Definition and epidemiology
Diphtheria is an acute bacterial infection caused by toxigenic strains of Corynebacterium diphtheriae, a gram-positive bacillus. The disease is characterized by local pharyngeal inflammation with pseudomembrane formation and systemic toxin-mediated complications affecting the heart and nervous system.
Diphtheria was once a leading cause of childhood mortality worldwide but has become rare in countries with comprehensive vaccination programs. Global incidence has declined by >90% since widespread DTaP/DTP vaccine introduction. Endemic transmission persists in parts of South Asia, Southeast Asia, Africa, and South America. Sporadic outbreaks occur in populations with low vaccine coverage.
The disease predominantly affects children aged 1-10 years in endemic regions, though adults with waning immunity are increasingly affected in low-incidence countries. Respiratory diphtheria is the most common form, but cutaneous diphtheria occurs in tropical regions and among homeless populations. Case-fatality rates range from 5-10% overall, reaching 20% in children under 5 and adults over 40 years.
- Diphtheria toxin inhibits protein synthesis by ADP-ribosylation of elongation factor-2 (EF-2).
- Gray pseudomembrane that bleeds when scraped is pathognomonic for diphtheria.
- Myocarditis occurring 1-2 weeks after pharyngeal symptoms is the leading cause of death.
- Diphtheria antitoxin must be given immediately on clinical suspicion; do not wait for culture.
- Bull neck refers to massive cervical edema from lymphadenopathy in severe diphtheria.
- Cranial nerve palsies (palatal weakness, diplopia) occur 2-12 weeks after infection.
- C. diphtheriae grows on Loeffler medium and tellurite agar; metachromatic granules seen on staining.
- Disease does not confer reliable immunity; patients must complete vaccination series after recovery.
Etiology and risk factors
Diphtheria is caused by Corynebacterium diphtheriae, an aerobic, non-motile, gram-positive bacillus that produces diphtheria toxin when lysogenized by a β-phage carrying the tox gene. Only toxigenic strains cause classic diphtheria; non-toxigenic strains may cause pharyngitis but not systemic disease. The organism has four biotypes: gravis, mitis, intermedius, and belfanti.
Risk factors:
- Lack of vaccination — unvaccinated or incompletely vaccinated individuals
- Waning immunity — adults >10 years from last booster
- Crowded living conditions — refugee camps, prisons, urban slums
- Low socioeconomic status — limited healthcare access
- Endemic travel — visitors to regions with active transmission
- Immunocompromised states — HIV, malnutrition, chronic illness
- Alcoholism — increases risk of severe disease
Transmission occurs through respiratory droplets from infected individuals or asymptomatic carriers. Close contact with a case or carrier is the primary mode. Cutaneous diphtheria can spread via direct contact with skin lesions. Fomites play a minor role. The incubation period is typically 2-5 days.
Pathophysiology
Corynebacterium diphtheriae colonizes the respiratory mucosa, multiplying locally without invading deeper tissues. The organism remains confined to the upper respiratory tract but secretes diphtheria exotoxin, a 62-kDa protein responsible for all systemic manifestations.
The exotoxin has two subunits: fragment B binds to heparin-binding epidermal growth factor precursor (HB-EGF) on cell surfaces, facilitating entry; fragment A is the active enzymatic component. Once internalized, fragment A catalyzes ADP-ribosylation of elongation factor-2 (EF-2), irreversibly inactivating it. This halts protein synthesis, leading to cell death.
Local tissue necrosis, fibrin deposition, and inflammatory infiltrate produce the characteristic gray-white pseudomembrane composed of fibrin, dead epithelial cells, white blood cells, and bacteria. The membrane adheres tightly to underlying tissues; attempts to remove it cause bleeding.
Systemically absorbed toxin targets organs with high metabolic demand:
- Myocardium — toxic myocarditis with fatty degeneration, myocyte necrosis, and conduction system damage; occurs 1-2 weeks post-infection
- Peripheral nerves — demyelination causing cranial and peripheral neuropathies; occurs 2-12 weeks post-infection
- Kidneys — tubular necrosis leading to acute kidney injury
- Adrenal glands — rarely, adrenal insufficiency
The severity of disease correlates with toxin load, which depends on bacterial burden, strain toxigenicity, and timing of antitoxin administration.
