1. Introduction and Etiology

Diphtheria is an acute, toxin-mediated infectious disease caused by Corynebacterium diphtheriae, an aerobic, gram-positive, non-spore-forming bacillus. Occasionally, toxigenic strains of C. ulcerans also cause the disease. The organism is non-invasive and remains localized to mucosal surfaces, but its virulence is attributed to the production of a potent exotoxin (diphtheria toxin). The toxin inhibits protein synthesis in host cells, leading to local tissue necrosis and systemic toxicity affecting the heart, kidneys, and nervous system.

2. Epidemiology

Although the incidence has declined globally due to immunization, diphtheria remains endemic in many developing regions, particularly in Southeast Asia and Africa.

• Transmission: Spread primarily occurs via respiratory droplets or direct contact with respiratory secretions or exudate from infected skin lesions.
• Incubation Period: Typically 2–5 days (range 1–10 days).
• Communicability: Patients are infectious for up to 2–3 weeks without treatment but become non-infectious within 24 hours of appropriate antibiotic therapy.

3. Pathogenesis and Pathology

The diphtheria toxin causes local necrosis of the epithelium, resulting in the formation of a characteristic pseudomembrane composed of fibrin, bacteria, epithelial cells, and inflammatory cells.

• Local Effect: The membrane is gray-brown, leathery, and adherent; attempts to remove it cause bleeding.
• Systemic Effect: Absorption of the toxin leads to distant organ damage, specifically toxic cardiomyopathy, demyelinating neuropathy, and renal tubular necrosis.

4. Clinical Manifestations

Clinical features depend on the anatomic site of infection.

• Faucial/Pharyngeal Diphtheria: The most common form. Onset is insidious with malaise, low-grade fever, and sore throat. A pseudomembrane forms on the tonsils and may extend to the soft palate and uvula. Extensive soft tissue edema and lymphadenopathy create the characteristic "bull-neck" appearance.
• Laryngeal Diphtheria: May be primary or an extension from the pharynx. Presents with fever, hoarseness, stridor, and a croupy cough. There is a high risk of airway obstruction by the membrane.
• Nasal Diphtheria: Primarily affects infants. Manifests as unilateral or bilateral serosanguinous or purulent discharge that may excoriate the upper lip. Systemic toxicity is usually mild due to poor toxin absorption from this site.
• Cutaneous Diphtheria: Presents as chronic, non-healing ulcers with a gray membrane.

5. Diagnosis

Diagnosis is primarily clinical and treatment should not be delayed for laboratory confirmation.

• Microscopy: Albert stain of a swab may show metachromatic granules (Chinese letter pattern), but is not definitive.
• Culture: The gold standard. Requires selective media like Tellurite blood agar (black colonies) or Loeffler's serum slope.
• Toxigenicity Testing: Essential to confirm the strain produces toxin. Methods include the Elek test (immunoprecipitation) or PCR for the toxin gene.

6. Differential Diagnosis

• Streptococcal Pharyngitis: Higher fever, more intense pain, absence of adherent membrane.
• Infectious Mononucleosis: Generalized lymphadenopathy, splenomegaly, atypical lymphocytes.
• Viral Croup/Epiglottitis: Differentiated from laryngeal diphtheria by the absence of a pharyngeal membrane and different clinical progression.

7. Complications

• Respiratory: Airway obstruction by the pseudomembrane or edema, leading to respiratory failure.
• Cardiac: Toxic cardiomyopathy (myocarditis) occurs in 10–25% of cases, typically in the 1st or 2nd week.
• Neurologic: Toxic neuropathy. Palatal palsy (nasal regurgitation) in week 2; ocular palsy (accommodation loss) in week 3; generalized polyneuritis in weeks 3–6.

8. Management

• Isolation: Strict droplet precautions until two consecutive negative cultures are obtained.
• Airway: Immediate securing of the airway (tracheostomy or intubation) if obstruction is present.
• Antitoxin: Equine Diphtheria Antitoxin (DAT) is the mainstay of treatment. It neutralizes only free toxin and must be given immediately.
  • Dose: 20,000 to 120,000 units depending on severity and site.
  • Sensitivity Test: Mandatory prior to administration due to risk of anaphylaxis.
• Antibiotics: Penicillin or Erythromycin for 14 days to eradicate the organism, stop toxin production, and prevent transmission.
  • Procaine Penicillin: 300,000–600,000 U IM q12h.
  • Erythromycin: 40–50 mg/kg/day.
• Bed Rest: Essential for at least 2 weeks to minimize cardiac strain.

9. Prevention

• Vaccination: Diphtheria toxoid (contained in DTaP, Tdap, DT) is highly effective. Primary series in infancy with boosters is required.
• Contacts: Close contacts should receive chemoprophylaxis (erythromycin or benzathine penicillin) and a booster dose of vaccine.

Diphtheria Myocarditis

1. Incidence and Pathophysiology

Myocarditis is the most serious complication of diphtheria and is responsible for 20–25% of deaths. It occurs in approximately 10–25% of patients with respiratory diphtheria.

