most commonly caused by the Epstein-Barr virus. Clinical manifestations include fever, tonsillar pharyngitis, and lymphadenopathy. Diagnosis is clinical and confirmed through heterophile antibody testing.
  • Group A streptococcal tonsillopharyngitis: an infection of the pharynx caused by group A streptococci. Clinical manifestations of streptococcal pharyngitis include the absence of cough, the presence of tonsillar exudates, fever, and tender anterior cervical adenopathy. Diagnosis is confirmed via a rapid antigen detection test or culture.
  • Epiglottitis: inflammation of the epiglottis and surrounding structures, most commonly caused by bacteria. Symptoms are rapid in onset, severe, and include fever, sore throat, dysphagia, drooling, and respiratory distress. Diagnosis is mainly clinical but can be confirmed by pharyngoscopy. 
  • Viral pharyngitis: inflammation and infection of the pharynx and surrounding structures most commonly caused by a virus. Common etiologies include:
    • Adenovirus
    • Coxsackie A virus
    • Orthomyxoviridae
    • Epstein-Barr virus
    • Herpes simplex virus
    • Measles virus
    • Rhinovirus
    • Coronavirus
    • Respiratory syncytial virus
    • Parainfluenza virus
  • Vincent’s angina: an infection of the gums commonly caused by Bacillus and Borrelia bacteria. Clinical manifestations include acute onset of painful, bleeding gums, blunting of interdental papillae, and an ulcerative necrotic slough of the gingiva. Also referred to as acute necrotizing ulcerative gingivitis.
  • Oral candidiasis: an overgrowth of Candida in the oropharynx in typically immunocompromised patients. Clinical manifestations include white plaques on the buccal mucosa, palate, tongue, or oropharynx. Diagnosis is confirmed by Gram stain or potassium hydroxide preparation showing budding yeast.

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