Clinical features
Clinical presentation varies by site of infection and toxin effects.
Respiratory diphtheria
The most common form, affecting the pharynx, tonsils, and larynx.
Early symptoms (1-2 days):
- Low-grade fever (usually <39°C)
- Sore throat
- Malaise
- Dysphagia
- Cervical lymphadenopathy
Classic signs:
- Gray adherent pseudomembrane covering tonsils, pharynx, or larynx — bleeds when removal is attempted
- Bull neck — extensive cervical and submandibular edema due to lymphadenopathy and soft tissue swelling
- Foul-smelling breath
- Hoarseness or stridor if laryngeal involvement
Cutaneous diphtheria
Non-healing ulcers with a gray membrane, common in tropical regions. Systemic toxicity is rare but possible.
Systemic complications
Myocarditis (10-25% of cases):
- Occurs 1-2 weeks after symptom onset
- Tachycardia disproportionate to fever
- Cardiac arrhythmias (AV block, ventricular arrhythmias)
- Heart failure with pulmonary edema
- Sudden cardiac death
Neuropathy (weeks to months later):
- Cranial nerve palsies — palatal paralysis (nasal voice, regurgitation), ocular palsies, facial weakness
- Peripheral neuropathy — symmetric motor weakness, diminished reflexes, Guillain-Barré-like presentation
- Diaphragmatic paralysis
Renal failure:
- Acute tubular necrosis
Respiratory obstruction:
- Laryngeal membrane causing airway compromise
Diagnosis
Diagnosis is primarily clinical in the acute setting due to the need for immediate treatment. Laboratory confirmation follows.
Clinical diagnosis
Suspect diphtheria in any patient with:
- Membranous pharyngitis or tonsillitis, especially if membrane is adherent and bleeds when scraped
- Sore throat with bull neck
- Unexplained myocarditis or cranial neuropathy
- Recent travel to or residence in endemic area
- Inadequate vaccination history
Laboratory confirmation
Bacterial culture:
- Swab the membrane or area beneath it
- Inoculate onto Loeffler medium or tellurite agar (selective media)
- C. diphtheriae appears as gray-black colonies on tellurite
- Microscopy shows gram-positive rods with metachromatic granules (using Albert or methylene blue stain)
- Toxin testing is essential: Elek test (immunoprecipitation) or PCR for tox gene confirms toxigenicity
Other tests:
- ECG — prolonged PR interval, AV block, ST-T changes
- Troponin and CK-MB — elevated in myocarditis
- Throat swab PCR — rapid detection of C. diphtheriae and tox gene
- Serum antitoxin levels — low levels (<0.01 IU/mL) indicate susceptibility
Imaging
- Chest X-ray — if airway obstruction or aspiration suspected
- Echocardiography — assess for myocarditis if cardiac symptoms
Do not delay treatment waiting for culture results; empirical therapy is started on clinical suspicion.
Differential diagnosis
The differential includes other causes of membranous pharyngitis and systemic toxin-mediated disease.
| Condition | Distinguishing features |
|---|---|
| Streptococcal pharyngitis | Exudate is patchy, easily removed; no membrane; rapid antigen test positive |
| Infectious mononucleosis (EBV) | Tonsillar exudate; posterior cervical nodes; atypical lymphocytes; positive Monospot |
| Vincent angina | Ulcerative gingivitis with fetid breath; anaerobic organisms on Gram stain |
| Candida pharyngitis | White plaques easily scraped off; immunocompromised host |
| Viral pharyngitis | No membrane; rhinorrhea and cough common; self-limited |
| Peritonsillar abscess | Unilateral tonsillar swelling; uvular deviation; purulent drainage |
| Ludwig angina | Submandibular cellulitis; woody induration; dental infection source |
| Retropharyngeal abscess | Neck stiffness; drooling; CT shows fluid collection |
| Epiglottitis | Abrupt onset; drooling; thumb sign on lateral neck X-ray |
| Myocarditis (other causes) | No pharyngeal membrane; viral prodrome; different epidemiology |
Key differentiator: Adherent gray pseudomembrane that bleeds when scraped is pathognomonic for diphtheria and should prompt immediate treatment.