• Mechanism: Diphtheria toxin causes direct myonecrosis and inflammation. The risk of cardiac toxicity correlates directly with the extent of local disease and delay in antitoxin administration.
• Pathology: Histology reveals diffuse or focal myonecrosis with acute inflammatory response.

2. Clinical Presentation

The onset of cardiac involvement is characteristically between 7 and 14 days after the onset of respiratory symptoms, although it can occur as early as the first week or as late as the sixth week.

• Signs:
  • Tachycardia disproportionate to the degree of fever.
  • Muffled heart sounds or gallop rhythm.
  • Signs of congestive heart failure (hepatomegaly, hypotension).
  • Sudden death can occur due to ventricular fibrillation or asystole.

3. Electrocardiographic (ECG) Findings

ECG changes are frequent and may precede clinical signs.

• ST-T Wave Changes: Non-specific ST depression or T-wave inversion.
• Conduction Defects: Prolonged PR interval (1st-degree block) is common. Progression to 2nd-degree or 3rd-degree (complete) heart block indicates extensive myonecrosis and carries a poor prognosis.
• Arrhythmias: Atrioventricular dissociation and ventricular tachycardia.

4. Diagnosis and Monitoring

• Laboratory: Serum aspartate transaminase (AST) levels may be elevated and parallel the severity of myonecrosis.
• Imaging: Echocardiography may show dilated or hypertrophic cardiomyopathy with decreased contractility.
• Monitoring: Careful cardiac monitoring is essential for patients with diphtheria, especially those with extensive membrane formation or delayed treatment.

5. Treatment and Prognosis

• Specific Therapy: There is no specific treatment to reverse toxin binding once it has occurred. Antitoxin only neutralizes circulating toxin.
• Supportive Care: Strict bed rest is critical to reduce cardiac workload. Management of heart failure with diuretics and inotropes may be needed, although digoxin should be used with caution due to enhanced toxicity in myocarditis.
• Pacing: Temporary transvenous pacing may be required for high-grade heart blocks and can improve outcomes.
• Steroids: Corticosteroids do not diminish cardiac complications and are generally not recommended.
• Prognosis: Mortality in patients with toxic cardiomyopathy is high (35–60%). However, survivors usually recover complete cardiac function, although some may have permanent conduction defects.

Antitoxin Therapy in Diphtheria

1. Introduction

Diphtheria Antitoxin (DAT) is the cornerstone of management for diphtheria. It is a hyperimmune serum derived from horses (equine origin).

2. Mechanism of Action

• Neutralization: DAT neutralizes free, circulating toxin in the blood and extracellular fluid.
• Limitations: It has no effect on toxin that is already bound to cell receptors or has entered the cells. Therefore, early administration is the single most important prognostic factor. Efficacy diminishes significantly with every day of delay.

3. Indications

• Empiric Use: DAT is indicated for all suspected cases of respiratory diphtheria.
• Clinical Diagnosis: Administration should be based on clinical diagnosis (presence of pseudomembrane, toxic appearance) and should not be delayed pending culture results.
• Cutaneous Diphtheria: Its value is uncertain, but it is often recommended to prevent toxic sequelae.

4. Dosage and Administration

The dose is empirical and depends on the site of infection, severity of toxicity, and duration of illness.

• Pharyngeal/Laryngeal Disease ( < 48 hours): 20,000 – 40,000 Units.

• Nasopharyngeal Disease: 40,000 – 60,000 Units.

• Extensive Disease / > 3 Days Duration / Bull Neck: 80,000 – 120,000 Units.

• Route:

  • Intravenous (IV): Preferred for severe cases to achieve rapid neutralization. It should be mixed with saline and infused over 60 minutes.
  • Intramuscular (IM): Can be used for mild to moderate cases, but absorption is slower.

5. Hypersensitivity and Precautions

Since DAT is a foreign protein (equine), there is a significant risk of hypersensitivity reactions.

• Sensitivity Testing: Must be performed before administration.
  • Skin Prick/Intradermal Test: Diluted serum is injected; a wheal >3mm indicates a positive reaction.
  • Conjunctival Test: One drop of 1:10 dilution in the eye.
• Desensitization: If the patient is sensitive, a Besredka desensitization protocol (gradual administration of increasing small doses) must be followed.
• Adverse Reactions:
  • Anaphylaxis: Immediate, life-threatening reaction (<1%). Epinephrine must always be available at the bedside.
  • Serum Sickness: A delayed reaction occurring 7–12 days after administration, characterized by fever, rash, urticaria, arthritis, and lymphadenopathy. Occurs in up to 15% of patients.

6. Role of IVIG

Human Intravenous Immunoglobulin (IVIG) contains low titers of diphtheria antibodies but is not a substitute for equine antitoxin and is not FDA approved for this indication. It may be considered only if equine antitoxin is unavailable.