Management
Diphtheria is a medical emergency requiring immediate treatment without waiting for laboratory confirmation.
Acute management
1. Diphtheria antitoxin (DAT)
The cornerstone of therapy, neutralizing circulating toxin. It does not reverse toxin already bound to tissues, so early administration is critical.
- Administer as soon as diphtheria is suspected
- Dose is determined based on the site and severity of disease
- Test for horse serum hypersensitivity before giving (skin test); desensitization may be needed
- Antitoxin is available through CDC or equivalent agencies in most countries
2. Antibiotics
Eradicate the organism and halt toxin production.
- Erythromycin (first choice) or penicillin G
- Continue for 14 days
- Azithromycin is an alternative
- Repeat throat culture 24 hours after treatment completion to confirm eradication; if positive, treat for 10 more days
3. Supportive care
- Airway management — intubation or tracheostomy if laryngeal obstruction; do not remove membrane forcibly
- Cardiac monitoring — continuous ECG for arrhythmias; telemetry for at least 4-6 weeks
- Bed rest — strict for at least 2-3 weeks to reduce myocarditis risk
- Treat arrhythmias — temporary pacemaker for complete heart block
- Respiratory support — mechanical ventilation if diaphragmatic paralysis
4. Isolation
- Strict droplet precautions until two negative cultures (24 hours apart, ≥24 hours after antibiotic completion)
Prophylaxis for contacts
- Antibiotic prophylaxis: Erythromycin or penicillin for 7-10 days for all close contacts, regardless of vaccination status
- Booster vaccination: If last dose >5 years ago
- Surveillance cultures from contacts
Immunization
- Primary series: DTaP (diphtheria-tetanus-acellular pertussis) at 2, 4, 6, 15-18 months, and 4-6 years
- Booster: Tdap (adolescent/adult formulation) at 11-12 years, then Td every 10 years
- Patients recovering from diphtheria should complete vaccination series, as disease does not always confer immunity
Special considerations
- Pregnancy: Antitoxin and antibiotics are safe and should be given
- Cutaneous diphtheria: Treat with antibiotics; antitoxin usually not needed unless severe
Guidelines follow WHO, CDC, and IDSA recommendations. All suspected cases should be reported to public health authorities immediately.
Complications and prognosis
Complications arise from toxin-mediated organ damage and local airway obstruction.
Major complications
Myocarditis (10-25%):
- Leading cause of death
- Occurs 1-2 weeks post-infection
- Presents with arrhythmias (AV block most common), heart failure, cardiogenic shock
- Mortality 50-60% if myocarditis develops
Neuropathy (cranial and peripheral):
- Cranial nerve palsies: palatal weakness (week 2-3), ocular palsies (week 3-5), facial weakness
- Peripheral polyneuropathy: symmetric motor weakness with areflexia (weeks 10-12)
- Usually reversible over weeks to months
Airway obstruction:
- Laryngeal membrane causes stridor and respiratory distress
- May require emergency tracheostomy
Acute kidney injury:
- Toxin-induced tubular necrosis
- Usually reversible with supportive care
Sepsis:
- Secondary bacterial infection
Hemorrhage:
- Thrombocytopenia from toxin effect
Prognosis
Overall case-fatality rate: 5-10%
- Higher in extremes of age (<5 years: 10-20%; >40 years: 20%)
- Higher with delayed antitoxin administration (>3 days from symptom onset)
- Higher with bull neck, extensive membrane, or myocarditis
Favorable prognostic factors:
- Early antitoxin administration
- Mild disease (tonsillar only)
- Immunized individuals (disease less severe)
Recovery:
- Most survivors recover fully, though neuropathy may take months to resolve
- Cardiac conduction abnormalities may persist
Disease does not reliably induce lifelong immunity; vaccination should still be completed. With prompt antitoxin and supportive care, mortality can be reduced to <5%.
DIPHTHERIA toxin effects: Demyelination (neuropathy), Inhibits EF-2, Pharyngeal membrane, Heart block (myocarditis), Toxigenic strains only, HB-EGF receptor, Early antitoxin critical, Respiratory obstruction, Isolation required, ADP-ribosylation mechanism.
Practice questions
1. A 7-year-old unvaccinated boy presents with a 3-day history of low-grade fever and sore throat. Examination reveals a gray adherent membrane covering both tonsils and the posterior pharynx. The membrane bleeds when the physician attempts to scrape it. Cervical lymphadenopathy and submandibular edema are present. Which of the following is the most appropriate immediate management?
2. A 35-year-old man who recently immigrated from Southeast Asia develops pharyngitis with a gray membrane. He is treated appropriately with antitoxin and antibiotics. Two weeks later, he develops palpitations and dyspnea. ECG shows first-degree AV block with prolonged PR interval, and troponin is elevated. Which of the following mechanisms best explains this complication?
3. A 10-year-old girl with confirmed diphtheria is recovering from the acute illness after receiving antitoxin and antibiotics. Four weeks later, she presents with nasal-sounding speech and difficulty swallowing liquids, which regurgitate through her nose. Examination shows decreased gag reflex and palatal weakness. Which of the following is the most likely diagnosis?
Frequently asked questions
What causes diphtheria?
Diphtheria is caused by toxigenic strains of Corynebacterium diphtheriae, a gram-positive bacterium that produces diphtheria exotoxin. Only strains lysogenized by a bacteriophage carrying the tox gene cause classic disease with systemic complications. The exotoxin inhibits protein synthesis by ADP-ribosylating elongation factor-2, leading to cell death in target organs. Transmission occurs via respiratory droplets from infected individuals or asymptomatic carriers. Cutaneous diphtheria can also transmit through direct contact with skin lesions.
What are the first symptoms of diphtheria?
The first symptoms appear 2-5 days after exposure and include low-grade fever, sore throat, malaise, and difficulty swallowing. Within 1-2 days, a characteristic gray-white pseudomembrane forms on the tonsils, pharynx, or larynx. The membrane is firmly adherent and bleeds when attempts are made to remove it. Cervical lymphadenopathy and mild fever are common. Unlike streptococcal pharyngitis, diphtheria typically causes less severe throat pain relative to the extent of membrane formation. Hoarseness or stridor indicates laryngeal involvement.
How is diphtheria diagnosed?
Diagnosis is primarily clinical based on the presence of an adherent gray pharyngeal membrane in a patient with sore throat and inadequate vaccination history. Laboratory confirmation requires throat swab culture on Loeffler medium or tellurite agar, where C. diphtheriae grows as gray-black colonies. Gram stain shows gram-positive rods with metachromatic granules. Crucially, the Elek test or PCR must confirm toxigenicity of the isolated strain. Treatment with diphtheria antitoxin should not be delayed while awaiting culture results, as early administration is critical for preventing complications.
Is diphtheria curable?
Yes, diphtheria is curable with prompt treatment, but the disease can be fatal if untreated or if treatment is delayed. The mainstay of therapy is diphtheria antitoxin, which neutralizes circulating toxin before it binds to tissues, combined with antibiotics (erythromycin or penicillin) to eradicate the bacteria. Early antitoxin administration within 48-72 hours of symptom onset significantly improves outcomes. However, once toxin has bound to cardiac or neural tissue, damage is irreversible. Overall case-fatality rate is 5-10%, rising to 20% in severe cases with myocarditis. Most survivors recover fully with appropriate treatment.
Diphtheria vs strep throat — what is the difference?
The key difference is the pharyngeal membrane: diphtheria produces a thick, gray, adherent pseudomembrane that bleeds when scraped, whereas strep throat causes patchy white exudate that is easily removed. Diphtheria typically has milder throat pain relative to the severity of findings and causes systemic toxin effects (myocarditis, neuropathy) not seen in strep pharyngitis. Strep throat presents with high fever, severe odynophagia, and anterior cervical adenopathy. Diphtheria patients often have bull neck (massive cervical edema) and low-grade fever. Rapid antigen testing confirms strep; diphtheria requires culture confirmation but treatment is started on clinical suspicion.
Key drugs
Related conditions and differentials
Sources and further reading
StatPearls (NCBI Bookshelf)MedlinePlusWHO ICD-10: A36
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.